January 31, 2008
DRAFT BIBLIOGRAPHY OF
PROPOSED KEY LITERATURE FOR THE
TOXICOLOGICAL REVIEW
OF
MANGANESE
(CAS No. 7439-96-5)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
for
National Center for Environmental Assessment
U.S. ENVIRONMENTAL PROTECTION AGENCY
Research Triangle Park, North Carolina 27711
Prepared by
Justin G. Teeguarden and Jessica D. Sanford
BATTELLE
505 King Avenue
Columbus, Ohio 43201-2693
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TABLE OF CONTENTS
Page
OVERVIEW 1
SEARCH STRATEGY 1
ORGANIZATION OF RESULTS 1
SUBJECT BIBLIOGRAPHY FOR MANGANESE 2
1. INTRODUCTION 2
2. CHEMICAL AND PHYSICAL INFORMATION 2
3. TOXICOKINETICS 3
3.1 TOXICOKINETICS 3
3.2 PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS 3
3.3 LIVER/GI FUNCTION 3
4. HAZARD IDENTIFICATION 3
4.1 STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, AND
CLINICAL CONTROLS 4
4.2 LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER
BIOASSAYS IN ANIMALS—ORAL AND INHALATION 4
4.3 EPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
4.4 OTHER ENDPOINT-SPECIFIC STUDIES 4
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE
MODE OF ACTION 4
4.6 REVIEW ARTICLES 5
APPENDIX A: COMPLETE ALPHABETIZED BIBLIOGRAPHYWITHOUT ABSTRACTS A-1
APPENDIX B: KEY REFERENCES AND ABSTRACTS BY SUBJECT B-1
APPENDIX C: SUPPORTING REFERENCES AND ABSTRACTS BY SUBJECT C-1
APPENDIX D: KEY AND SUPPORTING REFERENCES WITH ABSTRACTS BY SUBJECT D-1
APPENDIX E: KEY REFERENCES NOT OBTAINED IN PDF E-1
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OVERVIEW
This document contains a summary description of the literature search process employed to
support a toxicological review of manganese (Mn). The relevant articles identified in the literature
search are then described in relation to the Toxicological Review template contents and the
associated topics of interest.
SEARCH STRATEGY
Battelle performed a literature search that included a comprehensive investigation of the
database sources listed in the work assignment. This list of sources included links to appropriate
EPA health assessment documents, guidelines, articles offered in response to the Federal
Register Notice, and source of other federal documents (e.g., U.S. Agency for Toxic Substances
Disease Registry [ATSDR] Toxicological Profiles) that were used to identify information to
assess the potential adverse human health effects that may occur from exposure to manganese.
All sources were searched for the period covering 1995 to date. Because manganese is a
chemical with both nutritional benefits and potential toxic effects, there was a large body of
published literature available. To aid in the performance of more targeted literature searches, the
Table of Contents of the Toxicological Review template was consulted for guidance in selection
of search terms covering the subject areas of interest. In doing so, Battelle also ensured that the
literature search addressed all health effects in animals and humans resulting from inhalation,
oral, dermal, and intravenous exposure studies related to the assessment of cancer and
non-cancer endpoints. Also of interest was literature addressing absorption, distribution,
metabolism, and elimination studies that are relevant to the toxicity of manganese. The literature
search also included all physiologically-based toxicokinetic models available for manganese. In
addition, information was sought that might be specifically useful to addressing risks to children
and other susceptible subgroups, including women. Finally, an attempt was made to ensure that
the literature search product was inclusive of toxicological-type studies across all durations,
including chronic (i.e., lifetime), less-than-lifetime, acute (single exposure in a single day),
short-term (e.g., from 1 to 30 days) and subchronic (> 30 days < lifetime).
Studies identified in the searches of the various resources were reviewed for relevance and
incorporated into an ENDNOTE™ library. The final review and curation of the ENDNOTE™
library for categorization and determination of principle studies was made by Justin Teeguarden,
the task leader and a board certified toxicologist. Determination of relevancy was based on
study abstracts or other detailed information found within the literature. Whenever possible, the
determination of relevancy was not based solely on the study title.
ORGANIZATION OF RESULTS
No relevant, in-progress health assessment activities within EPA or other federal agencies
were identified. Therefore, no summary documentation was submitted to the EPA WAM for
review or is included in the summary reference list.
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The literature search process resulted in 539 references identified as potentially relevant. Of
those, 201 are categorized as potential key references with the remaining 338 serving as
supporting references. The literature search product detailing all the key and supporting studies
identified is provided in the following sections. This detailed description of the bibliography
contents and a report on the resulting articles is structured in a manner consistent with the layout
of the Table of Contents of the Toxicological Review template. Full reference citations are
provided separately in Appendices in various formats. Appendix A contains the complete
alphabetical list of 539 references without abstracts. Appendix B contains the list of proposed
key studies without abstract divided by subject. Appendix C contains a similar list of supporting
studies without abstract divided by subject. Appendix D contains a subject bibliography, in
which each subject section provides a list of the relevant key and supporting references and their
abstracts.
The lists of key references are proposed based on an evaluation of the abstract. However,
additional evaluation of report contents for each reference will need to be performed to
accurately access whether a study should be classified as a key study or if it instead provides
supporting evidence. Battelle has made an effort to acquire readily available PDF copies of the
key articles in the given time frame and is providing an electronic copy to EPA on the project
Sharepoint site as agreed by the EPA WAM. However, given the large number of potential key
studies identified, it was not possible to acquire copies of all the references. A list of the key
studies Battelle was not able to acquire within the given time constraint and resources is
provided in Appendix E of this report.
The complete list of 539 citations in an ENDNOTE™ Library is also being provided to EPA
on the project Sharepoint site. Where available, links to electronic versions of selected literature
retrieved in the search are included in the ENDNOTE™ Library.
Because of the large number of references identified and categorized, a table of contents is
provided to aid in the navigation of this report of the results. As described above, the
organization of the resulting references closely follows the organizational structure of the
Toxicological Review template, with subcategory breakdowns where necessary.
SUBJECT BIBLIOGRAPHY FOR MANGANESE
1. INTRODUCTION
No specific studies were identified for this section. The EPA boilerplate text provided in the
template should be used and tailored for the manganese search where appropriate.
2. CHEMICAL AND PHYSICAL INFORMATION
Information from review articles should largely be used to populate this section. A listing
and discussion of the review articles can be found in section 4.6 of this report.
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3. TOXICOKINETICS
The incorporation of toxicokinetic data in the risk assessment of manganese is complicated
by its status as an essential micronutrient. Establishing normal levels of tissue and blood Mn are
important because deficiency leads to specific pathologies. The toxicokinetics data here includes
some human and rodent studies whose focus was not toxicokinetics, but contain information on
normal blood and tissues levels of Mn.
Manganese tissue and blood concentrations are under strict, coordinated control of the liver
and GI tract. A series of publications reporting the consequences of liver/GI tract disease or the
bypass of liver/GI tract regulation of Mn on blood and tissue Mn are included (topic area:
Liver/GI function). In vitro and in vivo studies of the role of divalent metal transporters on the
cellular uptake of Mn are listed because they provide important insights into regulation of Mn
uptake and disposition.
Publications in these two groupings are not listed as key studies because they do not report
relationships between exposure/dose and tissue blood Mn time course. Nonetheless, they deserve
review in the IRIS assessment.
The literature of relevance to this section is organized below into three categories:
toxicokinetics, physiologically based pharmacokinetic models (PBPK) and Liver/GI Function.
3.1 TOXICOKINETICS
This section contains articles on toxicokinetics, excluding physiologically based
toxicokinetic (PBPK) models and liver/GI function studies. For this topic, 72 key articles and 45
supplementary articles were identified.
3.2 PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
This section contains references associated with PBPK modeling. Seven key articles were
identified on this topic but no supporting references were found.
3.3 LIVER/GI FUNCTION
There were no key studies identified in this grouping, but 12 supporting references on
liver/GI function were found.
4. HAZARD IDENTIFICATION
All references found for this topic are divided into the following subsections of relevance.
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4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, AND CLINICAL
CONTROLS
This section contains epidemiological studies, case reports, and clinical controls but does not
contain any kinetic studies. There were 34 key studies and 57 supporting references identified
on this topic.
4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
Studies found for this section are divided into the following subsections.
4.2.1 Less-than-lifetime and Chronic Studies
Both subchronic and chronic studies are contained in this section. On this subject, 32 key
references and 3 supporting references were found.
4.2.2 Cancer bioassays
No key or supporting studies concerning cancer bioassays were identified.
4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Studies with reproductive and developmental endpoints are combined for this study from
both oral and inhalation exposures. There were 12 key studies and 93 supporting references
identified on this topic.
4.4. OTHER ENDPOINT-SPECIFIC STUDIES [e.g., in vivo neurological,
immunological studies\
Chronic and subchronic studies reporting or focused on neurological endpoints are reported
in Section 4.2. No other key or supporting references discussing other standard endpoint specific
studies were identified.
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE
OF ACTION \e.g., in vitro and ex vivo studies using isolated target tissues/organs or cells,
metabolite studies, genotoxicity, SAR, etc.\
A large body of literature exploring possible mechanisms of Mn induced neurotoxicity has
accumulated in the last decade. Because there appears to be no consensus regarding the MO A, it
is not possible to separate key studies from the larger pool of mechanistic studies. We list as key
studies, several important review articles and selected in vivo studies we felt should be the
starting point for the review of literature on this topic. For this section there were 25 key studies
and 146 supporting studies.
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4.6. REVIEW ARTICLES
Review articles of general interest regarding risk assessment of Mn are listed below. These
articles comprise those believed to be valuable but either are not associated with specific topics
in the IRIS document or were not key studies in those topic areas. They may also provide content
for the Background/Introduction Section. Eighteen key and 71 supporting studies were found.
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APPENDIX A:
COMPLETE ALPHABETIZED BIBLIOGRAPHY
WITHOUT ABSTRACTS
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All References in Alphabetical Order (539)
1. (1998) Is airborne manganese a hazard? Environmental Health Perspectives 106(2):A57-A58.
2. Reaney SH, Smith DR. (2005) Manganese oxidation state mediates toxicity in PC12 cells.
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3. Agte V, Jahagirdar M, Chiplonkar S. (2005) Apparent absorption of eight micronutrients and
phytic acid from vegetarian meals in ileostomized human volunteers. Nutrition 21(6):678-685.
4. Ahn SS, Lee KM. (1998) Neurotoxicity of chronic manganese exposure causing frontal lobe
dysfunction. Journal of Neurochemistry 70:S29-S29.
5. Alarcon OM, ReinosaFuller JA, Silva T, DeFernandez MR, Gamboa J. (1996) Manganese
levels in serum of healthy Venezuelan infants living in Merida. Journal of Trace Elements in
Medicine and Biology 10(4):210-213.
6. Alcaraz-Zubeldia M, Montes S, Rios C. (2001) Participation of manganese-superoxide
dismutase in the neuroprotection exerted by copper sulfate against 1-methyl 4-phenylpyridinium
neurotoxicity. Brain Research Bulletin 55(2):277-279.
7. Ali SF, Duhart HM, Newport GD, Lipe GW, Slikker W. (1995) Manganese-Induced Reactive
Oxygen Species - Comparison between Mn+2 and Mn+3. Neurodegeneration 4(3):329-334.
8. Alinovi R, Vettori MV, Mutti A, Cavazzini S, Bacchini A, Bergamaschi E. (1996) Dopamine
(DA) metabolism in PC12 cells exposed to manganese (Mn) at different oxidation states.
Neurotoxicology (Little Rock) 17(3-4):743-750.
9. Alves G, Thiebot J, Tracqui A, Delangre T, Lerebours E, et al. (1997) Neurologic disorders
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10. Anantharam V, Kitazawa M, Latchoumycandane C, Kanthasamy A, Kanthasamy AG.
(2004) Blockade of PKC delta proteolytic activation by loss of function mutants rescues
mesencephalic dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl
(MMT)-induced apoptotic cell death. Protective Strategies for Neurodegenerative Diseases.
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11. Anantharam V, Kitazawa M, Wagner J, Kaul S, Kanthasamy AG. (2002) Caspase-3-
dependent proteolytic cleavage of protein kinase C delta is essential for oxidative stress-
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12. Anastassopoulou J, Theophanides T. (2002) Magnesium-DNA interactions and the possible
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13. Andersen ME, Gearhart JM, Clewell HJ. (1999) Pharmacokinetic data needs to support risk
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14. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
15. Anderson JG, Cooney PT, Erikson KM. (2007) Inhibition of DAT function attenuates
manganese accumulation in the globus pallidus. Environmental Toxicology and Pharmacology
23(2): 179-184.
16. Anderson JG, Fordahl SC, Cooney PT, Erikson KM. (2007) Iron deficiency and manganese
exposure are associated with decreases in neurotransmitter uptake. Faseb Journal 21(6):A1065-
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17. anon. (1997) Manganese toxicity: hazard of intravenous food. Drugs Q. 1(1):31-32.
18. Anonymous. (1997) Manganese. RAIS Toxicity Profiles (1997).
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threshold limit values and biological exposure indices Vol:7th Ed (2001) 6 p.
20. Anonymous. (2001) Manganese Cyclopentadienyl Tricarbonyl. ACGIH. Documentation of
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21. Anonymous. (2003) Methylcyclopentadienyl Manganese Tricarbonyl (MMT). NICNAS:
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22. Antonini JM. (2006) Potential neurotoxic responses in rats after pulmonary administration
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23. Antonini JM, Santaimaria AB, Jenkins NT, Albini E, Lucchini R. (2006) Fate of manganese
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24. Antonini JM, Taylor MD, Zimmer AT, Roberts JR. (2004) Pulmonary responses to welding
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25. Arnaud J, Bourlard P, Denis B, Favier AE. (1996) Plasma and erythrocyte manganese
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26. Arnich N, Cunat L, Lanhers MC, Burnel D. (2004) Comparative in situ study of the
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27. Arnold ML, McNeill FE, Chettle DR. (1999) The feasibility of measuring manganese
concentrations in human liver using neutron activation analysis. Neurotoxicology 20(2-3):407-
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28. Aschner JL, Furlong H, Daily D, Aschner M. (2006) Neuroimaging and neurodevelopmental
correlates of intravenous manganese exposure in parente rally-fed infants: A clinical trial in the
neonatal intensive care unit (NICU). Neurotoxicology 27(6): 1168-1168.
29. Aschner M. (2000) Manganese: Brain transport and emerging research needs.
Environmental Health Perspectives 108:429-432.
30. Aschner M. (2005) Manganese transport, toxicity and speciation in the CNS. Journal of
Neurochemistry 94:8-8.
31. Aschner M. (2006) The transport of manganese across the blood-brain barrier.
Neurotoxicology 27(3):311-314.
32. Aschner M, Erikson KM. (2003) Manganese and iron deficiency in neurodegeneration.
Journal of Neurochemistry 87:129-129.
33. Aschner M, Erikson KM, Dorman DC. (2005) Manganese dosimetry: Species differences
and implications for neurotoxicity. Critical Reviews in Toxicology 35(1): 1-32.
34. Aschner M, Fitsanakis VA, Milatovic D, Erikson KM. (2006) Dietary iron modulates
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35. Aschner M, Lukey B, Tremblay A. (2006) The manganese health research program
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37. ATSDR. 2000. Public Health Statement Manganese. In: CDC, editor: ATSDR.
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41. Azin F, Raie RM, Mahmoudi MM. (1998) Correlation between the levels of certain
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42. Baek SY, Kim YH, Oh SO, Lee CR, Yoo CI, Lee JH, Lee H, Sim CS, Park J, Kim JW and
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45. Barbee JY, Prince TS. (1999) Acute respiratory distress syndrome in a welder exposed to
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46. Barceloux DG. (1999) Manganese. Journal of Toxicology-Clinical Toxicology 37(2):293-
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50. Beuter A, Edwards R, De Geoffroy A, Mergler D, Hudnell K. (1999) Quantification of
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distribution of trace elements and trace element-containing proteins in the lung of the rat. Trace
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81. Butterworth RF, Spahr L, Fontaine S, Layrargues GP. (1995) Manganese toxicity,
dopaminergic dysfunction and hepatic encephalopathy. Metabolic Brain Disease 10(4):259-267.
82. Calabresi P, Ammassari-Teule M, Gubellini P, Sancesario G, Morello M, Centonze D,
Marfia GA, Saulle E, Passino E, Picconi B and others. (2001) A synaptic mechanism underlying
the behavioral abnormalities induced by manganese intoxication. Neurobiology of Disease
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538. Zwingmann C, Leibfritz D, Hazell AS. (2003) Energy metabolism in astrocytes and
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APPENDIX B:
KEY REFERENCES BY SUBJECT
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3.1
TOXICOKINETICS (72)
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8. Brenneman KA, Wong BA, Buccellato MA, Costa ER, Gross EA, Dorman DC. (2000) Direct
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9. Chen MK, Lee JS, McGlothan JL, Furukawa E, Adams RJ, Alexander M, Wong DF, Guilarte
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10. Chen MT, Cheng GW, Lin CC, Chen BH, Huang YL. (2006) Effects of acute manganese
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11. Chen MT, Yiin SJ, Sheu JY, Huang YL. (2002) Brain lipid peroxidation and changes of
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12. Chua ACG, Morgan EH. (1996) Effects of iron deficiency and iron overload on manganese
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14. Dorman DC. (2003) Metal speciation in human health risk assessment: Challenges posed by
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combined in utero and lactation exposure to inhaled manganese sulfate. Toxicological Sciences
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16. Dorman DC, McManus BE, Marshall MW, James RA, Struve MF. (2004) Old age and
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18. Dorman DC, Struve MF, James RA, Marshall MW, Parkinson CU, Wong BA. (2001)
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19. Dorman DC, Struve MF, James RA, McManus BE, Marshall MW, Wong BA. (2001)
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20. Dorman DC, Struve MF, Marshall MW, Parkinson CU, James RA, Wong BA. (2006) Tissue
manganese concentrations in young male rhesus monkeys following subchronic manganese
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22. Dorman DC, Struve MF, Wong BA, Dye JA, Robertson ID. (2006) Correlation of brain
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23. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A,
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24. Erikson KA, Shihabi ZK, Aschner JL, Aschner M. (2002) Manganese accumulates in iron-
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alterations. Biological Trace Element Research 87(1-3): 143-156.
25. Erikson KA, Syversen T, Steinnes E, Aschner M. (2004) Globus pallidus: a target brain
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26. Erikson KM, Jones SR, Aschner M. (2005) Brain manganese accumulation due to toxic
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28. Fechter LD, Johnson DL, Lynch RA. (2002) The relationship of particle size to olfactory
nerve uptake of a non-soluble form of manganese into brain. Neurotoxicology 23(2): 177-183.
29. Fitsanakis VA, Erikson KM, Aschner M. (2006) Manganese transport in the CNS.
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30. Gallez B, Demeure R, Baudelet C, Abdelouahab N, Beghein N, Jordan B, Geurts M, Roels
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measurement of NMR proton T-l relaxation times. Neurotoxicology 22(3):387-392.
31. Garcia SJ, Gellein K, Syversen T, Aschner M. (2006) A manganese-enhanced diet alters
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32. Garcia SJ, Gellein K, Syversen T, Aschner M. (2007) Iron deficient and manganese
supplemented diets alter metals and transporters in the developing rat brain. Toxicological
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36. Gwiazda R, Kern C, Smith D. (2005) Progression Of Neurochemical Effects In Different
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37. Henriksson J, Tallkvist J, Tjalve H. (1999) Transport of manganese via the olfactory
pathway in rats: Dosage dependency of the uptake and subcellular distribution of the metal in the
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38. Henriksson J, Tjalve H. (2000) Manganese taken up into the CNS via the olfactory pathway
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and brain regional distribution of manganese in mice, (vol 22, pg 679, 2003). Journal of
Toxicology-Toxin Reviews 23(4):556-557.
43. Kostial K, Blanusa M, Piasek M. (2005) Regulation of manganese accumulation in
perinatally exposed rat pups. Journal of Applied Toxicology 25(2):89-93.
44. Lewis J, Bench G, Myers O, Tinner B, Staines W, Barr E, Divine KK, Barrington W,
Karlsson J. (2005) Trigeminal uptake and clearance of inhaled manganese chloride in rats and
mice. Neurotoxicology 26(1): 113-123.
45. Li G, Liu J, Waalkes MP, Zheng W. (2005) Manganese Exposure Alters Iron Regulatory
Mechanisms At Blood-Cerebrospinal Fluid Barrier (BCB) And Selected Regions Of Bloodbrain
Barrier (BBB) In Rats. Toxicol Sci 84(1-S): 121 -122.
46. Malecki EA, Devenyi AG, Beard JL, Connor JR. (1999) Existing and emerging mechanisms
for transport of iron and manganese to the brain. Journal of Neuroscience Research 56(2): 113-
122.
47. Normandin L, Beaupre LA, Salehi F, St-Pierre A, Kennedy G, Mergler D, Butterworth RE,
Philippe S, Zayed J. (2004) Manganese distribution in the brain and neurobehavioral changes
following inhalation exposure of rats to three chemical forms of manganese. Neurotoxicology
25(3):433-441.
Draft Bibliography: Manganese Lit. Search
B-4
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48. Ponzoni S, Gaziri LCJ, Britto LRG, Barreto WJ, Blum D. (2002) Clearance of manganese
from the rat substantia nigra following intra-nigral microinjections. Neuroscience Letters
328(2): 170-174.
49. Roels H, Meiers G, Delos M, Ortega I, Lauwerys R, Buchet JP, Lison D. (1997) Influence of
the route of administration and the chemical form [MnC12, Mn02) on the absorption and
cerebral distribution of manganese in rats. Archives of Toxicology 71(4):223-230.
50. Roth JA. (2006) Homeostatic and toxic mechanisms regulating manganese uptake, retention,
and elimination. Biological Research 39(l):45-57.
51. Roughead ZK, Finley JW. (2001) Mucosal uptake and whole-body retention of dietary
manganese are not altered in beta(2)-microglobulin knockout mice. Biological Trace Element
Research 80(3):231-244.
52. Sato I, Matsusaka N, Kobayashi H, Nishimura Y. (1996) Effects of dietary manganese
contents on 54Mn metabolism in mice. Journal of Radiation Research 37(2): 125-132.
53. Schafer U, Anke M, Seifert M, Fischer AB. (2004) Influences on the manganese intake,
excretion and balance of adults, and on the manganese concentration of the consumed food
determined by means of the duplicate portion technique. Trace Elements and Electrolytes
21(2):68-77.
54. St-Pierre A, Normandin L, Carrier G, Kennedy G, Butterworth R, Zayed J. (2001)
Bioaccumulation and locomotor effect of manganese dust in rats. Inhalation Toxicology
13(7):623-632.
55. Takeda A, Ishiwatari S, Okada S. (1999) Manganese uptake into rat brain during
development and aging. Journal of Neuroscience Research 56(l):93-98.
56. Takeda A, Kodama Y, Ishiwatari S, Okada S. (1998) Manganese transport in the neural
circuit of rat CNS. Brain Research Bulletin 45(2): 149-152.
57. Takeda A, Sawashita J, Okada S. (1995) Biological Half-Lives of Zinc and Manganese in
Rat-Brain. Brain Research 695(l):53-58.
58. Takeda A, Sawashita J, Okada S. (1998) Manganese concentration in rat brain: manganese
transport from the peripheral tissues. Neuroscience Letters 242(l):45-48.
59. Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2005) Olfactory
uptake of manganese is upregulated by iron deficiency and involves DMT1. Faseb Journal
19(5):A1483-A1484.
60. Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2006) The influence
of high iron diet on rat lung manganese absorption. Toxicology and Applied Pharmacology
210(l-2):17-23.
Draft Bibliography: Manganese Lit. Search
B-5
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61. Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M. (2007)
Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. Faseb Journal
21(l):223-230.
62. Tjalve H, Henriksson J, Tallkvist J, Larsson BS, Lindquist NG. (1996) Uptake of manganese
and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in
rats. Pharmacology & Toxicology 79(6):347-356.
63. Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B. (2002) Effect of
high dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine
levels, and neurodevelopmental status. Neurotoxicology 23(4-5):635-643.
64. Tran TT, Kelleher SL, Lonnerdal B. (2002) Effect of high manganese intake and iron
deficiency in infant rats on DMT-1 expression and tissue mineral accumulation. Faseb Journal
16(4):A617-A617.
65. Vezer T, Papp A, Hoyk Z, Varga C, Naray M, Nagymajtenyi L. (2005) Behavioral and
neurotoxicological effects of subchronic manganese exposure in rats. Environmental Toxicology
and Pharmacology 19(3):797-810.
66. Vitarella D, Moss O, Dorman DC. (2000) Pulmonary clearance of manganese phosphate,
manganese sulfate, and manganese tetraoxide by CD rats following intratracheal instillation.
Inhalation Toxicology 12(10):941-957.
67. Yasui M, Ota K, Garruto RM. (1995) Effects of calcium-deficient diets on manganese
deposition in the Central Nervous system and bones of rats. Neurotoxicology (Little Rock)
16(3): 511-517.
68. Yokel RA, Crossgrove JS, Bukaveckas BL. (2003) Manganese distribution across the blood-
brain barrier II. Manganese efflux from the brain does not appear to be carrier mediated.
Neurotoxicology 24(1): 15-22.
69. Yu IJ, Park JD, Park ES, Song KS, Han KT, Han JH, Chung YH, Choi BS, Chung KH, Cho
MH. (2003) Manganese distribution in brains of Sprague-Dawley rats after 60 days of stainless
steel welding-fume exposure. Neurotoxicology 24(6):777-785.
70. Zaloglu N, Yildirim G, Bastug M, Koc E, Ficicilar H, Sayal A. (2002) High dosage of
manganese chloride application and iron zinc copper status in rats. Trace Elements and
Electrolytes 19(3): 138-142.
71. Zheng W, Kim H, Zhao QQ. (2000) Comparative toxicokinetics of manganese chloride and
methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats. Toxicological
Sciences 54(2):295-301.
72. Zheng W, Zhao QQ, Slavkovich V, Aschner M, Graziano JH. (1999) Alteration of iron
homeostasis following chronic exposure to manganese in rats. Brain Research 833(1): 125-132.
Draft Bibliography: Manganese Lit. Search
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January 31, 2008
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3.2
PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS (7)
1. Andersen ME, Gearhart JM, Clewell HJ. (1999) Pharmacokinetic data needs to support risk
assessments for inhaled and ingested manganese. Neurotoxicology 20(2-3): 161-171.
2. Aschner M, Erikson KM, Dorman DC. (2005) Manganese dosimetry: Species differences and
implications for neurotoxicity. Critical Reviews in Toxicology 35(1): 1-32.
3. Dorman DC, Struve MF, Clewell HJ, Andersen ME. (2006) Application of pharmacokinetic
data to the risk assessment of inhaled manganese. Neurotoxicology 27(5):752-764.
4. Heilig E, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2005) Pharmacokinetics
of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading
in iron-deficient rats. American Journal of Physiology-Lung Cellular and Molecular Physiology
288(5):L887-L893.
5. Teeguarden JG, Dorman DC, Covington TR, Clewell HJ, 3rd, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. I. Dose dependencies of uptake and elimination. J
Toxicol Environ Health A 70(18): 1493-1504.
6. Teeguarden JG, Dorman DC, Nong A, Covington TR, Clewell HJ, 3rd, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. II. Hepatic processing after ingestion and inhalation. J
Toxicol Environ Health A 70(18):1505-1514.
7. Teeguarden JG, Gearhart J, Clewell HJ, 3rd, Covington TR, Nong A, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. III. Physiological approaches accounting for
background and tracer kinetics. J Toxicol Environ Health A 70(18): 1515-1526.
3.3 LIVER/GI FUNCTION (0)
There were no key studies identified for this group.
4.1 STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS (34)
1. Beuter A, Lambert G, MacGibbon B. (2004) Quantifying postural tremor in workers exposed
to low levels of manganese. Journal of Neuroscience Methods 139(2):247-255.
2. Boojar MMA, Goodarzi F. (2002) A longitudinal follow-up of pulmonary function and
respiratory symptoms in workers exposed to manganese. Journal of Occupational and
Environmental Medicine 44(3):282-290.
Draft Bibliography: Manganese Lit. Search
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3. Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D. (2007) Hair manganese and
hyperactive behaviors: Pilot study of school-age children exposed through tap water.
Environmental Health Perspectives 115(1): 122-127.
4. Bowler RM, Gysens S, Diamond E, Nakagawa S, Drezgic M, Roels HA. (2006) Manganese
exposure: Neuropsychological and neurological symptoms and effects in welders.
Neurotoxicology 27(3):315-326.
5. Bowler RM, Koller W, Schulz PE. (2006) Parkinsonism due to manganism in a welder:
Neurological and neuropsychological sequelae. Neurotoxicology 27(3):327-332.
6. Bowler RM, Nakagawa S, Drezgic M, Roels HA, Park RM, Diamond E, Mergler D,
Bouchard M, Bowler RP, Koller W. (2007) Sequelae of fume exposure in confined space
welding: A neurological and neuropsychological case series. NeuroToxicology 28(2):298-311.
7. Bowler RM, Roels HA, Nakagawa S, Drezgic M, Diamond E, Park R, Koller W, Bowler RP,
Mergler D, Bouchard M and others. (2007) Dose-effect relationships between manganese
exposure and neurological, neuropsychological and pulmonary function in confined space bridge
welders. Occupational and Environmental Medicine 64(3): 167-177.
8. Cersosimo MG, Koller WC. (2006) The diagnosis of manganese-induced parkinsonism.
Neurotoxicology 27(3):340-346.
9. Deschamps FJ, Guillaumot A, Raux S. (2001) Neurological effects in workers exposed to
manganese. Journal of Occupational and Environmental Medicine 43(2): 127-132.
10. Finley BL, Santamaria AB. (2005) Current evidence and research needs regarding the risk of
manganese-induced neurological effects in welders. Neurotoxicology 26(2):285-289.
11. Fored CM, Fryzek JP, Brandt L, Nise G, Sjogren B, McLaughlin JK, Blot WJ, Ekbom A.
(2006) Parkinson's disease and other basal ganglia or movement disorders in a large nationwide
cohort of Swedish welders. Occupational and Environmental Medicine 63(2): 135-140.
12. Fryzek JP, Hansen J, Cohen S, Bonde JP, Llambias MT, Kolstad HA, Skytthe A, Lipworth
L, Blot W, Olsen JH. (2005) A cohort study of Parkinson's disease and other neurodegenerative
disorders in Danish welders. Journal of Occupational and Environmental Medicine 47(5):466-
472.
13. Gibbs JP, Crump KS, Houck DP, Warren PA, Mosley WS. (1999) Focused medical
surveillance: A search for subclinical movement disorders in a cohort of U.S. workers exposed to
low levels of manganese dust. Neurotoxicology (Little Rock) 20(2-3):299-314.
14. Hernandez EH, Discalzi G, Valentini C, Venturi F, Chio A, Carmellino C, Rossi L,
Sacchetti A, Pira E. (2006) Follow-up of patients affected by manganese-induced Parkinsonism
after treatment with CaNa(2)EDTA. Neurotoxicology 27(3):333-339.
Draft Bibliography: Manganese Lit. Search
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January 31, 2008
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15. Hochberg F, Miller G, Valenzuela R, McNelis S, Crump KS, Covington T, Valdivia G,
Hochberg B, Trustman JW. (1996) Late motor deficits of Chilean manganese miners: A blinded
control study. Neurology 47(3):788-795.
16. Hudnell HK. (1999) Effects from environmental Mn exposures: A review of the evidence
from non-occupational exposure studies. Neurotoxicology 20(2-3):379-397.
17. Iregren A. (1999) Manganese neurotoxicity in industrial exposures: Proof of effects, critical
exposure level, and sensitive tests. Neurotoxicology 20(2-3):315-323.
18. Jiang YM, Zheng W. (2005) Cardiovascular toxicities upon manganese exposure.
Cardiovascular Toxicology 5(4):345-354.
19. Kim Y, Kim KS, Yang JS, Park IJ, Kim E, Jin YW, Kwon KR, Chang KH, Kim JW, Park
SH and others. (1999) Increase in signal intensities on T1-weighted magnetic resonance images
in asymptomatic manganese-exposed workers. Neurotoxicology 20(6):901-907.
20. Klos KJ, Chandler M, Kumar N, Ahlskog JE, Josephs KA. (2006) Neuropsychological
profiles of manganese neurotoxicity. European Journal of Neurology 13(10): 1139-1141.
21. Lees-Haley PR, Greiffenstein MF, Larrabee GJ, Manning EL. (2004) Methodological
problems in the neuropsychological assessment of effects of exposure to welding fumes and
manganese. Clinical Neuropsychologist 18(3):449-464.
22. Levy BS, Nassetta WJ. (2003) Neurologic effects of manganese in humans: A review.
International Journal of Occupational and Environmental Health 9(2): 153-163.
23. Levy LS, Aitken R, Holmes P, Hughes J, Hurley F, Rumsby PC, Searl A, Shuker LK,
Spurgeon A, Warren FC. (2004) The derivation of a health-based occupational exposure limit for
maganese using human neurobehaviour/neurotoxicity data. Toxicology 202(1-2): 133-134.
24. Lucchini R, Selis L, Folli D, Apostoli P, Mutti A, Vanoni O, Iregren A, Alessio L. (1995)
Neurobehavioral Effects of Manganese in Workers from a Ferroalloy Plant after Temporary
Cessation of Exposure. Scandinavian Journal of Work Environment & Health 21(2): 143-149.
25. Myers JE, Thompson ML, Ramushu S, Young T, Jeebhay MF, London L, Esswein E,
Renton K, Spies A, Boulle A and others. (2003) The nervous system effects of occupational
exposure on workers in a South African manganese smelter. Neurotoxicology 24(6):885-894.
26. Nagatomo S, Umehara F, Hanada K, Nobuhara Y, Takenaga S, Arimura K, Osame M.
(1999) Manganese intoxication during total parenteral nutrition: report of two cases and review
of the literature. Journal of the Neurological Sciences 162(1): 102-105.
27. Ohtake T, Negishi K, Okamoto K, Oka M, Maesato K, Moriya H, Kobayashi S. (2005)
Manganese-induced parkinsonism in a patient undergoing maintenance hemodialysis. American
Journal of Kidney Diseases 46(4):749-753.
Draft Bibliography: Manganese Lit. Search
B-9
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28. Pal PK, Samii A, Calne DB. (1999) Manganese neurotoxicity: A review of clinical features,
imaging and pathology. Neurotoxicology 20(2-3):227-238.
29. Roels HA, Eslava MIO, Ceulemans E, Robert A, Lison D. (1999) Prospective study on the
reversibility of neurobehavioual effects in workers exposed to manganese dioxide.
Neurotoxicology 20(2-3):255-271.
30. Vieregge P, Heinzow B, Korf G, Teichert HM, Schleifenbaum P, Mosinger HU. (1995)
Long-Term Exposure to Manganese in Rural Well Water Has No Neurological Effects. Canadian
Journal of Neurological Sciences 22(4):286-289.
31. Walczak, Jakubowski M, Matczak W. (2001) Neurological and neurophysiological
examinations of workers occupationally exposed to manganese. International Journal of
Occupational Medicine and Environmental Health 2001, Vol. 14, No. 4, p. 329-337. 16 ref.
32. Wirth JJ, Rossano MG, Daly DC, Paneth N, Puscheck E, Potter RC, Diamond MP. (2007)
Ambient manganese exposure is negatively associated with human sperm motility and
concentration. Epidemiology 18(2):270-273.
33. Young T, Myers JE, Thompson ML. (2005) The nervous system effects of occupational
exposure to manganese - Measured as respirable dust - in a South African manganese smelter.
Neurotoxicology 26(6):993-1000.
34. Yuan H, He SC, He MW, Niu Q, Wang L, Wang S. (2006) A comprehensive study on
neurobehavior, neurotransmitters and lymphocyte subsets alteration of Chinese manganese
welding workers. Life Sciences 78(12): 1324-1328.
4.2 LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
4.2.1 Less-than-lifetime and Chronic Studies (32)
1. Ahn SS, Lee KM. (1998) Neurotoxicity of chronic manganese exposure causing frontal lobe
dysfunction. Journal of Neurochemistry 70:S29-S29.
2. Chen MT, Yiin SJ, Sheu JY, Huang YL. (2002) Brain lipid peroxidation and changes of trace
metals in rats following chronic manganese chloride exposure. Journal of Toxicology and
Environmental Health-Part A 65(3-4):305-316.
3. Desole MS, Esposito G, Migheli R, Fresu L, Sircana S, Zangani D, Miele M, Miele E. (1995)
Cellular Defense-Mechanisms in the Striatum of Young and Aged Rats Sub chronically Exposed
to Manganese. Neuropharmacology 34(3):289-295.
4. Dorman DC, McManus BE, Parkinson CU, Manuel CA, McElveen AM, Everitt JI. (2004)
Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following
subchronic (13-week) inhalation exposure. Inhalation Toxicology 16(6-7):481-488.
Draft Bibliography: Manganese Lit. Search B-10
January 31, 2008
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5. Dorman DC, Struve MF, Gross EA, Wong BA, Howroyd PC. (2005) Sub-chronic inhalation
of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys.
Respiratory Research 6.
6. Dorman DC, Struve MF, Vitarella D, Byerly FL, Goetz J, Miller R. (2000) Neurotoxicity of
manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral
exposure. Journal of Applied Toxicology 20(3): 179-187.
7. Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde
CA, Syversen T, Decamp E and others. (2006) Nigrostriatal dopamine system dysfunction and
subtle motor deficits in manganese-exposed non-human primates. Experimental Neurology
202(2):381-390.
8. Guilarte TR, McGlothan JL, Degaonkar M, Chen MK, Barker PB, Syversen T, Schneider JS.
(2006) Evidence for cortical dysfunction and widespread manganese accumulation in the
nonhuman primate brain following chronic manganese exposure: A H-l-MRS and MRI study.
Toxicological Sciences 94(2):351-358.
9. Gwiazda R, Kern C, Smith D. (2005) Progression Of Neurochemical Effects In Different
Brain Regions As A Function Of The Magnitude And Duration Of Manganese Exposure.
Toxicol Sci 84(1-S): 122-123.
10. Gwiazda R, Lucchini R, Smith D. (2007) Adequacy and consistency of animal studies to
evaluate the neurotoxicity of chronic low-level manganese exposure in humans. Journal of
Toxicology and Environmental Health-Part a-Current Issues 70(7):594-605.
11. Gwiazda RH, Lee D, Sheridan J, Smith DR. (2002) Low cumulative manganese exposure
affects striatal GABA but not dopamine. Neurotoxicology 23(l):69-76.
12. Hussain S, Lipe GW, Slikker W, Ali SF. (1997) The effects of chronic exposure of
manganese on antioxidant enzymes in different regions of rat brain. Neuroscience Research
Communications 21(2): 135-144.
13. Komiskey H. (2005) Influence Of Subacute Manganese Sulfate On Dopamine And N-
Methyl-D-Aspartate Receptors. Toxicol Sci 84(1-S):122.
14. Lipe GW, Duhart H, Newport GD, Slikker W, Ali SF. (1999) Effect of manganese on the
concentration of amino acids in different regions of the rat brain. Journal of Environmental
Science and Health Part B-Pesticides Food Contaminants and Agricultural Wastes 34(1): 119-
132.
15. Newland MC. (1999) Animal models of manganese's neurotoxicity. Neurotoxicology 20(2-
3):415-432.
16. Normandin L, Beaupre LA, Salehi F, St-Pierre A, Kennedy G, Mergler D, Butterworth RE,
Philippe S, Zayed J. (2004) Manganese distribution in the brain and neurobehavioral changes
Draft Bibliography: Manganese Lit. Search B-ll
January 31, 2008
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following inhalation exposure of rats to three chemical forms of manganese. Neurotoxicology
25(3):433-441.
17. Normandin L, Carrier G, Gardiner PF, Kennedy G, Hazell AS, Mergler D, Butterworth RF,
Philippe S, Zayed J. (2002) Assessment of bioaccumulation, neuropathology, and neurobehavior
following subchronic (90 days) inhalation in Sprague-Dawley rats exposed to manganese
phosphate. Toxicology and Applied Pharmacology 183(2):135-145.
18. Ponnapakkam T, Iszard M, Henry-Sam G. (2003) Effects of oral administration of
manganese on the kidneys and urinary bladder of Sprague-Dawley rats. International Journal of
Toxicology 22(3):227-232.
19. Reaney SH, Bench G, Smith DR. (2006) Brain accumulation and toxicity of Mn(II) and
Mn(III) exposures. Toxicological Sciences 93(1): 114-124.
20. Salehi F, Carrier G, Normandin L, Kennedy G, Butterworth RF, Hazell A, Therrien G,
Mergler D, Philippe S, Zayed J. (2001) Assessment of bioaccumulation and neurotoxicity in rats
with portacaval anastomosis and exposed to manganese phosphate: A pilot study. Inhalation
Toxicology 13(12): 1151-1163.
21. Salehi F, Krewski D, Mergler D, Normandin L, Kennedy G, Philippe S, Zayed J. (2003)
Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-
Dawley rats following subchronic (90 days) inhalation exposure. Toxicology and Applied
Pharmacology 191(3):264-271.
22. Salehi F, Normandin L, Krewski D, Kennedy G, Philippe S, Zayed J. (2006)
Neuropathology, tremor and electromyogram in rats exposed to manganese phosphate/sulfate
mixture. Journal of Applied Toxicology 26(5):419-426.
23. Schneider JS, Decamp E, Koser AJ, Fritz S, Gonczi H, Syversen T, Guilarte TR. (2006)
Effects of chronic manganese exposure on cognitive and motor functioning in non-human
primates. Brain Research 1118:222-231.
24. Shinotoh H, Snow BJ, Hewitt KA, Pate BD, Doudet D, Nugent R, Perl DP, Olanow W,
Calne DB. (1995) MRI and PET studies of manganese-intoxicated monkeys. Neurology
45(6): 1199-1204.
25. Spadoni F, Stefani A, Morello M, Lavaroni F, Giacomini P, Sancesario G. (2000) Selective
vulnerability of pallidal neurons in the early phases of manganese intoxication. Experimental
Brain Research 135(4):544-551.
26. St-Pierre A, Normandin L, Carrier G, Kennedy G, Butterworth R, Zayed J. (2001)
Bioaccumulation and locomotor effect of manganese dust in rats. Inhalation Toxicology
13(7):623-632.
Draft Bibliography: Manganese Lit. Search B-12
January 31, 2008
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27. Tapin D, Kennedy G, Lambert J, Zayed J. (2006) Bioaccumulation and locomotor effects of
manganese sulfate in Sprague-Dawley rats following subchronic (90 days) inhalation exposure.
Toxicology and Applied Pharmacology 211(2): 166-174.
28. Taylor MD, Erikson KM, Dobson AW, Fitsanakis VA, Dorman DC, Aschner M. (2006)
Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain. Neurotoxicology
27(5):788-797.
29. Torrente M, Colomina MT, Domingo JL. (2005) Behavioral effects of adult rats
concurrently exposed to high doses of oral manganese and restraint stress. Toxicology 211(1-
2):59-69.
30. Vezer T, Papp A, Hoyk Z, Varga C, Naray M, Nagymajtenyi L. (2005) Behavioral and
neurotoxicological effects of subchronic manganese exposure in rats. Environmental Toxicology
and Pharmacology 19(3):797-810.
31. Witholt R, Gwiazda RH, Smith DR. (2000) The neurobehavioral effects of subchronic
manganese exposure in the presence and absence of pre-parkinsonism. Neurotoxicology and
Teratology 22(6):851-861.
32. Yang PY, Klimis-Tavantzis DJ. (1998) Manganese deficiency alters arterial
glycosaminoglycan structure in the Sprague-Dawley rat. Journal of Nutritional Biochemistry
9(6):324-331.
4.2.2 Cancer bioassays (0)
No cancer bioassays were found.
4.3 REPRODUCTIVE AND DEVELOPMENTAL STUDIES-ORAL AND
INHALATION (12)
1. Colomina MT, Domingo JL, Llobet JM, Corbella J. (1996) Effect of day of exposure on the
developmental toxicity of manganese in mice. Veterinary and Human Toxicology 38(l):7-9.
2. Eder K, Kralik A, Kirchgessner M. (1996) The effect of manganese supply on thyroid
hormone metabolism in the offspring of manganese-depleted dams. Biological Trace Element
Research 55(1-2): 137-145.
3. Garcia SJ, Syversen T, Gellein K, Aschner M. (2005) Iron Deficient And Manganese
Enhanced Diets Alter Metals And Transporters In The Developing Rat Brain. Toxicol Sci 84(1-
S):122.
4. Pappas BA, Zhang D, Davidson CM, Crowder T, Park GA, Fortin T. (1997) Perinatal
manganese exposure: Behavioral, neurochemical, and histopathological effects in the rat.
Neurotoxicology and Teratology 19(1): 17-25.
Draft Bibliography: Manganese Lit. Search B-13
January 31, 2008
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5. Ponnapakkam TP, Bailey KS, Graves KA, Iszard MB. (2003) Assessment of male
reproductive system in the CD-I mice following oral manganese exposure. Reproductive
Toxicology 17(5): 547-551.
6. Ponnapakkam TP, Henry-Sam GA, Iszard MB. (2001) A comparative study of the
reproductive toxicity of manganese in rats and mice. Faseb Journal 15(4):A585-A585.
7. Torrente M, Albina ML, Colomina MT, Corbella J, Domingo JL. (2000) Interactions in
developmental toxicology: effects of combined administration of manganese and hydrocortisone.
Trace Elements and Electrolytes 17(4): 173-179.
8. Torrente M, Colomina MT, Domingo JL. (2002) Effects of prenatal exposure to manganese
on postnatal development and behavior in mice: Influence of maternal restraint. Neurotoxicology
and Teratology 24(2):219-225.
9. Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B. (2002) Effect of high
dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine
levels, and neurodevelopmental status. Neurotoxicology 23(4-5):635-643.
10. Tran TT, Kelleher SL, Lonnerdal B. (2002) Effect of high manganese intake and iron
deficiency in infant rats on DMT-1 expression and tissue mineral accumulation. Faseb Journal
16(4):A617-A617.
11. Weber S, Dorman DC, Lash LH, Erikson K, Vrana KE, Aschner M. (2002) Effects of
manganese (Mn) on the developing rat brain: Oxidative-stress related endpoints.
Neurotoxicology 23(2): 169-175.
12. Zhang BY, Chen S, Ye FL, Zhu CC, Zhang HX, Wang RB, Xiao CF, Wu TC, Zhang GG.
(2002) Effect of manganese on heat stress protein synthesis of new-born rats. World Journal of
Gastroenterology 8(1):114-118.
4.4 OTHER ENDPOINT-SPECIFIC STUDIES [e.g., in vivo neurological,
immunological studies] (0)
No other standard endpoint specific studies were identified.
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE
OF ACTION (25)
1. Ali SF, Duhart HM, Newport GD, Lipe GW, Slikker W. (1995) Manganese-Induced Reactive
Oxygen Species - Comparison between Mn+2 and Mn+3. Neurodegeneration 4(3):329-334.
2. Brown S, Taylor NL. (1999) Could mitochondrial dysfunction play a role in manganese
toxicity? Environmental Toxicology and Pharmacology 7(l):49-57.
Draft Bibliography: Manganese Lit. Search B-14
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3. Chetty CS, Reddy GR, Suresh A, Desaiah D, Ali SF, Slikker WJ. (2001) Effects of
manganese on inositol polyphosphate receptors and nitric oxide synthase activity in rat brain.
International Journal of Toxicology 20(5):275-280.
4. Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. (1998) The influence
of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat. Proceedings
of the Society for Experimental Biology and Medicine 219(l):41-47.
5. Diaz-Veliz G, Mora S, Gomez P, Dossi MT, Monti el J, Arriagada C, Aboitiz F, Segura-
Aguilar J. (2004) Behavioral effects of manganese injected in the rat substantia nigra are
potentiated by dicumarol, a DT-diaphorase inhibitor. Pharmacology Biochemistry and Behavior
77(2):245-251.
6. Erikson KM, Dobson AW, Dorman DC, Aschner M. (2004) Manganese exposure and
induced oxidative stress in the rat brain. Science of the Total Environment 334-35:409-416.
7. Erikson KM, Jones SR, Aschner M. (2005) Brain manganese accumulation due to toxic
exposure is mediated by the dopamine transporter. Faseb Journal 19(5):A1033-A1034.
8. Gonzalez-Reyes RE, Gutierrez-Alvarez AM, Moreno CB. (2007) Manganese and epilepsy: A
systematic review of the literature. Brain Research Reviews 53(2):332-336.
9. HaMai D, Bondy SC. (2004) Oxidative basis of manganese neurotoxicity. Redox-Active
Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp 129-141.
10. Hussain SM, Javorina AK, Schrand AM, Duhart HM, Ali SF, Schlager JJ. (2006) The
interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion.
Toxicological Sciences 92(2):456-463.
11. Malecki EA, Devenyi AG, Beard JL, Connor JR. (1999) Existing and emerging mechanisms
for transport of iron and manganese to the brain. Journal of Neuroscience Research 56(2): 113-
122.
12. Martin CJ. (2006) Manganese neurotoxicity: Connecting the dots along the continuum of
dysfunction. Neurotoxicology 27(3):347-349.
13. Normandin L, Hazell AS. (2002) Manganese neurotoxicity: An update of pathophysiologic
mechanisms. Metabolic Brain Disease 17(4):375-387.
14. Pamphlett R, McQuilty R, Zarkos K. (2001) Blood levels of toxic and essential metals in
motor neuron disease. Neurotoxicology 22(3):401-410.
15. Ranasinghe JGS, Liu MC, Sakakibara Y, Suiko M. (2000) Manganese administration
induces the increased production of dopamine sulfate and depletion of dopamine in Sprague-
Dawley rats. Journal of Biochemistry 128(3):477-480.
Draft Bibliography: Manganese Lit. Search B-15
January 31, 2008
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16. Rovetta F, Catalani S, Steimberg N, Bonlottl J, Gilberti ME, Mariggio MA, Mazzoleni G.
(2007) Organ-specific manganese toxicity: a comparative in vitro study on five cellular models
exposed to MnC12. Toxicology in Vitro 21(2):284-292.
17. Sloot WN, Korf J, Koster JF, DeWit LEA, Gramsbergen JBP. (1996) Manganese-induced
hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron
chelation in vivo. Experimental Neurology 138(2):236-245.
18. Takeda A. (2003) Manganese action in brain function. Brain Research Reviews 41(l):79-87.
19. Takeda A. (2004) Analysis of brain function and prevention of brain diseases: the action of
trace metals. Journal of Health Science 50(5):429-442.
20. Takeda A, Sotogaku N, Oku N. (2002) Manganese influences the levels of neurotransmitters
in synapses in rat brain. Neuroscience 114(3):669-674.
21. Tjalkens R. (2005) Neuro-Glial Interactions In Basal Ganglia Dysfunction: Insights From
Manganese Neurotoxicity. Toxicol Sci 84(1-S):337.
22. Villalobos V, Estevez J, Novo E, Bonilla E. (2001) Effects of chronic manganese treatment
on mouse brain (H-3) spiroperidol binding parameters: In vivo and in vitro studies. Revista
Cientifica-Facultad De Ciencias Veterinarias 11(4):306-313.
23. Yavorskaya V, Pelekhova O, Grebenyuk G, Chernyshova T. (2006) Manganese toxic
encephalopathy with parkinsonism. European Journal of Neurology 13:289-290.
24. Zheng W, Ren S, Graziano JH. (1998) Manganese inhibits mitochondrial aconitase: A
mechanism of manganese neurotoxicity. Brain Research 799(2):334-342.
25. Zwingmann C, Leibfritz D, Hazell AS. (2004) Brain energy metabolism in a sub-acute rat
model of manganese neurotoxicity: An ex vivo nuclear magnetic resonance study using [1-C-
13]glucose. Neurotoxicology 25(4):573-587.
4.6 REVIEW ARTICLES (18)
1. Anonymous. (1997) Manganese. RAIS Toxicity Profiles (1997).
2. Anonymous. (2001) Manganese and inorganic compounds. ACGIH. Documentation of the
threshold limit values and biological exposure indices Vol:7th Ed (2001) 6 p.
3. Anonymous. (2001) Manganese Cyclopentadienyl Tricarbonyl. ACGIH. Documentation of
the threshold limit values and biological exposure indices Vol:7th Ed (2001) 2 p.
4. Anonymous. (2003) Methylcyclopentadienyl Manganese Tricarbonyl (MMT). NICNAS:
Priority existing chemical assessment report Vol:24 (2003) 149 p.
Draft Bibliography: Manganese Lit. Search B-16
January 31, 2008
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5. ATSDR. 2000. Public Health Statement Manganese. In: CDC, editor: ATSDR.
6. Clewell HJ, Lawrence GA, Calne DB, Crump KS. (2003) Determination of an occupational
exposure guideline for manganese using the benchmark method. Risk Analysis 23(5): 1031-1046.
7. EPA. 2003. Health Effects Support Document for Manganese
8. Gerber GB, Leonard A, Hantson P. (2002) Carcinogenicity, mutagenicity and teratogenicity
of manganese compounds. Critical Reviews in Oncology Hematology 42(l):25-34.
9. Goldhaber SB. (2003) Trace element risk assessment: essentiality vs. toxicity. Regulatory
Toxicology and Pharmacology 38(2):232-242.
10. Greger JL. (1998) Dietary standards for manganese: Overlap between nutritional and
toxicological studies. Journal of Nutrition 128(2):368S-371S.
11. Greger JL. (1999) Nutrition versus toxicology of manganese in humans: Evaluation of
potential biomarkers. Neurotoxicology 20(2-3):205-212.
12. Gwiazda R, Lucchini R, Smith D. (2007) Adequacy and consistency of animal studies to
evaluate the neurotoxicity of chronic low-level manganese exposure in humans. Journal of
Toxicology and Environmental Health-Part a-Current Issues 70(7):594-605.
13. Jankovic J. (2005) Searching for a relationship between manganese and welding and
Parkinson's disease. Neurology 64(12):2021-2028.
14. Newland MC. (1999) Animal models of manganese's neurotoxicity. Neurotoxicology 20(2-
3):415-432.
15. OEHHA. 2004. Chronic Toxicity Summary Managenese and Compounds. In: Assessment
OoEHH, editor: California Environmental Protection Agency (Cal/EPA).
16. Olanow CW. (2004) Manganese-induced parkinsonism and Parkinson's disease. Redox-
Active Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp
209-223.
17. Roth JA, Garrick MD. (2003) Iron interactions and other biological reactions mediating the
physiological and toxic actions of manganese. Biochemical Pharmacology 66(1): 1-13.
18. Santamaria A, Cushing C, Antonini J, Finley B, Mowat F. (2007) State-of-the-Science
Review: Does Manganese Exposure During Welding Pose a Neurological Risk? Journal of
Toxicology and Environmental Health Part B: Critical Reviews 10(6):416-475(449).
Draft Bibliography: Manganese Lit. Search B-17
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APPENDIX C:
SUPPORTING REFERENCES BY SUBJECT
Draft Bibliography: Manganese Lit. Search
January 31, 2008
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3.1
TOXICOKINETICS (45)
1. Alarcon OM, ReinosaFuller JA, Silva T, DeFernandez MR, Gamboa J. (1996) Manganese
levels in serum of healthy Venezuelan infants living in Merida. Journal of Trace Elements in
Medicine and Biology 10(4):210-213.
2. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
3. Anderson JG, Cooney PT, Erikson KM. (2007) Inhibition of DAT function attenuates
manganese accumulation in the globus pallidus. Environmental Toxicology and Pharmacology
23(2): 179-184.
4. Anderson JG, Fordahl SC, Cooney PT, Erikson KM. (2007) Iron deficiency and manganese
exposure are associated with decreases in neurotransmitter uptake. Faseb Journal 21(6):A1065-
A1065.
5. Arnaud J, Bourlard P, Denis B, Favier AE. (1996) Plasma and erythrocyte manganese
concentrations - Influence of age and acute myocardial infarction. Biological Trace Element
Research 53(1-3): 129-136.
6. Arnold ML, McNeill FE, Chettle DR. (1999) The feasibility of measuring manganese
concentrations in human liver using neutron activation analysis. Neurotoxicology 20(2-3):407-
412.
7. Aschner M. (2000) Manganese: Brain transport and emerging research needs. Environmental
Health Perspectives 108:429-432.
8. Aschner M, Vrana KE, Zheng W. (1999) Manganese uptake and distribution in the central
nervous system (CNS). Neurotoxicology 20(2-3): 173-180.
9. Boojar MMA, Goodarzi F, Basedaghat MA. (2002) Long-term follow-up of workplace and
well water manganese effects on iron status indexes in manganese miners. Archives of
Environmental Health 57(6):519-528.
10. Bouchard M, Mergler D, Baldwin M, Sassine MP, Bowler R, MacGibbon B. (2003) Blood
manganese and alcohol consumption interact on mood states among manganese alloy production
workers. Neurotoxicology 24(4-5):641-647.
11. Bressler JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D. (2007) Metal transporters
in intestine and brain: their involvement in metal-associated neurotoxicities. Human &
Experimental Toxicology 26(3):221-229.
Draft Bibliography: Manganese Lit. Search C-1
January 31, 2008
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12. Bukalis K, Kyriakopoulos A, Alber D, Richarz AN, Behne D. (2006) Study on the
distribution of trace elements and trace element-containing proteins in the lung of the rat. Trace
Elements and Electrolytes 23(2): 108-112.
13. Chaki H, Furuta S, Matsuda A, Yamauchi K, Yamamoto K, Kokuba Y, Fujibayashi Y.
(2000) Magnetic resonance image and blood manganese concentration as indices for manganese
content in the brain of rats. Biological Trace Element Research 74(3):245-257.
14. Chen GT, Zhao L, Bao SF, Cong T. (2006) Effects of different proteins on the metabolism
of Zn, Cu, Fe, and Mn in rats. Biological Trace Element Research 113(2): 165-175.
15. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
16. Chua ACG, Stonell LM, Savigni DL, Morgan EH. (1996) Mechanisms of manganese
transport in rabbit erythroid cells. Journal of Physiology-London 493(1):99-112.
17. Crossgrove JS, Yokel RA. (2004) Manganese distribution across the blood-brain barrier III -
The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake.
Neurotoxicology 25(3):451-460.
18. Erikson KM, Aschner M. (2006) Increased manganese uptake by primary astrocyte cultures
with altered iron status is mediated primarily by divalent metal transporter. Neurotoxicology
27(1): 125-130.
19. Erikson KM, John CE, Jones SR, Aschner M. (2005) Manganese accumulation in striatum
of mice exposed to toxic doses is dependent upon a functional dopamine transporter.
Environmental Toxicology and Pharmacology 20(3):390-394.
20. Finley JW. (1998) Manganese uptake and release by cultured human hepato-carcinoma
(Hep-G2) cells. Biological Trace Element Research 64(1-3): 101-118.
21. Finley JW, BriskeAnderson M, Gregoire B. (1996) Metabolism of manganese by isolated rat
hepatocytes and by the Hep-G2 cell line. Faseb Journal 10(3):4736-4736.
22. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2005) Manganese transport by rat brain
endothelial (RBE4) cell-based transwell model in the presence of astrocyte conditioned media.
Journal of Neuroscience Research 81(2):235-243.
23. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2006) Characteristics of manganese
(Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier.
Neurotoxicology 27(l):60-70.
24. Fitsanakis VA, Piccola G, dos Santos AP, Aschner JL, Aschner M. (2007) Putative proteins
involved in manganese transport across the blood-brain barrier. Human & Experimental
Toxicology 26(4):295-302.
Draft Bibliography: Manganese Lit. Search
C-2
January 31, 2008
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25. Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N. (1997) Accumulation of manganese
in the brain of mice after intravenous injection of manganese-based contrast agents. Chemical
Research in Toxicology 10(4):360-363.
26. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG,
Hainsworth LN, Umbreit JN, Conrad ME and others. (2003) DMT1: A mammalian transporter
for multiple metals. Biometals 16(l):41-54.
27. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
28. Harris WR. (2003) Modeling methods to determine A1 and Mn speciation for toxicity
assessment. Toxicological Sciences 72:117-117.
29. Heilig EA, Thompson KJ, Molina RM, Ivanov AR, Brain JD, Wessling-Resnick M. (2006)
Manganese and iron transport across pulmonary epithelium. American Journal of Physiology-
Lung Cellular and Molecular Physiology 290(6):L1247-L1259.
30. Kim Y, Park JK, Choi Y, Yoo CI, Lee CR, Lee H, Lee JH, Kim SR, Jeong TH, Yoon CS
and others. (2005) Blood manganese concentration is elevated in iron deficiency anemia patients,
whereas globus pallidus signal intensity is minimally affected. Neurotoxicology 26(1): 107-111.
31. Kucera J, Bencko V, Sabbioni E, Vandervenne MT. (1995) Review of Trace-Elements in
Blood, Serum and Urine for the Czech and Slovak Populations and Critical-Evaluation of Their
Possible Use as Reference Values. Science of the Total Environment 166(1-3):211-234.
32. Lai JCK, Minski MJ, Chan AWK, Leung TKC, Lim L. (1999) Manganese mineral
interactions in brain. Neurotoxicology 20(2-3):433-444.
33. Li GJJ, Zhang LL, Lu L, Wu P, Zheng W. (2004) Occupational exposure to welding fume
among welders: Alterations of manganese, iron, zinc, copper, and lead in body fluids and the
oxidative stress status. Journal of Occupational and Environmental Medicine 46(3):241-248.
34. Malecki EA, Cable EE, Connor JR. (2000) Short-term dietary manganese deficiency
increases intestinal expression of DMT-1. Faseb Journal 14(4):A229-A229.
35. Malecki EA, Cook BM, Devenyi AG, Beard JL, Connor JR. (1999) Transferrin is required
for normal distribution of Fe-59 and Mn-54 in mouse brain. Journal of the Neurological Sciences
170(2): 112-118.
36. Malecki EA, Devenyi AG, Connor JR. (1997) Manganese (Mn) transport in mice
heterozygotic for hypotransferrinemia mutation: Effects of iron (Fe) deficiency.
Gastroenterology 112(4):A891-A891.
37. Matsumoto K, Inagaki T, Hirunuma R, Enomoto S, Endo K. (2001) Contents and uptake
rates of Mn, Fe, Co, Zn, and Se in Se-deficient rat liver cell fractions. Analytical Sciences
17(5):587-591.
Draft Bibliography: Manganese Lit. Search
C-3
January 31, 2008
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38. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
39. Slikker W, Keenan F. (1998) Toxicokinetics and bioavailability of manganese: Session II
summary and research needs. Neurotoxicology 19(3):475-478.
40. Takeda A, Devenyi A, Connor JR. (1998) Evidence for non-transferrin-mediated uptake and
release of iron and manganese in glial cell cultures from hypotransferrinemic mice. Journal of
Neuroscience Research 51(4):454-462.
41. Tiffany-Castiglioni E, Qian YC. (2001) Astroglia as metal depots: Molecular mechanisms
for metal accumulation, storage and release. Neurotoxicology 22(5):577-592.
42. Wang X, Li JG, Zheng W. (2005) Overexpression Of Dmtl In The Choroid Plexus
Following Manganese (Mn) Exposure. Toxicol Sci 84(1-S):122.
43. Yokel RA, Lasley SM, Dorman DC. (2006) The speciation of metals in mammals influences
their toxicokinetics and toxicodynamics and therefore human health risk assessment. Journal of
Toxicology and Environmental Health-Part B-Critical Reviews 9(l):63-85.
44. Zheng W, Aschner M, Ghersi-Egea JF. (2003) Brain barrier systems: a new frontier in metal
neurotoxicological research. Toxicology and Applied Pharmacology 192(1): 1-11.
45. Zheng YX, Chan P, Pan ZF, Shi NN, Wang ZX, Pan J, Liang HM, Niu Y, Zhou XR, He FS.
(2002) Polymorphism of metabolic genes and susceptibility to occupational chronic manganism.
Biomarkers 7(4):337-346.
3.2 PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS (0)
No supporting studies were identified for this section.
3.3 LIVER/GI FUNCTION (12)
1. Agte V, Jahagirdar M, Chiplonkar S. (2005) Apparent absorption of eight micronutrients and
phytic acid from vegetarian meals in ileostomized human volunteers. Nutrition 21(6):678-685.
2. Aschner JL, Furlong H, Daily D, Aschner M. (2006) Neuroimaging and neurodevelopmental
correlates of intravenous manganese exposure in parente rally-fed infants: A clinical trial in the
neonatal intensive care unit (NICU). Neurotoxicology 27(6): 1168-1168.
3. Davis CD, Schafer DM, Finley JW. (1998) Effect of biliary ligation on manganese
accumulation in rat brain. Biological Trace Element Research 64(l-3):61-74.
Draft Bibliography: Manganese Lit. Search
C-4
January 31, 2008
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4. Fell JME, Reynolds AP, Meadows N, Khan K, Long SG, Quaghebeur G, Taylor WJ, Milla
PJ. (1996) Manganese toxicity in children receiving long-term parenteral nutrition. Lancet
347(9010): 1218-1221.
5. Finley JW, Penland JG, Pettit RE, Davis CD. (2003) Dietary manganese intake and type of
lipid do not affect clinical or neuropsychological measures in healthy young women. Journal of
Nutrition 133(9):2849-2856.
6. Fitzgerald K, Mikalunas V, Rubin H, McCarthy R, Vanagunas A, Craig RM. (1999)
Hypermanganesemia in patients receiving total parenteral nutrition. Journal of Parenteral and
Enteral Nutrition 23(6):333-336.
7. Ikeda S, Yamaguchi Y, Sera Y, Ohshiro H, Uchino S, Yamashita Y, Ogawa M. (2000)
Manganese deposition in the globus pallidus in patients with biliary atresia. Transplantation
69(11):2339-2343.
8. Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. (1998) Long term outcome of
brain manganese deposition in patients in home parenteral nutrition. Archives of Disease in
Childhood 79(3):263-265.
9. Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H. (1995) Manganese and
Chronic Hepatic-Encephalopathy. Lancet 346(8970):270-274.
10. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro
L. (1999) Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal Tl-
weighted magnetic resonance signal hyperintensity. Neurotoxicology 20(4):647-652.
11. Ono J, Harada K, Kodaka R, Sakurai K, Tajiri H, Takagi Y, Nagai T, Harada T, Nihei A,
Okada A and others. (1995) Manganese deposition in the brain during long-term total parenteral
nutrition. Journal of Parenteral and Enteral Nutrition 19(4):310-312.
12. Reynolds N, Blumsohn A, Baxter JP, Houston G, Pennington CR. (1998) Manganese
requirement and toxicity in patients on home parenteral nutrition. Clinical Nutrition 17(5):227-
230.
4.1 STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS (57)
1. Alves G, Thiebot J, Tracqui A, Delangre T, Lerebours E, et al. (1997) Neurologic disorders
due to brain manganese deposition in a jaundiced patient receiving long term parenteral
nutrition. JPEN J. Parenter. Enteral Nutr. 21(Jan-Feb):41-45.
2. Azin F, Raie RM, Mahmoudi MM. (1998) Correlation between the levels of certain
carcinogenic and anticarcinogenic trace elements and esophageal cancer in northern Iran.
Ecotoxicology and Environmental Safety 39(3): 179-184.
Draft Bibliography: Manganese Lit. Search
C-5
January 31, 2008
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3. Barbee JY, Prince TS. (1999) Acute respiratory distress syndrome in a welder exposed to
metal fumes. Southern Medical Journal 92(5):510-512.
4. Barrington WW, Angle CR, Willcockson NK, Padula MA, Korn T. (1998) Autonomic
function in manganese alloy workers. Environmental Research 78(l):50-58.
5. Beath. (1996) Manganese toxicity and parenteral nutrition (vol 347, pg 1773, 1996). Lancet
348(9024):416-416.
6. Beuter A, Edwards R, De Geoffroy A, Mergler D, Hudnell K. (1999) Quantification of
neuromotor function for detection of the effects of manganese. Neurotoxicology (Little Rock)
20(2-3):355-366.
7. Bocca B, Alimonti A, Bomboi G, Giubilei F, Forte G. (2006) Alterations in the level of trace
metals in Alzheimer's disease. Trace Elements and Electrolytes 23(4):270-276.
8. Bouchard M, Mergler D, Baldwin M. (2005) Manganese exposure and age: neurobehavioral
performance among alloy production workers. Environmental Toxicology and Pharmacology
19(3):687-694.
9. Chia SE, Gan SL, Chua LH, Foo SC, Jeyaratnam J. (1995) Postural stability among
manganese exposed workers. Neurotoxicology (Little Rock) 16(3):519-526.
10. Crump KS, Rousseau P. (1999) Results from eleven years of neurological health
surveillance at a manganese oxide and salt producing plant. Neurotoxicology (Little Rock) 20(2-
3):273-286.
11. Degner D, Bleich S, Riegel A, Sprung R, Poser W, Ruther E. (2000) A follow-up study in
enteral manganese intoxication: clinical, laboratory, and neuroradiological aspects. Nervenarzt
71 (5):416-419.
12. Ericson JE, Crinella FM, Clarke-Stewart KA, Allhusen VD, Chan T, Robertson RT. (2007)
Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicology and
Teratology 29(2): 181-187.
13. Forte G, Bocca B, Senofonte O, Petrucci F, Brusa L, Stanzione P, Zannino S, Violante N,
Alimonti A, Sancesario G. (2004) Trace and major elements in whole blood, serum,
cerebrospinal fluid and urine of patients with Parkinson's disease. Journal of Neural
Transmission 111(8): 1031-1040.
14. Fortoul TI, Mendoza ML, Avila MD, Torres AQ, Osorio LS, Espejel GM, Fernandez GO.
(2001) Manganese in lung tissue: Study of Mexico City residents' autopsy records from the
1960s and 1990s. Archives of Environmental Health 56(2): 187-190.
15. Fredstrom S, Rogosheske J, Gupta P, Burns LJ. (1995) Extrapyramidal Symptoms in a Bmt
Recipient with Hyperintense Basal Ganglia and Elevated Manganese. Bone Marrow
Transplantation 15(6):989-992.
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16. Goldman SM, Quinlan PJ, Smith AR, Langston J, Tanner CM. (2004) Manganese exposure
and risk of Parkinson's disease in twins. Movement Disorders 19:S162-S162.
17. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ.
(1997) Occupational exposures to metals as risk factors for Parkinson's disease. Neurology
48(3):650-658.
18. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ.
(1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of
Parkinson's disease. Neurotoxicology 20(2-3):239-247.
19. Gorell JM, Rybicki BA, Johnson CC, Peterson EL. (1999) Occupational metal exposures
and the risk of Parkinson's disease. Neuroepidemiology 18(6):303-308.
20. Greiffenstein MF, Lees-Haley PR. (2007) Neuropsychological correlates of manganese
exposure: A meta-analysis. Journal of Clinical and Experimental Neuropsychology 29(2): 113-
126.
21. Ha@l/atek T, Sinczuk-Walczak H, Szymczak M, Rydzynski K. (2005) Neurological and
respiratory symptoms in shipyard welders exposed to manganese. International Journal of
Occupational Medicine and Environmental Health 3rd quarter 2005, Vol. 18, No. 3, p. 265-274.
Illus. 51 ref.
22. Hernandez EH, Discalzi G, Dassi P, Jarre L, Pira E. (2003) Manganese intoxication: The
cause of an inexplicable epileptic syndrome in a 3 year old child. Neurotoxicology 24(4-5):633-
639.
23. Hobbesland A, Kjuus H, Thelle DS. (1999) Study of cancer incidence among 6363 male
workers in four Norwegian ferromanganese and silicomanganese producing plants. Occupational
and Environmental Medicine 56(9):618-624.
24. Hossny E, Mokhtar G, El-Awady M, El-Wahab AA. (1998) Serum manganese deficiency in
Egyptian children with bronchial asthma. Journal of Allergy and Clinical Immunology
101(1):S117-S117.
25. Hsieh CT, Liang JS, Peng SSF, Lee WT. (2007) Seizure associated with total parenteral
nutrition-related hypermanganesemia. Pediatric Neurology 36(3): 181-183.
26. Jimenezjimenez FJ, Molina JA, Aguilar MV, Arrieta FJ, Jorgesantamaria A, Cabreravaldivia
F, Ayusoperalta L, Rabasa M, Vazquez A, Garciaalbea E and others. (1995) Serum and Urinary
Manganese Levels in Patients with Parkinsons-Disease. Acta Neurologica Scandinavica
91(5):317-320.
27. Kenangil G, Ertan S, Sayilir I, Ozekmekci S. (2006) Progressive motor syndrome in a
welder with pallidal T1 hyperintensity on MRI: A two-year follow-up. Movement Disorders
21(12):2197-2200.
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28. Kessler KR, Wunderlich G, Hefter H, Seitz RJ. (2003) Secondary progressive chronic
manganism associated with markedly decreased striatal D2 receptor density. Movement
Disorders 18(2):216-218.
29. Kilic E, Saraymen R, Demiroglu A, Ok E. (2004) Chromium and manganese levels in the
scalp hair of normals and patients with breast cancer. Biological Trace Element Research 102(1-
3):19-25.
30. Kim JW, Kim Y, Cheong HK, Ito K. (1998) Manganese induced Parkinsonism: A case
report. Journal of Korean Medical Science 13(4):437-439.
31. Kim Y, Kim JM, Kim JW, Yoo CI, Lee CR, Lee JH, Kim HK, Yang SO, Chung HK, Lee
DS and others. (2002) Dopamine transporter density is decreased in parkinsonian patients with a
history of manganese exposure: What does it mean? Movement Disorders 17(3):568-575.
32. Kim YH, Kim JW, Ito KG, Lim HS, Cheong HK, Kim JY, Shin YC, Kim KS, Moon YH.
(1999) Idiopathic parkinsonism with superimposed manganese exposure: Utility of positron
emission tomography. Neurotoxicology 20(2-3):249-252.
33. Kocyigit A, Zeyrek D, Keles H, Koylu A. (2004) Relationship among manganese, arginase,
and nitric oxide in childhood asthma. Biological Trace Element Research 102(1-3): 11-18.
34. Komaki H, Maisawa S, Sugai K, Kobayashi Y, Hashimoto T. (1999) Tremor and seizures
associated with chronic manganese intoxication. Brain & Development 21(2): 122-124.
35. Kondoh H, Iwase K, Higaki J, Tanaka Y, Yoshikawa M, Hori S, Osuga K, Kamiike W.
(1999) Manganese deposition in the brain following parenteral manganese administration in
association with radical operation for esophageal cencer: Report of a case. Surgery Today-the
Japanese Journal of Surgery 29(8):773-776.
36. Lucchini R, Bergamaschi E, Smargiassi A, Festa D, Apostoli P. (1997) Motor function,
olfactory threshold, and hematological indices in manganese-exposed ferroalloy workers.
Environmental Research 73(1-2): 175-180.
37. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M,
Mihara F. (2001) Manganese intoxication during intermittent parenteral nutrition: Report of two
cases. Journal of Parenteral and Enteral Nutrition 25(2):95-99.
38. Mergler D, Baldwin M, Belanger S, Larribe F, Beuter A, Bowler R, Panisset M, Edwards R,
de Geoffroy A, Sassine MP and others. (1999) Manganese neurotoxicity, a continuum of
dysfunction: Results from a community based study. Neurotoxicology 20(2-3):327-342.
39. Molina JA, Jimenez-Jimenez FJ, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-
Munoz MJ, de Bustos F, Porta J, Orti-Pareja M, Zurdo M and others. (1998) Cerebrospinal fluid
levels of transition metals in patients with Alzheimer's disease. Journal of Neural Transmission
105(4-5):479-488.
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40. Muhtaseb MS, O'Reilly D, McKee R, Anderson J, Finlay IG. (2004) Patients who have had
ileal-anal pouch surgery are at risk of manganese and vitamin B toxicity. British Journal of
Surgery 91:5-5.
41. Myers JE, teWaterNaude J, Fourie M, Zogoe HBA, Naik I, Theodorou P, Tassel H, Daya A,
Thompson ML. (2003) Nervous system effects of occupational manganese exposure on South
African manganese mineworkers. Neurotoxicology 24(4-5):649-656.
42. Park J, Yoo CI, Sim CS, Kim HK, Kim JW, Jeon BS, Kim KR, Bang OY, Lee WY, Yi Y
and others. (2005) Occupations and Parkinson's disease: A multi-center case-control study in
South Korea. Neurotoxicology 26(1):99-105.
43. Park J, Yoo CI, Sim CS, Kim JW, Yi Y, Shin YC, Kim DH, Kim Y. (2006) A retrospective
cohort study of Parkinson's disease in Korean shipbuilders. Neurotoxicology 27(3):445-449.
44. Ransom-Schwaeber MM. (2007) Manganese toxicity due to oral ingestion as an acne
treatment. Neurology 68(12):A327-A327.
45. Rodriguez-Agudelo Y, Riojas-Rodriguez H, Rios C, Rosas I, Pedraza ES, Miranda J, Siebe
C, Texcalac JL, Santos-Burgoa C. (2006) Motor alterations associated with exposure to
manganese in the environment in Mexico. Science of the Total Environment 368(2-3):542-556.
46. Ross C, O'Reilly DS, McKee R. (2006) Potentially clinically toxic concentrations of whole
blood manganese in a patient fed enterally with a high tea consumption. Annals of Clinical
Biochemistry 43:226-228.
47. Sadek AH, Rauch R, Schulz PE. (2003) Parkinsonism due to Manganism in a Welder.
International Journal of Toxicology 22(5):393-401.
48. Sassine MP, Mergler D, Bowler R, Hudnell HK. (2002) Manganese accentuates adverse
mental health effects associated with alcohol use disorders. Biological Psychiatry 51(11):909-
921.
49. Shinotoh H, Snow BJ, Chu NS, Huang CC, Lu CS, Lee C, Takahashi H, Calne DB. (1997)
Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese
intoxication: A positron emission tomography study. Neurology 48(4): 1053-1056.
50. Sjogren B, Iregren A, Freeh W, Hagman M, Johansson L, Tesarz M, Wennberg A. (1996)
Effects on the nervous system among welders exposed to aluminium and manganese.
Occupational and Environmental Medicine 53(l):32-40.
51. Staunton M, Phelan DM. (1995) Manganese Toxicity in a Patient with Cholestasis
Receiving Total Parenteral-Nutrition. Anaesthesia 50(7):665-665.
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52. Wardle CA, Forbes A, Roberts NB, Jawhari AV, Shenkin A. (1999) Hypermanganesemia in
long-term intravenous nutrition and chronic liver disease. Journal of Parenteral and Enteral
Nutrition 23(6):350-355.
53. Wasserman GA, Liu XH, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A,
Slavkovich V, Lolacono NJ and others. (2006) Water manganese exposure and children's
intellectual function in Araihazar, Bangladesh. Environmental Health Perspectives 114(1): 124-
129.
54. Woolf A, Wright R, Amarasiriwardena C, Bellinger D. (2002) A child with chronic
manganese exposure from drinking water. Environmental Health Perspectives 110(6):613-616.
55. Yanik M, Kocyigit A, Tutkun H, Vural H, Herken H. (2004) Plasma manganese, selenium,
zinc, copper, and iron concentrations in patients with schizophrenia. Biological Trace Element
Research 98(2): 109-117.
56. Yiin SJ, Lin TH, Shih TS. (1996) Lipid peroxidation in workers exposed to manganese.
Scandinavian Journal of Work Environment & Health 22(5):381-386.
57. Yoshikawa K, Matsumoto M, Hamanaka M, Nakagawa M. (2003) A case of manganese
induced parkinsonism in hereditary haemorrhagic telangiectasia. Journal of Neurology
Neurosurgery and Psychiatry 74(9): 1312-1314.
4.2 LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
4.2.1 Less-than-lifetime and Chronic Studies (3)
1. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
2. Desole MS, Serra PA, Esposito G, Delogu MR, Migheli R, Fresu L, Rocchitta G, Miele M.
(2000) Glutathione deficiency potentiates manganese-induced increases in compounds
associated with high-energy phosphate degradation in discrete brain areas of young and aged
rats. Aging Clinical and Experimental Research 12(6):470-477.
3. Husain M, Khanna VK, Roy A, Tandon R, Pradeep S, Seth PK. (2001) Platelet dopamine
receptors and oxidative stress parameters as markers of manganese toxicity. Human &
Experimental Toxicology 20(12):631-636.
4.2.2 Cancer bioassays (0)
No supporting studies of cancer bioassays were found.
Draft Bibliography: Manganese Lit. Search C-10
January 31, 2008
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4.3 REPRODUCTIVE AND DEVELOPMENTAL STUDIES—ORAL AND
INHALATION (93)
1. Agte V, Jahagirdar M, Chiplonkar S. (2005) Apparent absorption of eight micronutrients and
phytic acid from vegetarian meals in ileostomized human volunteers. Nutrition 21(6):678-685.
2. Anastassopoulou J, Theophanides T. (2002) Magnesium-DNA interactions and the possible
relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical Reviews in
Oncology Hematology 42(1):79-91.
3. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
4. Anderson JG, Cooney PT, Erikson KM. (2007) Inhibition of DAT function attenuates
manganese accumulation in the globus pallidus. Environmental Toxicology and Pharmacology
23(2): 179-184.
5. Antonini JM, Santaimaria AB, Jenkins NT, Albini E, Lucchini R. (2006) Fate of manganese
associated with the inhalation of welding fumes: Potential neurological effects. Neurotoxicology
27(3):304-310.
6. Aschner M. (2000) Manganese: Brain transport and emerging research needs. Environmental
Health Perspectives 108:429-432.
7. Aschner M, Lukey B, Tremblay A. (2006) The manganese health research program (MHRP):
Status report and future research needs and directions. Neurotoxicology 27(5):733-736.
8. Aschner M, Vrana KE, Zheng W. (1999) Manganese uptake and distribution in the central
nervous system (CNS). Neurotoxicology 20(2-3): 173-180.
9. Azin F, Raie RM, Mahmoudi MM. (1998) Correlation between the levels of certain
carcinogenic and anticarcinogenic trace elements and esophageal cancer in northern Iran.
Ecotoxicology and Environmental Safety 39(3): 179-184.
10. Barrington WW, Angle CR, Willcockson NK, Padula MA, Korn T. (1998) Autonomic
function in manganese alloy workers. Environmental Research 78(l):50-58.
11. Bizarro P, Sanchez I, Lopez I, Pasos F, Delgado V, Gonzalez-Villalva A, Colin-Barenque L,
Acevedo S, Nino-Cabrera G, Mussali-Galante P and others. (2004) Morphological Changes In
Testes. After Manganese Inhalation. Study In Mice. Toxicologist 78(1-S): 157.
12. Blakey DH, Bayley JM. (1995) Induction of chromosomal aberrations by the fuel addictive
methylcyclopentadienyl-manganese tricarbonyl mmt in Chinese hamster ovary cells. 26th Annual
Meeting of the Environmental Mutagen Society, St. Louis, Missouri, USA, March 12-16, 1995.
Environmental and Molecular Mutagenesis 25(SUPPL. 25):6.
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13. Blazak WF, Brown GL, Gray TJB, Treinen KA, Denny KH. (1996) Developmental toxicity
study of mangafodipir trisodium injection (MnDPDP) in New Zealand white rabbits.
Fundamental and Applied Toxicology 33(1):11-15.
14. Bouchard M, Mergler D, Baldwin M, Sassine MP, Bowler R, MacGibbon B. (2003) Blood
manganese and alcohol consumption interact on mood states among manganese alloy production
workers. Neurotoxicology 24(4-5):641-647.
15. Bowler RM, Mergler D, Sassine MP, Larribe F, Hudnell K. (1999) Neuropsychiatry effects
of manganese on mood. Neurotoxicology 20(2-3):367-378.
16. Bredow S, Falgout MM, Divine KK. (2005) A Potential Mechanism For Pulmonary
Manganese-Toxicity: Manganese Induces Pulmonary VEGF Expression In Vitro. Toxicol Sci
84(1-S):234.
17. Brurok H, Schjott J, Berg K, Karlsson JOG, Jynge P. (1997) Manganese and the heart:
Acute cardiodepression and myocardial accumulation of manganese. Acta Physiologica
Scandinavica 159(l):33-40.
18. Buchman AL, Neely M, Grossie VB, Truong L, Lykissa E, Ahn C. (2001) Organ heavy-
metal accumulation during parenteral nutrition is associated with pathologic abnormalities in
rats. Nutrition 17(7-8):600-606.
19. Cardozo-Pelaez F, Cox DP, Bolin C. (2005) Lack of the DNA repair enzyme OGG1
sensitizes dopamine neurons to manganese toxicity during development. Gene Expression 12(4-
6):315-323.
20. Chaki H, Furuta S, Matsuda A, Yamauchi K, Yamamoto K, Kokuba Y, Fujibayashi Y.
(2000) Magnetic resonance image and blood manganese concentration as indices for manganese
content in the brain of rats. Biological Trace Element Research 74(3):245-257.
21. Chang JY, Liu LZ. (1999) Manganese potentiates nitric oxide production by microglia.
Molecular Brain Research 68(l-2):22-28.
22. Chen CJ, Ou YC, Lin SY, Liao SL, Chen SY, Chen JH. (2006) Manganese modulates pro-
inflammatory gene expression in activated glia. Neurochemistry International 49(1):62-71.
23. Cheng J, Fu JL, Zhou ZC. (2003) The inhibitory effects of manganese on steroidogenesis in
rat primary Leydig cells by disrupting steroidogenic acute regulatory (StAR) protein expression.
Toxicology 187(2-3): 139-148.
24. Chua ACG, Stonell LM, Savigni DL, Morgan EH. (1996) Mechanisms of manganese
transport in rabbit erythroid cells. Journal of Physiology-London 493(1):99-112.
25. Cox D, Bolin C, Cardozo-Pelaez F. (2003) Assessment of dopaminergic neurons, DNA
damage, DNA repair, and antioxidants in a model for manganese (MN) neurotoxicity. Free
Radical Biology and Medicine 35:S156-S156.
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26. Crossgrove J, Zheng W. (2004) Manganese toxicity upon overexposure. Nmr in
Biomedicine 17(8):544-553.
27. Davis CD, Schafer DM, Finley JW. (1998) Effect of biliary ligation on manganese
accumulation in rat brain. Biological Trace Element Research 64(l-3):61-74.
28. Degner D, Bleich S, Riegel A, Sprung R, Poser W, Ruther E. (2000) A follow-up study in
enteral manganese intoxication: clinical, laboratory, and neuroradiological aspects. Nervenarzt
71 (5):416-419.
29. Desoize B. (2003) Metals and metal compounds in carcinogenesis. In Vivo 17(6):529-539.
30. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R. (1996) Manganese and l-methyl-4-
(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine induce apoptosis in PC12 cells. Neuroscience Letters
209(3):193-196.
31. DiLorenzo D, Ferrari F, Agrati P, deVos H, Apostoli P, Alessio L, Albertini A, Maggi A.
(1996) Manganese effects on the human neuroblastoma cell line SK-ER3. Toxicology and
Applied Pharmacology 140(1):51-57.
32. Dodd CA, Ward DL, Klein BG. (2005) Basal ganglia accumulation and motor assessment
following manganese chloride exposure in the C57BL/6 mouse. International Journal of
Toxicology 24(6):389-397.
33. Dorman DC. (2000) An integrative approach to neurotoxicology. Toxicologic Pathology
28(l):37-42.
34. Egyed M, Wood GC. (1996) Risk assessment for combustion products of the gasoline
additive MMT in Canada. Science of the Total Environment 190:11-20.
35. Elbetieha A, Bataineh H, Darmani H, Al-Hamood MH. (2001) Effects of long-term
exposure to manganese chloride on fertility of male and female mice. Toxicology Letters
119(3): 193-201.
36. EPA. 2004. Drinking Water Health Advisory for Manganese. U.S. Environmental Protection
Agency Office of Water. Report nr EPA-822-R-04-003.
37. Ericson JE, Crinella FM, Clarke-Stewart KA, Allhusen VD, Chan T, Robertson RT. (2007)
Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicology and
Teratology 29(2): 181-187.
38. Erikson K, Aschner M. (2002) Manganese causes differential regulation of glutamate
transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.
Neurotoxicology 23(4-5):595-602.
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39. Erikson KM, Aschner M. (2003) Manganese neurotoxicity and glutamate-GABA
interaction. Neurochemistry International 43(4-5):475-480.
40. Erikson KM, Dorman DC, Fitsanakis V, Lash LH, Aschner M. (2006) Alterations of
oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.
Biological Trace Element Research 111(1-3): 199-215.
41. Erikson KM, Dorman DC, Lash LH, Aschner M. (2005) Persistent alterations in biomarkers
of oxidative stress resulting from combined in utero and neonatal manganese inhalation.
Biological Trace Element Research 104(2): 151-163.
42. Erikson KM, Suber RL, Aschner M. (2002) Glutamate/aspartate transporter (GLAST),
taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes
exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology
23(3):281-288.
43. Erikson KM, Thompson K, Aschner J, Aschner M. (2007) Manganese neurotoxicity: A
focus on the neonate. Pharmacology & Therapeutics 113(2):369-377.
44. Finley JW. (2004) Does environmental exposure to manganese pose a health risk to healthy
adults? Nutrition Reviews 62(4): 148-153.
45. Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M. (2006) The use of
magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology
27(5):798-806.
46. Fitzgerald K, Mikalunas V, Rubin H, McCarthy R, Vanagunas A, Craig RM. (1999)
Hypermanganesemia in patients receiving total parenteral nutrition. Journal of Parenteral and
Enteral Nutrition 23(6):333-336.
47. Fortoul TI, Mendoza ML, Avila MD, Torres AQ, Osorio LS, Espejel GM, Fernandez GO.
(2001) Manganese in lung tissue: Study of Mexico City residents' autopsy records from the
1960s and 1990s. Archives of Environmental Health 56(2): 187-190.
48. Fredstrom S, Rogosheske J, Gupta P, Burns LJ. (1995) Extrapyramidal Symptoms in a Bmt
Recipient with Hyperintense Basal Ganglia and Elevated Manganese. Bone Marrow
Transplantation 15(6):989-992.
49. FreelandGraves JH, Turnlund JR. (1996) Deliberations and evaluations of the approaches,
endpoints and paradigms for manganese and molybdenum dietary recommendations. Journal of
Nutrition 126(9):S2435-S2440.
50. Friberg L, Nordberg GF, Vouk VB. (2007) Handbook of the Toxicology of Metals. 3rd ed. :
Elsevier Science Publishing Company; pp. 476.
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51. Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N. (1997) Accumulation of manganese
in the brain of mice after intravenous injection of manganese-based contrast agents. Chemical
Research in Toxicology 10(4):360-363.
52. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG,
Hainsworth LN, Umbreit JN, Conrad ME and others. (2003) DMT1: A mammalian transporter
for multiple metals. Biometals 16(l):41-54.
53. Gassmann B. (2001) Dietary reference intakes, report 4: Trace elements. Ernahrungs-
Umschau 48(4): 148-+.
54. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
55. Grandjean P, Landrigan PJ. (2006) Developmental neurotoxicity of industrial chemicals.
Lancet 368(9553):2167-2178.
56. Halatek T, Opalska B, Rydzynski K, Bernard A. (2006) Pulmonary response to
methylcyclopentadienyl manganese tricarbonyl treatment in rats: injury and repair evaluation.
Histology and Histopathology 21(11): 1181-1192.
57. Hernandez EH, Discalzi G, Dassi P, Jarre L, Pira E. (2003) Manganese intoxication: The
cause of an inexplicable epileptic syndrome in a 3 year old child. Neurotoxicology 24(4-5):633-
639.
58. Hirata Y, Adachi E, Kiuchi K. (1998) Activation of JNK pathway and induction of apoptosis
by manganese in PC12 cells. Journal of Neurochemistry 71(4): 1607-1615.
59. Hirata Y, Kiuchi K, Nagatsu T. (2001) Manganese mimics the action of l-methyl-4-
phenylpyridinium ion, a dopaminergic neurotoxin, in rat striatal tissue slices. Neuroscience
Letters 3ll(l):53-56.
60. Hsieh CT, Liang JS, Peng SSF, Lee WT. (2007) Seizure associated with total parenteral
nutrition-related hypermanganesemia. Pediatric Neurology 36(3): 181-183.
61. Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. (1998) Long term outcome of
brain manganese deposition in patients in home parenteral nutrition. Archives of Disease in
Childhood 79(3):263-265.
62. Kessler KR, Wunderlich G, Hefter H, Seitz RJ. (2003) Secondary progressive chronic
manganism associated with markedly decreased striatal D2 receptor density. Movement
Disorders 18(2):216-218.
63. Kim JW, Kim Y, Cheong HK, Ito K. (1998) Manganese induced Parkinsonism: A case
report. Journal of Korean Medical Science 13(4):437-439.
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64. Kondoh H, Iwase K, Higaki J, Tanaka Y, Yoshikawa M, Hori S, Osuga K, Kamiike W.
(1999) Manganese deposition in the brain following parenteral manganese administration in
association with radical operation for esophageal cencer: Report of a case. Surgery Today-the
Japanese Journal of Surgery 29(8):773-776.
65. Kucera J, Bencko V, Sabbioni E, Vandervenne MT. (1995) Review of Trace-Elements in
Blood, Serum and Urine for the Czech and Slovak Populations and Critical-Evaluation of Their
Possible Use as Reference Values. Science of the Total Environment 166(1-3):211-234.
66. Lambert LB, Singer TM, Boucher SE, Douglas GR. (2005) Detailed review of transgenic
rodent mutation assays. Mutation Research-Reviews in Mutation Research 590(1-3): 1-280.
67. Laurant P, Chanut E, Bobillier-Chaumont S, Gaillard E, Jacquot C, Trouvin JH, Berthelot A.
(2003) Attenuation of the development of DOCA salt hypertension by a high Mn intake in the
rat. Trace Elements and Electrolytes 20(3): 172-180.
68. Lee B, Hiney JK, Pine MD, Srivastava VK, Dees WL. (2007) Manganese stimulates
luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site
and mechanism of action. Journal of Physiology-London 578(3):765-772.
69. Lee B, Pine M, Johnson L, Rettori V, Hiney JK, Dees WL. (2006) Manganese acts centrally
to activate reproductive hormone secretion and pubertal development in male rats. Reproductive
Toxicology 22(4):580-585.
70. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro
L. (1999) Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal Tl-
weighted magnetic resonance signal hyperintensity. Neurotoxicology 20(4):647-652.
71. Malecki EA, Lo HC, Yang H, Davis CD, Ney DM, Greger JL. (1995) Tissue Manganese
Concentrations and Antioxidant Enzyme-Activities in Rats Given Total Parenteral-Nutrition
with and without Supplemental Manganese. Journal of Parenteral and Enteral Nutrition
19(3):222-226.
72. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M,
Mihara F. (2001) Manganese intoxication during intermittent parenteral nutrition: Report of two
cases. Journal of Parenteral and Enteral Nutrition 25(2):95-99.
73. Mergler D, Baldwin M. (1997) Early manifestations of manganese neurotoxicity in humans:
An update. Environmental Research 73(l-2):92-100.
74. Miller KB, Caton JS, Finley JW. (2006) Manganese depresses rat heart muscle respiration.
Biofactors 28(l):33-46.
75. Oikawa S, Hirosawa I, Tada-Oikawa S, Furukawa A, Nishiura K, Kawanishi S. (2006)
Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and
neuronal cell death. Free Radical Biology and Medicine 41(5):748-756.
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76. Ostiguy C, Asselin P, Malo S. (2006) The emergence of manganese-related health problems
in Quebec: An integrated approach to evaluation, diagnosis, management and control.
Neurotoxicology 27(3):350-356.
77. Park J, Yoo CI, Sim CS, Kim HK, Kim JW, Jeon BS, Kim KR, Bang OY, Lee WY, Yi Y
and others. (2005) Occupations and Parkinson's disease: A multi-center case-control study in
South Korea. Neurotoxicology 26(1):99-105.
78. Park RM, Bowler RM, Eggerth DE, Diamond E, Spencer KJ, Smith D, Gwiazda R. (2006)
Issues in neurological risk assessment for occupational exposures: The Bay Bridge welders.
Neurotoxicology 27(3):373-384.
79. Pecze L, Papp A, Nagymajtenyi L. (2004) Changes in the spontaneous and stimulus-evoked
activity in the somatosensory cortex of rats on acute manganese administration. Toxicology
Letters 148(1-2): 125-131.
80. Ramesh GT, Ghosh D, Gunasekar PG. (2002) Activation of early signaling transcription
factor, NF-kappaB following low-level manganese exposure. Toxicology Letters 136(2): 151-
158.
81. Rao KVR, Norenberg MD. (2004) Manganese induces the mitochondrial permeability
transition in cultured astrocytes. Journal of Biological Chemistry 279(31):32333-32338.
82. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
83. Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C, Paez E, Crespo E. (2000)
Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats - A
morphometric and densitomeric study. European Journal of Obstetrics Gynecology and
Reproductive Biology 90(1):97-101.
84. Ross C, O'Reilly DS, McKee R. (2006) Potentially clinically toxic concentrations of whole
blood manganese in a patient fed enterally with a high tea consumption. Annals of Clinical
Biochemistry 43:226-228.
85. Seth P, Husain MM, Gupta P, Schoneboom BA, Grieder FB, Mani H, Maheshwari RK.
(2003) Early onset of virus infection and up-regulation of cytokines in mice treated with
cadmium and manganese. Biometals 16(2):359-368.
86. Sjogren B, Iregren A, Freeh W, Hagman M, Johansson L, Tesarz M, Wennberg A. (1996)
Effects on the nervous system among welders exposed to aluminium and manganese.
Occupational and Environmental Medicine 53(l):32-40.
87. Sunderman FW. (2001) Review: Nasal toxicity, carcinogenicity, and olfactory uptake of
metals. Annals of Clinical and Laboratory Science 31(l):3-24.
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88. Takeda A. (2004) Essential trace metals and brain function. Yakugaku Zasshi-Journal of the
Pharmaceutical Society of Japan 124(9):577-585.
89. TERA. 2008. ITER Database. Concurrent Technologies Corporation and Toxicology
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90. Wasserman GA, Liu XH, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A,
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91. Yokel RA, Lasley SM, Dorman DC. (2006) The speciation of metals in mammals influences
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92. Yoritaka A, Hattori N, Mori H, Kato K, Mizuno Y. (1997) An immunohistochemical study
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93. Zheng W, Aschner M, Ghersi-Egea JF. (2003) Brain barrier systems: a new frontier in metal
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4.4 OTHER ENDPOINT-SPECIFIC STUDIES [e.g., in vivo neurological,
immunological studies] (0)
No other standard endpoint specific studies were identified.
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE
OF ACTION (146)
1. Reaney SH, Smith DR. (2005) Manganese oxidation state mediates toxicity in PC12 cells.
Toxicology and Applied Pharmacology 205(3):271-281.
2. Alcaraz-Zubeldia M, Montes S, Rios C. (2001) Participation of manganese-superoxide
dismutase in the neuroprotection exerted by copper sulfate against 1-methyl 4-phenylpyridinium
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3. Alinovi R, Vettori MV, Mutti A, Cavazzini S, Bacchini A, Bergamaschi E. (1996) Dopamine
(DA) metabolism in PC12 cells exposed to manganese (Mn) at different oxidation states.
Neurotoxicology (Little Rock) 17(3-4):743-750.
4. Anantharam V, Kitazawa M, Latchoumycandane C, Kanthasamy A, Kanthasamy AG. (2004)
Blockade of PKC delta proteolytic activation by loss of function mutants rescues mesencephalic
dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl (MMT)-induced
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5. Anantharam V, Kitazawa M, Wagner J, Kaul S, Kanthasamy AG. (2002) Caspase-3-
dependent proteolytic cleavage of protein kinase C delta is essential for oxidative stress-
mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese
tricarbonyl. Journal of Neuroscience 22(5): 1738-1751.
6. Anastassopoulou J, Theophanides T. (2002) Magnesium-DNA interactions and the possible
relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical Reviews in
Oncology Hematology 42(1):79-91.
7. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
8. Anderson JG, Fordahl SC, Cooney PT, Erikson KM. (2007) Iron deficiency and manganese
exposure are associated with decreases in neurotransmitter uptake. Faseb Journal 21(6):A1065-
A1065.
9. Antonini JM, Santaimaria AB, Jenkins NT, Albini E, Lucchini R. (2006) Fate of manganese
associated with the inhalation of welding fumes: Potential neurological effects. Neurotoxicology
27(3):304-310.
10. Baek SY, Kim YH, Oh SO, Lee CR, Yoo CI, Lee JH, Lee H, Sim CS, Park J, Kim JW and
others. (2007) Manganese does not alter the severe neurotoxicity of MPTP. Human &
Experimental Toxicology 26(3):203-211.
11. Baek SY, Lee MJ, Jung HS, Kim HJ, Lee CR, Yoo C, Lee JH, Lee H, Yoon CS, Kim YH
and others. (2003) Effect of manganese exposure on MPTP neurotoxicities. Neurotoxicology
24(4-5):657-665.
12. Bairati C, Goi G, Bollini D, Roggi C, Luca M, Apostoli P, Lombardo A. (1997) Effects of
lead and manganese on the release of lysosomal enzymes in vitro and in vivo. Clinica Chimica
Acta 261(1):91-101.
13. Blakey DH, Bayley JM. (1995) Induction of chromosomal aberrations by the fuel addictive
methylcyclopentadienyl-manganese tricarbonyl mmt in Chinese hamster ovary cells. 26th Annual
Meeting of the Environmental Mutagen Society, St. Louis, Missouri, USA, March 12-16, 1995.
Environmental and Molecular Mutagenesis 25(SUPPL. 25):6.
14. Bredow S, Falgout MM, Divine KK. (2005) A Potential Mechanism For Pulmonary
Manganese-Toxicity: Manganese Induces Pulmonary VEGF Expression In Vitro. Toxicol Sci
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15. Brurok H, Schjott J, Berg K, Karlsson JOG, Jynge P. (1997) Manganese and the heart:
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16. Btaiche IF, Khalidi N. (2004) Metabolic complications of parenteral nutrition in adults, part
1. American Journal of Health-System Pharmacy 61(18): 1938-1949.
17. Btaiche IF, Khalidi N. (2004) Metabolic complications of parenteral nutrition in adults, part
2. American Journal of Health-System Pharmacy 61(19):2050-2057.
18. Butterworth RF, Spahr L, Fontaine S, Layrargues GP. (1995) Manganese toxicity,
dopaminergic dysfunction and hepatic encephalopathy. Metabolic Brain Disease 10(4):259-267.
19. Cano G, SuarezRoca H, Bonilla E. (1997) Alterations of excitatory amino acid receptors in
the brain of manganese-treated mice. Molecular and Chemical Neuropathology 30(l-2):41-52.
20. Cardozo-Pelaez F, Cox DP, Bolin C. (2005) Lack of the DNA repair enzyme OGG1
sensitizes dopamine neurons to manganese toxicity during development. Gene Expression 12(4-
6):315-323.
21. Centonze D, Gubellini P, Bernardi G, Calabresi P. (2001) Impaired excitatory transmission
in the striatum of rats chronically intoxicated with manganese. Experimental Neurology
172(2):469-476.
22. Chang JY, Liu LZ. (1999) Manganese potentiates nitric oxide production by microglia.
Molecular Brain Research 68(l-2):22-28.
23. Chen CJ, Liao SL. (2002) Oxidative stress involves in astrocytic alterations induced by
manganese. Experimental Neurology 175(l):216-225.
24. Chen CJ, Ou YC, Lin SY, Liao SL, Chen SY, Chen JH. (2006) Manganese modulates pro-
inflammatory gene expression in activated glia. Neurochemistry International 49(1):62-71.
25. Chen JY, Tsao GC, Zhao QQ, Zheng W. (2001) Differential cytotoxicity of Mn(II) and
Mn(III): Special reference mitochondrial [Fe-S] containing enzymes. Toxicology and Applied
Pharmacology 175(2): 160-168.
26. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
27. Cheng J, Fu JL, Zhou ZC. (2003) The inhibitory effects of manganese on steroidogenesis in
rat primary Leydig cells by disrupting steroidogenic acute regulatory (StAR) protein expression.
Toxicology 187(2-3): 139-148.
28. Cheng J, Fu JL, Zhou ZC. (2005) The mechanism of manganese-induced inhibition of
steroidogenesis in rat primary Leydig cells. Toxicology 211(1-2): 1-11.
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29. Choi C, Anantharam V, Kanthasamy A, Kanthasamy A. (2006) Effect of prion proteins on
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30. Chukhlovin AB, Tokalov SV, Yagunov AS, Zharskaya VD. (1996) Acute effects of copper,
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31. Chun HS, Lee H, Son JH. (2001) Manganese induces endoplasmic reticulum (ER) stress and
activates multiple caspases in nigral dopaminergic neuronal cells, SN4741. Neuroscience Letters
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32. Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. (1996) Manganese
deficiency effects circulating growth hormone (GH), IGF-I, and IGFBPS in the male rat. Faseb
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33. Cox D, Bolin C, Cardozo-Pelaez F. (2003) Assessment of dopaminergic neurons, DNA
damage, DNA repair, and antioxidants in a model for manganese (MN) neurotoxicity. Free
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34. Crittenden PL, Filipov NM. (2004) Enhanced Proinflammatory Cytokine Production By
Activated Microglial And Macrophage Cell Lines Exposed To Manganese In Vitro. Toxicologist
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35. Crittenden PL, Filipov NM. (2005) Manganese-Induced Alterations In Nf-kappaB-related
Gene Expression By Activated Microglia. Toxicol Sci 84(1-S):126.
36. Davis CD, Feng Y. (1999) Dietary copper, manganese and iron affect the formation of
aberrant crypts in colon of rats administered 3,2 '-dimethyl-4-aminobiphenyl. Journal of
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37. Dedizio MCC, Gomez G, Bonilla E, Suarezroca H. (1995) Autoreceptor Presynaptic Control
of Dopamine Release from Striatum Is Lost at Early Stages of Manganese Poisoning. Life
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38. Defazio G, Soleo L, Zefferino R, Livrea P. (1996) Manganese toxicity in serumless
dissociated mesencephalic and striatal primary culture. Brain Research Bulletin 40(4):257-262.
39. Desjardins P, Bandeira P, Hazell AS, Buu NT, Ledoux S, Butterworth RF. (1997) Increased
peripheral-type benzodiazepine receptor ptbr gene expression in brain and kidney in hepatic
encephalopathy he results from exposure to ammonia or manganese. 48th Annual Meeting of the
American Association for the Study of Liver Diseases, Chicago, Illinois, USA, November 7-11,
1997. Hepatology 26(4 PART 2):249A.
40. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R. (1996) Manganese and l-methyl-4-
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41. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R, Miele E. (1997) Role of oxidative
stress in the manganese and l-methyl-4-(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine-induced
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42. Desole MS, Serra PA, Esposito G, Delogu MR, Migheli R, Fresu L, Rocchitta G, Miele M.
(2000) Glutathione deficiency potentiates manganese-induced increases in compounds
associated with high-energy phosphate degradation in discrete brain areas of young and aged
rats. Aging Clinical and Experimental Research 12(6):470-477.
43. DiLorenzo D, Ferrari F, Agrati P, deVos H, Apostoli P, Alessio L, Albertini A, Maggi A.
(1996) Manganese effects on the human neuroblastoma cell line SK-ER3. Toxicology and
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44. Dodd CA, Ward DL, Klein BG. (2005) Basal ganglia accumulation and motor assessment
following manganese chloride exposure in the C57BL/6 mouse. International Journal of
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45. Dorman DC. (2000) An integrative approach to neurotoxicology. Toxicologic Pathology
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46. Dukhande VV, Malthankar-Phatak GH, Hugus JJ, Daniels CK, Lai JCK. (2006) Manganese-
induced neurotoxicity is differentially enhanced by glutathione depletion in astrocytoma and
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47. Eder K, Kirchgessner M, Kralik A. (1996) The effect of trace element deficiency (iron,
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48. Ensunsa JL, Symons JD, Lanoue L, Schrader HR, Keen CL. (2004) Reducing arginase
activity via dietary manganese deficiency enhances endothelium-dependent vasorelaxation of rat
aorta. Experimental Biology and Medicine 229(11): 1143-1153.
49. Erikson K, Aschner M. (2002) Manganese causes differential regulation of glutamate
transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.
Neurotoxicology 23(4-5):595-602.
50. Erikson KM, Dorman DC, Fitsanakis V, Lash LH, Aschner M. (2006) Alterations of
oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.
Biological Trace Element Research 111(1-3): 199-215.
51. Erikson KM, Dorman DC, Lash LH, Aschner M. (2005) Persistent alterations in biomarkers
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52. Erikson KM, Dorman DC, Lash LH, Dobson AW, Aschner M. (2004) Airborne manganese
exposure differentially affects end points of oxidative stress in an age and sex-dependent
manner. Biological Trace Element Research 100(l):49-62.
53. Erikson KM, Suber RL, Aschner M. (2002) Glutamate/aspartate transporter (GLAST),
taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes
exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology
23(3):281-288.
54. Fernandes A, Ferreira JG, de Oliveira E, Ponzoni S. (2004) L-Deprenyl (selegiline)
neuroprotective failure in a manganese neurotoxicity model. Movement Disorders 19:S41-S41.
55. Filipov NM, Seegal RF, Lawrence DA. (2005) Manganese potentiates in vitro production of
proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa In-
dependent mechanism. Toxicological Sciences 84(1): 139-148.
56. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2005) Manganese transport by rat brain
endothelial (RBE4) cell-based transwell model in the presence of astrocyte conditioned media.
Journal of Neuroscience Research 81(2):235-243.
57. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2006) Characteristics of manganese
(Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier.
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58. Fitsanakis VA, Piccola G, dos Santos AP, Aschner JL, Aschner M. (2007) Putative proteins
involved in manganese transport across the blood-brain barrier. Human & Experimental
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59. Fong CS, Wu RM, Shieh JC, Chao YT, Fu YP, Kuao CL, Cheng CW. (2007) Pesticide
exposure on southwestern Taiwanese with MnSOD and NQOl polymorphisms is associated with
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60. Galvani P, Fumagalli P, Santagostino A. (1995) Vulnerability of Mitochondrial Complex-I
in Pcl2 Cells Exposed to Manganese. European Journal of Pharmacology-Environmental
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61. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
62. Gong HQ, Amemiya T. (1996) Ultrastructure of retina of manganese-deficient rats.
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63. Gong HQ, Amemiya T. (1999) Corneal changes in manganese-deficient rats. Cornea
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64. Gong HQ, Amemiya T. (1999) Optic nerve changes in manganese-deficient rats.
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68. HaMai D, Rinderknecht AL, Guo-Sharman K, Kleinman MT, Bondy SC. (2006) Decreased
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69. Hazell AS, Gros P, Normandin L, Yi JH. (2005) Focal accumulation of manganese is
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70. Hazell AS, Norenberg MD, Yi JH. (2004) Involvement of oxidative stress in astrocytic
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71. Hazell AS, Normandin L. (2002) Up-regulation of'peripheral-type' benzodiazepine
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73. Hirata Y. (2002) Manganese-induced apoptosis in PC12 cells. Neurotoxicology and
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76. Hirata Y, Kiuchi K, Nagatsu T. (2001) Manganese mimics the action of l-methyl-4-
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78. Hsiao WL, Mendosa G, Kothari NH, Fan H. (1996) Comparison of transformation by
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79. Huang CC, Weng YH, Lu CS, Chu NS, Yen TC. (2003) Dopamine transporter binding in
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80. Husain M, Khanna VK, Roy A, Tandon R, Pradeep S, Seth PK. (2001) Platelet dopamine
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81. Isaac AO, Kawikova I, Bothwell ALM, Daniels CK, Lai JCK. (2006) Manganese treatment
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92. Kumar R, Srivastava S, Agrawal AK, Seth PK. (1996) Alteration in some membrane
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93. Lai JCK, Chan AWK, Minski MJ, Lim L. (1995) Trace-Metals in Brain Mitochondria and
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96. Ledig M, Copin JC, Tholey G, Leroy M, Rastegar F, Wedler F. (1995) Effect of manganese
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97. Lee B, Hiney JK, Pine MD, Srivastava VK, Dees WL. (2007) Manganese stimulates
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98. Lison D, Lardot C, Huaux F, Zanetti G, Fubini B. (1997) Influence of particle surface area
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107. Miller KB, Caton JS, Finley JW. (2006) Manganese depresses rat heart muscle respiration.
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112. Oner G, Senturk UK. (1995) Reversibility of Manganese-Induced Learning Defect in Rats.
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113. Papp A, Pecze L, Szabo A, Vezer T. (2006) Effects on the central and peripheral nervous
activity in rats elicited by acute administration of lead, mercury and manganese, and their
combinations. Journal of Applied Toxicology 26(4):374-380.
114. Pascal LE, Tessier DM. (2004) Cytotoxicity of chromium and manganese to lung epithelial
cells in vitro. Toxicology Letters 147(2): 143-151.
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115. Pecze L, Papp A, Nagymajtenyi L. (2004) Changes in the spontaneous and stimulus-
evoked activity in the somatosensory cortex of rats on acute manganese administration.
Toxicology Letters 148(1-2): 125-131.
116. Puli S, Lai JCK, Edgley KL, Daniels CK, Bhushan A. (2006) Signaling pathways
mediating manganese-induced toxicity in human glioblastoma cells (U87). Neurochemical
Research 31(10): 1211-1218.
117. Ramesh GT, Ghosh D, Gunasekar PG. (2002) Activation of early signaling transcription
factor, NF-kappaB following low-level manganese exposure. Toxicology Letters 136(2): 151-
158.
118. Rao KVR, Norenberg MD. (2004) Manganese induces the mitochondrial permeability
transition in cultured astrocytes. Journal of Biological Chemistry 279(31):32333-32338.
119. Rao KVR, Pichili VB, Bellam N, Norenberg MD. (2006) Manganese upregulates
aquaporin-4 in cultured astrocytes: role of oxidative stress. Journal of Neurochemistry 96:129-
129.
120. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
121. Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C, Paez E, Crespo E. (2000)
Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats - A
morphometric and densitomeric study. European Journal of Obstetrics Gynecology and
Reproductive Biology 90(1):97-101.
122. Rojas P, Rios C. (1995) Short-term manganese pretreatment partially protects against 1-
methyl-4-phenyl-l,2,3,6-tetrahydropyridine neurotoxicity. Neurochemical Research
20(10):1217-1223.
123. Roth JA, Horbinski C, Higgins D, Lein P, Garrick MD. (2002) Mechanisms of manganese-
induced rat pheochromocytoma (PC 12) cell death and cell differentiation. Neurotoxicology
23(2): 147-157.
124. Roth JA, Walowitz J. (1999) Mechanism of manganese-induced neurotoxicity and neurite
outgrowth in ratPC12 cells. Faseb Journal 13(4):A237-A237.
125. Seth K, Agrawal AK, Date I, Seth PK. (2002) The role of dopamine in manganese-induced
oxidative injury in rat pheochromocytoma cells. Human & Experimental Toxicology 21(3): 165-
170.
126. Seth P, Husain MM, Gupta P, Schoneboom BA, Grieder FB, Mani H, Maheshwari RK.
(2003) Early onset of virus infection and up-regulation of cytokines in mice treated with
cadmium and manganese. Biometals 16(2):359-368.
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127. Smith DR, Whitman S, Reaney S, Kwik-Uribe C, Arnold C, Gwiazda R, Holman T. (2003)
2-D DIGE proteomic analsyes of mn exposure in dopamine and GABA producing cell lines:
Implications for Mn neurotoxicity. Toxicological Sciences 72:20-21.
128. Soliman EF, Slikker W, Ali SF. (1995) Manganese-Induced Oxidative Stress as Measured
by a Fluorescent-Probe - an in-Vitro Study. Neuroscience Research Communications 17(3): 185-
193.
129. Spranger M, Schwab S, Desiderato S, Bonmann E, Krieger D, Fandrey J. (1998)
Manganese augments nitric oxide synthesis in murine astrocytes: A new pathogenetic
mechanism in manganism? Experimental Neurology 149(l):277-283.
130. Stredrick DL, Stokes AH, Worst TJ, Freeman WM, Johnson EA, Lash LH, Aschner M,
Vrana KE. (2004) Manganese-induced cytotoxicity in dopamine-producing cells.
Neurotoxicology 25(4):543-553.
131. Suarez N, Walum E, Eriksson H. (1995) Cellular Neurotoxicity of Trivalent Manganese
Bound to Transferrin or Pyrophosphate Studied in Human Neuroblastoma (Sh-Sy5y) Cell-
Cultures. Toxicology in Vitro 9(5):717-721.
132. Tomas-Camardiel M, Herrera AJ, Venero JL, Sanchez-Hidalgo MC, Cano J, Machado A.
(2002) Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase
mRNA expression in the aged manganese-treated rats. Molecular Brain Research 103(1-2): 116-
129.
133. Vettori MV, Gatti R, Orlandini G, Belletti S, Alinovi R, Smargiassi A, Mutti A. (1999) An
in vitro model for the assessment of manganese neurotoxicity. Toxicology in Vitro 13(6):931-
938.
134. Vidal L, Alfonso M, Campos F, Faro LRF, Cervantes RC, Duran R. (2005) Effects of
manganese on extracellular levels of dopamine in rat striatum: An analysis in vivo by brain
microdialysis. Neurochemical Research 30(9): 1147-1154.
135. Wang RG, Zhu XZ. (2003) Subtoxic concentration of manganese synergistically
potentiates l-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells. Brain Research
961(1): 131-138.
136. Yang HJ, Wang TN, Li JY, Gu L, Zheng XX. (2006) Decreasing expression of alpha(lc)
calcium L-type channel subunit mRNA in rat ventricular myocytes upon manganese exposure.
Journal of Biochemical and Molecular Toxicology 20(4): 159-166.
137. Yazbeck C, Moreau T, Sahuquillo J, Takser L, Huel G. (2006) Effect of maternal
manganese blood levels on erythrocyte calcium-pump activity in newborns. Science of the Total
Environment 354(l):28-34.
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138. Yoritaka A, Hattori N, Mori H, Kato K, Mizuno Y. (1997) An immunohistochemical study
on manganese superoxide dismutase in Parkinson's disease. Journal of the Neurological Sciences
148(2): 181-186.
139. Zaidi S, Patel A, Mehta N, Patel K, Takiar R, Saiyed H. (2005) Early biochemical
alterations in manganese toxicity: Ameliorating effects of magnesium nitrate and vitamins.
Industrial Health 43(4):663-668.
140. Zaloglu N, Koc E, Yildirim G, Bastug M, Ficicilar H. (2003) How does chronic manganese
chloride application affect the rat isolated ileal contractility? Trace Elements and Electrolytes
20(3):154-159.
141. Zhang SR, Fu JL, Zhou ZC. (2004) In vitro effect of manganese chloride exposure on
reactive oxygen species generation and respiratory chain complexes activities of mitochondria
isolated from rat brain. Toxicology in Vitro 18(l):71-77.
142. Zhang SR, Zhou ZC, Fu JL. (2003) Effect of manganese chloride exposure on liver and
brain mitochondria function in rats. Environmental Research 93(2): 149-157.
143. Zheng W, Zhao QQ. (2001) Iron overload following manganese exposure in cultured
neuronal, but not neuroglial cells. Brain Research 897(1-2): 175-179.
144. Zhong WX, Yan T, Webber MM, Oberley TD. (2004) Alteration of cellular phenotype and
responses to oxidative stress by manganese superoxide dismutase and a superoxide dismutase
mimic in RWPE-2 human prostate adenocarcinoma cells. Antioxidants & Redox Signaling
6(3):513-522.
145. Zwingmann C, Leibfritz D, Hazell AS. (2003) Altered metabolic trafficking via glutamine-
glutamate-cycle between astrocytes and neurons in manganese neurotoxicity. Journal of
Neurochemistry 87:142-142.
146. Zwingmann C, Leibfritz D, Hazell AS. (2003) Energy metabolism in astrocytes and
neurons treated with manganese: Relation among cell-specific energy failure, glucose
metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis.
Journal of Cerebral Blood Flow and Metabolism 23(6):756-771.
4.6 REVIEW ARTICLES (71)
1. (1998) Is airborne manganese a hazard? Environmental Health Perspectives 106(2):A57-A58.
2. anon. (1997) Manganese toxicity: hazard of intravenous food. Drugs Q. 1(1):31-32.
3. Antonini JM, Taylor MD, Zimmer AT, Roberts JR. (2004) Pulmonary responses to welding
fumes: Role of metal constituents. Journal of Toxicology and Environmental Health-Part a -
Current Issues 67(3):233-249.
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4. Aschner M, Erikson KM. (2003) Manganese and iron deficiency in neurodegeneration.
Journal of Neurochemistry 87:129-129.
5. Aschner M, Lukey B, Tremblay A. (2006) The manganese health research program (MHRP):
Status report and future research needs and directions. Neurotoxicology 27(5):733-736.
6. ATSDR. 2001. AT SDR - ToxFAQs": Manganese.
7. ATSDR. 2004. Interaction Profile: Lead, Manganese, Zinc, and Copper.
8. Barceloux DG. (1999) Manganese. Journal of Toxicology-Clinical Toxicology 37(2):293-
307.
9. Bizarro P, Sanchez I, Lopez I, Pasos F, Delgado V, Gonzalez-Villalva A, Colin-Barenque L,
Acevedo S, Nino-Cabrera G, Mussali-Galante P and others. (2004) Morphological Changes In
Testes. After Manganese Inhalation. Study In Mice. Toxicologist 78(1-S): 157.
10. Bourre JM. (2004) The role of nutritional factors on the structure and function of the brain:
an update on dietary requirements. Revue Neurologique 160(8-9):767-792.
11. Bourre JM. (2006) Effects of nutrients (in food) on the structure and function of the nervous
system: Update on dietary requirements for brain. Part 1: Micronutrients. Journal of Nutrition
Health & Aging 10(5):377-385.
12. Bowler RM, Mergler D, Sassine MP, Larribe F, Hudnell K. (1999) Neuropsychiatry effects
of manganese on mood. Neurotoxicology 20(2-3):367-378.
13. Breault JL, Campbell H. (1997) Manganese toxicity. Journal of Family Practice 45(1): 15-16.
14. Chu NS, Hochberg FH, Calne DB, Olanow CW. (1995) Neurotoxicology of manganese.
Chang, L. W. and R. S. Dyer (Ed.). Neurological Disease and Therapy, Vol. 36. Handbook of
Neurotoxicology. Xxi+1103p. Marcel Dekker, Inc.: New York, New York, USA; Basel,
Switzerland. Isbn 0-8247-8873-7.; 0 (0). 1995. 91-103.
15. Crossgrove J, Zheng W. (2004) Manganese toxicity upon overexposure. Nmr in
Biomedicine 17(8):544-553.
16. Davis JM. (1998) Methylcyclopentadienyl manganese tricarbonyl: Health risk uncertainties
and research directions. Environmental Health Perspectives 106:191-201.
17. Davis JM. (1999) Inhalation health risks of manganese: An EPA perspective.
Neurotoxicology 20(2-3):511-518.
18. Davis JM, Dorman D. (1998) Health risk assessments of manganese - Differing
perspectives: Session VIII summary and research needs. Neurotoxicology 19(3):488-489.
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19. De Miguel E, Iribarren I, Chacon E, Ordonez A, Charlesworth S. (2007) Risk-based
evaluation of the exposure of children to trace elements in playgrounds in Madrid (Spain).
Chemosphere 66(3):505-513.
20. Desoize B. (2003) Metals and metal compounds in carcinogenesis. In Vivo 17(6):529-539.
21. Dobson AW, Erikson KM, Aschner M. (2004) Manganese neurotoxicity. Redox-Active
Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp 115-128.
22. Egyed M, Wood GC. (1996) Risk assessment for combustion products of the gasoline
additive MMT in Canada. Science of the Total Environment 190:11-20.
23. EPA. 2004. Drinking Water Health Advisory for Manganese. U.S. Environmental Protection
Agency Office of Water. Report nr EPA-822-R-04-003.
24. Erikson KM, Aschner M. (2003) Manganese neurotoxicity and glutamate-GABA
interaction. Neurochemistry International 43(4-5):475-480.
25. Erikson KM, Syversen T, Aschner JL, Aschner M. (2005) Interactions between excessive
manganese exposures and dietary iron-deficiency in neurodegeneration. Environmental
Toxicology and Pharmacology 19(3):415-421.
26. Erikson KM, Syversen T, Soldin OP, Wu Q, Aschner M. (2003) Iron deficiency-induced
manganese accumulation in the developing rat brain is associated with increased DMT-1 protein
levels. Drug Metabolism Reviews 35:96-96.
27. Erikson KM, Thompson K, Aschner J, Aschner M. (2007) Manganese neurotoxicity: A
focus on the neonate. Pharmacology & Therapeutics 113(2):369-377.
28. Finley JW. (2004) Does environmental exposure to manganese pose a health risk to healthy
adults? Nutrition Reviews 62(4): 148-153.
29. Finley JW, Davis CD. (1999) Manganese deficiency and toxicity: Are high or low dietary
amounts of manganese cause for concern? Biofactors 10(1): 15-24.
30. Fitsanakis VA, Aschner M. (2005) The importance of glutamate, glycine, and gamma-
aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity.
Toxicology and Applied Pharmacology 204(3):343-354.
31. Fitsanakis VA, Au C, Erikson KM, Aschner M. (2006) The effects of manganese on
glutamate, dopamine and gamma-aminobutyric acid regulation. Neurochemistry International
48(6-7):426-433.
32. Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M. (2006) The use of
magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology
27(5):798-806.
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33. Forbes A, Jawhari A. (1996) Manganese toxicity and parenteral nutrition. Lancet
347(9017): 1774-1774.
34. FreelandGraves JH, Turnlund JR. (1996) Deliberations and evaluations of the approaches,
endpoints and paradigms for manganese and molybdenum dietary recommendations. Journal of
Nutrition 126(9):S2435-S2440.
35. Friberg L, Nordberg GF, Vouk VB. (2007) Handbook of the Toxicology of Metals. 3rd ed. :
Elsevier Science Publishing Company; pp. 476.
36. Gassmann B. (2001) Dietary reference intakes, report 4: Trace elements. Ernahrungs-
Umschau 48(4): 148-+.
37. Grandjean P, Landrigan PJ. (2006) Developmental neurotoxicity of industrial chemicals.
Lancet 368(9553):2167-2178.
38. Hazell AS. (2002) Astrocytes and manganese neurotoxicity. Neurochemistry International
41(4):271-277.
39. Keen CL, Ensunsa JL, Clegg MS. (2000) Manganese metabolism in animals and humans
including the toxicity of manganese. Metal Ions in Biological Systems, Vol 37. NEW YORK:
MARCEL DEKKER. pp 89-121.
40. Keen CL, Ensunsa JL, Watson MH, Baly DL, Donovan SM, Monaco MH, Clegg MS.
(1999) Nutritional aspects of manganese from experimental studies. Neurotoxicology 20(2-
3):213-223.
41. Kim Y. (2006) Neuroimaging in manganism. Neurotoxicology 27(3):369-372.
42. Lee JW. (2000) Manganese intoxication. Archives of Neurology 57(4): 597-599.
43. Lewis RJS. 2004. Sax's Dangerous Properties of Industrial Materials: Manganese 7439-96-5.
Sax's Dangerous Properties of Industrial Materials John Wiley & Sons, Inc.
44. Liang Yx, Su Z, Wu Wa, Lu Bq, Fu Wz, Yang L, Gu Jy. (2003) New trends in the
development of occupational exposure limits for airborne chemicals in China. Regulatory
Toxicology and Pharmacology 38(2): 112-123.
45. McMillan DE. (1999) A brief history of the neurobehavioral toxicity of manganese: Some
unanswered questions. Neurotoxicology 20(2-3):499-507.
46. Mergler D, Baldwin M. (1997) Early manifestations of manganese neurotoxicity in humans:
An update. Environmental Research 73(l-2):92-100.
47. Misselwitz B, Muhler A, Weinmann HJ. (1995) A Toxicologic Risk for Using Manganese
Complexes - a Literature Survey of Existing Data through Several Medical Specialties.
Investigative Radiology 30(10):611-620.
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48. Montgomery EB. (1995) Heavy-Metals and the Etiology of Parkinsons-Disease and Other
Movement-Disorders. Toxicology 97(l-3):3-9.
49. Neu E, Gebefuegi I, Graw J, Jaekl G, Magour S, Michailov MC, Seidenbusch W, Weiss DG,
Welscher U. (2001) Complex pathophysiological and genotoxic effects of radiation, heavy
metals (Cd, Hg, Mn, Pb, Pu, U), and other toxicants. Toxicology 164(l-3):72-72.
50. NIOSH. 2007. Pocket Guide to Chemical Hazards: Manganese compounds and fume (as
Mn) In: NIOSH, editor. NIOSH Pocket Guide: NIOSH.
51. OEHHA. 2001. Prioritization of Toxic Air Contaminants - Children's Environmental Health
Protection Act for Manganese & Compounds California Environmental Protection Agency
(Cal/EPA). 1-8 p.
52. Ostiguy C, Asselin P, Malo S. (2006) The emergence of manganese-related health problems
in Quebec: An integrated approach to evaluation, diagnosis, management and control.
Neurotoxicology 27(3):350-356.
53. Park RM, Bowler RM, Eggerth DE, Diamond E, Spencer KJ, Smith D, Gwiazda R. (2006)
Issues in neurological risk assessment for occupational exposures: The Bay Bridge welders.
Neurotoxicology 27(3):373-384.
54. Pfeifer GD, Roper JM, Dorman D, Lynam DR. (2004) Health and environmental testing of
manganese exhaust products from use of methylcyclopentadienyl manganese tricarbonyl in
gasoline. Science of the Total Environment 334-35:397-408.
55. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT, Swanson PD, Checkoway H.
(2003) Parkinson's disease risks associated with dietary iron, manganese, and other nutrient
intakes. Neurology 60(11): 1761-1766.
56. Sayre LM, Perry G, Atwood CS, Smith MA. (2000) The role of metals in neurodegenerative
diseases. Cellular and Molecular Biology 46(4):731-741.
57. Solomons NW, Ruz M. (1998) Trace element requirements in humans: An update. Journal
of Trace Elements in Experimental Medicine 11(2-3): 177-195.
58. Sunderman FW. (2001) Review: Nasal toxicity, carcinogenicity, and olfactory uptake of
metals. Annals of Clinical and Laboratory Science 31(l):3-24.
59. Takeda A. (2004) Essential trace metals and brain function. Yakugaku Zasshi-Journal of the
Pharmaceutical Society of Japan 124(9):577-585.
60. Taylor A. (1996) Detection and monitoring of disorders of essential trace elements. Annals
of Clinical Biochemistry 33:486-510.
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61. Tenorio FA, Ensunsa JL, Keen CL, Symons JD. (2002) Does manganese deficiency reduce
arginase activity to an extent whereby vascular function is altered? Arteriosclerosis Thrombosis
and Vascular Biology 22(5):A45-A45.
62. Tilson HA. (1996) Evolution and current status of neurotoxicity risk assessment. Drug
Metabolism Reviews 28(1-2): 121-139.
63. Verity MA. (1999) Manganese neurotoxicity: A mechanistic hypothesis. Neurotoxicology
20(2-3):489-497.
64. Weiss B. (1999) Manganese in the context of an integrated risk and decision process.
Neurotoxicology 20(2-3):519-525.
65. WHO. 2000. Air Quality Guidelines for Europe. Report nr 91. 288 p.
66. Yokel RA. (2005) Selective Blood-Brain Barrier Transport Of Aluminum, Manganese, And
Other Metals In Metal-Induced Neurodegeneration. Toxicol Sci 84(l-S):338-339.
67. Yokel RA. (2006) Blood-brain barrier flux of aluminum, manganese, iron and other metals
suspected to contribute to metal-induced neurodegeneration. Journal of Alzheimers Disease
10(2-3):223-253.
68. Zatta P, Lucchini R, van Rensburg SJ, Taylor A. (2003) The role of metals in
neurodegenerative processes: aluminum, manganese, and zinc. Brain Research Bulletin
62(1): 15-28.
69. Zayed J. (2001) Use of MMT in Canadian gasoline: Health and environment issues.
American Journal of Industrial Medicine 39(4):426-433.
70. Zheng W. (2001) Neurotoxicology of the brain barrier system: New implications. Journal of
Toxicology-Clinical Toxicology 39(7):711-719.
71. Zheng W. (2001) Toxicology of choroid plexus: Special reference to metal-induced
neurotoxicities. Microscopy Research and Technique 52(1):89-103.
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APPENDIX D:
KEY AND SUPPORTING REFERENCES WITH ABSTRACTS BY SUBJECT
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Key and Supporting References by Subject with Abstracts
3.1 TOXICOKINETICS
Key References (72)
1. Arnich N, Cunat L, Lanhers MC, Burnel D. (2004) Comparative in situ study of the intestinal
absorption of aluminum, manganese, nickel, and lead in rats. Biological Trace Element Research
99(1-3): 157-171.
This comparative study of the intestinal absorption of four toxic metals (aluminum, manganese,
nickel, and lead) carried out in rats using the in situ intestinal perfusion technique was able to
measure the partition of each metal between the intestine (intestinal retention), the blood
circulation, and target tissues after 1 h. The perfused metal solutions were at concentrations
likely to occur during oral intoxication. It was found that aluminum (48 and 64 mM), even as a
citrate complex, crossed the brush border with difficulty (0.4% of the perfused amount); about
60% of this was retained in the intestine and the remainder was found in target tissues (about
36%). Conversely, lead (4.8-48 muM) penetrated the intestine more easily (about 35% of the
perfused amount), was slightly retained (about 12% of the input), and was soon found in the
tissues (about 58% of the input) and to a lesser degree in circulation (about 29%). Within the
same concentration range, nickel and manganese showed certain similarities, such as a reduced
crossing of the brush border proportional to the increase in the concentration perfused (0.17-9.5
mM). There was similar intestinal retention and absorption (about 80% and 20% of the input,
respectively). Manganese crossed the brush border more easily and was diffused more rapidly
into tissues. Finally, the addition of equimolar amounts of iron (4.7 mM) produced opposite
effects on the absorption of the two elements, inhibiting manganese and showing a trend to
increase in nickel absorption. This could be the result of competition between Fe2+ and Mn2+
for the same transcellular transporters and the slight predominance of paracellular mechanism in
the event of "Fe2+-Ni2+" association.
2. Aschner M. (2005) Manganese transport, toxicity and speciation in the CNS. Journal of
Neurochemistry 94:8-8.
3. Aschner M. (2006) The transport of manganese across the blood-brain barrier.
Neurotoxicology 27(3):311-314.
The mammalian central nervous system (CNS) possesses a unique and specialized capillary
adaptation, referred to as the blood-brain barrier (BBB). The BBB maintains an optimal neuronal
microenvironment, regulating blood-tissue exchange of macromolecules and nutrients. The BBB
is characterized by individual endothelial cells that are continuously linked by tight junctions,
inhibiting the diffusion of macromolecules and solutes between adjacent endothelial cells. This
review will focus on pertinent issues to BBB maintenance, and survey recent dogmas on the
transport mechanisms for the essential metal, manganese, across this barrier. Specifically,
putative carriers for manganese into and out of the brain will be discussed, (c) 2006 Elsevier Inc.
All rights reserved.
4. Aschner M, Fitsanakis VA, Milatovic D, Erikson KM. (2006) Dietary iron modulates
manganese neurotoxicity. Journal of Neurochemistry 96:89-89.
Draft Bibliography: Manganese Lit. Search D-1
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5. Beaupre LA, Salehi F, Zayed J, Plamondon P, L'Esperance G. (2004) Physical and chemical
characterization of Mn phosphate/sulfate mixture used in an inhalation toxicology study.
Inhalation Toxicology 16(4):231-244.
The use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline has
given rise to numerous debates on the potential public health risk associated with manganese
emissions. In fact, combustion products are mainly Mn phosphate, Mn sulfate, and Mn
phosphate/sulfate mixture. Our research group did several inhalation studies in order to assess
the toxicity of each Mn species. The objective of this study is to determine the physical and the
chemical characteristics of a mixture of Mn phosphate/sulfate used in one of these inhalation
toxicology studies. First, the mixture was analyzed by X-ray diffraction in order to obtain the
specific peak of Mn phosphate and Mn sulfate. These peaks were used as reference. Second,
samples of the mixture were collected on filters in the inhalation chamber at a concentration
level of 3000 mug/m(3). They were analyzed by scanning electron microscopy (SEM), analytical
transmission electron microscopy (ATEM), and x-ray energy-dispersive spectrometry (EDS) to
show their size, morphology, and chemical composition. Results indicate that 33% of the
particles were found to be agglomerated, while free particles accounted for 44% for Mn
phosphate and 23% for Mn sulfate.
6. Brain JD, Heilig E, Donaghey TC, Knutson MD, Wessling-Resnick M, Molina RM. (2006)
Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe.
American Journal of Respiratory Cell and Molecular Biology 34(3):330-337.
Manganese transport into the blood can result from inhaling metal-containing particles. Intestinal
manganese and iron absorption is mediated by divalent metal transporter 1 (DMT1) and is
upregulated in iron deficiency. Since iron status alters absorption of Fe and Mn in the gut, we
tested the hypothesis that iron status may alter pulmonary transport of these metals. DMT1
expression in the lungs was evaluated to explore its role in metal transport. The
pharmacokinetics of intratracheally instilled Mn-54 or Fe-59 in repeatedly bled or iron oxide-
exposed rats were compared with controls. Iron oxide exposure caused a reduction in pulmonary
transport of Mn-54 and Fe-59, and decreased uptake in other major organs. Low iron status from
repeated bleeding also reduced pulmonary transport of iron but not of manganese. However,
uptake of manganese in the brain and of iron in the spleen increased in bled rats. DMT1
transcripts were detected in airway epithelium, alveolar macrophages, and bronchial-associated
lymphoid tissue in all rats. Focal increases were seen in particle-containing macrophages and
adjacent epithelial cells, but no change was observed in bled rats. Although lung DMT1
expression did not correlate with iron status, differences in pharmacokinetics of instilled metals
suggest that their potential toxicity can be modified by iron status.
7. Brenneman KA, Cattley RC, Ali SF, Dorman DC. (1999) Manganese-induced developmental
neurotoxicity in the CD rat: Is oxidative damage a mechanism of action? Neurotoxicology 20(2-
3):477-487.
Inhalation of high concentrations of manganese (Mn) is associated with an extrapyramidal motor
disorder in humans. Oxidative damage, mediated by increased levels of Mn in dopaminergic
brain regions and mitochondria, is a hypothesized mechanism of action for Mn-induced neuronal
degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an
increased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of
Draft Bibliography: Manganese Lit. Search
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MnC12 from postnatal day (PND) I to 49 Brain regional and mitochondrial Mn levels, brain
regional reactive oxygen species (ROS) levels, and whole-brain nuclear and mitochondrial 8-
OHdG levels were used to evaluate Mn-mediated oxidative damage. High-dose Mn exposure
was associated with increased spontaneous motor activity on PND 21 and decreased body
weights on PND 49. On PND 21, Mn concentrations were increased in brain regions and
mitochondrial fractions in both low- and high-dose groups. ROS levels were elevated in
cerebellum but not striatum. On PND 49, Mn concentrations in brain regions and mitochondrial
fractions were increased only in the high-dose group. Mn exposure did not significantly alter 8-
OHdG levels in either mitochondrial or nuclear DNA. Selective uptake of Mn by the striatum or
mitochondrial fraction was not demonstrated at either time point. These data allow us to
conclude that oral exposure to high levels of Mn in developing CD rats resulted in increased
brain regional and mitochondrial Mn levels, increased motor activity, and decreased body
weights but not in selective accumulation of Mn in the striatum or mitochondr ial fraction of any
brain region or elevations in striatal ROS or whole-brain 8-OHdG levels. These findings do not
support the hypothesis that oxidative damage, as assessed by ROS and 8-OHdG levels, is a
mechanism of action in Mn-induced developmental neurotoxicity in the CD rat. (C) 1999 Inter
Press, Inc.
8. Brenneman KA, Wong BA, Buccellato MA, Costa ER, Gross EA, Dorman DC. (2000) Direct
olfactory transport of inhaled manganese ((MnC12)-Mn-54) to the rat brain: Toxicokinetic
investigations in a unilateral nasal occlusion model. Toxicology and Applied Pharmacology
169(3):238-248.
Inhalation exposure of humans to high concentrations of manganese (Mn) is associated with
elevated Mn levels in the basal ganglia and an extrapyramidal movement disorder. In the rat,
direct olfactory transport of Mn from the nose to the brain has been demonstrated following
intranasal instillation of (MnC12)-Mn-54. However, the contribution this route makes to brain
Mn delivery following inhalation is unknown and was the subject of our study. Male 8-week old
CD rats underwent a single 90-min nose-only exposure to a (MnC12)-Mn-54 aerosol (0.54 mg
Mn/m(3); MMAD 2.51 mum). The left and right sides of the nose and brain, including the
olfactory pathway and striatum, were sampled at 0, 1, 2, 4, and 8 days postexposure. Control rats
were exposed to (MnC12)-Mn-54 with both nostrils patent to evaluate the symmetry of Mn
delivery. Another group of rats had the right nostril plugged to prevent nasal deposition of
(MnC12)-Mn-54 on the occluded side. Gamma spectrometry (n = 6 rats/group/time point) and
autoradiography (n 1 rat/group/time point) were used to compare the levels of Mn-54 found on
the left and right sides of the nose and brain to determine the contribution of olfactory uptake to
brain Mn-54 levels. Brain and nose samples from the side with the occluded nostril had
negligible levels of Mn-54 activity, validating the nasal occlusion procedure. High levels of Mn-
54 were observed in the olfactory bulb and tract/tubercle on the side or sides with an open nostril
within 1-2 days following inhalation exposure. These results demonstrated, for the first time, that
the olfactory route contributes the majority (up to > 90%) of the Mn-54 found in the olfactory
pathway, but not in the striatum, of the rat brain up to 8 days following a single inhalation
exposure. These findings suggest that the olfactory route may make a significant contribution to
brain Mn levels following inhalation exposure in the rat. (C) 2000 Academic Press.
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9. Chen MK, Lee JS, McGlothan JL, Furukawa E, Adams RJ, Alexander M, Wong DF, Guilarte
TR. (2006) Acute manganese administration alters dopamine transporter levels in the non-human
primate striatum. Neurotoxicology 27(2):229-236.
We used positron emission tomography (PET) to measure non-invasively the effect of acute
systemic administration to manganese sulfate (MnS04) on dopamine transporter (DAT) levels in
the living non-human primate brain. Baboons received [C-l 1]-WIN 35,428 PET scans to
measure DAT levels before and after acute MnS04 administration. In one animal, we observed a
46% increase in DAT binding potential (BP), a measure of DAT binding site availability, I week
after Mn administration. DAT levels returned to baseline values at 4 months and remained
constant at 10 months after treatment. A subsequent single MnS04 injection to the same animal
also resulted in a 57% increase in DAT-BP, 2 days after administration. In a second animal, a
76%) increase in DAT-BP relative to baseline was observed at 3 days after Mn injection. In this
animal, the DAT-BP returned to baseline levels after I month. Using in vitro receptor binding
assays, we found that Mn inhibits [H-3J-WIN 35,428 binding to rat striatal DAT with an
inhibitory constant (K-i) of 2.0 +/- 0.3 mM (n = 4). Saturation isotherms and Scatchard analysis
of [H-3J-WIN 35,428 binding to rat striatal DAT showed a significant decrease (30%, p < 0.001)
in the maximal number of binding sites (B-max) in the presence of 2 mM MnS04. No significant
effect of Mn was found on binding affinity (K-d). We also found that Mn inhibits [H-3]-
dopamine uptake with an IC50 of 11.4 +/- 1.5 mM (n = 4). Kinetic studies and Lineweaver-Burk
analysis showed a significant decrease (40%, p < 0.001) in the maximal velocity of uptake (V-
max) with 5 mM MnS04. No significant effect of Mn was found on Michael is-Menton constant
(K-m). These in vitro findings Suggest that the increase in DAT levels in vivo following acute
Mn administration may be a compensatory response to its inhibitory action on DAT. These
findings provide helpful insights on potential mechanisms of Mn-induced neurotoxicity and
indicate that the DAT in the striatum is a target for Mn in the brain, (c) 2005 Elsevier Inc. All
rights reserved.
10. Chen MT, Cheng GW, Lin CC, Chen BH, Huang YL. (2006) Effects of acute manganese
chloride exposure on lipid peroxidation and alteration of trace metals in rat brain. Biological
Trace Element Research 110(2): 163-177.
Although manganese (Mn) is an essential element, exposure to excessive levels of Mn and its
accumulation in the brain can cause neurotoxicity and extrapyramidal syndrome. We have
investigated the differences in the accumulated levels of Mn, the degree of lipid peroxidation,
and its effects on the levels of trace elements (Fe, Cu, and Zn) in various regions in the brain of
rats having undergone acute Mn exposure. The rats in the dose-effect group were injected
intraperitoneally (ip) with MnC12 (25, 50, or 100 mg MnC12/kg) once a day for 24 h. The Mn
significantly accumulated (p < 0.05) in the frontal cortex, corpus callosum, hippocampus,
striatum, hypothalamus, medulla, cerebellum, and spinal cord in each case. The rats in the time-
course group were ip injected with MnC12 (50 mg MnC12/kg) and then monitored 12, 24, 48, and
72 h after exposure. The Mn accumulated in the frontal cortex, corpus callosum, hippocampus,
striatum hypothalamus, medulla, cerebellum, and spinal cord after these periods of time, In both
the dose-effect and time-course studies, we observed that the concentration of malondialdehyde,
an end product of lipid peroxidation, increased significantly in the frontal cortex, hippocampus,
striatum, hypothalamus, medulla, and cerebellum. However, no relationship between the
concentrations of Mn in the brain and the extent of lipid peroxidation was observed. In addition,
we found that there was a significant increase (p < 0.05) in the level of Fe in the hippocampus,
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striatum, hypothalamus, medulla, and cerebellum, but the Cu and Zn levels had not changed
significantly. These findings indicated that Mn induces an increase in the iron level, which
provides direct evidence for Fe-mediated lipid peroxidation in the rats' brains; these phenomena
might play important roles in the mechanisms of Mn-induced neurotoxicology.
11. Chen MT, Yiin SJ, Sheu JY, Huang YL. (2002) Brain lipid peroxidation and changes of
trace metals in rats following chronic manganese chloride exposure. Journal of Toxicology and
Environmental Health-Part A 65(3-4):305-316.
The aim of this study was to investigate the effects of chronic daily, 30-d administration of
manganese chloride (MnC12) to male Sprague-Dawley rats on lipid peroxidation and changes of
trace elements (manganese, iron, copper, zinc) in various brain regions. Rats were
intraperitoneally injected with MnC2 (20 mg/kg) once daily for 30 consecutive days. The Mn
accumulated in frontal cortex, corpus callosum, hippocampus, striatum, hypothalamus, medulla,
cerebellum, and spinal cord. Malondialdehyde, an end product of lipid peroxidation, was
markedly decreased in frontal cortex and cerebellum. An increased level of Cu was observed in
frontal cortex, medulla, and a cerebellum. A decreased Fe level was found only in cerebellum,
and a decreased Zn level was observed in hippocampus and striatum. In a second group of
animals, Mn (20 mg/kg/d) and glutathione (CSH, 75 mg/kg/d) were administered ip for 30 d. In
CSH-Mn-treated rats, compared to Mn-treated rats, MDA concentrations were significantly
reduced in frontal cortex, medulla and cerebellum. The changes of trace elements in rat brain
were similar to the Mn-treated group. We suggest that Mn is an atypical antioxidant, as well as
not involved in oxidative damage in rat brain. Fe and Cu may play roles in the protective effect
of Mn against lipid peroxidation in rat brain.
12. Chua ACG, Morgan EH. (1996) Effects of iron deficiency and iron overload on manganese
uptake and deposition in the brain and other organs of the rat. Biological Trace Element
Research 55(l-2):39-54.
Manganese (Mn) is an essential trace element at low concentrations, but at higher concentrations
is neurotoxic. It has several chemical and biochemical properties similar to iron (Fe), and there is
evidence of metabolic interaction between the two metals, particularly at the level of absorption
from the intestine. The aim of this investigation was to determine whether Mn and Fe interact
during the processes involved in uptake from the plasma by the brain and other organs of the rat.
Dams were fed control (70 mg Fe/kg), Fe-deficient (5-10 mg Fe/kg), or Fe-loaded (20 g carbonyl
Fe/kg) diets, with or without Mn-loaded drinking water (2 g Mn/L), from day 18-19 of
pregnancy, and, after weaning the young rats, were continued on the same dietary regimens.
Measurements of brain, liver, and kidney Mn and nonheme Fe levels, and the uptake of Mn-54
and Fe-59 from the plasma by these organs and the femurs, were made when the rats were aged
15 and 63 d. Organ nonheme Fe levels were much higher than Mn levels, and in the liver and
kidney increased much more with Fe loading than did Mn levels with Mn loading. However, in
the brain the increases were greater for Mn. Both Fe depletion and loading led to increased brain
Mn concentrations in the 15-d/rats, while Fe loading also had this effect at 63 d. Mn loading did
not have significant effects on the nonheme Fe concentrations. Mn-54, injected as MnC12 mixed
with serum, was cleared more rapidly from the circulation than was Fe-59, injected in the form
of diferric transferrin. In the 15-d-rats, the uptake of Mn-54 by brain, liver, kidneys, and femurs
was increased by Fe loading, but this was not seen in the 63-d rats. Mn supplementation led to
increased Fe-59 uptake by the brain, Liver, and kidneys of the rats fed the control and Fe-
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deficient diets, but not in the Fe-loaded rats. It is concluded that Mn and Fe interact during
transfer from the plasma to the brain and other organs and that this interaction is synergistic
rather than competitive in nature. Hence, excessive intake of Fe plus Mn may accentuate the risk
of tissue damage caused by one metal alone, particularly in the brain.
13. Crossgrove JS, Allen DD, Bukaveckas BL, Rhineheimer SS, Yokel RA. (2003) Manganese
distribution across the blood-brain barrier I. Evidence for carrier-mediated influx of manganese
citrate as well as manganese and manganese transferrin. Neurotoxicology 24(1):3-13.
Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement
across the blood-brain barrier (BBB) contributes to whether the brain Mn concentration is
functional or toxic. In plasma, Mn associates with water small molecular weight ligands and
proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the
present work, the brain influx rates of Mn-54(2+), Mn-54 citrate and Mn-54 transferrin (54) Mn
Tf) were determined using the in situ brain perfusion technique. The influx rates were compared
to their predicted diffusion rates, which were determined from their octanol/aqueous partitioning
coefficients and molecular weights. The in situ brain perfusion fluid contained (54) Mn2+, (54)
Mn citrate or (54) Mn Tf and a vascular volume/extracellular space marker C-14-sucrose, which
did not appreciably cross the BBB during these short experiments (15-180 s). The influx transfer
coefficient (K-in) was determined from four perfusion durations for each Mn species in nine
brain regions and the lateral ventricular choroid plexus. The brain K-in was (5-13) X 10(-5), (3-
51) x 10(-5) and (2-13) X 10(-5) Mn-54 citrate, and Mn-54 Tf respectively. Brain K-in values for
any one of the three Mn species generally did not significantly differ among the nine brain
regions and the choroid plexus. However the brain Kin for Mn citrate was greater than Mn2+
and Mn Tf K-in values in a number of brain regions. When compared to calculated diffusion
rates, brain K-in values suggest carrier-mediated brain influx of Mn-54(2+), Mn-54 citrate and
Mn-54 Tf. Mn-55 citrate inhibited Mn-54 citrate uptake, and Mn-55(2+) inhibited Mn-54(2+)
Uptake, supporting the conclusion o carrier-mediated brain Mn influx. The greater Kin values
for Mn citrate than Mn2+ and its presence as a major non-protein-bound Mn species in blood
plasma suggest Mn citrate may be a major Mn species entering the brain. (C) 2002 Elsevier
Science Inc. All rights reserved.
14. Dorman DC. (2003) Metal speciation in human health risk assessment: Challenges posed by
manganese, iron, and other essential nutrients. Toxicological Sciences 72:117-117.
15. Dorman DC, McElveen AM, Marshall MW, Parkinson CU, James RA, Struve MF, Wong
BA. (2005) Tissue manganese concentrations in lactating rats and their offspring following
combined in utero and lactation exposure to inhaled manganese sulfate. Toxicological Sciences
84(1): 12-21.
There is little information regarding the tissue distribution of manganese in neonates following
inhalation. This study determined tissue manganese concentrations in lactating CD rats and their
offspring following manganese sulfate (MnS04) aerosol inhalation. Except for the period of
parturition, dams and their offspring were exposed to air or MnS04 (0.05, 0.5, or 1 mg Mn/m(3))
for 6 h/day, 7 days/week starting 28 days prior to breeding through postnatal day (PND) 18.
Despite increased manganese concentrations in several maternal tissues, MnS04 inhalation
exposure did not affect body weight gain, terminal ( PND 18) body weight, or organ weights in
the dams. Exposure to MnS04 at 1 mg Mn/m(3) resulted in decreased pup body weights on PND
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19 and decreased brain weights in some PND 14 to PND 45 pups. Exposure to MnS04 at similar
to 0.05 mg Mn/m(3) was associated with increased stomach content, blood, liver, and skull cap
manganese concentrations in PND 1 pups, increased brain, lung, and femur manganese
concentrations in PND 14 pups, and elevated olfactory bulb, cerebellum, and striatum
manganese concentrations in PND 19 pups. When compared to controls, MnS04 exposure to
greater than or equal to 0.5 mg Mn/m(3) increased liver and blood manganese concentrations in
PND 14 pups and increased liver, pancreas, and femur manganese concentrations in PND 19
pups. Manganese concentrations returned to control values in all offspring tissues by PND 45 +/-
1. Our data demonstrate that neonatal tissue manganese concentrations observed following
MnS04 inhalation are dependent on the MnS04 exposure concentration and the age of the
animal.
16. Dorman DC, McManus BE, Marshall MW, James RA, Struve MF. (2004) Old age and
gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate
in rats. Toxicology and Applied Pharmacology 197(2): 113-124.
In this study, we examined whether gender or age influences the pharmacokinetics of manganese
sulfate (MnS04) or manganese phosphate (as the mineral form hureaulite). Young male and
female rats and aged male rats (16 months old) were exposed 6 h day(-l) for 5 days week(-l) to
air, MnS04 (at 0.01, 0.1, or 0.5 mg Mn m(-3)), or hureaulite (0.1 mg Mn m(-3)). Tissue
manganese concentrations were determined in all groups at the end of the 90-day exposure and
45 days later. Tissue manganese concentrations were also determined in young male rats
following 32 exposure days and 91 days after the 90-day exposure. Intravenous 54 Mn tracer
studies were also performed in all groups immediately after the 90-day inhalation to assess
whole-body manganese clearance rates. Gender and age did not affect manganese delivery to the
striatum, a known target site for neurotoxicity in humans, but did influence manganese
concentrations in other tissues. End-of-exposure olfactory bulb, lung, and blood manganese
concentrations were higher in young male rats than in female or aged male rats and may reflect a
portal-of-entry effect. Old male rats had higher testis but lower pancreas manganese
concentrations when compared with young males. Young male and female rats exposed to
MnS04 at 0.5 mg Mn m-3 had increased 54 Mn clearance rates when compared with air-
exposed controls, while senescent males did not develop higher 54 Mn clearance rates. Data
from this study should prove useful in developing dosimetry models for manganese that consider
age or gender as potential sensitivity factors. (C) 2004 Elsevier Inc. All rights reserved.
17. Dorman DC, McManus BE, Parkinson CU, Manuel CA, McElveen AM, Everitt JI. (2004)
Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following
subchronic (13-week) inhalation exposure. Inhalation Toxicology 16(6-7):481-488.
Growing evidence suggests that nasal deposition and transport along the olfactory nerve
represents a route by which inhaled manganese and certain other metals are delivered to the
rodent brain. The toxicological significance of olfactory transport of manganese remains poorly
defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the
olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein
(GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to
further characterize the nasal toxicity of manganese sulfate (MnS04) and manganese phosphate
(as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnS04
(0.01, 0.1, and 0.5 mg Mn/m(3)), or hureaulite (0.1 mg Mn/m(3)). Nasal pathology, brain GFAP
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levels, and brain manganese concentrations were assessed immediately following the end of the
90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and
cerebellum manganese concentrations were observed following MnS04 exposure to greater than
or equal toO.Ol, greater than or equal toO. 1, and 0.5 mg Mn/m(3), respectively. Exposure to
MnS04 or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations.
Exposure to MnS04 (0.5 mg Mn/m(3)) was also associated with reversible inflammation within
the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese
inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity
(irritation) and increased delivery of manganese to the brain; however, we could not confirm that
manganese inhalation would result in altered brain GFAP concentrations.
18. Dorman DC, Struve MF, James RA, Marshall MW, Parkinson CU, Wong BA. (2001)
Influence of particle solubility on the delivery of inhaled manganese to the rat brain: Manganese
sulfate and manganese tetroxide pharmacokinetics following repeated (14-day) exposure.
Toxicology and Applied Pharmacology 170(2):79-87.
Dissolution rate can influence the pulmonary clearance of a metal and thus affect its delivery to
the brain and other organs. The goal of this study was to determine the exposure-response
relationship for the relatively soluble sulfate (MnS04) and insoluble tetroxide (Mn304) forms of
inhaled manganese in adult male CD rats. Rats were exposed 6 h/day for 7 days/week (14
exposures) to either MnS04 or Mn304 at 0, 0.03, 0.3, or 3 mg Mn/m(3). End-of-exposure
olfactory bulb, striatum, cerebellum, bile, lung, liver, femur, serum, and testes (n = 6
rats/concentration/chemical) manganese concentrations and whole-body Mn-54 elimination were
then determined. Increased whole-body Mn-54 clearance rates were observed in animals from
the high-dose (3 mg Mn/m3) MnS04 and Mn304 exposure groups. Elevated manganese
concentrations in the lung were observed following MnS04 and Mn304 exposure to greater than
or equal to0.3 mg Mn/m(3). Increased olfactory bulb and femur manganese concentrations were
also observed following MnS04 exposure at greater than or equal to0.3 mg Mn/m(3). Elevated
striatal, testes, liver, and bile manganese concentrations were observed following exposure to
MnS04 at 3 mg Mn/m(3). Elevated olfactory bulb, striatal, femur, and bile manganese
concentrations were observed following exposure to Mn304 at 3 mg Mn/m(3). Animals exposed
to MnS04 (3 mg Mn/m(3)) had lower lung and higher olfactory bulb and striatal manganese
concentrations compared with levels achieved following similar Mn304 exposures. Our results
suggest that inhalation exposure to soluble forms of manganese results in higher brain
manganese concentrations than those achieved following exposure to an insoluble form of
manganese. (C) 2001 Academic Press.
19. Dorman DC, Struve MF, James RA, McManus BE, Marshall MW, Wong BA. (2001)
Influence of dietary manganese on the pharmacokinetics of inhaled manganese sulfate in male
CD rats. Toxicological Sciences 60(2):242-251.
Concerns exist as to whether individuals with relative manganese deficiency or excess may be at
increased risk for manganese toxicity following inhalation exposure. The objective of this study
was to determine whether manganese body burden influences the pharmacokinetics of inhaled
manganese sulfate (MnS04,). Postnatal day (PND) 10 rats were placed on either a low (2 ppm),
sufficient (10 ppm), or high (100 ppm) manganese diet. The feeding of the 2 ppm manganese
diet was associated with a number of effects, including reduced body weight gain, decreased liter
manganese concentrations, and reduced whole-body manganese clearance rates. Beginning on
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PND 77 +/- 2, male littermates were exposed 6 h/day for 14 consecutive days to 0, 0.092, or 0.92
mg MnS04/m(3). End-of-exposure tissue manganese concentrations and whole-body Mn-54
elimination rates were determined. Male rats exposed to 0.092 mg MnS04/m(3) had elevated
lung manganese concentrations when compared to air-exposed male rats. Male rats exposed to
0.92 mg MnS04/m(3) developed increased striatal, lung, and bile manganese concentrations
when compared to air-exposed male rats. There were no significant interactions between the
concentration of inhaled MnS04 and dietary manganese level on tissue manganese
concentrations. Rats exposed to 0.92 mg MnS04/m(3) also had increased Mn-54 clearance rates
and shorter initial phase elimination half-lives when compared with air-exposed control rats.
These results suggest that, marginally manganese-deficient animals exposed to high levels of
inhaled manganese compensate by increasing biliary manganese excretion. Therefore, they do
not appear to be at increased risk for elevated brain manganese concentrations.
20. Dorman DC, Struve MF, Marshall MW, Parkinson CU, James RA, Wong BA. (2006) Tissue
manganese concentrations in young male rhesus monkeys following subchronic manganese
sulfate inhalation. Toxicological Sciences 92(1):201-210.
High-dose human exposure to manganese results in manganese accumulation in the basal ganglia
and dopaminergic neuropathology. Occupational manganese neurotoxicity is most frequently
linked with manganese oxide inhalation; however, exposure to other forms of manganese may
lead to higher body burdens. The objective of this study was to determine tissue manganese
concentrations in rhesus monkeys following subchronic (6 h/day, 5 days/week) manganese
sulfate (MnS04) inhalation. A group of monkeys were exposed to either air or MnS04 (0.06,
0.3, or 1.5 mg Mn/m(3)) for 65 exposure days before tissue analysis. Additional monkeys were
exposed to MnS04 at 1.5 mg Mn/m(3) for 15 or 33 exposure days and evaluated immediately
thereafter or for 65 exposure days followed by a 45- or 90-day delay before evaluation. Tissue
manganese concentrations depended upon the aerosol concentration, exposure duration, and
tissue. Monkeys exposed to MnS04 at >= 0.06, mg Mn/m(3) for 65 exposure days or to MnS04
at 1.5 mg Mn/m(3) for >=15 exposure days developed increased manganese concentrations in
the olfactory epithelium, olfactory bulb, olfactory cortex, globus pallidus, putamen, and
cerebellum. The olfactory epithelium, olfactory bulb, globus pallidus, caudate, putamen,
pituitary gland, and bile developed the greatest relative increase in manganese concentration
following MnS04 exposure. Tissue manganese concentrations returned to levels observed in the
air-exposed animals by 90 days after the end of the subchronic MnS04 exposure. These results
provide an improved understanding of MnS04 exposure conditions that lead to increased
concentrations of manganese within the nonhuman primate brain and other tissues.
21. Dorman DC, Struve MF, Wong BA. (2002) Brain manganese concentrations in rats
following manganese tetroxide inhalation are unaffected by dietary manganese intake.
Neurotoxicology 23(2): 185-195.
Manganese-deficient individuals hate decreased manganese elimination. This observation has
prompted suggestions that relative manganese deficiency may increase the risk for manganese
neurotoxicity following inhalation exposure. The objective of this study was to determine
whether dietary manganese intake influences the pharmacokinetics of inhaled manganese
tetroxide (Mn304). Postnatal day (PND) 10 rats were placed on either a low (2 ppm), sufficient
(10 ppm), or high-normal (700 ppm) manganese diet for 2 months. Beginning on PND 77 +/- 2,
male littermates were exposed 6 h per day for 14 consecutive days to 0, 0.042, or 0.42 mg
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Mn304/m(3). End-of-exposure tissue manganese concentrations and whole-body Mn-54
elimination rates were determined. Tissue manganese concentrations were dependent on the
dietary intake of manganese, thus confirming that altered hepatic manganese disposition or
metabolism occurred. Male rats given 100 ppm manganese diet developed increased manganese
concentrations in the femur; liver, and bile and had elevated whole-body Mn-54 clearance rates
when compared to animals given 2 ppm manganese diet. Male rats exposed to 0.42 mg
Mn304/m(3) had increased manganese concentrations in the olfactory bulb, lung, liver, and bile
when compared to air-exposed male rats. A significant interaction between the concentration of
inhaled Mn304 and dietary manganese level was observed only with the end-of-exposure liver
manganese concentration. Our results indicate that animals maintained on either a manganese-
deficient or high manganese diet do not appear to be at increased risk for elevated brain
manganese concentrations following inhalation exposure to high levels of Mn304. (C) 2002
Elsevier Science Inc. All rights reserved.
22. Dorman DC, Struve MF, Wong BA, Dye JA, Robertson ID. (2006) Correlation of brain
magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys
following subchronic manganese inhalation. Toxicological Sciences 92(l):219-227.
High-dose manganese exposure is associated with parkinsonism. Because manganese is
paramagnetic, its relative distribution within the brain can be examined using magnetic
resonance imaging (MRI). Herein, we present the first comprehensive study to use MRI, pallidal
index (PI), and T-l relaxation rate (Rl) in concert with chemical analysis to establish a direct
association between MRI changes and pallidal manganese concentration in rhesus monkeys
following subchronic inhalation of manganese sulfate (MnS04). Monkeys exposed to MnS04 at
>= 0.06 mg Mn/m(3) developed increased manganese concentrations in the globus pallidus,
putamen, olfactory epithelium, olfactory bulb, and cerebellum. Manganese concentrations within
the olfactory system of the MnS04-exposed monkeys demonstrated a decreasing rostralcaudal
concentration gradient, a finding consistent with olfactory transport of inhaled manganese.
Marked MRI signal hyperintensities were seen within the olfactory bulb and the globus pallidus;
however, comparable changes could not be discerned in the intervening tissue. The Rl and PI
were correlated with the pallidal manganese concentration. However, increases in white matter
manganese concentrations in MnS04-exposed monkeys confounded the PI measurement and
may lead to underestimation of pallidal manganese accumulation. Our results indicate that the
Rl can be used to estimate regional brain manganese concentrations and may be a reliable
biomarker of occupational manganese exposure. To our knowledge, this study is the first to
provide evidence of direct olfactory transport of an inhaled metal in a non-human primate.
Pallidal delivery of manganese, however, likely arises primarily from systemic delivery and not
directly from olfactory transport.
23. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A,
Finkelstein J, Oberdorster G. (2006) Translocation of inhaled ultrafine manganese oxide
particles to the central nervous system. Environmental Health Perspectives 114(8): 1172-1178.
BACKGROUND: Studies in monkeys with intranasally instilled gold ultrafine particles (UFPs;
<100 nm) and in rats with inhaled carbon UFPs suggested that solid UFPs deposited in the nose
travel along the olfactory nerve to the olfactory bulb. METHODS: To determine if olfactory
translocation occurs for other solid metal UFPs and assess potential health effects, we exposed
groups of rats to manganese (Mn) oxide UFPs (30 nm; similar to 500 mu g/m(3)) with either
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both nostrils patent or the right nostril occluded. We analyzed Mn in lung, liver, olfactory bulb,
and other brain regions, and we performed gene and protein analyses. RESULTS: After 12 days
of exposure with both nostrils patent, Mn concentrations in the olfactory bulb increased 3.5-fold,
whereas lung Mn concentrations doubled; there were also increases in striatum, frontal cortex,
and cerebellum. Lung lavage analysis showed no indications of lung inflammation, whereas
increases in olfactory bulb tumor necrosis factor-alpha mRNA (similar to 8-fold) and protein
(similar to 30-fold) were found after 11 days of exposure and, to a lesser degree, in other brain
regions with increased Mn levels. Macrophage inflammatory protein-2, glial fibrillary acidic
protein, and neuronal cell adhesion molecule mRNA were also increased in olfactory bulb. With
the right nostril occluded for a 2-day exposure, Mn accumulated only in the left olfactory bulb.
Solubilization of the Mn oxide UFPs was < 1.5% per day. CONCLUSIONS: We conclude that
the olfactory neuronal pathway is efficient for translocating inhaled Mn oxide as solid UFPs to
the central nervous system and that this can result in inflammatory changes. We suggest that
despite differences between human and rodent olfactory systems, this pathway is relevant in
humans.
24. Erikson KA, Shihabi ZK, Aschner JL, Aschner M. (2002) Manganese accumulates in iron-
deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical
alterations. Biological Trace Element Research 87(1-3): 143-156.
Previous studies have shown that iron deficiency (ID) increases brain manganese (Mn), but
specific regional changes have not been addressed. Weanling rats were fed one of three
semi purified diets: control (CN), iron deficient (ID), or iron deficient/ manganese fortified
(IDMn+). Seven brain regions were analyzed for Mn concentration and amino acid (glutamate,
glutamine, taurine, gamma-aminobutyric acid) concentrations. Both ID and IDMn+ diets caused
significant (p<0.05) increases in Mn concentration across brain regions compared to CN. The
hippocampus was the only brain region in which the IDMn+ group accumulated significantly
more Mn than both the CN and ID groups. ID significantly decreased GABA concentration in
hippocampus, caudate putamen, and globus pallidus compared to CN rats. Taurine was
significantly increased in the substantia nigra of the IDMn+ group compared to both ID and CN.
ID also altered glutamate and glutamine concentrations in cortex, caudate putamen, and thalamus
compared to CN. In the substantia nigra, Mn concentration positively correlated with increased
taurine concentration, whereas in caudate putamen, Mn concentration negatively correlated with
decreased GABA. These data show that ID is a significant risk factor for central nervous system
Mn accumulation and that some of the neurochemical alterations associated with ID are
specifically attributable to Mn accumulation.
25. Erikson KA, Syversen T, Steinnes E, Aschner M. (2004) Globus pallidus: a target brain
region for divalent metal accumulation associated with dietary iron deficiency. Journal of
Nutritional Biochemistry 15(6):335-341.
Recently, iron deficiency has been connected with a heterogeneous accumulation of manganese
in the rat brain. The striatum is particularly vulnerable, for there is a significant negative
correlation between accumulated manganese and gamma-aminobutyric acid levels. The effect of
dietary iron deficiency on the distribution of zinc and copper, two other divalent metals with
essential neurobiological roles, is relatively unexplored. Thus, the primary goal of this study was
to examine the effect of manipulating dietary iron and manganese levels on the concentrations of
copper, iron, manganese and zinc in five rat brain regions as determined with inductively
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coupled plasma mass spectrometry analysis. Because divalent metal transporter has been
implicated as a transporter of brain iron, manganese, and to a lesser extent zinc and copper,
another goal of the study was to measure brain regional changes in transporter levels using
Western blot analysis. As expected, there was a significant effect of iron deficiency (P < 0.05) on
decreasing iron concentrations in the cerebellum and caudate putamen; and increasing
manganese concentrations in caudate putamen, globus pallidus and substantia nigra.
Furthermore, there was a significant effect of iron deficiency (P < 0.05) on increasing zinc
concentration and a statistical trend (P = 0.08) toward iron deficiency-induced copper
accumulation in the globus pallidus. Transporter protein in all five regions increased due to iron
deficiency compared to control levels (P < 0.05); however, the globus pallidus and substantia
nigra revealed the greatest increase. Therefore, the globus pallidus appears to be a target for
divalent metal accumulation that is associated with dietary iron deficiency, potentially caused by
increased transporter protein levels. (C) 2004 Elsevier Inc. All rights reserved.
26. Erikson KM, Jones SR, Aschner M. (2005) Brain manganese accumulation due to toxic
exposure is mediated by the dopamine transporter. Faseb Journal 19(5):A1033-A1034.
27. Fechter LD. (1999) Distribution of manganese in development. Neurotoxicology 20(2-
3):197-201.
Elimination of manganese is closely related to uptake in the normal adult and is believed to play
a critical role in maintaining manganese homeostasis in the face of changing manganese intake.
Data from immature rats, mice and cats have suggested that elimination of manganese undergoes
a period of maturation with adult patterns of excretion developing at about the time of weaning.
In addition, the uptake of manganese from the intestine appears to be more efficient in young
animals than in adults. These two sets of findings raise the possibility that exposure to elevated
manganese levels during the perinatal period might yield excessive concentrations of this metal
in the developing organism. Such an outcome might lead to manganese accumulations in organ
systems where subsequent mobilization might be difficult and might produce permanent toxic
injury. This review evaluates the patterns of manganese uptake and distribution following
prenatal and pre-weaning exposure using a variety of model systems. The data demonstrate that
manganese does cross the placenta and enter fetal tissue although the extent of material crossing
the placenta appears to be limited. The issue of neonatal manganese elimination following tracer
and toxic exposure levels to manganese is addressed. The data show that that the neonatal rodent
is significantly more effective in eliminating manganese than previously believed based upon
tracer studies. Finally, data are presented on regional brain manganese distribution. These data
highlight the lack of agreement on whether manganese is concentrated in specific brain areas.
(C) 1999 Inter Press, Inc.
28. Fechter LD, Johnson DL, Lynch RA. (2002) The relationship of particle size to olfactory
nerve uptake of a non-soluble form of manganese into brain. Neurotoxicology 23(2): 177-183.
The essential element, manganese, can produce chronic neuromotor impairment related to basal
ganglia (BG) damage when it is presented in excessive quantities. The uptake and elimination
patterns of manganese following ingestion have been well studied and, under normal conditions,
excretion appears to keep manganese levels under tight, control. Less is known about inhalation
exposure, but it has been proposed that the lung might serve as a long-tern reservoir for
manganese transport into blood. Recent data suggest that a third route of exposure, transport by
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the olfactory nerve directly to the brain, might have importance in toxicology since such a route
would bypass liver uptake and biliary excretion of manganese. In this study, we sought to
determine how particle size and the use of a poorly soluble form of manganese might influence
net systemic absorption of manganese dust and the potential role of the olfactory nerve in
transport of manganese dioxide. Rats were exposed in nose-only exposure chambers to
manganese dioxide (Mn02) aerosols of 1.3 and 18 mum mass median aerodynamic diameter
(MMAD). The concentration of aerosols was kept constant at 3 mg/m(3); as Mn. Following 15
days of exposure (fire times per week for 3 weeks), rats were euthanized and tissues harvested
for manganese determination carried out by graphite furnace atomic absorption spectroscopy.
Small-particle Mn02 exposure resulted in an elevation in olfactory, bulb manganese
concentration, presumably through uptake by the olfactory nerve, but the effect was highly
variable. While small increases in cortical and neostriatal manganese levels were also observed
in these rats, they did not reach statistical significance. By contrast, there was no evidence of
olfactory nerve Mn02 uptake in rats receiving the large-particle exposure. (C) 2002 Elsevier
Science Inc. All rights reserved.
29. Fitsanakis VA, Erikson KM, Aschner M. (2006) Manganese transport in the CNS.
Neurotoxicology 27(5):895-896.
30. Gallez B, Demeure R, Baudelet C, Abdelouahab N, Beghein N, Jordan B, Geurts M, Roels
HA. (2001) Non invasive quantification of manganese deposits in the rat brain by local
measurement of NMR proton T-l relaxation times. Neurotoxicology 22(3):387-392.
Up to now, there is no reliable non invasive biomarker for the concentration of manganese (Mn)
in the brain after intoxication to this metal. The aim of the present experimental study was to
determine the predictive value of the localized measurement of the proton NMR relaxation time
T-l as a quantitative estimation of the concentration of Mn in brain. The relationship of the
proton relaxation rates (1/T-l) was established in rat brain homogenates as a function of the Mn,
iron, and copper concentration. Subsequently, an experimental model of Mn neurotoxicity was
used: rats were stereotactically injected with increasing amounts of Mn2+ (as MnC12) in the
ventricles. After 3 weeks, local measurements of T-l were carried out in live rats. They were
then sacrificed in order to sample the striatum, the cortex and the cerebellum from the brain and
to perform a quantitative determination of the concentration of Mn in these tissues by atomic
absorption spectrometry (AAS). The results indicate excellent correlation coefficients between
relaxation rates and tissue Mn concentrations (r = 0.84, 0.77 and 0.92 for the striatum, the cortex
and the cerebellum, respectively). This methodology offers a unique tool for monitoring the
degree of Mn concentration in different areas of the brain in animal models of Mn intoxication.
In will be useful for evaluating the efficacy of treatments aimed at decreasing the metal in the
brain. The method could be potentially useful for being transposed in the clinical situation for
monitoring Mn-exposed workers. (C) 2001 Elsevier Science Inc. All rights reserved
31. Garcia SJ, Gellein K, Syversen T, Aschner M. (2006) A manganese-enhanced diet alters
brain metals and transporters in the developing rat. Toxicological Sciences 92(2):516-525.
Manganese (Mn) neurotoxicity in adults can result in psychological and neurological
disturbances similar to Parkinson's disease, including extrapyramidal motor system defects and
altered behaviors. However, virtually nothing is known regarding excess Mn accumulation
during central nervous system development. Developing rats were exposed to a diet high in Mn
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via maternal milk during lactation (PN4-21). The high Mn diet resulted in changes in
hematological parameters similar to those seen with iron (Fe) deficiency in dams (decreased
plasma Fe; increased plasma transferrin [Tf]) and pups (decreased hemoglobin [Hb] and plasma
Fe; increased plasma Tf and total iron binding capacity). Mn-exposed pups showed an increase
in brain Mn, chromium, and zinc concurrent with a decrease in brain Fe. In conjunction with the
altered transport and distribution of essential metals within the brain, there was enhanced protein
expression of the divalent metal transporter-1 (DMT-1) and transferrin receptor (TfR) overall in
the brain; there was a general increase in each region analyzed (cerebellum, cortex,
hippocampus, midbrain, and striatum). Neurochemical changes were observed as an increase in
gamma-aminobutyric acid (GAB A) and the ratio of GABA to glutamate, indicating enhanced
inhibitory transmission in the brain. The results of this study demonstrate that developing rats
undergo alterations in the transport and distribution of essential metals translating to
neurochemical perturbations after maternal exposure to a diet supplemented with excess levels of
Mn.
32. Garcia SJ, Gellein K, Syversen T, Aschner M. (2007) Iron deficient and manganese
supplemented diets alter metals and transporters in the developing rat brain. Toxicological
Sciences 95(1):205-214.
Manganese (Mn) neurotoxicity in adults can result in psychological and neurological
disturbances similar to Parkinson's disease, including extrapyramidal motor system defects and
altered behaviors. Iron (Fe) deficiency is one of the most prevalent nutritional disorders in the
world, affecting approximately 2 billion people, especially pregnant and lactating women,
infants, toddlers, and adolescents. Fe deficiency can enhance brain Mn accumulation even in the
absence of excess Mn in the environment or the diet. To assess the neurochemical interactions of
dietary Fe deficiency and excess Mn during development, neonatal rats were exposed to either a
control diet, a low-Fe diet (ID), or a low-Fe diet supplemented with Mn (IDMn) via maternal
milk during the lactation period (postnatal days [PN] 4-21). In PN21 pups, both the ID and
IDMn diets produced changes in blood parameters characteristic of Fe deficiency: decreased
hemoglobin (Hb) and plasma Fe, increased plasma transferrin (Tf), and total iron binding
capacity (TIBC). Treated ID and IDMn dams also had decreased Hb throughout lactation and ID
dams had decreased plasma Fe and increased Tf and TIBC on PN21. Both ID and IDMn pups
had decreased Fe and increased copper brain levels; in addition, IDMn pups also had increased
brain levels of several other essential metals including Mn, chromium, zinc, cobalt, aluminum,
molybdenum, and vanadium. Concurrent with altered concentrations of metals in the brain,
transport proteins divalent metal transporter-1 and transferrin receptor were increased. No
significant changes were determined for the neurotransmitters gamma aminobutyric acid and
glutamate. The results of this study confirm that there is homeostatic relationship among several
essential metals in the brain and not simply between Fe and Mn.
33. Garcia SJ, Syversen T, Gellein K, Aschner M. (2005) Iron Deficient And Manganese
Enhanced Diets Alter Metals And Transporters In The Developing Rat Brain. Toxicol Sci 84(1-
S):122.
Fe-deficiency is a prevalent nutritional disorder, affecting ~2 billion people, mostly pregnant and
lactating women and children. Fe and Mn share similar transport mechanisms, competing for
transport. In adults Mn toxicity leads to neurological disturbances, but little is known about
developmental Mn toxicity. To study the interactions of Fe and Mn during brain development,
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pregnant Sprague-Dawley rats were fed one of four semi-purified diets from gestational day 7
until postnatal day (PN)21: control (35 Fe:10 Mn mg/kg diet), low Fe (ID; 3 Fe:10 Mn), high Mn
(Mn; 35 Fe: 100 Mn), or low Fe with high Mn (IDMn; 3 Fe: 100 Mn). Control neonates were
cross-fostered to experimental or control dams on PN4 and exposed to the diets via lactation
until PN21. Hematological measurements confirmed Fedeficiency (decreased Fe, hemoglobin;
increased transferrin (Tf), total Fe binding capacity) in dams and pups fed "ID" or "IDMn" diets,
while those fed "Mn" had some trends toward similar hematological changes. Western blot
analysis revealed that both "ID" and "IDMn" increased expression of the metal transporters, Tf
receptor and divalent metal transporter 1 (DMT1). Inductively coupled plasma mass
spectrometry (ICP-MS) showed that all three experimental diets decreased brain Fe levels, while
both Mn enhanced diets increased brain Mn levels. In addition, "ID" increased copper (Cu);
"Mn" increased chromium (Cr); and "IDMn" increased Cr, Cu, cobalt (Co), zinc (Zn), and
vanadium (V). Upregulated DMT1, a non-specific transporter, may be a route for increased
metals in the brain following dietary manipulations. Because each of the metals affected by low
Fe and/or high Mn are esessential metals for normal development and function, homeostatic
disturbances may contribute to later consequences.
34. Gianutsos G, Morrow GR, Morris JB. (1997) Accumulation of manganese in rat brain
following intranasal administration. Fundamental and Applied Toxicology 37(2): 102-105.
Manganese chloride (50-500 mu g) was injected unilaterally into the right nostril of rats and its
accumulation in the central nervous system (CNS) was monitored. Brain manganese levels were
elevated in a dose-dependent, time-dependent, and tissue-dependent manner. Elevated levels of
manganese were detected in the right olfactory bulb and olfactory tubercle within 12 hr after
instillation and remained elevated for at least 3 days. As little as 100 mu g of manganese chloride
was sufficient to increase brain manganese levels, No changes were detected on the left side of
the brain. The manganese content of the striatum, the target site for manganese neurotoxicity,
was unchanged following acute administration, but was elevated when two injections were made
1 week apart, These results suggest that air-borne manganese can be retrogradely transported
along olfactory neurons to the CNS and can reach deeper brain structures under appropriate
exposure conditions. (C) 1997 Society of Toxicology.
35. Guidotti TL, Audette RJ, Martin CJ. (1997) Interpretation of the trace metal analysis profile
for patients occupationally exposed to metals. Occupational Medicine-Oxford 47(8):497-503.
Trace element profile analysis detects and quantifies the presence of several metals
simultaneously at low concentrations in the body. In occupational medicine, it may be used to
monitor exposure or to evaluate suspected toxicity. Clinical interpretation is often difficult
because, with the exception of lead and possibly cadmium, there is little firm information on
toxicity thresholds. For these tests, the reference ranges typically reflect low levels of exposure
in the general population and it is expected that workers handling metals in occupations such as
welding and industries such as steelmaking will have higher levels. Interpretation requires some
knowledge of the toxicokinetics of the metal of interest and the preferred medium for analysis
for each: serum, whole blood or urine (preferably 24-hour collection). Trends are often more
informative than concentrations at one time. Trace element values are reported together with a
reference range which must be distinguished from the normal range of other clinical tests. As a
practical matter, the greatest interpretation problems tend to be found with manganese because
serum levels have a poor correlation with both recent exposure and neurological symptoms.
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Molybdenum and vanadium are often found to be elevated among workers exposed to metals
who show no evidence of clinical illness. Interpretation of the trace element profile analysis
overall when an elevation occurs generally requires close attention to the pattern of elevation,
clinical context, absolute and relative magnitude of the elevation and knowledge of the exposure
history.
36. Gwiazda R, Kern C, Smith D. (2005) Progression Of Neurochemical Effects In Different
Brain Regions As A Function Of The Magnitude And Duration Of Manganese Exposure.
Toxicol Sci 84(1-S): 122-123.
Manganese (Mn) is known to elicit symptoms resembling those of Parkinson's disease (PD) at
high exposure levels, but its effects at low levels of exposure are uncertain. Because of the
similarity of behavioral deficits at elevated Mn exposure to PD symptoms, earlier Mn toxicity
studies have proposed that striatal dopamine (DA) depletion, a hallmark of PD, is also produced
by Mn, despite the observation in humans that Mn accumulates in the globus pallidus. To
reconcile this, we have proposed the hypothesis that there is a progression of effects from the
globus pallidus to striatum as a function of increasing magnitude of Mn dose and treatment
duration (Gwiazda et al., NeuroToxicology, 95:1-8, 2002). To test this, we administered Mn ip 3
times/wk to Sprague-Dawley rats at nominal doses of 0, 1.2, 4.8 and 9.6 mg/Kg over 5 wks, and
0, 1.2, 4.8 mg/Kg over 15 wks. We conducted a battery of motor tests, spontaneous motor
activity (SMA) and rotorod measurements, evaluated brain, blood, and plasma Mn levels, and
neurochemical levels in the striatum, globus pallidus, substantia nigra and motor regions of the
thalamus. Mn treatment increased DA levels in the globus pallidus in animals receiving the
highest Mn doses over both 5 and 15 wks, but had no effect on striatal or substantia nigra DA
levels. Motor deficits measured as impairment in the balance beam and in hind limb hopping,
and shorter latency to fall from the rotorod were observed at the highest dose at 5 weeks. No Mn
effects were detected on SMA. Blood and brain Mn showed similar relative increases as a
function of nominal dose at 5 and 15 wks, even though the cumulative Mn doses of 15 wks
animals were three times higher than in animals exposed for 5 wks. These results suggest that 1)
Across a wide range of Mn doses the globus pallidus is a more sensitive locus of Mn toxicity
compared to the striatum, and 2) The magnitude of the Mn nominal dose is more important than
exposure duration in bringing about an increase in Mn body burden and eliciting Mn toxicity.
37. Henriksson J, Tallkvist J, Tjalve H. (1999) Transport of manganese via the olfactory
pathway in rats: Dosage dependency of the uptake and subcellular distribution of the metal in the
olfactory epithelium and the brain. Toxicology and Applied Pharmacology 156(2): 119-128.
The dosage dependency of the uptake of Mn from the olfactory epithelium via olfactory neurons
into the brain was studied after intranasal administration of the metal in rats. The results indicate
that the Mn transport is saturable both regarding the uptake into the olfactory epithelium and the
transfer to the olfactory bulb. Further, our data indicate that Mn moves relatively freely from the
olfactory bulb to the olfactory cortex at an amount dependent on the level of influx into the bulb.
The transport to the rest of the brain was related to the amounts in the olfactory bulb and the
olfactory cortex, but the relative proportion reaching this area increased with increasing doses.
Cell fractionations showed that the Mn was present both in the cytosol and in association with
various cell constituents, Gel filtrations of the cytosol on a Superdex 30 column showed that
about 20% of the Mn in the brain and about 3% in the olfactory epithelium was eluted together
with high-molecular-weight materials (MW > 10,000), whereas the rest was eluted in the total
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volume and may represent unbound metal. It is likely that the metal has been loosely associated
with protein(s) or other constituents at the application to the column, but that this association is
too loose to be retained during the passage through the column, Our results show that the
olfactory neurons provide a pathway with a considerable capacity to transport Mn into the brain.
We propose that the neurotoxicity of inhaled Mn is related to an uptake via this route. (C) 1999
Academic Press.
38. Henriksson J, Tjalve H. (2000) Manganese taken up into the CNS via the olfactory pathway
in rats affects astrocytes. Toxicological Sciences 55(2):392-398.
Manganese (Mn), administered intranasally in rats, is effectively taken up in the CNS via the
olfactory system. In the present study, Mn (as MnC12) dissolved in physiological saline, was
instilled intranasally in rats at doses of 0 (control), 10, 250, or 1000 mu g. At the start of the
experiment each rat received an intranasal instillation. Some rats were killed after one week
without further treatment (the 1-w group), whereas the remaining rats received further
instillations after one and two weeks and were killed after an additional week (the 3-w group).
The brains were removed and either used for ELISA-determination of the astrocytic proteins
glial fibrillary acidic protein (GFAP) and S-lOOb or histochemical staining of GFAP and S-lOOb,
microglia (using an antibody against the ibal-protein) and the neuronal marker Fluoro-Jade.
There were no indications that the Mn induced neuronal damage. On the other hand, the ELISA
showed that both GFAP and S-lOOb decreased in the olfactory cortex, the hypothalamus, the
thalamus, and the hippocampus of the 3-w group. The only effect observed in the 1-w group was
a decrease of S-lOOb in the olfactory cortex at the highest dose. The immunohistochemistry
showed no noticeable reduction in the number of astrocytes. We assume that the decreased levels
of GFAP and S-lOOb are due to an adverse effect of Mn on the astrocytes, although this effect
does not result in astrocytic demise. In the 3-w group, exposed to the highest dose of Mn,
increased levels of GFAP and S-lOOb were observed in the olfactory bulbs, but these effects are
probably secondary to a Mn-induced damage of the olfactory epithelium. Our results indicate
that the astrocytes are the initial targets of Mn toxicity in the CNS.
39. Ingersoll RT, Montgomery EB, Aposhian HV. (1995) Central-Nervous-System Toxicity of
Manganese .1. Inhibition of Spontaneous Motor-Activity in Rats after Intrathecal Administration
of Manganese Chloride. Fundamental and Applied Toxicology 27(1): 106-113.
The intrathecal administration of MnC12 to young male rats caused dopamine depletion in the
caudate-putamen and a decrease in spontaneous motor activity. Our experiments demonstrate
that in the young rat: (a) the lateral choroid plexus protects the cerebrospinal fluid (CSF) from
high concentrations of Mn in the blood by sequestering and thus preventing large amounts of this
metal ion from entering the CSF. As blood Mn levels rise, the lateral choroid plexus may
become overwhelmed and leak an increasing amount of Mn into the CSF. (b) The lateral choroid
plexus does not remove Mn2+ from the CSF. (c) The injection of MnC12 into the CSF of rats
caused a rapid decrease in spontaneous motor activity which is dose-dependent and reversible
under the present experimental conditions. Intrathecal Mn results in a substantial decrease in
striatal dopamine but not homovanillic acid or 3,4-dihydroxyphenylacetic acid (DOPAC)
concentrations and is associated with an increase in the Mn concentration of the substantia nigra
and caudate-putamen. (C) 1995 Society of Toxicology.
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40. Kanayama Y, Tsuji T, Enomoto S, Amano R. (2005) Multitracer screening: Brain delivery
of trace elements by eight different administration methods. Biometals 18(6):553-565.
Trace elements are closely associated with the normal functioning of the brain. Therefore, it is
important to determine how trace elements enter, accumulate, and are retained in the brain.
Using the multitracer technique, which allows simultaneous tracing of many elements and
comparison of their behavior under identical experimental conditions, we examined the influence
of different administration methods, i.e., intravenous (IV), intraperitoneal (IP), intramuscular
(IM), subcutaneous (SC), intracutaneous (IC), intranasal (IN), peroral (PO), and percutaneous
(PC) administration, on the uptake of trace elements. A multitracer solution containing 16
radionuclides (i.e.,Be-7, Sc-46, V-48, Cr-51, Mn-54, Fe-59, Co-56, Zn-65, As-74, Se-75, Rb-83,
Sr-85, Y-88, Zr-88, Tc-95m, and Ru-103) was used. The results indicated that the Rb-83 brain
uptake rate with intranasal administration was approximately twice those obtained with the other
administration methods. This result indicated that a portion of Rb was delivered into the brain
circumventing the blood circulation and that delivery could be accomplished mainly by olfactory
transport. Multitracer screening of trace element delivery revealed differences in brain uptake
pathways among administration methods.
41. Kimura M, Ujihara M, Yokoi K. (1996) Tissue manganese levels and liver pyruvate
carboxylase activity in magnesium-deficient rats. Biological Trace Element Research 52(2): 171-
179.
To investigate the manganese status in mag,nesium deficiency, 40 male Wistar rats, 3 wk old,
were divided into two groups and fed a magnesium deficient diet or a normal synthetic diet for 2
wk. Dietary magnesium depletion decreased magnesium levels in brain, spinal cord, lung,
spleen, kidney, testis, bone, blood, and plasma, while it elevated the magnesium level in liver. In
magnesium-depleted rats, calcium concentration was increased in lung, liver, spleen, kidney, and
testis, while it was decreased in tibia. In magnesium-depleted rats, manganese concentration was
decreased in plasma and all tissues except adrenal glands and blood. Dietary magnesium
depletion diminished pyruvate carboxylase (EC 6.4.1.1) activity in the crude mitochondrial
fraction of liver. Positive correlation was found between the liver manganese concentration and
the pyruvate carboxylase activity. In the magnesium-depleted rats, glucose was decreased while
plasma lipids (triglycerides, phospholipids, and total cholesterol) were increased. These results
suggest that dietary magnesium deficiency changes manganese metabolism in rats.
42. Kobayashi H, Uchida M, Sato I, Suzuki T, Hossain MM, Suzuki K. (2004) Neurotoxicity
and brain regional distribution of manganese in mice, (vol 22, pg 679, 2003). Journal of
Toxicology-Toxin Reviews 23(4):556-557.
43. Kostial K, Blanusa M, Piasek M. (2005) Regulation of manganese accumulation in
perinatally exposed rat pups. Journal of Applied Toxicology 25(2):89-93.
The risk of manganese (Mn)-related ill effects in the neonate has been the topic of several
investigations because in formula-fed infants Mn intake is much higher than in breast-fed
infants. In the young, when Mn homeostasis is not yet developed, increased Mn intake might
pose a neurotoxic risk. Our work aimed at collecting new data on Mn accumulation during the
perinatal period by using an experimental rat model in pups whose mothers were exposed orally
to Mn in drink (as manganese chloride; dose of 2000 ppm, Mn) throughout pregnancy and 11
days of lactation. Pups were cross-fostered at birth and placental and mammary transfer of Mn at
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birth and at the age of 11 days was evaluated. The total pup body burden of Mn was analysed by
atomic absorption spectrometry. Concentrations of iron (Fe), zinc (Zn) and calcium (Ca) also
were analysed at the end of the experiment. The concentration of Mn in perinatally exposed pups
was 6-8 times higher than in controls, irrespective of the period and duration of exposure. After
cessation of exposure, the Mn concentration decreased almost to control levels. Concentrations
of other essential elements (Fe, Zn, Ca) were not affected by Mn exposure. Our results indicate
the existence of an accurate regulation of Mn accumulation in pups exposed to Mn during the
perinatal period. Copyright (c) 2005 John Wiley T Sons, Ltd.
44. Lewis J, Bench G, Myers O, Tinner B, Staines W, Barr E, Divine KK, Barrington W,
Karlsson J. (2005) Trigeminal uptake and clearance of inhaled manganese chloride in rats and
mice. Neurotoxicology 26(1): 113-123.
Inhaled manganese (Mn) can enter the olfactory bulbs via the olfactory epithelium, and can then
be further transported trans-synaptically to deeper brain structures. In addition to olfactory
neurons, the nasal cavity is innervated by the maxillary division of the trigeminal nerve that
projects to the spinal trigeminal nucleus. Direct uptake and transport of inhaled metal particles in
the trigeminal system has not been investigated previously. We studied the uptake, deposition,
and clearance of soluble Mn in the trigeminal system following nose-only inhalation of
environmentally relevant concentrations. Rats and mice were exposed for 10-days (6 h/day, 5
days/week) to air or MnC12 aerosols 3 containing 2.3 +/- 1.3 mg/m(3) Mn with mass median
aerodynamic diameter (MMAD) of 3.1 +/- 1.4 mum for rats and 2. 0 +/- 0.09 mg/n(3) Mn
MnC12 with MMAD of 1.98 +/- 0.12 mum for mice. Mn concentrations in the trigeminal ganglia
and spinal trigeminal nucleus were measured 2 h (0-day), T, 14-, or 30-days post-exposure using
proton induced X-ray emission (PIXE). Manganese-exposed rats and mice showed statistically
elevated levels of Mn in trigeminal ganglia 0-, 7- and 14days after the 10-days exposure period
when compared to control animals. The Mn concentration gradually decreased over time with a
clearance rate (t(l/2)) of 7-8-days. Rats and mice were similar in both average accumulated Mn
levels in trigeminal ganglia and in rates of clearance. We also found a small but significant
elevation of Mn in the spinal trigeminal nucleus of mice 7-days post-exposure and in rats 0- and
7-days post-exposure. Our data demonstrate that the trigeminal nerve can serve as a pathway for
entry of inhaled Mn to the brain in rodents following nose-only exposure and raise the question
of whether entry of toxicants via this pathway may contribute to development of
neurodegenerative diseases. (C) 2004 Elsevier Inc. All rights reserved.
45. Li G, Liu J, Waalkes MP, Zheng W. (2005) Manganese Exposure Alters Iron Regulatory
Mechanisms At Blood-Cerebrospinal Fluid Barrier (BCB) And Selected Regions Of Bloodbrain
Barrier (BBB) In Rats. Toxicol Sci 84(1-S): 121 -122.
Previous in vitro data suggest that manganese (Mn) exposure increases the expression of
mRNAs encoding transferrin receptor (TfR), which possess an iron (Fe) response element (IRE),
by altering binding of iron regulatory protein-1 (IRP1) to TfR mRNA. The current study tested
the hypothesis that in vivo exposure to Mn alters TfR expression at both BBB and BCB, leading
to altered Fe transport at brain barriers. Male SD rats received daily oral gavages at doses of 5 or
15 mg Mn/kg as MnC12 for 30 days. Blood, cerebrospinal fluid (CSF) and choroids plexus were
collected. Brain capillaries from striatum, hippocampus, frontal cortex, and cerebellum, were
separated from parenchyma. Atomic absorption spectrophotometry revealed that the Fe
concentration in controls was about 17-22 fold higher in choroid plexus than in other brain
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regions. Mn exposure resulted in a 67% decrease of serum Fe and an increased Fe in CSF (25%)
and choroid plexus {61%) compared to control, while the concentrations of Mn and Fe in most
brain regions tested did not change significantly. Capillary depletion followed by gel shift assay
using SI00 cytosolic extracts showed that binding of IRP1 to [32P] IRE-RNA probes was
significantly enhanced in choroid plexus and capillaries of striatum, hippocampus, and frontal
cortex (p < 0.01). Quantitative real-time RT-PCR demonstrated increased levels of TfR mRNA
in choroid plexus and capillaries of striatum and hippocampus (p < 0.05), but not in frontal
cortex and cerebellum capillaries, suggesting an up-regulation of TfR in BCB and selected
regional BBB. The mRNA levels of ferritin, an Fe storage protein, were reduced by 87% in the
choroid plexus and 34% in striatum capillary. Taken together, these data indicate that Mn, on the
way to brain, alters Fe regulatory mechanisms at BCB and selected regions of BBB. This may
underlie the distorted Fe homeostasis in the CSF.
46. Malecki EA, Devenyi AG, Beard JL, Connor JR. (1999) Existing and emerging mechanisms
for transport of iron and manganese to the brain. Journal of Neuroscience Research 56(2): 113-
122.
The metals iron (Fe) and manganese (Mn) are essential for normal functioning of the brain. This
review focuses on recent developments in the literature pertaining to Fe and Mn transport, These
metals are treated together because they appear to share several transport mechanisms. In
addition, several neurological diseases such as Alzheimer's Disease, Parkinson's Disease, and
Huntington's Disease are all associated with Fe mismanagement in the brain, particularly in the
striatum and basal ganglia. Similarly, Mn accumulation in brain also appears to target the same
brain regions. Therefore, stringent regulation of the concentration of these metals in the brain is
essential, The homeostatic mechanisms for these metals must be understood in order to design
neurotoxicity prevention strategies. J, Neurosci, Res. 56:113-122, 1999, (C) 1999 Wiley-Liss,
Inc.
47. Normandin L, Beaupre LA, Salehi F, St-Pierre A, Kennedy G, Mergler D, Butterworth RE,
Philippe S, Zayed J. (2004) Manganese distribution in the brain and neurobehavioral changes
following inhalation exposure of rats to three chemical forms of manganese. Neurotoxicology
25(3):433-441.
The central nervous system is an important target for manganese (Mn) intoxication in humans; it
may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted
from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are
primarily Mn phosphate, Mn sulfate, and Mn phosphate/ sulfate mixture. The purpose of this
study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb,
frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver
kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn
species. Rats (n = 15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13
consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/ sulfate mixture at about
3000 mug m(-3) and compared to controls. At the end of the exposure period, spontaneous motor
activity was measured for 36 h using a computerized autotrack system. Mn in tissues was
determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the
brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate
mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate
mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results
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confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.
(C) 2003 Elsevier Inc. All rights reserved.
48. Ponzoni S, Gaziri LCJ, Britto LRG, Barreto WJ, Blum D. (2002) Clearance of manganese
from the rat substantia nigra following intra-nigral microinjections. Neuroscience Letters
328(2): 170-174.
Chronic exposure to manganese (Mn) positively correlates with the occurrence of Parkinsonism
but little is known about mechanisms of its neurotoxicity. In the present study, we determined
the clearance of Mn from rat substantia nigra after its nigral injection and correlated it with the
establishment of apomorphine-induced rotational behaviour and loss of striatal tyrosine
hydroxylase (TH) immunoreactivity. Our results suggest that Mn is slowly cleared from the
substantia nigra, following a first-order kinetics with a t(l/2) of 3 days. Appearance of
apomorphine-induced rotational behaviour and loss of TH immunoreactivity within the striatum
follows metal clearance were both detected 24 hours after intra-nigral Mn microinjection and
maximal 72 hours after injection. The present data suggest that the cellular mechanisms induced
by Mn and leading to dopaminergic cell death, occurred shortly after its injection and that the
metal concentration needs to reach a threshold value to induce neurotoxic effects. This would
indicate that nigral damages are a direct consequence of Mn accumulation. (C) 2002 Elsevier
Science Ireland Ltd. All rights reserved.
49. Roels H, Meiers G, Delos M, Ortega I, Lauwerys R, Buchet JP, Lison D. (1997) Influence of
the route of administration and the chemical form [MnC12, Mn02) on the absorption and
cerebral distribution of manganese in rats. Archives of Toxicology 71(4):223-230.
The absorption and cerebral distribution of manganese (Mn) have been studied with respect to
the route of administration and the chemical form of the Mn compound. Different groups of adult
male rats received either MnC12 . 4H(2)0 or Mn02 once a week for 4 weeks at a dose of 24.3
mg Mn/kg body wt. (b.w.) by oral gavage (g.) or 1.22 mg Mn/kg b.w. by intraperitoneal injection
(i.p.) or intratracheal instillation (i.t.). Control rats were treated with 0.9% saline. Four days after
the last administration the rats were killed and the concentration of Mn measured in blood,
hepatic and cerebral tissues (cortex, cerebellum, and striatum). The liver Mn concentration was
not affected by the treatments whatever the chemical form or the route of administration of the
Mn compound. Administration of MnC12 by g., i.p., and i.t. routes produced equivalent steady-
state blood Mn concentrations (about 1000 ng Mn/100 mi), representing increases of 68, 59, and
68% compared with controls, respectively. Mn concentrations were significantly increased in the
cortex but to a lesser extent (g., 22%; i.p., 36%; i.t., 48%) and were higher in the cerebellum
after i.p. and i.t. administrations than after oral gavage. Rats treated i.t. with MnC12 showed an
elective increase of the striatal Mn concentration (205%). In contrast, Mn02 given orally did not
significantly increase blood and cerebral tissue Mn concentrations; the low bioavailability is
most likely due to the lack of intestinal resorption. Administration of Mn02 i.p. and i.t.,
however, led to significant increases of Mn concentrations in blood and cerebral tissues. These
increments were not significantly different from those measured after MnC12 administration,
except for striatal Mn after i.t. which was markedly less (48%) after Mn02 administration. A
comparison of the blood Mn kinetics immediately after g. and i.t. treatment with MnC12 or
Mn02 indicated that the higher elevation of blood Mn concentration (> 2000 ng Mn/100 mi)
after i.t. administration of MnC12 could account for the elective uptake of Mn in the striatum
observed in repeated dosing experiments. It is concluded that the modulation of Mn distribution
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in brain regions according to the route of administration and the chemical form of the Mn
compound may be explained on the basis of different blood Mn kinetics and regional anatomic
specificities of the striatal region.
50. Roth JA. (2006) Homeostatic and toxic mechanisms regulating manganese uptake, retention,
and elimination. Biological Research 39(l):45-57.
This review attempts to summarize and clarify our basic knowledge as to the various factors that
potentially influence the risks imposed from chronic exposure to high atmospheric levels of
manganese (Mn). The studies describe the interrelationship of the different systems in the body
that regulate Mn homeostasis by characterizing specific, biological components involved in its
systemic and cellular uptake and its elimination from the body, A syndrome known as
manganism occurs when individuals are exposed chronically to high levels of Mn, consisted of
reduced speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages
of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling
Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with
occupations in which abnormally high atmospheric concentrations prevail, such as in welding
and mining. There are three potentially important, routes by which Mn in inspired air can gain
access the body to: 1) direct uptake into the CNS via uptake into the olfactory or trigeminal
presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal
transport directly into the CNS: 2) transport across the pulmonary epithelial lining and its
subsequent deposition into lymph or blood: and/or 3) mucocilliary elevator clearance from the
lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these
processes and their overall contribution to the uptake of Mn in the body is discussed in this
review as well as a description of the various mechanisms that have been proposed for the
transport of Mn across the blood-brain barrier which include both a transferrin-dependent and a
transferrin-independent process that may involve store-operated Ca channels.
51. Roughead ZK, Finley JW. (2001) Mucosal uptake and whole-body retention of dietary
manganese are not altered in beta(2)-microglobulin knockout mice. Biological Trace Element
Research 80(3):231-244.
To further examine the interrelationships between manganese and iron absorption, the mucosal
uptake, initial rate of loss, whole-body retention, and tissue distribution of an orally administered
Mn-54 radiotracer were compared between normal and beta (2)-microglobulin knockout [beta
(2)m(-/-)] mice. These mutant mice are commonly used as a model for the study of human
hemochromatosis, a hereditary iron-overload disease. Initial uptake of Mn-54 by the intestinal
mucosa, the liver, and the brain was not different between the two strains. The mutant mice had
much higher concentrations of nonheme and total iron in the liver, but hepatic manganese,
copper, magnesium, and zinc concentrations were similar between the two strains. In summary,
the mucosal uptake and whole-body retention of manganese and tissue manganese
concentrations were not altered in beta (2)m(-/-) mice; this suggests that normal homeostasis of
manganese is not affected by the altered HFE protein-beta (2)m complex in these mice.
52. Sato I, Matsusaka N, Kobayashi H, Nishimura Y. (1996) Effects of dietary manganese
contents on 54Mn metabolism in mice. Journal of Radiation Research 37(2): 125-132.
BIOSIS COPYRIGHT: BIOL ABS. Several parameters of 54Mn metabolism were noted in mice
maintained on diets with manganese contents of 80 to 8000 mg/kg. Excretion of 54Mn was
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promoted as the dietary manganese contents increased. Clearance of 54Mn from the liver,
kidneys, pancreas, and spleen was markedly accelerated by feeding mice a high-manganese diet,
but clearance from the muscles, femurs, and brain was relatively insensitive to the dietary
manganese. Manganese concentrations in the tissues were regulated homeostatically upto the
dietary manganese content of 2400 mg/kg, but marked accumulations of manganese occurred
when mice were given 8000 mg/kg diet. No toxic symptoms were found up to the 2400 mg/kg
diet, but consumption of the 8000 mg/kg diet was less than for other diets. These results suggest
that an oral intake of excess manganese is effective for promoting the excretion of 54Mn from a
body contaminated with this isotope.
53. Schafer U, Anke M, Seifert M, Fischer AB. (2004) Influences on the manganese intake,
excretion and balance of adults, and on the manganese concentration of the consumed food
determined by means of the duplicate portion technique. Trace Elements and Electrolytes
21(2):68-77.
Manganese intake, excretion and balance were investigated in German adults with mixed and
vegetarian diets as well as in breast-feeding and not breast-feeding women. The daily manganese
consumption and excretion were related to time, location, gender and a manganese
supplementation. In addition, in 1996, the manganese intake of the persons consuming a mixed
diet in Germany (2.4 mg/day for women and 2.7 mg/day for men) was compared with that in
Mexico (2.0 and 2.1 mg/day, respectively). Breast-feeding women ingested 2.3 mg Mn/day. The
supplementation with 300 mug Mn/day increased the manganese intake by 10% in young non-
nursing and by 15% in breast-feeding women. These values analyzed by means of the duplicate
portion technique were well within the assessment of the German Society of Nutrition (DGE)
and the estimated safe and adequate daily dietary intake (ESADDI) of the Food and Nutrition
Board of the National Research Council (NRC) of the USA, both of which provisionally
recommend 2-5 mg Mn/day for adults. However, in our studies, German vegetarians consumed
with 5.5 mg Mn/day (women) and 5.9 mg Mn/day (men) more than twice as much as individuals
with a mixed diet. The manganese balances were found to be mostly negative. From the results
of our intake, balance and placebo-controlled, double-blind studies, we assessed the normative
requirement for manganese at 15 mug/kg body weight/day or 1 mg/day, as weekly average.
Therefore, we recommend a mean intake of 30 mug Mn/kg body weight/day or 2 mg Mn/day,
which we consider to be sufficient intake values for adult humans. The type of diet, year, gender,
country, location and partly the Mn supplementation were found to have a statistically significant
influence on daily manganese intake, whereas, interestingly, the concentration of consumed food
was not influenced by gender. Though manganese is an essential trace element, manganese
deficiency symptoms were not recognized in humans under healthy conditions and balanced
nutrition.
54. St-Pierre A, Normandin L, Carrier G, Kennedy G, Butterworth R, Zayed J. (2001)
Bioaccumulation and locomotor effect of manganese dust in rats. Inhalation Toxicology
13(7):623-632.
The primary goal of this study is to determine the effects of Mn exposure via inhalation. The
bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters,
and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were
exposed to 3750 mug/m(3) of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and
compared to a control group of 12 rats (C) exposed to 4 mug/m(3). After exposure, neurological
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evaluation was carried out for 36 h ( a night-day-night cycle) using a computerized autotrack
system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was
determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum
were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p < .01),
as well as in the kidney, frontal cortex, and globus pallidus ( 1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs.
0.55 ppm; p < .05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79
mmol/L; p < .05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p < .01). Locomotor
activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p
< .05) and lower resting time in the last 12-h period for E ( 36 326 vs. 37 393 s; p < .05). This
study is the first of several ongoing studies in our laboratory that address health concerns
associated with inhalation exposure to different Mn species and to different levels of exposure.
55. Takeda A, Ishiwatari S, Okada S. (1999) Manganese uptake into rat brain during
development and aging. Journal of Neuroscience Research 56(l):93-98.
Manganese (Mn) is an essential metal and plays an important role in the brain. To evaluate Mn
uptake into the brain during development and aging, Mn-54 concentrations in the brain of rats
aged from 5 days to 95 weeks were measured after injection of (MnC12)-Mn-54. Mn-54
concentration in the brain of 5-day-old rats was the highest of all age groups tested. The liver and
blood of 5-day-old rats also showed the highest Mn-54 concentrations among the age groups.
These results suggest that Mn is required in a high amount during infancy and that a sufficient
Mn supply is critical for normal brain development, The high uptake of Mn into the brain of
neonatal rats may be due to high levels of Mn in the blood, which may be supplied from the
liver. In the 5-day-old brain, Mn-54 was relatively concentrated in the hippocampal CA3 and
dentate gyrus and the pens. In the aging brain, Mn-54 was relatively concentrated in the inferior
colliculi, olivary nuclei and red nuclei. J, Neurosci, Res. 56:93-98, 1999, (C) 1999 Wiley-Liss,
Inc.
56. Takeda A, Kodama Y, Ishiwatari S, Okada S. (1998) Manganese transport in the neural
circuit of rat CNS. Brain Research Bulletin 45(2): 149-152.
To study manganese (Mn) transport in the neural circuit of rat CNS, brain isotope distribution
after Mn-54 injection into the brain was analyzed by autoradiography, One day after (MnC12)-
Mn-54 injection into the striatum, Mn-54 was highly distributed in the ipsilateral thalamus,
hypothalamus, and substantia nigra, When (MnC12)-Mn-54 was bilaterally injected into the
striata after unilateral treatment with colchicine or vehicle into the medial forebrain bundle, Mn-
54 was distributed in both sides of the substantia nigra of vehicle-treated rats, On the other hand,
unilateral colchicine treatment caused a decrease of Mn-54 distribution in the ipsilateral
substantia nigra, suggesting that Mn is subjected to axonal transport in the striatonigra and/or
nigrostriatal pathways, In the case of unilateral injection of (MnC12)-Mn-54 into the olfactory
bulb, Mn-54 was distributed in the ipsilateral piriform, amygdaloid areas (the primary olfactory
cortex), and entorhinal area (the secondary olfactory cortex), These results suggest that Mn is
subject to widespread axonal transport in the neural circuits, Moreover, Mn may be taken up by
the piriform neurons (the third olfactory neuron) after release from the secondary olfactory
neuron terminals and transported to the entorhinal area. (C) 1998 Elsevier Science Inc.
57. Takeda A, Sawashita J, Okada S. (1995) Biological Half-Lives of Zinc and Manganese in
Rat-Brain. Brain Research 695(l):53-58.
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The brains of rats injected intravenously with (ZnC12)-Zn-65 or (MnC12)-Mn-54 were subjected
to high-resolution autoradiography. The distribution of Zn-65 and Mn-54 in each brain region
gradually decreased from 6 days to 42 days for Zn-65 and from 15 days to 60 days for Mn-54
after the injection. The biological half-lives of Zn in each region studied were in the range of 16-
43 days; the longest was observed in the amygdaloid nuclei. The regions where the long
biological half-life was observed were consistent with the ones with the high density of Zn-
containing neuron terminals reported previously. The biological half-lives of Mn in each region
determined were 51-74 days; the longest were those in the hypothalamic nuclei and thalamus.
58. Takeda A, Sawashita J, Okada S. (1998) Manganese concentration in rat brain: manganese
transport from the peripheral tissues. Neuroscience Letters 242(l):45-48.
Mn-54 distribution in the brain and peripheral tissues was studied with the course of time after
intravenous injection of (MnC12)-Mn-54 to see manganese (Mn) transport from the peripheral
tissues, i.e. the liver, to the brain. One hour after injection, Mn-54 concentrations in the brain
were 0.15-0.25% dose/g, and Mn-54 was largely concentrated in the choroid plexus. One day
after injection, Mn-54 in the choroid plexus decreased remarkably. Mn-54 in other brain regions
increased gradually after then, and reached 0.30-0.40% dose/g 6 days after injection. This
increase of Mn-54 was due to the redistribution from the peripheral tissues such as liver and
pancreas, in which Mn-54 was maintained at high levels (2.0-4.0% dose/g). The increment of
Mn-54 1 h to 6 days after injection was the largest in the hippocampus, but not in the striatum.
These results suggest that the delivery of Mn from the liver to the brain is not involved in
preferential Mn accumulation in the basal nuclei under physiological condition. This delivery
may be important for brain function. (C) 1998 Elsevier Science Ireland Ltd.
59. Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2005) Olfactory
uptake of manganese is upregulated by iron deficiency and involves DMT1. Faseb Journal
19(5):A1483-A1484.
60. Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2006) The influence
of high iron diet on rat lung manganese absorption. Toxicology and Applied Pharmacology
210(l-2):17-23.
Individuals chronically exposed to manganese are at high risk for neurotoxic effects of this
metal. A primary route of exposure is through respiration, although little is known about
pulmonary uptake of metals or factors that modify this process. High dietary iron levels
inversely affect intestinal uptake of manganese, and a major goal of this study was to determine
if dietary iron loading could increase lung non-heme iron levels and alter manganese absorption.
Rats were fed a high iron (1% carbonyl iron) or control diet for 4 weeks. Lung non-heme iron
levels increased similar to 2-fold in rats fed the high iron diet. To determine if iron-loading
affected manganese uptake, Mn-54 was administered by intratracheal (it) instillation or
intravenous (iv) injection for pliarmacokinetic studies. Mn-54 absorption from the lungs to the
blood was lower in it-instilled rats fed the 1% carbonyl iron diet. Pharmacokinetics of iv-injected
Mn-54 revealed that the isotope was cleared more rapidly from the blood of iron-loaded rats. In
situ analysis of divalent metal transporter-1 (DMTI) expression in lung detected mRNA in
airway epithelium and bronchus-associated lymphatic tissue (BALT). Staining of the latter was
significantly reduced in rats fed the high iron diet, in situ analysis of transferrin receptor (TfR)
mRNA showed staining in BALT alone. These data demonstrate that manganese absorption from
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the lungs to the blood can be modified by iron status and the route of administration, (c) 2005
Elsevier Inc. All rights reserved.
61. Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M. (2007)
Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. Faseb Journal
21(l):223-230.
Manganese, an essential nutrient, can also elicit toxicity in the central nervous system (CNS).
The route of exposure strongly influences the potential neurotoxicity of manganese-containing
compounds. Recent studies suggest that inhaled manganese can enter the rat brain through the
olfactory system, but little is known about the molecular factors involved. Divalent metal
transporter-1 (DMT1) is the major transporter responsible for intestinal iron absorption and its
expression is regulated by body iron status. To examine the potential role of this transporter in
uptake of inhaled manganese, we studied the Belgrade rat, since these animals display significant
defects in both iron and manganese metabolism due to a glycine-to-arginine substitution
(G185R) in their DMT1 gene product. Absorption of intranasally instilled Mn-54 was
significantly reduced in Belgrade rats and was enhanced in iron-deficient rats compared to iron-
sufficient controls. Immunohistochemical experiments revealed that DMT1 was localized to both
the lumen microvilli and end feet of the sustentacular cells of the olfactory epithelium.
Importantly, we found that DMT1 protein levels were increased in anemic rats. The apparent
function of DMT 1 in olfactory manganese absorption suggests that the neurotoxicity of the metal
can be modified by iron status due to the iron-responsive regulation of the transporter.
62. Tjalve H, Henriksson J, Tallkvist J, Larsson BS, Lindquist NG. (1996) Uptake of manganese
and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in
rats. Pharmacology & Toxicology 79(6):347-356.
In the olfactory epithelium the primary olfactory neurones are in contact with the environment
and via the axonal projections they are also connected to the olfactory bulbs of the brain.
Therefore, the primary olfactory neurones provide a pathway by which foreign materials may
gain access to the brain. In the present study we used autoradiography and gamma spectrometry
to show that intranasal instillation of manganese (Mn-54(2+)) in rats results in initial uptake of
the metal in the olfactory bulbs. The metal was then seen to migrate via secondary and tertiary
olfactory pathways and via further connections into most parts of the brain and also to the spinal
cord. Intranasal instillation of cadmium (Cd-109(2+)) resulted in uptake of the metal in the
anterior parts of the olfactory bulbs but not in other areas of the brain. This indicates that this
metal is unable to pass the synapses between the primary and secondary olfactory neurones in
the bulbs. Intraperitoneal administration of Mn-54(2+) or Cd-109(2+) showed low uptake of the
metals in the olfactory bulbs, an uptake not different from the rest of the brain. Manganese is a
neurotoxic metal which in man can induce an extrapyramidal motor system dysfunction
associated with occupational inhalation of manganese-containing dusts or fumes. We propose
that the neurotoxicity of inhaled manganese is related to an uptake of the metal into the brain via
the olfactory pathways. In this way manganese can circumvent the blood-brain barrier and gain
direct access to the central nervous system.
63. Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B. (2002) Effect of
high dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine
levels, and neurodevelopmental status. Neurotoxicology 23(4-5):635-643.
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Mn is an essential element, but may become neurotoxic at high levels. Recent reports of high Mn
levels in hair of children with neurodevelopmental deficits suggest that these deficits could be
due to Mn-induced neurotoxic effects on brain dopamine (DA) systems, although the mechanism
is not well understood. Infant formulas contain considerably higher concentrations of Mn than
human milk. Thus, formula-fed infants are exposed to high levels of Mn at a time when Mn
homeostasis is incompletely developed. We studied the effects of dietary Mn supplementation of
rat pups on tissue Mn accumulation, brain dopamine levels, infant neurodevelopmental status,
and behavior at maturity. Newborn rats were supplemented daily with 0, 50, 250, or 500 mug
Mn given orally from day I to day 20. Mineral analysis of small intestine and brain at day 14
showed a significant increase of tissue Mn in supplemented rats. Neurodevelopmental tests
conducted at various ages showed significant delays as a function of Mn supplementation. At
day 32, there was a significant positive relationship between passive avoidance errors and Mn
supplementation levels. Brains of animals killed on day 40 showed a significant inverse
relationship between Mn supplementation level and striatal dopamine concentration. These
observations suggest that dietary exposure to high levels of Mn during infancy can be neurotoxic
to rat pups and result in developmental deficits. (C) 2002 Elsevier Science Inc. All rights
reserved.
64. Tran TT, Kelleher SL, Lonnerdal B. (2002) Effect of high manganese intake and iron
deficiency in infant rats on DMT-1 expression and tissue mineral accumulation. Faseb Journal
16(4):A617-A617.
65. Vezer T, Papp A, Hoyk Z, Varga C, Naray M, Nagymajtenyi L. (2005) Behavioral and
neurotoxicological effects of subchronic manganese exposure in rats. Environmental Toxicology
and Pharmacology 19(3):797-810.
In male Wistar rats, behavioral and electrophysiological investigations, and blood and brain
manganese level determinations, were performed; during 10 weeks treatment with low-dose
manganese chloride and a 12 weeks post-treatment period. Three groups of 16 animals each
received daily doses of 14.84 and 59.36 mg/kg b.w. MnC12 (control: distilled water) via gavage.
During treatment period, Mn accumulation was seen first in the blood, then in the brain samples
of the high-dose animals. Short- and long-term spatial memory performance of the treated
animals decreased, spontaneous open field activity (OF) was reduced. The number of acoustic
startle responses (ASR), and the pre-pulse inhibition (PPI) of these, diminished. In the cortical
and hippocampal spontaneous activity, power spectrum was shifted to higher frequencies. The
latency of the sensory evoked potentials increased, and their duration, decreased. By the end of
the post-treatment period, Mn levels returned to the control in all samples. The impairment of
long-term spatial memory remained, as did the number of acoustic startle responses. Pre-pulse
inhibition, however, returned to the pre-treatment levels. The changes of the open field activity
disappeared but a residual effect could be revealed by administration Of D-amphetamine. The
electrophysiological effects were partially reversed. By applying a complex set of methods, it
was possible to obtain new data for a better-based relationship between the known effects of Mn
at neuronal level and the behavioral and electrophysiological outcomes of Mn exposure.
© 2005 Elsevier B.V. All rights reserved.
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66. Vitarella D, Moss O, Dorman DC. (2000) Pulmonary clearance of manganese phosphate,
manganese sulfate, and manganese tetraoxide by CD rats following intratracheal instillation.
Inhalation Toxicology 12(10):941-957.
Manganese (Mn) is ubiquitous in ambient air due to both industrial and crustal sources. It is also
a component of the octane-enhancing fuel additive methylcyclopentadienyl manganese
tricarbonyl (MMT). The combustion of MMT by the automobile engine results in the formation
of Mn particulates including phosphate, sulfate, and oxide forms. The objectives of this study
were to determine the contribution of particle dissolution on pulmonary clearance rates of Mn
sulfate (MnS04), Mn phosphate, and Mn tetraoxide (Mn304) in CD rats following an
intratracheal instillation exposure. In addition, brain (striatal) Mn concentrations were evaluated
following exposure. Adult CD rats were intratracheally instilled with 0, 0.04, 0.08, or 0.16 mu g
Mn/g of either MnS04, Mn phosphate, or Mn304. Rats were euthanized at 0, 1, 3, or 14 days
after instillation. Lung and striatal Mn concentrations were measured by neutron activation
analysis. Pulmonary clearance following single intratracheal instillation of MnS04, Mn
phosphate, or Mn304 was similar for each of the three compounds at each of the three doses
used. All pulmonary clearance half-times were less than 0.5 day. At the concentrations used,
striatal Mn levels were unaffected, and lung pathology was unremarkable. The dissolution rate
constant of the Mn particles was determined in vitro using lung simulant fluids. The solubility of
the Mn compounds was in general 20 to 40 times greater in Hatch artificial lung lining fluid than
in Gamble lung simulant fluid. The dissolution rate constant of the water-soluble MnS04
particles in Hatch artificial lung fluid containing protein was 7.5 x 10(-4) g (Mn)/cm(2)/day,
which was 54 times that of relatively water-insoluble Mn phosphate and 3600 times that of
Mn304. The dissolution rate constants for these compounds were sevenfold slower in Gamble
lung fluid simulant. For both solutions, the time for half the material to go into solution differed
only by factors of 1/83 to 1/17 to 1 for MnS04, Mn phosphate, and Mn304, respectively,
consistent with measured differences in size distribution, specific surface, and dissolution rate
constant. These data suggest that dissolution mechanisms only played a role in the pulmonary
clearance of MnS04, while nonabsorptive (e.g., mechanical transport) mechanisms predominate
for the less soluble phosphate and oxide forms of Mn.
67. Yasui M, Ota K, Garruto RM. (1995) Effects of calcium-deficient diets on manganese
deposition in the Central Nervous system and bones of rats. Neurotoxicology (Little Rock)
16(3): 511-517.
BIOSIS COPYRIGHT: BIOL ABS. The presence of both aluminum (AI) and manganese (Mn)
in central nervous system tissues (CNS) has been reported in Parkinson's disease and in
parkinsonism-dementia (PD) on Guam. Epidemiological surveys on Guam have suggested that
low calcium (Ca), magnesium (Mg) and high Al and Mn in river, soil and drinking water may be
implicated in the pathogenesis of PD. Experimentally, low Ca-Mg diets with or without added Al
have been found to accelerate All deposition in the CNS of rats and monkeys. Although
excessive deposition of Mn produces similar neurotoxic action to Al in CNS tissues, the
mechanism of Mn deposition coupled with All loading in the presence of low Ca-Mg intake is
not yet known. In this study, the deposition and metal-metal interaction of both Al and Mn in the
CNS, visceral organs and bones of rats fed unbalanced mineral diets were analyzed. Male Wistar
rats, weighing 200 g, were maintained for 90 days on the following diets: (A) standard diet, (B)
low Ca diet
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68. Yokel RA, Crossgrove JS, Bukaveckas BL. (2003) Manganese distribution across the blood-
brain barrier II. Manganese efflux from the brain does not appear to be carrier mediated.
Neurotoxicology 24(1): 15-22.
There is concern about manganese (Mn) neurotoxicity. Mn can enter the brain by carrier-
mediated influx. There have been no previous reports of investigation of Mn efflux from the
brain. We used an established method that determines the rate of efflux out of the brain across
the blood-brain barrier (BBB) from the product of the brain distribution volume (V-brain) and
the apparent elimination rate constant (K-el). V-brain is determined as Mn-54 uptake into rat
parietal brain slices versus time. Ke, is determined from the percentage of Mn-54 remaining in
the brain at various times after its discrete injection into the parietal cortex, compared to a
reference compound which is expected to very slowly diffuse out of the brain. The Mn ion, Mn
citrate and Mn transferrin (Mn Tf) were studied. C-14-sucrose and C-14-dextran were used as
reference compounds. The volume of distribution of the Mn species in brain slices was similar
to3-5 ml/g, indicating concentrative uptake. Mn, as the Mn ion or Mn citrate, was injected into
the brain with sucrose or dextran to determine K-el. Based on the rapid exchange rate of Mn with
ligands and on thermodynamic calculations, injection of Mn ion or Mn citrate into the brain
would be expected to result in rapid formation of the same Mn species, predominantly the Mn
ion, Mn citrates and Mn phosphate, in brain extracellular fluid. After injection into the brain Mn
did not efflux from the brain more rapidly than sucrose or dextran, which diffuse across the
BBB. Brain capillary diffusion of the Mn ion and Mn citrate would be expected to be slower
than sucrose or dextran. The rate of Mn efflux from the brain is consistent with diffusion. (C)
2002 Elsevier Science Inc. All rights reserved.
69. Yu IJ, Park JD, Park ES, Song KS, Han KT, Han JH, Chung YH, Choi BS, Chung KH, Cho
MH. (2003) Manganese distribution in brains of Sprague-Dawley rats after 60 days of stainless
steel welding-fume exposure. Neurotoxicology 24(6):777-785.
Welders working in a confined space, as in the shipbuilding industry, are at risk of being
exposed to high concentrations of welding fumes and developing pneumoconiosis or other
welding-fume exposure related diseases. Among such diseases, manganism resulting from
welding-fume exposure remains a controversial issue, as the movement of manganese into
specific brain regions has not yet been clearly established. Accordingly, to investigate the
distribution of manganese in the brain after welding-fume exposure, male Sprague-Dawley rats
were exposed to welding fumes generated from manual metal arc-stainless steel (MMA-SS) at
concentrations of 63.6 +/- 4.1 mg/m(3) (low dose, containing 1.6 mg/m(3) Mn) and 107.1 +/- 63
mg/m(3) (high dose, containing 3.5 mg/m(3) Mn) total suspended particulate (TSP) for 2 h per
day in an inhalation chamber over a 60-day period. Blood, brain, lung, and liver samples were
collected after 2 h, 15, 30, and 60 days of exposure and the tissues analyzed for their manganese
concentrations using an atomic absorption spectrophotometer Although dose- and time-
dependent increases in the manganese concentrations were found in the lungs and livers of the
rats exposed for 60 days, only slight manganese increases were observed in the blood during this
period. Major statistically significant increases in the brain manganese concentrations were
detected in the cerebellum after 15 days of exposure and up until 60 days. Slight increases in the
manganese concentrations were also found in the substantia nigra, basal ganglia (caudate
nucleus, putamen, and globus pallidus), temporal cortex, and frontal cortex, thereby indicating
that the pharmacokinetics and distribution of the manganese inhaled from the welding fumes
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were different from those resulting from manganese-only exposure. (C) 2003 Elsevier Science
Inc. All rights reserved.
70. Zaloglu N, Yildirim G, Bastug M, Koc E, Ficicilar H, Sayal A. (2002) High dosage of
manganese chloride application and iron zinc copper status in rats. Trace Elements and
Electrolytes 19(3): 138-142.
We examined the distribution of manganese in rat liver, ileum and brain tissues after chronic
administration (50 days) of high-dose MnC12 and investigated spectrophotometrically the
interactions between manganese and some other trace metals (iron, copper, zinc) levels. In the
experimental group (n = 10), MnC12 (30 mg/kg/day) was injected for 50 days intraperitoneally.
Plasma, erythrocyte, brain, liver and ileum manganese levels were found elevated compared to
control group (n = 10). Brain iron levels did not change whereas liver and ileum iron levels
increased significantly. Moreover, brain copper and zinc levels did not change, but liver copper
and zinc levels were found elevated. Ileum copper levels also increased, but ileum zinc levels did
not change compared to control group. The significant increase in erythrocyte manganese
content may be due to mitochondrial MnSOD in red blood cells. This situation might have
helped to potantiate the antioxidant defense system of organism against free oxygen radicals
produced by Mn-induced oxidation reaction.
71. Zheng W, Kim H, Zhao QQ. (2000) Comparative toxicokinetics of manganese chloride and
methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats. Toxicological
Sciences 54(2):295-301.
The toxicokinetics of manganese (Mn) was investigated in male and female rats either following
a single intravenous (iv) or oral dose of MnC12 (6.0 mg Mn/kg), or following a single oral dose
of methylcyclopentadienyl manganese tricarbonyl (MMT) (20 mg MMT/kg or 5.6 mg Mn/kg).
The plasma concentrations of manganese were quantified by atomic absorption
spectrophotometry (AAS). Upon iv administration of MnC12, manganese rapidly disappeared
from blood with a terminal elimination t(l/2) of 1.83 h and CLs of 0.43 L/h/kg. The plasma
concentration-time profiles of manganese could be described by C = 41.9e(-4.24t) + 2.1e(-0.44t).
Following oral administration of MnC12, manganese rapidly entered the systemic circulation (T-
max = 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT resulted in a
delayed T-max (7.6 h), elevated C-max (0.93 mu g/ml), and prolonged terminal t(l/2) (55.1 h).
The rats receiving MMT had an apparent clearance (CL/F = 0.09 L/h.kg) about 37-fold less than
did those who were dosed with MnC12. Accordingly, the area under the plasma concentration-
time curves (AUC) of manganese in MMT-treated rats was about 37-fold greater than that in
MnC12-treated rats. A gender-dependent difference in toxicokinetic profiles of plasma
manganese was also observed. Female rats displayed a greater AUC than that of male rats.
Although the apparent volume of distribution of manganese was similar in both sexes, the
apparent clearance in males was about twice that observed in females. The results indicated that
after oral administration, the MMT-derived manganese displayed higher and more prolonged
plasma concentration-time profiles than MnC12-derived manganese. Thus, MMT-derived
manganese appeared likely to accumulate in the body following repeated exposure.
72. Zheng W, Zhao QQ, Slavkovich V, Aschner M, Graziano JH. (1999) Alteration of iron
homeostasis following chronic exposure to manganese in rats. Brain Research 833(1): 125-132.
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Recent studies suggest that manganese-induced neurodegenerative toxicity may be partly due to
its action on aconitase, which participates in cellular iron regulation and mitochondrial energy
production. This study was performed to investigate whether chronic manganese exposure in rats
influenced the homeostasis of iron in blood and cerebrospinal fluid (CSF). Groups of 8-10 rats
received intraperitoneal injections of MnC12 at the dose of 6 mg Mn/kg/day or equal volume of
saline for 30 days. Concentrations of manganese and iron in plasma and CSF were determined
by atomic absorption spectrophotometry. Rats exposed to manganese showed a greatly elevated
manganese concentration in both plasma and CSF. The magnitude of increase in CSF manganese
(11-fold) was equivalent to that of plasma (10-fold). Chronic manganese exposure resulted in a
32% decrease in plasma iron (p < 0.01) and no changes in plasma total iron binding capacity
(TIBC). However, it increased CSF iron by 3-fold as compared to the controls(p < 0.01).
Northern blot analyses of whole brain homogenates revealed a 34% increase in the expression of
glutamine synthetase (p < 0.05) with unchanged metallothionein-I in manganese-intoxicated rats.
When the cultured choroidal epithelial cells derived from rat choroid plexus were incubated with
MnC12 (100 mu M) for four days, the expression of transferrin receptor mRNA appeared to
exceed by 50% that of control(p < 0.002). The results indicate that chronic manganese exposure
alters iron homeostasis possibly by expediting unidirectional influx of iron from the systemic
circulation to cerebral compartment. The action appears likely to be mediated by manganese-
facilitated iron transport at brain barrier systems. (C) 1999 Elsevier Science B.V. All rights
reserved.
Supporting References (45)
1. Alarcon OM, ReinosaFuller JA, Silva T, DeFernandez MR, Gamboa J. (1996) Manganese
levels in serum of healthy Venezuelan infants living in Merida. Journal of Trace Elements in
Medicine and Biology 10(4):210-213.
Taking up where a previous paper had left off (10) the purpose of this study was to examine in
further detail the serum concentration of manganese of 180 apparently healthy Venezuelan
infants (96 boys and 84 girls) ranging from 5 days to 12 months old, all residents of Merida. The
flow injection analysis-atomic absorption spectrophotometric technique was used for the
determination of manganese. The mean values of serum manganese were 0.42+/-0.12, 0.41+/-
0.11, 0.39+/-0.13, 0.39+/-. 1, 0.38+/-0.09. 0.37+/-0.11, 0.36+/-0.12 and 0.29+/-0.10 mu g/L in
infants 5 days and 1,3,5,7,10,11 and 12 months old, respectively. These values indicate that the
average concentration of manganese in serum decreases with age, but the mechanism involved is
not yet known, nor are the consequences of the decrease. The statistical analysis did not show
any significant influence of sex on the serum value of the metal in the age range of 5 days to 12
months.
2. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1): 188-195.
Iron (Fe) is an essential trace metal involved in numerous cellular processes. Iron deficiency (ID)
is reported as the most prevalent nutritional problem worldwide. Increasing evidence suggests
that ID is associated with altered neurotransmitter metabolism and a risk factor for manganese
(Mn) neurotoxicity. Though recent studies have established differences in which the female
brain responds to ID-related neurochemical alterations versus the male brain, little is known
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about the interactions of dietary ID, Mn exposure, and sex on gamma-amino butyric acid
(GABA). Male and female Sprague-Dawley rats were randomly divided into four dietary
treatment groups: control (CN), control/ Mn supplemented, ID, and ID/Mn supplemented. After
6 weeks of treatment, both ID diets caused a highly significant decrease in Fe concentrations
across all brain regions compared to CN in both sexes. Both ID and Mn supplementation led to
significant accumulation of Mn across all brain regions in both sexes. There was no main effect
of sex on Fe or Mn accumulation. Striatal synaptosomes were utilized to examine the effect of
dietary intervention on H-3-GABA uptake. At 4 weeks, there was a significant correlation
between Fe concentration and H-3-GABA uptake in male rats (p < 0.05). At 6 weeks, there was
a significant inverse correlation between Mn concentration and 3H-GAB A uptake in male and
female rats and a postitive correlation between Fe concentration and H-3-GABA uptake in
female rats (p < 0.05). In conclusion, ID-associated Mn accumulation is similar in both sexes,
with Mn levels affecting GABA uptake in both sexes in a comparable fashion.
3. Anderson JG, Cooney PT, Erikson KM. (2007) Inhibition of DAT function attenuates
manganese accumulation in the globus pallidus. Environmental Toxicology and Pharmacology
23(2): 179-184.
Manganese (Mn) is an essential nutrient, though exposure to high concentrations may result in
neurotoxicity characterized by alterations in dopamine neurobiology. To date, it remains elusive
how and why Mn targets dopaminergic neurons although recently the role of the dopamine
transporter has been suggested. Our primary goal of this study was to examine the potential roles
of the monoamine transporters, dopamine transporter (DAT), serotonin transporter (SERT), and
norepinephrine transporter (NET), in neuronal Mn transport. Using striatal synaptosomes, we
found that only inhibition of DAT significantly decreased Mn accumulation. Furthermore,
weanling rats chronically exposed to Mn significantly accumulated Mn in several brain regions.
However, rats receiving the specific DAT inhibitor GBR 12909 (1 mg/kg bw, three times/week;
4 weeks) had significantly lower Mn levels only in the globus pallidus compared to saline-
treated rats (p < 0.05). Our data show that inhibition of DAT exclusively inhibits Mn
accumulation in the globus pallidus during chronic exposure, (c) 2006 Elsevier B.V. All rights
reserved.
4. Anderson JG, Fordahl SC, Cooney PT, Erikson KM. (2007) Iron deficiency and manganese
exposure are associated with decreases in neurotransmitter uptake. Faseb Journal 21(6):A1065-
A1065.
5. Arnaud J, Bourlard P, Denis B, Favier AE. (1996) Plasma and erythrocyte manganese
concentrations - Influence of age and acute myocardial infarction. Biological Trace Element
Research 53(1-3): 129-136.
This study was carried out to assess manganese (Mn) status after an acute episode of myocardial
infarction. Plasma and erythrocyte Mn concentrations were measured from admission to hospital
to day 15 postadmission in 21 patients suffering from acute myocardial infarction and in three
control groups. The determination of Mn in these biological fluids was performed by
electrothermal atomic absorption spectrometry. Plasma Mn was higher (p <0.01) and erythrocyte
Mn was similar in the acute myocardial infarction group compared to healthy age-matched
control group. Plasma and erythrocyte Mn remained unchanged during the 2 wk after acute
myocardial infarction and were not correlated to enzyme activities. A decrease of erythrocyte
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Mn with age, expressed in nmol/L, was noted (p <0.02). These results suggest that plasma and
erythrocyte Mn do not provide an indication of myocardial damage. Nonetheless, Mn status in
elderly merits further attention.
6. Arnold ML, McNeill FE, Chettle DR. (1999) The feasibility of measuring manganese
concentrations in human liver using neutron activation analysis. Neurotoxicology 20(2-3):407-
412.
Manganese is an element which is required by the human body. However, as with most metals,
in large amounts manganese can be toxic. People who suffer from severe manganese intoxication
have symptoms similar to those of Parkinson's disease. Preclinical symptoms of manganese
intoxication have recently been detected in individuals working in industries which have
manganese dioxide dust in the air. The concentration of many toxic elements can be measured in
vivo using neutron activation. A small dose of neutrons is delivered to the organ of interest, the
neutrons are readily captured by the target nuclei, and the gamma rays given off can be detected
outside of the body. A neutron activation analysis system is being developed to measure
manganese concentrations in humans. The McMaster KN-accelerator supplies the neutron beam
and the thermal neutron capture reaction Mn-55(n,gamma)Mn-56 is used. The half-life of Mn-56
is 2.58 hr and thus counting can occur after irradiation. The 847 keV gamma ray given off when
56Mn decays is detected using a Nal detector. Calibration curves are made using phantoms with
known concentrations of Mn. This system will be used to monitor manganese levels in
individuals who have occupational exposure to the element. Preliminary measurements, using
liver phantoms, give a minimum detectable limit for Mn in the liver of less than one part per
million, which is well below normal levels. (C) 1999 Inter Press, Inc.
7. Aschner M. (2000) Manganese: Brain transport and emerging research needs. Environmental
Health Perspectives 108:429-432.
Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder. An
estimated 2% of the U.S. population, age 65 and older, develops IPD. The number of IPD
patients will certainly increase over the next several decades as the baby-boomers gradually step
into this high-risk age group, concomitant with the increase in the average life expectancy. While
many studies have suggested that industrial chemicals and pesticides may underlie [PD, its
etiology remains elusive. Among the toxic metals, the relationship between manganese
intoxication and IPD has long been recognized. The neurological signs of manganism have
received close attention because they resemble several clinical disorders collectively described
as extrapyramidal motor system dysfunction, and in particular, IPD and dystonia. However,
distinct dissimilarities between IPD and manganism are well established, and it remains to be
determined whether Mn plays an etiologic role in IPD. It is particularly noteworthy that as a
result of a recent court decision, methylcyclopentadienyl Mn tricarbonyl (MMT) is presently
available in the United States and Canada for use in fuel, replacing lead as an antiknock additive.
The impact of potential long-term exposure to low levels of MMT combustion products that may
be present in emissions from automobiles has yet to be fully evaluated. Nevertheless, it should
be pointed out that recent studies with Various environmental modeling approaches in the
Montreal metropolitan (where MMT has been used for more than 10 years) suggest that airborne
Mn revels were quite similar to those in areas where MMT was not used. These studies also
show that Mn is emitted from the tail pipe of motor vehicles primarily as a mixture of manganese
phosphate and manganese sulfate. This brief review characterizes the Mn speciation in the blood
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and the transport kinetics of Mn into the central nervous system, a critical step in the
accumulation of Mn within the brain, outlines the potential susceptibility of selected populations
(e.g., iron-deficient) to Mn exposure, and addresses future research needs for Mn.
8. Aschner M, Vrana KE, Zheng W. (1999) Manganese uptake and distribution in the central
nervous system (CNS). Neurotoxicology 20(2-3): 173-180.
Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its
transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have
focused on distribution, excretion, and accumulation of intravenous and intraperitoneal solutions
of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation
state (Mn2+) and crosses the BBB via specific carriers ata rate far slower than in other tissues.
Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn
accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme,
glutamine synthetase (GS) represents an important regulatory target of Mn. Compared to Mn2+,
Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in
tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron
(Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential
distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in
experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn
emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to
endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying
protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and
3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the
transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.
(C) 1999 Inter Press, Inc.
9. Boojar MMA, Goodarzi F, Basedaghat MA. (2002) Long-term follow-up of workplace and
well water manganese effects on iron status indexes in manganese miners. Archives of
Environmental Health 57(6):519-528.
The authors assessed the effect of water reconstitution in the workplace by evaluating the iron
status of manganese mine workers during a long-term study. Subsequent analyses and biological
monitoring were performed in a group of 150 manganese miners before, and 2.8 yr after,
reconstitution of drinking water in the miners' workplace. The authors found significantly high
concentrations of manganese in the workplace well water, as well as in the miners' blood, urine,
and hair. There was a considerable prevalence of epithelial lesions, which resulted from iron
deficiency, in the miners, compared with controls. The authors assessed the prevalence of iron
deficiency grades (i.e., I > II > III > IV) before and after water reconstitution. Reconstitution of
drinking water for the ultimate attainment of healthy levels of manganese and other minerals
resulted in a significant improvement in the miners' iron status and a decreased prevalence of
epithelial lesions. The authors concluded that alterations in iron status may result from the
cumulative effect of high levels of manganese in consumed water, as well as in airborne dust, in
the workplace. Such elevated levels should be considered as an occupational hazard because they
have an ability to interfere with iron absorption.
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10. Bouchard M, Mergler D, Baldwin M, Sassine MP, Bowler R, MacGibbon B. (2003) Blood
manganese and alcohol consumption interact on mood states among manganese alloy production
workers. Neurotoxicology 24(4-5):641-647.
Long-term exposure to manganese (Mn) can induce neurotoxic effects including neuromotor,
neurocognitive and neuropsychiatric effects, but there is a great interpersonal variability in the
occurrence of these effects. It has recently been suggested that blood Mn (MnB) may interact
with alcohol use disorders, accentuating neuropsychiatric symptoms. The objective of the
present study was to explore a possible interaction between alcohol consumption and MnB on
mood states, using an existing data set on Mn exposed workers. Respirable Mn exposure in the
plant averaged 0.23 mg/m(3) and was correlated with MnB. All participants for whom all data on
MnB concentration and mood (assessed with the Profile of Mood States (POMS)) were available
and who reported currently drinking alcohol were included in the analyses (n = 74). Workers
were grouped according to their MnB concentration (<10 and greater than or equal to 10 mug/1)
and alcohol consumption (<400 and greater than or equal to400 g per week). Two-way ANOVAs
were performed on each POMS scale and Mann-Whitney tests were used to assess group
differences. Workers in the higher alcohol consumption group had higher scores on three POMS
scales: tension, anger and fatigue. There was no difference for POMS scale scores between MnB
subgroups. Dividing the group with respect to alcohol consumption and MnB showed that the
group with high alcohol consumption and high MnB displayed the highest scores. In the lower
MnB category, those in the higher alcohol consumption group did not have higher scores than
the others. The interaction term for alcohol consumption and MnB concentration was statistically
significant (P < 0.05) for the depression, anger fatigue and confusion POMS scales. There was a
tendency for tension (P < 0.06), and it was not significant for vigor. This study shows the first
evidence of an interaction between MnB and alcohol consumption on mood states among Mn
exposed workers and supports the results from a previous population-based study. (C) 2003
Elsevier Science Inc. All rights reserved.
11. Bressler JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D. (2007) Metal transporters
in intestine and brain: their involvement in metal-associated neurotoxicities. Human &
Experimental Toxicology 26(3):221-229.
The transport of essential metals and other nutrients across tight membrane barriers such as the
gastrointestinal tract and blood-brain barrier is mediated by specific transport mechanisms.
Specific transporters take up metals at the apical surface and export them at the basolateral
surface, and are involved in their intracellular distribution. Transporters for each of the major
essential metals, calcium, iron and zinc, have been identified. These transporters also mediate the
transport of non-essential metals across tight membrane barriers. For example, the intestinal iron
transporter divalent metal transporter 1 mediates the uptake of lead and cadmium. The levels of
essential metals are strictly regulated by transporters. When dietary levels of essential metals are
low, levels of the corresponding transporters increase in the intestine, after which there is a
greater potential for increased transport of toxic metals. In the brain, the strict regulation of
metals prevents injury that potentially would result from oxidative damage induced by the
essential metals iron, copper and zinc. Indeed, the oxidative damage found in neurodegenerative
diseases is likely to be due to higher levels of these metals. Involvement of intracellular
transporters for copper and zinc has been shown in animal models of Alzheimer's disease, raising
the possibility that higher levels of iron, zinc and copper might be due to a disruption in the
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activity of transporters. Accordingly, exposure to toxicants that affect the activity of transporters
potentially could contribute to the aetiology/progression of neurodegenerative diseases.
12. Bukalis K, Kyriakopoulos A, Alber D, Richarz AN, Behne D. (2006) Study on the
distribution of trace elements and trace element-containing proteins in the lung of the rat. Trace
Elements and Electrolytes 23(2): 108-112.
The concentrations of arsenic, chromium, cobalt, iron, manganese, rubidium, selenium and zinc
were determined by instrumental neutron activation analysis (INAA) in the homogenate and the
subcellular fractions of lungs from rats fed either a selenium-adequate or a selenium-deficient
diet. Feeding of the selenium-deficient diet led to a considerable decrease in the selenium levels
in all samples investigated but had no significant effect on the concentrations of the other
elements. All elements were distributed inhomogeneously among the subcellular fractions.
Selenium, iron and zinc had their highest concentrations in the microsomal fraction, chromium
and cobalt in the nuclear fraction and arsenic and rubidium in the cytosol. Information about the
trace element-containing proteins in the lung cytosol was obtained by size exclusion
chromatography and online multi-element analysis of the separated protein fractions by mass
spectrometry in conjunction with an inductively coupled plasma (ICP-MS). The results
suggested that arsenic, cadmium, cobalt, copper, iron, manganese, molybdenum, nickel,
selenium and zinc are present in the rat lung cytosol in several protein-bound forms.
13. Chaki H, Furuta S, Matsuda A, Yamauchi K, Yamamoto K, Kokuba Y, Fujibayashi Y.
(2000) Magnetic resonance image and blood manganese concentration as indices for manganese
content in the brain of rats. Biological Trace Element Research 74(3):245-257.
Neurological disorders similar to parkinsonian syndrome and signal hyperintensity in brain on
Tl-weighted magnetic resonance (MR) images have been reported in patients receiving long-
term total parenteral nutrition (TPN). These symptoms have been associated with manganese
(Mn) depositions in brain. Although alterations of signal intensity on T-l-weighted MR images
in brain and of Mn concentration in blood are theoretically considered good indices for
estimating Mn deposition in brain, precise correlations between these parameters have not been
demonstrated as yet. Male Sprague-Dawley rats received TPN with 10-fold the clinical dose of
the trace element preparation (TE-5) for 7 d. At 0, 2, 4, 6, and 8 wk post-TPN, the cortex,
striatum, midbrain, and cerebellum were evaluated by MR images, and Mn concentration in
blood and Mn content in these brain sites were measured by atomic absorption spectrometry.
Immediately after TPN termination, signal hyperintensity in brain sites and elevated Mn content
in blood and brain sites were observed. These values recovered at 4 wk post-TPN. A positive
correlation was observed between either the signal intensity in certain brain sites or Mn content
in blood and the relevant brain sites.
14. Chen GT, Zhao L, Bao SF, Cong T. (2006) Effects of different proteins on the metabolism
of Zn, Cu, Fe, and Mn in rats. Biological Trace Element Research 113(2): 165-175.
Many factors are known to influence trace element metabolism and one of them is dietary
protein. The present study examines the effects of casein, soybean protein, and peanut protein on
the metabolism of the Zn, Cu, Fe, and Mn in growing rats. The results showed that Zn, Fe, and
Mn excretions in the feces of peanut protein-fed rats (PPERs) were similar to that of casein-fed
rats (CPFRs) (p > 0.05), whereas all of the Zn, Cu, Fe, and Mn excretions in the urine of PPFRs
were significantly higher than that of CPFRs (p < 0.05), but its apparent absorption rate (AAR)
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of Cu, Fe and its apparent retention rate (ARR) of Cu were all higher than that of CPFRs (p <
0.05). Hepatic Zn content of soybean protein-fed rats (SPFRs) was higher than that of CPFRs
and PPFRs (p < 0.05 respectively) and serum, renal, and femoral Cu contents of SPFRs were
significantly lower; however, hepatic Cu, and renal Mn contents were significantly higher than
that of CPFRs (p < 0.05, respectively); The hepatic Fe content of SPFRs was significantly higher
than that of CPFRs and PPFRs (p < 0.01, respectively). To sum up, compared to casein, soybean
protein might be a good dietary source to make up for Zn and Fe deficiency, and also peanut
protein to make up for Cu and Fe deficiency.
15. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
The aim of this study was to investigate the effects of chronic, daily, 30-d administration of
manganese chloride (MnC12) to male Sprague-Dawley rats on lipid peroxidation in various
tissues. Rats were intraperitoneally injected with MnC12 (20 mg/kg) once daily for 30
consecutive days. The Mn accumulated in liver, spleen, adrenal glands, heart, kidneys, lung, and
testes. This was associated with decreased lipid peroxidation in liver, spleen, and adrenal glands
and a decrease in the levels of Fe in these tissues. In a second group of animals, Mn (20
mg/kg/d) and glutathione (GSH, 15 mg/kg/d) were administered ip for 30 d. GSH counteracted
the Mn-induced protective fall in lipid peroxidation, but Fe levels remained lower in liver and
spleen. Mn decreases lipid peroxidation in certain tissues, which may involve lowering Fe
content, but interaction with Fe is not the sole mechanism.
16. Chua ACG, Stonell LM, Savigni DL, Morgan EH. (1996) Mechanisms of manganese
transport in rabbit erythroid cells. Journal of Physiology-London 493(1):99-112.
1. The mechanisms of manganese transport into erythroid cells were investigated using rabbit
reticulocytes and mature erythrocytes and Mn-54-labelled MnC12 and Mn-2-transferrin. In some
experiments iron uptake was also studied. 2. Three saturable manganese transport mechanisms
were identified, two for Mn2+ (high and low affinity processes) and one for transferrin-bound
manganese (Mn-Tf). 3. High affinity Mn2+ transport occurred in reticulocytes but not
erythrocytes, was active only in low ionic strength media such as isotonic sucrose and had a K-m
of 0.4 mu M. It was inhibited by metabolic inhibitors and several metal ions. 4. Low affinity
Mn2+ transport occurred in erythrocytes as well as in reticulocytes and had K-m values of
approximately 20 and 50 mu M for the two types of cells, respectively. The rate of Mn2+
transport was maximal in isotonic KC1, RbCl or CsCl, and was inhibited by NaCl and by
amiloride, valinomycin, diethylstilboestrol and other ion transport inhibitors. The direction of
Mn2+ transport was reversible, resulting in Mn2+ efflux from the cells. 5. The uptake of
transferrin-bound manganese occurred only with reticulocytes and depended on receptor-
mediated endocytosis of Mn-Tf. 6. The characteristics of the three saturable manganese transport
mechanisms were similar to corresponding mechanisms of iron uptake by erythroid cells,
suggesting that the two metals are transported by the same mechanisms. 7. It is proposed that
high affinity manganese transport is a surface representation of the process responsible for the
transport of manganese across the endosomal membrane after its release from transferrin. Low
affinity transport probably occurs by the previously described Na+ - Mg2+ antiport, and may
function in the regulation of intracellular manganese concentration by exporting manganese from
the cells.
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17. Crossgrove JS, Yokel RA. (2004) Manganese distribution across the blood-brain barrier III -
The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake.
Neurotoxicology 25(3):451-460.
Manganese (Mn) is essential for and toxic to the brain. Brain Mn uptake utilizes both diffusion
and transporter-mediated pathways. The divalent metal transporter-1 (DMT-1) has been
suggested to mediate brain Mn uptake. The b/b Belgrade rat does not express significant
amounts of functional DMT-1. In the present work, brain influx transfer coefficients of Mn-54
ion and Mn-54 transferrin (Mn Tf) were determined in b/b and +/b Belgrade and Wistar rats
using the in situ brain perfusion technique. Brain Mn uptake was not significantly different
among the three rat strains for either Mn species. We hypothesized that Mn may enter brain
endothelial cells by a DMT-1-independent process but not be able to distribute across those cells
into brain tissue due to the absence of DMT-1 activity. To test this hypothesis the brain capillary
endothelial cells were isolated from b/b and +/b Belgrade rats and Wistar rats after in situ brain
perfusion. Some animals received cerebrovascular washout after in situ brain perfusion to
ascertain any affect of genotype on Mn-54 adsorption to the endothelial cell luminal surface.
Less than 30% of the brain Mn-54 after Mn-54 ion or Mn-54 Tf perfusion remained associated
with endothelial cells, suggesting the majority had distributed into brain extracellur fluid (ECF)
and/or brain cells. Mn appears to distribute across the rat blood-brain barrier (BBB) into the
brain by one or more carrier-mediated processes other than the DMT-1. (C) 2003 Elsevier Inc.
All rights reserved.
18. Erikson KM, Aschner M. (2006) Increased manganese uptake by primary astrocyte cultures
with altered iron status is mediated primarily by divalent metal transporter. Neurotoxicology
27(1): 125-130.
Neurotoxicity due to excessive brain manganese (Mn) accumulation can occur via occupational
exposure to aerosols or dusts that contain extremely high levels (>1-5 mg Mn/m(3)) of Mn, or
metabolic aberrations (decreased biliary excretion). Given the putative role of astrocytes in
regulating the movement of metals across the blood-brain barrier, we sought to examine the
relationship between iron (Fe) status and Mn transport in astrocytes. Furthermore, our study
examined the effect of Fe status on astrocytic transferrin receptor (TfR) and divalent metal
transporter (DMT1) levels and their relationship to Mn uptake, as both have been implicated as
putative Mn transporters. All experiments were carried out in primary astrocyte cultures derived
from neonatal rats when the cells reached full confluency (about three weeks in culture).
Astrocytes were incubated for 24 h in astrocyte growth medium (AGM) containing 200 mu M
desferoxamine (11)), 500 mu M ferrous sulfate (+Fe), or no compound (CN). After 24 h, 5 min
Mn-54 uptake was measured and protein was harvested from parallel culture plates for DMT-1
and TfR immunoblot analysis. Both iron deprivation (ID) and iron overload (+Fe) caused
significant increases (p < 0.05) in 54 Mn uptake in astrocytes. TfR levels were significantly
increased (p < 0.05) due to ID and decreased in astrocytes exposed to +Fe treatments. As
expected, DMT-1 was increased due to Fe deprivation, but surprisingly, DMT-1 levels were also
increased due to +Fe treatment, albeit not to the extent noted in ID. The decreased TfR
associated with +Fe treatment and the increased DMT-1 levels suggest that DMT-1 is a likely
putative transporter of Mn in astrocytes. (C) 2005 Elsevier Inc. All rights reserved.
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19. Erikson KM, John CE, Jones SR, Aschner M. (2005) Manganese accumulation in striatum
of mice exposed to toxic doses is dependent upon a functional dopamine transporter.
Environmental Toxicology and Pharmacology 20(3):390-394.
The objective of this study was to determine the importance of the dopamine transporter (DAT)
in manganese transport. Excessive manganese exposure is associated with a neurotoxicological
disease known as manganism characterized by a specific accumulation of manganese in
dopamine-rich brain regions. It has been hypothesized that the DAT mediates this specific
transport, but its role in manganese neurotoxicity has not been directly examined. We examined
brain tissues from manganese-ex posed dopamine transporter knockout (DAT-KO) and wildtype
(WT) mice. There was significantly less (p < 0.05) manganese in the striatum of exposed DAT-
KO mice compared to WT. However, the absence of a functioning DAT did not affect
manganese accumulation in other brain regions examined. Furthermore, both iron and divalent
metal transporter levels (two known modulators of brain manganese) were similar between
DAT-KO and WT mice in all brain regions. These studies demonstrate that the DAT is involved
in the facilitation of striatal manganese accumulation and that it may play a critical role in
mediating manganese neurotoxicity, (c) 2005 Elsevier B.V. All rights reserved.
20. Finley JW. (1998) Manganese uptake and release by cultured human hepato-carcinoma
(Hep-G2) cells. Biological Trace Element Research 64(1-3): 101-118.
The liver is the primary organ involved in manganese (Mn) homeostasis. The human hepato-
carcinoma cell line, Hep-G2, shows many liver specific functions. Consequently, Hep-G2 cells
were investigated as a possible model of hepatic metabolism of Mn. Initial experiments showed
that the concentration of Mn in the diet, or culture medium, similarly affected the retention of
Mn by isolated rat hepatocytes and Hep-G2 cells. Manganese uptake by Hep-G2 cells suggested
that uptake was followed by release from the cell. Uptake was saturable and half-maximal at 2.0
mu mol Mn/L, and was inhibited by iodoacetate, vanadate, cold, and bepridil. The cations Fe2+,
Cu2+ Ni2+, Cd2+, and Zn2+ decreased Mn uptake. Uptake was dependent on Calcium (Ca)
concentration in a manner that resembled saturation kinetics. Cells that were pulsed with Mn-54
and then placed into nonradioactive medium quickly released a large portion of their internalized
Mn. Release of internalized Mn could be inhibited by low temperature, nocodozole, quinacrine
and sodium azide. These data show that Hep-G2 cells are a potentially good model of hepatic
Mn metabolism. Mn is taken up by a facilitated process that may be related to Ca uptake.
Release apparently is an active, controlled process, that may involve microtubules and
lysosomes.
21. Finley JW, BriskeAnderson M, Gregoire B. (1996) Metabolism of manganese by isolated rat
hepatocytes and by the Hep-G2 cell line. Faseb Journal 10(3):4736-4736.
22. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2005) Manganese transport by rat brain
endothelial (RBE4) cell-based transwell model in the presence of astrocyte conditioned media.
Journal of Neuroscience Research 81(2):235-243.
Manganese (Mn), an essential nutrient, is neurotoxic at high levels and has been associated with
the development of a parkinsonian syndrome termed manganism. Currently, the mechanisms
responsible for transporting Mn across the blood-brain barrier (BBB) are unknown. By using rat
brain endothelial 4 (RBE4) cell monolayers cultured in astrocyte-conditioned media (ACM), we
examine the effects of temperature, energy, proton (pH), iron (Fe), and sodium (Na+)
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dependence on Mn transport. Our results suggest that Mn transport is temperature, energy, and
pH dependent, but not Fe or Na+-dependent. These data suggest that Mn transport across the
BBB is an active process, but they also demonstrate that the presence of ACM in endothelial cell
cultures decreases the permeability of these cells to Mn, reinforcing the use of ACM or astrocyte
cocultures in studies examining metal transport across the BBB. (c) 2005 Wiley-Liss, Inc.
23. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2006) Characteristics of manganese
(Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier.
Neurotoxicology 27(l):60-70.
Manganese (Mn), an essential elemental nutrient, is known to be neurotoxic at high occupational
levels. We examined the transport of Mn across a monolayer of rat brain endothelial cell (RBE4)
to evaluate whether an electromotive permeability mechanism is responsible for Mn transport
across the blood-brain barrier (BBB). The Mn-54(2+) apparent permeability and flux showed
significant temperature-, energy- and pH-dependence, as well as partial sodium-dependence.
Additionally, iron (Fe)-rich and Fe-deficient media significantly increased the apparent
permeability of Mn-54(2+). Finally, Mn flux and permeability decreased when RBE4 cells were
grown in astrocyte-conditioned media (ACM), compared to standard alpha-media. These data
reinforce observations that transport of Mn across the BBB occurs in part through active
transport process. (C) 2005 Elsevier Inc. All rights reserved.
24. Fitsanakis VA, Piccola G, dos Santos AP, Aschner JL, Aschner M. (2007) Putative proteins
involved in manganese transport across the blood-brain barrier. Human & Experimental
Toxicology 26(4):295-302.
Manganese (Mn) is an essential nutrient required for proper growth and maintenance of
numerous biological systems. At high levels it is known to be neurotoxic. While focused
research concerning the transport of Mn across the blood-brain barrier (BBB) is on-going, the
exact identity of the transporteds) responsible is still debated. The transferrin receptor (TfR) and
the divalent metal transporter-1 (DMT-1) have long been thought to play a role in brain Mn
deposition. However, evidence suggests that Mn may also be transported by other proteins. One
model system of the BBB, rat brain endothelial (RBE4) cells, are known to express many
proteins suspected to be involved in metal transport. This review will discuss the biological
importance of Mn, and then briefly describe several proteins that may be involved in transport of
this metal across the BBB. The latter section will examine the potential usefulness of RBE4 cells
in characterizing various aspects of Mn transport, and basic culture techniques involved in
working with these cells. It is hoped that ideas put forth in this article will stimulate further
investigations into the complex nature of Mn transport, and address the importance as well as the
limitation of in vitro models in answering these questions.
25. Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N. (1997) Accumulation of manganese
in the brain of mice after intravenous injection of manganese-based contrast agents. Chemical
Research in Toxicology 10(4):360-363.
Because the manganese-based contrast agents used in magnetic resonance imaging are unstable
in vivo, some concern exists about the potential toxicity coming from the Mn2+ released by the
complexes. This potential problem arises because the manganese is known to accumulate in the
brain of people intoxicated by this metal (manganism): this central accumulation leads to
neurological disorders (i.e., parkinsonism-like syndrome). The aim of this study was to assess
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the amount of Mn found in the brain after administration of MnC12 or different chelates of Mn in
normal mice as well as in mice with impaired biliary elimination. Male NMRI mice received an
intravenous injection in a caudal vein of 5 mu mol/kg of Mn-54 compounds as MnC12,
manganese-diethylenetriaminepentaacetate (Mn-DTPA), or manganese-dipyridoxal diphosphate
(Mn-DPDP). The radiolabeled complexes (1:1) were prepared by direct chelation (Mn-DTPA) or
transchelation of preformed complex (Mn-DPDP), and the radiochemical purity was assessed by
paper chromatography. The mice were killed at various times post-exposure (0-3 months), and
the radioactivity present in the organs was determined by gamma counting. For each compound
analyzed in the present study, we observed an accumulation of Mn (0.25-0.3% of the amount
injected/g of tissue) in the mouse brain, reaching a plateau after 24 h, while the Mn content in the
liver was decreasing with time. The amount of Mn accumulated in the brain remained unchanged
1 month later, but decreased to 40% of the maximum amount 3 months after the exposure. In
mice whose bile ducts had been ligated 24 h before the administration of the manganese
compound, we observed, 1 week after the injection, an amount of manganese accumulated in the
brain 2 times higher than in normal mice.
26. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG,
Hainsworth LN, Umbreit JN, Conrad ME and others. (2003) DMT1: A mammalian transporter
for multiple metals. Biometals 16(l):41-54.
DMT1 has four names, transports as many as eight metals, may have four or more isoforms and
carries out its transport for multiple purposes. This review is a start at sorting out these
multiplicities. A G185R mutation results in diminished gastrointestinal iron uptake and
decreased endosomal iron exit in microcytic mice and Belgrade rats. Comparison of mutant to
normal rodents is one analytical tool. Ectopic expression is another. Antibodies that distinguish
the isoforms are also useful. Two mRNA isoforms differ in the 3' UTR: + IRE DMT1 has an IRE
(Iron Responsive Element) but -IRE DMT1 lacks this feature. The +/- IRE proteins differ in the
distal 18 or 25 amino acid residues after shared identity for the proximal 543 residues. A major
function is serving as the apical iron transporter in the lumen of the gut. The + IRE isoform
appears to have that role. Another role is endosomal exit of iron. Some evidence indicts the -IRE
isoform for this function. In our ectopic expression assay for metal uptake, four metals -
Fe2+,Mn2+,Ni2+ and Co2+ - respond to the normal DMT1 cDNA but not the G185 R mutant.
Two metals did not - Cd2+ and Zn2+ -andtwo -Cu2+ and Pb2+ -remain to be tested. In
competition experiments in the same assay, Cd2+,Cu2+ and Pb2+ inhibit Mn2+ uptake but Zn2+
did not. In rodent mutants, Fe and Mn appear more dependent on DMT1 than Cu and Zn.
Experiments based on ectopic expression, specific antibodies that inhibit metal uptake and
labeling data indicate that Fe3+ uptake depends on a different pathway in multiple cells. Two
isoforms localize differently in a number of cell types. Unexpectedly, the -IRE isoform is in the
nuclei of cells with neuronal properties. While the function of -IRE DMT1 in the nucleus is
speculative, one may safely infer that this localization identifies new role(s) for this
multifunctional transporter. Management of toxic challenges is another function related to metal
homeostasis. Airways represent a gateway tissue for metal entry. Preliminary evidence using
specific PCR primers and antibodies specific to the two isoforms indicates that -IRE mRNA and
protein increase in response to exposure to metal in lungs and in a cell culture model; the + IRE
form is unresponsive. Thus the -IRE form could be part of a detoxification system in which +
IRE DMT1 does not participate. How does iron status affect other metals' toxicity? In the case of
Mn, iron deficiency may enhance cellular responses.
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27. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
Mn2+ is sequestered by liver and brain mitochondria via the mitochondrial Ca2+ uniporter. The
mitochondrial Ca2+ uniporter is a cooperative transport mechanism possessing an external
activation site and a transport site. Ca2+ binding to the activation site greatly increases the
velocity of uptake of both Ca2+ and Mn2+. Electron paramagnetic resonance (EPR) shows that
over 97% of the Mn2+ in the mitochondrial matrix is normally bound to the membrane or to
matrix proteins. EPR measurements of manganese within living isolated mitochondria can be
repeat-ed for hours, and during this time most of the manganese remains in the Mn2+ state.
Mn2+ is transported out of mitochondria via the very slow Na+-independent efflux mechanism,
which is an active (energy-requiring) mechanism. Mn2+ is not significantly transported over the
Na+-dependent efflux mechanism, which is the dominant efflux mechanism in heart and brain
mitochondria. Mn2+ inhibits the efflux of Ca2+ through both of these efflux mechanisms, having
an apparent K-i of 7.9 nmol/mg protein on the Na+-independent efflux mechanism and an
apparent K-i of 5.1 nmol/mg on the Na+-dependent efflux mechanism. Mn2+ inhibition of Ca2+
efflux may increase the probability of the mitochondria undergoing the mitochondrial
permeability transition (MPT). Intramitochondrial Mn2+ also inhibits State 3 mitochondrial
respiration using either succinate or malate plus glutamate as substrate. The data suggest that
Mn2+ depletes cellular energy supplies by interfering with oxidative phosphorylation at the level
of the F(l)ATPase and at much higher concentrations, at Complex I. Effects such as these could
lead to apoptosis in active neurons. (C) 1999 Inter Press, Inc.
28. Harris WR. (2003) Modeling methods to determine A1 and Mn speciation for toxicity
assessment. Toxicological Sciences 72:117-117.
29. Heilig EA, Thompson KJ, Molina RM, Ivanov AR, Brain JD, Wessling-Resnick M. (2006)
Manganese and iron transport across pulmonary epithelium. American Journal of Physiology-
Lung Cellular and Molecular Physiology 290(6):L1247-L1259.
Pathways mediating pulmonary metal uptake remain unknown. Because absorption of iron and
manganese could involve similar mechanisms, transferrin (Tf) and transferrin receptor (TfR)
expression in rat lungs was examined. Tf mRNA was detected in bronchial epithelium, type II
alveolar cells, macrophages, and bronchus-associated lymphoid tissue (BALT). Tf protein levels
in lung and bronchoalveolar lavage fluid did not change in iron deficiency despite increased
plasma levels, suggesting that lung Tf concentrations are regulated by local synthesis in a
manner independent of body iron status. Iron oxide exposure upregulated Tf mRNA in bronchial
and alveolar epithelium, macrophages, and BALT, but protein was not significantly increased. In
contrast, TfR mRNA and protein were both upregulated by iron deficiency. To examine potential
interactions with lung Tf, rats were intratracheally instilled with Mn-54 or Fe-59. Unlike Fe-59,
interactions between Mn-54 and Tf in lung fluid were not detected. Absorption of intratracheally
instilled Mn-54 from the lungs to the blood was unimpaired in Belgrade rats homozygous for the
functionally defective G185R allele of divalent metal transporter-1, indicating that this
transporter is also not involved in pulmonary manganese absorption. Pharmacological studies of
Mn-54 uptake by A549 cells suggest that metal uptake by type II alveolar epithelial cells is
associated with activities of both L-type Ca2+ channels and TRPM7, a member of the transient
receptor potential melastatin subfamily. These results demonstrate that iron and manganese are
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absorbed by the pulmonary epithelium through different pathways and reveal the potential role
for nonselective calcium channels in lung metal clearance.
30. Kim Y, Park JK, Choi Y, Yoo CI, Lee CR, Lee H, Lee JH, Kim SR, Jeong TH, Yoon CS
and others. (2005) Blood manganese concentration is elevated in iron deficiency anemia patients,
whereas globus pallidus signal intensity is minimally affected. Neurotoxicology 26(1): 107-111.
Objectives: To determine whether blood manganese (Mn) concentration is elevated in patients
with iron deficiency anemia (IDA), and whether this affects signal intensities in the globus
pallidus. Methods: Twenty-seven patients with IDA and 10 control subjects were tested for
blood Mn, and brain magnetic resonance images (MRI) were also examined. Seventeen of the 27
patients were followed-up after iron therapy. Results: IDA patients had a mean blood Mn
concentration of 2.05 +/- 0.44 mug/dl, which was higher than controls. The mean pallidal index
(PI) of anemic patients was not different from that of controls. There was a correlation between
log blood Mn and PI (p = 0.384, P = 0.048; n = 27) in IDA patients. None of the patients showed
increased signals in the globus pallidus in Tl-weighted MRI Blood Mn levels decreased and
hemoglobin levels increased after iron therapy (P < 0.05). Conclusion: Although blood Mn is
elevated in IDA patients, there is no increase in globus pallidus MRI signal intensity. These
findings stand in contrast to those of our other studies showing patients with chronic liver
disease or occupational Mn exposure have elevated signal intensities remarkably. (C) 2004
Elsevier Inc. All rights reserved.
31. Kucera J, Bencko V, Sabbioni E, Vandervenne MT. (1995) Review of Trace-Elements in
Blood, Serum and Urine for the Czech and Slovak Populations and Critical-Evaluation of Their
Possible Use as Reference Values. Science of the Total Environment 166(1-3):211-234.
The availability of accurate trace element reference values in human tissues represents an
important indicator to the health status of the general population and occupational groups
exposed to trace elements. The EURO TERVIHT project (Trace Element Reference Values in
Human Tissues) aims to establish and compare trace element reference values in tissues from
inhabitants of the European countries as baseline values for clinical/toxicological assessment
studies [3], In this context, one of the first steps considered is the critical evaluation (state of the
art) of existing literature on trace element reference values in blood, serum and urine in the
general population of each European country. This paper reviews the Czech and Slovak situation
by assessing studies carried out in these countries for Al, As, Cd, Co, Cr, Cu, F, Mn, Hg, Ni, Pb,
Rb, Sc, Se, V and Zn in blood, serum and urine. These studies show that most of the data
available do not meet criteria designed recently for deriving reference intervals, especially
regarding the number of subjects, the age of population sample studies as well as the use of
appropriate sampling techniques and quality assurance procedures. Elements which present the
highest potential risk for health in Czech and Slovak populations and for which reference values
should be urgently established are: Cd, Hg, Pb (major pollutants); As, Cr, Ni (carcinogenic
metals); Al, F, Mn, Tl, V (released into the environment by coal combustion and other industrial
activities); Pt (increasing use of Pt catalyst in petrol-driven automobiles); essential trace
elements such as I, Se and Zn for which a deficiency in Czech and Slovak populations was
detected or is suspected.
32. Lai JCK, Minski MJ, Chan AWK, Leung TKC, Lim L. (1999) Manganese mineral
interactions in brain. Neurotoxicology 20(2-3):433-444.
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Manganese (Mn) is an essential mineral but is toxic when taken in excess. However, whether its
interactions with other minerals in organs and cells are involved in mechanisms underlying Mn
toxicity is poorly understood. We designed a developmental rat model of chronic Mn treatment
(Group A: 1 mg MnC12. 4H(2)0 per mi of drinking water; Group B: 10 mg MnC12. 4H(2)0 per
mi of drinking water; Group C: 20 mg MnC12. 4H(2)0 per mi of drinking water; Control Group
given water without manganese addition). Employing the model and instrumental neutron
activation analysis, we investigated two hypotheses: (i) chronic manganese treatment alters the
brain regional distribution of manganese and this altered manganese distribution also leads to
region-specific changes of other meta Is; (ii) chronic manganese treatment induces differential
changes in subcellular distributions of metals and electrolytes. In the treated rats, brain Mn level
showed dose-related increases, the most pronounced being noted in striatum, hypothalamus, and
hippocampus: these increases also led to alterations in regional distribution pattern of Mn. In the
treated rats, Fe level was increased in hypothalamus, cerebellum, hippocampus, pens and
medulla, and striatum. CLI level was increased in pens and medulla, hippocampus, midbrain,
and striatum. Se level was increased in cerebellum, striatum, midbrain, hypothalamus, and pens
and medulla. Zn level was increased in hypothalamus and striatum. Ca level was increased in
midbrain but decreased in cerebellum; however, Mg and A1 levels were not markedly affected, in
brains of fn-treated rats, Mn levels in subcellular fractions were all increased, being especially
marked in nuclei, mitochondria, and synaptosomes; the subcellular distributions of Fe, Cu, Zn,
and Mg were differentially altered although those of A1 and Ca were minimally affected. These
results are consistent with our hypotheses and may have implications in manganese
neurotoxicity. The cellular and molecular mechanisms underlying manganese-mineral
interactions in brain are still poorly defined and merit further investigation. (C) 1999 Inter Press,
Inc.
33. Li GJJ, Zhang LL, Lu L, Wu P, Zheng W. (2004) Occupational exposure to welding fume
among welders: Alterations of manganese, iron, zinc, copper, and lead in body fluids and the
oxidative stress status. Journal of Occupational and Environmental Medicine 46(3):241-248.
Welders in this study were selected from a vehicle manufacturer; control subjects were from a
nearby food factory. Airborne manganese levels in the breathing zones of welders and controls
were 1.45 +/- SD1.08 mg/m(3) and 0.11 +/- 0.07 mug/m(3), respectively. Serum levels of
manganese and iron in welders were 4.3-fold and 1.9-fold, respectively, higher than those of
controls. Blood lead concentrations in welders increased 2.5-fold, whereas serum zinc levels
decreased 1.2-fold, in comparison with controls. Linear regression revealed the lack of
associations between blood levels of five metals and welder's age. Furthermore, welders had
erythrocytic superoxide dismutase activity and serum malondialdehyde levels 24% less and 78%
higher, respectively, than those of controls. These findings suggest that occupational exposure to
welding fumes among welders disturbs the homeostasis of trace elements in systemic circulation
and induces oxidative stress.
34. Malecki EA, Cable EE, Connor JR. (2000) Short-term dietary manganese deficiency
increases intestinal expression of DMT-1. Faseb Journal 14(4):A229-A229.
35. Malecki EA, Cook BM, Devenyi AG, Beard JL, Connor JR. (1999) Transferrin is required
for normal distribution of Fe-59 and Mn-54 in mouse brain. Journal of the Neurological Sciences
170(2): 112-118.
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Hypotransferrinemia (hpx/hpx) is a genetic defect in mice resulting in <1% of normal plasma
transferrin (Tf) concentrations; heterozygotes for this mutation (+/hpx) have low circulating Tf
concentrations. These mice provide a unique opportunity to examine the role of Tf in Fe and Mn
transport in the brain. Twenty weanling wild-type BALB/cJ mice, 15 + /hpx mice, and 12
hpx/hpx mice of both sexes were injected i.v. with either (MnC12)-Mn-54, or (FeC13)-Fe-59
either 1 h or 1 week before killing at 12 weeks of age. Total brain counts of Mn-54 and Fe-59
were measured, and regional brain distributions were assessed by autoradiography.
Hypotransferrinemia did not affect total brain Mn uptake. However, 1 week after i.v. injection,
hpx/hpx mice had less Mn-54 in forebrain structures including cerebral cortex, corpus callosum,
striatum, and substantia nigra. The +/hpx mice had the highest total brain Fe-59 accumulation 1
h after i.v. injection. A striking effect of regional distribution of Fe-59 was noted I week after
injection; in hpx/hpx mice, Fe-59 was located primarily in choroid plexus, whereas in +/+ and
+/hpx mice Fe-59 was widely distributed, with relatively high amounts in cerebral cortex and
cerebellum. We interpret these data to mean that Tf is necessary for the transport of Fe but not
Mn across the blood-brain barrier, and that there is a Tf-independent uptake mechanism for iron
in the choroid plexus. Additionally, these data suggest that endogenous synthesis of Tf is
necessary for Fe transport from the choroid plexus. (C) 1999 Elsevier Science B.V. All rights
reserved.
36. Malecki EA, Devenyi AG, Connor JR. (1997) Manganese (Mn) transport in mice
heterozygotic for hypotransferrinemia mutation: Effects of iron (Fe) deficiency.
Gastroenterology 112(4):A891-A891.
37. Matsumoto K, Inagaki T, Hirunuma R, Enomoto S, Endo K. (2001) Contents and uptake
rates of Mn, Fe, Co, Zn, and Se in Se-deficient rat liver cell fractions. Analytical Sciences
17(5):587-591.
The contents of manganese (Mn), iron (Fe), cobalt (Co), zinc (Zn), and selenium (Se) in nuclear
(NU), mitochondrial (MT), microsomal (MC), and cytosolic (CS) fractions of liver homogenates
of normal and selenium-deficient (SeD) rats were determined by instrumental neutron activation
analysis (INAA). The uptake rates of these elements in the liver cell fractions of both groups of
rats were determined by multitracer analysis (MTA). The results indicated that Se-deficiency
caused a significant increase in the content of Fe in the MC fractions. The MTA showed that the
uptake rate of Fe was highest in the MC fraction, and that the uptake rate in the fraction was
similar between the SeD and normal rats.
38. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
Manganese (Mn) is ubiquitous in mammalian systems and is essential for proper development
and function, though it can also be toxic at elevated exposures. While essential biologic
functions of Mn depend on its oxidation state [e.g., Mn(II), Mn(III)], little is known about how
the oxidation state of elevated Mn exposures affect cellular uptake, and function/toxicity. Here
we report the dynamics of EPR measurable Mn(II) in fresh human plasma and cultured PC 12
cell lysates as a function of exposure to either manganese(II) chloride or manganese(III)
pyrophosphate, and the effects of exposure to Mn(II) versus Mn(III) on total cellular aconitase
activity and cellular Mn uptake. The results indicate that Mn(II) or Mn(III) added in vitro to
fresh human plasma or cell lysates yielded similar amounts of EPR measurable Mn(II). In
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contrast, Mn added as Mn(III) was significantly more effective in inhibiting total cellular
aconitase activity, and intact PC 12 cells accumulated significantly more Mn when exposures
occurred as Mn(III)., Collectively, these data reflect the dynamic nature of Mn speciation in
simple biological systems, and the importance of Mn oxidation/speciation state in mediating
potential cellular toxicity. This study supports concern over increased environmental exposures
to Mn in different oxidation states [Mn(II), Mn(III), and Mn(IV)] that may arise from
combustion products of. the gasoline antiknock additive methycyclopentadienyl manganese
tricarbonyl (MMT).
39. Slikker W, Keenan F. (1998) Toxicokinetics and bioavailability of manganese: Session II
summary and research needs. Neurotoxicology 19(3):475-478.
40. Takeda A, Devenyi A, Connor JR. (1998) Evidence for non-transferrin-mediated uptake and
release of iron and manganese in glial cell cultures from hypotransferrinemic mice. Journal of
Neuroscience Research 51(4):454-462.
Transferrin (Tf) is accepted as the iron mobilization protein, but its role in transport of other
metals is controversial, In this study, we used mixed glial cultures from hypotransferrinemic
(Hp) mice to determine the dependence of these cells on transferrin for iron and manganese
delivery and release, Hp mice have a splicing defect in the transferrin (Tf) gene, resulting in <
1% of the normal plasma levels of Tf, Cellular iron and manganese uptake increases over 24 hr
in cultures of normal and Hp glial cells in the presence of standard concentrations of Tf in the
media; although total (59)iron uptake in the Hp mouse cultures was 2X greater than normal, Mn-
54 uptake was similar between the two groups, The absence of Tf in the media resulted in a
significant increase in (59)iron uptake in both normal and Hp glial but did not affect Mn uptake,
Elevated Tf (10X normal) in the media reduced both (59)iron and Mn-54 uptake, Efflux of
(59)Iron and Mn-54 occurred in normal and Hp cultures, indicating the existence of a dynamic
exchange of metals, and that intracellular Tf is not necessary for metal release, However, in the
absence of Tf in the media, significantly more iron was retained in the cells than if Tf were
present in both normal and Hp glial cultures. Mn-54 release was minimally affected by
extracellular Tf. The data demonstrate that Tf is not required for iron and Mn uptake into glial
cells, These data further demonstrate a dynamic metal exchange system for glial cells which is
not dependent on intracellular Tf. (C) 1998 Wiley-Liss, Inc.
41. Tiffany-Castiglioni E, Qian YC. (2001) Astroglia as metal depots: Molecular mechanisms
for metal accumulation, storage and release. Neurotoxicology 22(5):577-592.
The brain is an organ that concentrates metals, and these metals are often localized to astroglia.
An examination of metal physiology of brain cells, particularly astroglia, offers insights into the
developmental neurotoxicity of certain metals, including lead (Pb), mercury (Hg), manganese
(Mn), and copper (Cu). Xenobiotic metals probably accumulate in cells by exploiting the normal
functions of proteins that transport and handle essential metals. In addition, essential metals may
become toxic by accumulating at levels that exceed the normal metal buffering capacity of the
cell. This review considers the uptake, accumulation, storage, and release of two xenobiotic
metals, Pb and Hg, as well as two essential nutrient metals that are neurotoxic in high amounts,
Mn and Cu. Evidence that each metal accumulates in astroglia is evaluated, together with the
mechanisms the host cell may invoke to protect itself from cytoxicity, (C) 2001 Elsevier Science
Inc. All rights reserved.
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42. Wang X, Li JG, Zheng W. (2005) Overexpression Of Dmtl In The Choroid Plexus
Following Manganese (Mn) Exposure. Toxicol Sci 84(1-S):122.
Divalent Metal Transporter 1 (DMT1), whose mRNA possesses a 3'-UTR stemloop structure,
has been identified in most organs and responsible for transport of various divalent metal ions.
Previous work from this laboratory has shown that Mn exposure alters the function of iron
regulatory protein (IRP) and increases iron (Fe) concentrations in blood-cerebrospinal fluid
(CSF). This study aimed to test the hypothesis that Mn treatment, by acting on protein-mRNA
binding between IRP and DMT1 mRNA, altered the expression of DMT 1 in the choroid plexus
(CP), where the blood-CSF barrier resides, leading to a compartmental shift of Fe from the blood
to CSF. Western blot and real time PCR confirmed the presence of DMT 1 in an immortalized
choroidal epithelial Z310 cell line. Following in vitro exposure to Mn at 100 |iM for 24 and 48
hrs, the expression of DMT1 mRNA in Z310 cells was significantly increased by 45.4% (p <
0.05) and 78.1% (p < 0.01), respectively, as compared to controls. Accordingly, Western blot
analysis revealed a significant increase of DMT 1 protein concentrations at 48 hr after Mn
exposure (100 |iM). When rats received, by oral gavage, 5 and 15 mg Mn/kg as MnC12 per day
for 30 consecutive days, the levels of DMT1 mRNA in choroids plexus tissues were significantly
increased by 258% and 305% (p < 0.05), respectively. An electrophoretic mobility shift assay
(EMSA), by using SI00 cytosolic extracts from both in vitro cells and in vivo brain tissues, was
conducted to investigate the effect of Mn exposure on the interaction between IRP and DMT1
mRNA. Results showed that Mn exposure increased binding of IRP to DMT1 mRNA in cultured
choroidal Z310 cells, in animal CP, as well as in selected brain tissues. These data suggest that
Mn appears to stabilize the binding of IRP to DMT1 mRNA, thereby increasing the expression
of DMTl. The facilitated transport of Fe by DMT1 at the blood-CSF barrier may partly
contribute to Mn-induced neurodegenerative Parkinsonism.
43. Yokel RA, Lasley SM, Dorman DC. (2006) The speciation of metals in mammals influences
their toxicokinetics and toxicodynamics and therefore human health risk assessment. Journal of
Toxicology and Environmental Health-Part B-Critical Reviews 9(l):63-85.
Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should
be considered to improve human health risk assessment. Factors that influence metal speciation
(and examples) include: (1) carrier-mediated processes for specific metal species (arsenic,
chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury),
(3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum,
arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic
species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum,
arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal
toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is
reviewed to illustrate how the physicochemical characteristics of metals and their handling in the
body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury,
arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences
mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal
speciation, uptake, and toxicity are evaluated. A classification system is presented to show that
the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics.
Essential metals, such as iron, are considered. These metals produce low oral toxicity under most
exposure conditions but become toxic when biological processes that utilize or transport them
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are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should
consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because
speciation can influence a metal's fate and toxicity, different exposure standards should be
established for different metal species. Many examples are provided which consider metal
essentiality and toxicity and that illustrate how consideration of metal speciation can improve the
risk assessment process. More examples are available at a website established as a repository for
summaries of the literature on how the speciation of metals affects their toxicokinetics.
44. Zheng W, Aschner M, Ghersi-Egea JF. (2003) Brain barrier systems: a new frontier in metal
neurotoxicological research. Toxicology and Applied Pharmacology 192(1): 1-11.
The concept of brain barriers or a brain barrier system embraces the blood-brain interface,
referred to as the blood-brain barrier, and the blood-cerebrospinal fluid (CSF) interface, referred
to as the blood-CSF barrier. These brain barriers protect the CNS against chemical insults, by
different complementary mechanisms. Toxic metal molecules can either bypass these
mechanisms or be sequestered in and therefore potentially deleterious to brain barriers.
Supportive evidence suggests that damage to blood-brain interfaces can lead to chemical-
induced neurotoxicities. This review article examines the unique structure, specialization, and
function of the brain barrier system, with particular emphasis on its toxicological implications.
Typical examples of metal transport and toxicity at the barriers, such as lead (Pb), mercury (Hg),
iron (Fe), and manganese (Mn), are discussed in detail with a special focus on the relevance to
their toxic neurological consequences. Based on these discussions, the emerging research needs,
such as construction of the new concept of blood-brain regional barriers, understanding of
chemical effect on aged or immature barriers, and elucidation of the susceptibility of tight
junctions to toxicants, are identified and addressed in this newly evolving field of
neurotoxicology. They represent both clear challenges and fruitful research domains not only in
neurotoxicology, but also in neurophysiology and pharmacology. (C) 2003 Elsevier Science
(USA). All rights reserved.
45. Zheng YX, Chan P, Pan ZF, Shi NN, Wang ZX, Pan J, Liang HM, Niu Y, Zhou XR, He FS.
(2002) Polymorphism of metabolic genes and susceptibility to occupational chronic manganism.
Biomarkers 7(4):337-346.
In this study we investigated genetic polymorphisms of five metabolizing genes and their
association with occupational chronic manganism. We recruited 49 patients with chronic
manganism and 50 unrelated healthy control subjects who were welders and ferromanganese
smelters and occupationally exposed to manganese dust and fume in the same workshops from
three metallurgical industries. The controls were matched to the cases by sex, age, cigarette and
alcohol intake, as well as the manganese exposure duration. Polymerase chain reaction-
restriction fragment length polymorphism (PCR-RFLP) was used to genotype the cytochrome
P450 2D6L gene (CYP2D6L) and the NAD(P) H: quinone oxidoreductase gene (NQOl). Allele-
specific PCR was used to detect the cytochrome P450 1A1 gene (CYP1 Al), and the glutathione-
S-transferase mu and theta genes (GSTM and GSTT). The frequency of polymorphic alleles, a
mutation of CYP2D6L, was significantly lower in patients with chronic manganism (16.3%)
than in controls (29.0%). Individuals with the homozygote polymorphism (L/L) of CYP2D6 had
a 90% decreased risk of chronic manganism compared with the wild-type (Wt/Wt) (odds ratio
=0.10, 95% confidence interval =0.01-0.82). A significant association between the CYP2D6
genotype subgroup and the latency of chronic manganese poisoning was also found. Patients
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who had homozygous (L/L) or heterozygous (Wt/L) mutant alleles developed manganism an
average of 10 years later than those who were homozygous wildtype (Wt/Wt). However, the
allele and genotype frequencies of CYP1A1 and NQOl genes were distributed similarly in cases
and controls. In addition, no difference in the frequencies of GSTM1 and GSTT1 null genotypes
were observed between cases and controls. The results suggest that CYP2D6L gene
polymorphism might influence susceptibility to manganese-induced neurotoxicity. However,
because of limited sample size, our results should be validated in large-scale studies.
3.2 PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
Key References (7)
1. Andersen ME, Gearhart JM, Clewell HJ. (1999) Pharmacokinetic data needs to support risk
assessments for inhaled and ingested manganese. Neurotoxicology 20(2-3): 161-171.
Manganese (Mn)-deficiency or Mn-excess can lead to adverse biological consequences. Central
nervous system tissues, rich in dopaminergic neurons, are the targets whether the Mn gains
entrance by inhalation, oral ingestion, or intravenous administration. Risk assessments with Mn
need to ensure that brain concentrations in the globus pallidus and striatum stay within the range
of normal. This paper first provides a critical review of the biological factors that determine the
disposition of Mn in tissues within the body. Secondly, it outlines specific data needs for
developing a physiologically based pharmacokinetic (PBPK) model for Mn to assist in
conducting risk assessments for inhaled and ingested Mn. Uptake of dietary Mn appears to be
controlled by several dose-dependent processes: biliary excretion, intestinal absorption, and
intestinal elimination. Mn absorbed in the divalent form from the gut via the portal blood is
complexed with plasma proteins that are efficiently removed by the liver. Absorption of Mn via
inhalation, intratracheal instillation or intravenous infusions bypasses the control processes in the
gastrointestinal tract. After absorption into the blood system by these alternate routes, Mn is
apparently oxidized by ceruloplasmin and the trivalent Mn binds to the iron carrying protein,
transferrin. Brain uptake of Mn occurs via transferrin receptors located in various brain regions.
Transferrin-bound trivalent Mn is not as readily removed by the liver, as are protein complexes
with divalent Mn. Thus, Mn delivered by these other dose routes would be available for uptake
into tissues for a longer period of time than the orally administered Mn, leading to quantitative
differences in tissue uptake for different dose routes. Several important data gaps impede
organizing these various physiological factors into a multi-dose route PK model for Mn. They
include knowledge of (1) oxidation rates of Mn in blood, (2) uptake rates of protein-bound forms
of Mn by the liver, (3) neuronal transfer rates within the CNS, and (4) quantitative analyses of
the control processes that regulate uptake of ingested Mn by the intestines and liver. These data
gaps are the main obstacles to developing a risk assessment strategy for Mn that considers
contributions of both inhalation and ingestion of this essential nutrient in determining brain Mn
concentrations. (C) 1999 Inter Press, Inc.
2. Aschner M, Erikson KM, Dorman DC. (2005) Manganese dosimetry: Species differences and
implications for neurotoxicity. Critical Reviews in Toxicology 35(1): 1-32.
Manganese (Mn) is an essential mineral that is found at low levels in food, water, and the air.
Under certain high-dose exposure conditions, elevations in tissue manganese levels can occur.
Excessive manganese accumulation can result in adverse neurological, reproductive, and
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respiratory effects in both laboratory animals and humans. In humans, manganese-induced
neurotoxicity (manganism) is the overriding concern since affected individuals develop a motor
dysfunction syndrome that is recognized as a form of parkinsonism. This review primarily
focuses on the essentiality and toxicity of manganese and considers contemporary studies
evaluating manganese dosimetry and its transport across the blood-brain barrier, and its
distribution within the central nervous system (CNS). These studies have dramatically improved
our understanding of the health risks posed by manganese by determining exposure conditions
that lead to increased concentrations of this metal within the CNS and other target organs. Most
individuals are exposed to manganese by the oral and inhalation routes of exposure; however,
parenteral injection and other routes of exposure are important. Interactions between manganese
and iron and other divalent elements occur and impact the toxicokinetics of manganese,
especially following oral exposure. The oxidation state and solubility of manganese also
influence the absorption, distribution, metabolism, and elimination of manganese. Manganese
disposition is influenced by the route of exposure. Rodent inhalation studies have shown that
manganese deposited within the nose can undergo direct transport to the brain along the
olfactory nerve. Species differences in manganese toxicokinetics and response are recognized
with nonhuman primates replicating CNS effects observed in humans while rodents do not.
Potentially susceptible populations, such as fetuses, neonates, individuals with compromised
hepatic function, individuals with suboptimal manganese or iron intake, and those with other
medical states (e.g., pre-parkinsonian state, aging), may have altered manganese metabolism and
could be at greater risk for manganese toxicity.
3. Dorman DC, Struve MF, Clewell HJ, Andersen ME. (2006) Application of pharmacokinetic
data to the risk assessment of inhaled manganese. Neurotoxicology 27(5):752-764.
There is increased interest within the scientific community concerning the neurotoxicity of
manganese owing in part to the use of methylcyclopentadienyl manganese tricarbonyl (MMT) as
a gasoline fuel additive and an enhanced awareness that this essential metal may play a role in
hepatic encephalopathy and other neurologic diseases. Neurotoxicity generally arises over a
prolonged period of time and results when manganese intake exceeds its elimination leading to
increases in brain manganese concentration. Neurotoxicity can occur following high dose oral,
inhalation, or parenteral exposure or when hepatobiliary clearance of this metal is impaired.
Studies completed during the past several years have substantially improved our understanding
of the health risks posed by inhaled manganese by determining exposure conditions that lead to
increased concentrations of manganese within the central nervous system and other target
organs. Many of these studies focused on phosphates, sulfates, and oxides of manganese since
these are formed and emitted following MMT combustion by an automobile. These studies have
evaluated the role of direct nose-to-brain transport of inhaled manganese and have examined
differences in manganese toxicokinetics in potentially sensitive subpopulations (e.g., fetuses,
neonates, individuals with compromised hepatic function or sub-optimal manganese intake, and
the aged). This manuscript reviews the U.S. Environmental Protection Agency's current risk
assessment for inhaled manganese, summarizes these contemporary pharmacokinetic studies,
and considers how these data could inform future risk assessments of this metal following
inhalation. (C) 2006 Elsevier Inc. All rights reserved.
4. Heilig E, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. (2005) Pharmacokinetics
of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading
Draft Bibliography: Manganese Lit. Search
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in iron-deficient rats. American Journal of Physiology-Lung Cellular and Molecular Physiology
288(5):L887-L893.
High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this
metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought
to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a
role in dietary iron absorption. To better characterize metal absorption from the lungs to the
blood and test whether iron deficiency may modify this process, the pharmacokinetics of
pulmonary manganese and iron absorption by control and iron-deficient rats were compared.
Levels of DMT1 expression in the lungs were determined to explore potential changes induced
by iron deficiency that might alter metal absorption. The pharmacokinetic curves for
intratracheally instilled Mn-54 and Fe-59 were significantly different, suggesting that pulmonary
uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient
rats had significantly higher blood Mn-54 levels, whereas blood Fe-59 levels were significantly
reduced compared with controls. The same trend was observed when radioisotopes were
delivered by intravenous injection, indicating that iron-deficient rats have altered blood
clearance of manganese. In situ analysis revealed the presence of DMT 1 transcripts in airway
epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1
levels and metal absorption did not appear to be influenced by iron deficiency, the differences in
blood clearance of instilled manganese identified by this study support the idea that iron status
can influence the potential toxicity of this metal.
5. Teeguarden JG, Dorman DC, Covington TR, Clewell HJ, 3rd, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. I. Dose dependencies of uptake and elimination. J
Toxicol Environ Health A 70(18): 1493-1504.
Homeostatic mechanisms controlling uptake, storage, and elimination of dietary manganese
(Mn) afford protection against fluctuations in tissue manganese (Mn) levels. Homeostatic control
of inhaled Mn is less well understood, but important in assessing likely risks of Mn inhalation.
Two compartmental kinetic models were used to characterize the influence of Mn exposure level
and route (oral, inhalation) on uptake, elimination, and transport of Mn. The models were fitted
to or used to interpret data from five whole-body Mn elimination studies: one dietary Mn
balance study, two biliary elimination studies, and one acute and one chronic. As dietary Mn
concentrations increased from low sufficiency (1.5 ppm) to sufficiency (20 ppm), control of Mn
uptake shifts from the intestine (principally) to more proportional control by both intestinal
tissues and liver. Using a two-compartment distribution model, the increased elimination of
54Mn tracer doses in response to increases in dietary Mn (rats and mice) or inhaled Mn (rats)
resulted from elevation in Mn elimination rate constants rather than changes in
intercompartmental transfer rate constants between a central compartment and deep
compartment. The pharmacokinetic (PK) analysis also indicated differential control of
absorption in single gavage oral dose studies versus continuous high oral doses in the feed. The
gavage study indicated increased elimination rate constants, and the chronic study showed
reduced rate constants for absorption. These dose dependencies in uptake and elimination are
necessary inputs for comprehensive PK models guiding human health risk assessments with Mn.
6. Teeguarden JG, Dorman DC, Nong A, Covington TR, Clewell HJ, 3rd, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. II. Hepatic processing after ingestion and inhalation. J
Toxicol Environ Health A 70(18):1505-1514.
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Current concerns regarding inhalation exposure to Mn, a component from oxidation of the
gasoline antiknock agent MMT, have stimulated interest in developing kinetic tools for
describing the inhalation and combined inhalation/oral route kinetics of Mn. Kinetic approaches
were integrated kinetic for (1) bulk tissue Mn kinetics and (2) hepato-intestinal control of oral-
route Mn uptake into a integrated model structure connecting systemic and oral Mn. Linkages
were developed between the hepato-intestinal and systemic tissues in order to evaluate
differences in hepatic processing of orally absorbed Mn and systemic Mn. The integrated,
unified model described the uptake, net absorption, and elimination of ingested Mn and the
elimination kinetics of i.v. administered (systemic) Mn by treating Mn arriving at the liver from
systemic versus portal blood differently. Hepatic extraction of orally absorbed Mn in rats
predicted through simulation of the oral uptake data was 19, 54, and 78% at dietary exposures of
1.5, 11.2, and 100 ppm, respectively. In contrast, hepatic extraction of systemic Mn predicted
through simulation of elimination kinetics i.v. tracer Mn was much less, 0.004, 0.005, or 0.009%
at dietary levels of 2, 10, and 100 ppm, respectively. These differences in hepatic processing of
blood Mn derived from different dose routes need to be accounted for in more complete PK
models for Mn that are intended to support human health risk assessments.
7. Teeguarden JG, Gearhart J, Clewell HJ, 3rd, Covington TR, Nong A, Andersen ME. (2007)
Pharmacokinetic modeling of manganese. III. Physiological approaches accounting for
background and tracer kinetics. J Toxicol Environ Health A 70(18): 1515-1526.
Manganese (Mn), an essential metal nutrient, produces neurotoxicity in workers exposed
chronically to high concentrations of Mn-containing dusts. Our long-term goal was to develop a
physiologically based pharmacokinetic (PBPK) model to support health risk assessments for Mn.
A PK model that accounts for Mn-tracer kinetics and steady-state tissue Mn in rats on normal
diets (about 45 ppm Mn) is described. The focus on normal dietary intakes avoids inclusion of
dose-dependent processes that maintain Mn homeostasis at higher dose rates. Data used for
model development were obtained from published literature. The model represents six tissues:
brain, respiratory tract, liver, kidneys, bone, and muscle. Each of these has a shallow tissue pool
in rapid equilibration with blood and a deep tissue store, connected to the shallow pool by
transfer rate constants. Intraperitoneal (i.p.) tracer Mn is absorbed into systemic blood and
equilibrated with the shallow and deep pools of tissue Mn. The model was calibrated to match
steady-state tissue concentrations and radiotracer kinetics following an i.p. dose of 54Mn.
Successful simulations showed uptake of 0.8% of dietary Mn, and estimated tissue partition
coefficients and transfer rate constants in the tissues. Inhalation tracer 54Mn studies could only
be adequately modeled by assuming that deposited Mn was absorbed into deep tissue stores in
the lung before becoming available to move via blood to other tissues. In summary, this present
effort provides the basic structure of a multiroute PBPK model for Mn that should now be easily
extended to include homeostatic control and inhalation exposures in order to support risk
assessment calculations for Mn.
Supporting References (0)
There were no supporting references identified for this section.
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3.3
LIVER/GI FUNCTION
Key References (0)
There were no key references identified for this section.
Supporting References (12)
1. Agte V, Jahagirdar M, Chiplonkar S. (2005) Apparent absorption of eight micronutrients and
phytic acid from vegetarian meals in ileostomized human volunteers. Nutrition 21(6):678-685.
Objectives: Apparent absorption of eight micronutrients and degradation of phytic acid were
studied in human subjects who underwent ileostomy. The prominent factors affecting
micronutrient absorption from vegetarian Indian meals (n = 11) were identified. Methods: Levels
of β-carotene, ascorbic acid, riboflavin, and thiamine in food and ileostomy contents were
estimated by spectrophotometry and spectrofluorometry. Contents of zinc iron, copper, and
manganese were estimated by atomic absorption spectrometry and that of phytic acid by gradient
elution ion exchange chromatography. Statistical analyses were done with SPSS 10.0. Results:
Absorption of β-carotene,. ascorbic acid, riboflavin, and thiamine was 63% to 75.6%.
There was a negative non-significant trend in values of β-carotene absorption with
increased intake of 0-carotene (r = -0.51, P > 0.1) and iron (r = -0.67, P = 0.1) but a positive
significant trend with riboflavin intakes (r = 0.84, P = 0.018). Percentage of absorption of
ascorbic acid showed weak positive associations with intakes of riboflavin (r = 0.71) and
ascorbic acid (r = 0.5). Percentage of absorption of ascorbic acid was positively correlated, with
percentage of absorption of β-carotene (r = 0.80, P < 0.05), iron, and riboflavin (r =
0.64, P = 0.086), indicating some common influencing factors. Percentages of absorption for
zinc (20.2), iron (9.9), and copper (17.6) was comparable with those reported for soy. protein-
based, high phytate diets. Pattern of phytic acid in the meals and output indicated partial
degradation and absorption (34%). Conclusions: For vegetarian Indian meals, apparent
absorptions of β-carotene and ascorbic acid were 76% and 12.5% and of riboflavin and
thiamine was 63%. Zinc, copper, and iron showed a lower absorption (10% to 20%). ©
2005 Elsevier Inc. All rights reserved.
2. Aschner JL, Furlong H, Daily D, Aschner M. (2006) Neuroimaging and neurodevelopmental
correlates of intravenous manganese exposure in parente rally-fed infants: A clinical trial in the
neonatal intensive care unit (NICU). Neurotoxicology 27(6): 1168-1168.
3. Davis CD, Schafer DM, Finley JW. (1998) Effect of biliary ligation on manganese
accumulation in rat brain. Biological Trace Element Research 64(l-3):61-74.
Neurologic and radiologic disorders have been reported to occur in miners inhaling manganese
(Mn)-laden dust and in humans receiving long-term parenteral nutrition. These abnormalities
have been attributed to Mn intoxication because of elevated serum Mn concentrations. Because
the liver, by way of the bile, is the major route of Mn excretion, it is possible that anything that
decreases biliary excretion could increase accumulation of Mn in the brain. The purpose of this
study was to determine whether biliary ligation would increase Mn accumulation in the brain of
rats that were exposed to deficient or adequate amounts of dietary manganese. The first
experiment had a 2 x 3 factorial design, two levels of Mn (0 or 45 mu g/g diet) and three surgical
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treatments (control, sham, or bile-ligation). Animals were sacrificed 10 d after being fed Mn-54.
In experiment 2, animals that had a sham operation or bile-ligation were sacrificed at 8 time
points after being injected intraportally with 54Mn complexed to albumin. The biliary-ligated
animals had a significantly (p < 0.001) smaller percentage of the 54Mn in their brains (when
expressed as a percentage of whole animal 54Mn) than the sham-operated animals. Mn
deficiency had a similar effect. However, we did observe an increased accumulation of the
radioisotope in the brain over time. Therefore, in short-term studies, biliary-ligated rats do not
appear to be a good model for Mn accumulation in the brains of people with cholestatic liver
disease.
4. Fell JME, Reynolds AP, Meadows N, Khan K, Long SG, Quaghebeur G, Taylor WJ, Milla
PJ. (1996) Manganese toxicity in children receiving long-term parenteral nutrition. Lancet
347(9010): 1218-1221.
Background In patients receiving long-term parenteral nutrition (PN), cholestatic disease acid
nervous system disorders have been associated with high blood concentrations of manganese. In
such patients, the normal homoeostatic mechanisms of the liver and gut ate bypassed and the
requirement for this trace element is not known; nor has it been certain whether
hypermanganesaemia causes the cholestasis or vice versa. We explored the direction of effect by
serial tests of liver function after withdrawal of manganese supplements from children receiving
long-term PN. We also examined the relation between blood manganese concentrations and
brain lesions, as indicated by clinical examination and magnetic resonance imaging (MRI).
Methods From a combined group of 57 children receiving PN we identified 11 with the
combination of hypermanganesaemia and cholestasis; one also had a movement disorder.
Manganese supplements were reduced in the first three and withdrawn in the remainder. MRI
was done in two of these children. We also looked at manganese concentrations and MRI scans
in six children who had received PN for more than 2 years without developing liver disease.
Findings In the hypermanganesaemia/cholestasis group, four of the 11 patients died. In the seven
survivors baseline whole-blood manganese was 615-1840 nmol/L, and after 4 months it had
declined by a median of 643 nmol/L (p<0 .01). Over the same interval total bilirubin declined
by a median of 70 mu mol/L (p<0 . 05). Two of these children had movement disorders, one of
whom survived to have an MRI scan; this showed, with T1 weighted images, bilateral
symmetrically increased signal intensity in the globus pallidus and subthalamic nuclei. Such
changes were also seen in five other children-one from the hypermanganesaemia/cholestasis
group and four of six in the long-term PN group without liver disease (in all of whom blood
manganese was above normal). Interpretation The cholestasis complicating PN is multifactorial,
but these results add to the evidence that manganese contributes. In view of the additional hazard
of basal ganglia damage from high manganese levels in children receiving long-term PN, we
recommend a low dose regimen of not more than 0.018 mu mol/kg per 24 h together with
regular examination of the nervous system.
5. Finley JW, Penland JG, Pettit RE, Davis CD. (2003) Dietary manganese intake and type of
lipid do not affect clinical or neuropsychological measures in healthy young women. Journal of
Nutrition 133(9):2849-2856.
Because manganese (Mn) is potentially toxic, and because dietary fat type may affect Mn
absorption, the objectives of the current study were to determine whether diets containing very
low or very high amounts of Mn and enriched in either saturated or unsaturated fats affected
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measures of neuropsychological and basic metabolic function. Healthy young women were fed
for 8 wk each, in a crossover design, diets that provided 0.8 or 20 mg of Mn/d. One half of the
subjects received 15% of energy as cocoa butter, and one half received 15% of energy as corn
oil. A meal containing Mn-54 was fed after 4 wk, and subjects underwent whole-body counting
for the next 21 d. Blood draws and neuropsychological tests were administered at regular
intervals during the dietary periods. When subjects consumed the diets low in Mn, compared
with the high Mn diets, they absorbed a significantly higher percentage of Mn-54, but had a
significantly longer biological half-life of the absorbed Mn-54. Manganese intake did not affect
any neurological measures and only minimally affected psychologic variables. These data show
that efficient mechanisms operate to maintain Mn homeostasis over the range of intakes that may
be encountered in a mixed Western diet. Thus, dietary intakes of Mn from 0.8 to 20 mg for 8 wk
likely do not result in Mn deficiency or toxicity signs in healthy adults.
6. Fitzgerald K, Mikalunas V, Rubin H, McCarthy R, Vanagunas A, Craig RM. (1999)
Hypermanganesemia in patients receiving total parenteral nutrition. Journal of Parenteral and
Enteral Nutrition 23(6):333-336.
Background: Manganese is one of the trace elements that is routinely administered to total
parenteral nutrition (TPN) patients. The recommended daily IV dosage ranges from 100 to 800
mu g. We have used 500 mu g daily. Recent reports have suggested neurologic symptoms seen in
some patients receiving home parenteral nutrition (HPN) may be due to hypermanganesemia.
Therefore, HPN patients and some short-term inpatients receiving TPN were studied to ascertain
the relationship between dose and blood levels. Methods: Red blood cell manganese levels were
obtained by atomic absorptiometry. Results: The levels in 36 hospitalized, short-term patients
obtained within 48 hours of initiating TPN were all normal. The 30 patients receiving TPN from
3 to 30 days had levels that ranged from 4.8 to 28 mu g/L (normal, 11 to 23 mu g/L). Two
patients had abnormal levels, at days 14 and 18. Fifteen of the 21 patients receiving inpatient
TPN or HPN for 36 to 5075 days had elevated Mn levels. Only one patient with
hypermanganesemia, an inpatient, had abnormal biochemical liver tests (bilirubin and alkaline
phosphatase). One of the patients with a high level had some vestibular symptoms attributed to
aminoglycoside use and had increased signal density in the globus pallidus on T1-weighted
images on magnetic resonance imaging (MRI). A second patient with Mn levels twice normal
had no neurologic symptoms, but had similar MRI findings. A third had some basal ganglia
symptoms, confirmed by a neurologic evaluation, seizures, and very high Mn levels. The MRI
showed no signal enhancement, but motion artifacts limited the study technically. Conclusions:
Hypermanganesemia is seen in HPN patients receiving 500 mu g manganese daily and may have
resulted in some neurologic damage in three patients. Hypermanganesemia is sometimes seen
after a short course of TPN in inpatients, as early as 14 days. Patients should be monitored for
hypermanganesemia if they receive Mn in their TPN for >30 days. A 500 mu g/d dose of Mn is
probably excessive, and 100 mu g/d should probably never be exceeded. Mn should be
eliminated from the solution if the Mn level is elevated and should not be readministered unless
the level returns to normal or subnormal. Mn should not be supplemented if the patient has liver
disease with an elevated bilirubin.
7. Ikeda S, Yamaguchi Y, Sera Y, Ohshiro H, Uchino S, Yamashita Y, Ogawa M. (2000)
Manganese deposition in the globus pallidus in patients with biliary atresia. Transplantation
69(11):2339-2343.
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Background. Chronic liver diseases may alter trace element contents in the brain. Among these
trace elements, manganese is a ubiquitous transition metal excreted by the liver into the bile.
Blood concentrations of manganese are elevated in patients with biliary atresia who have
undergone hepatic portoenterostomy. The present study investigated the effects of liver
transplantation on manganese deposition in the brain in such patients. Methods. The signal
intensity of the globus pallidus was calculated as an index defined as the percentile ratio of
signal intensity in the globus pallidus to the subcortical frontal white-matter in sagittal Tl-
weighted magnetic resonance imaging planes. Results. Brain magnetic resonance imaging
revealed hyperintense signals in the globus pallidus due to manganese deposition in biliary
atresia patients. Few neurologic symptoms related to manganese intoxication were observed.
However, one 23-year-old female with biliary atresia had depressive symptoms and dyskinesia;
she improved after oral administration of the dopamine precursor, L-DOPA. Manganese
deposition disappeared in two patients after living-related reduced-size hepatic transplantation.
Conclusions. Manganese accumulates in the brain during cholestasis associated with biliary
atresia and disappears after hepatic transplantation. Manganese deposition is likely to be
subclinical and reversible but may be associated with some age-related neurologic symptoms.
8. Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. (1998) Long term outcome of
brain manganese deposition in patients in home parenteral nutrition. Archives of Disease in
Childhood 79(3):263-265.
BIOSIS COPYRIGHT: BIOL ABS. Manganese intoxication has been described in children on
long term parenteral nutrition presenting with liver and nervous system disorders. Cases are
reported of a brother and sister on long term parenteral nutrition with hypermanganesaemia and
basal ganglia manganese deposition, detected by magnetic resonance imaging (MRI), without
overt neurological signs. Following reduction of manganese intake, basal ganglia manganese
was monitored by repeated MRI, and neurological and developmental examinations. An MRI
intensity index of the globus pallidus declined over a three year period from 0.318 and 0.385 to
0.205 and 0.134 with concomitant falls in whole blood manganese from 323 and 516 to 226 and
209 nmol/1 (normal range, 73-210 nmol/1). Unlike adult experience these children developed
normally without neurological signs. In conclusion, deposited manganese is removed from
neural tissue over time and the prognosis is good when neurological manifestations and liver
disease ar
9. Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H. (1995) Manganese and
Chronic Hepatic-Encephalopathy. Lancet 346(8970):270-274.
Clinical observations and animal studies have raised the hypothesis that increased concentrations
of manganese (Mn) in whole blood might lead to accumulation of this metal within the basal
ganglia in patients with end-stage liver disease. We studied ten patients with liver failure (and
ten controls) by magnetic resonance imaging (MRI) and measurement of Mn in brain tissue of
three patients who died of progressive liver failure (and three controls) was also done. Whole
blood Mn concentrations in patients with liver cirrhosis were significantly increased (median
34.4 mu g/L vs 10.3 mu g/L in controls; p=0.0004) and pallidal signal intensity indices
correlated with blood Mn (R(s)=0.8, p=0.0058). Brain tissue samples reveal highest Mn
concentrations in the caudate nucleus, followed by the quadrigeminal plate and globus pallidus.
Mn accumulates within the basal ganglia in liver cirrhosis. Similarities between Mn
neurotoxicity and chronic hepatic encephalopathy suggest that this metal may have a role in the
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pathogenesis of chronic hepatic encephalopathy. Further studies are warranted because the use of
chelating agents could prove to be a new therapeutic option to prevent or reverse this
neuropsychiatric syndrome.
10. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro
L. (1999) Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal Tl-
weighted magnetic resonance signal hyperintensity. Neurotoxicology 20(4):647-652.
The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic
resonance (MR) imaging has been postulated to arise from deposition of paramagnetic
manganese(2+) (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency;
iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the
relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic
liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary
sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha 1-antitrypsin deficiency
1). Signal hyperintensity in the pallidum on axial T1 weighted images repetition time/evolution
time: 500 ms/15ms was observed in 13 of 21 subjects: four patients had mild hyperintensity,
three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were
positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005).
The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron
status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe
concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings
confirm the association of Mn with the development of pallidal hyperintensity in patients with
liver disease. We further found that iron deficiency is an exacerbating factor probably because of
increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver
disease avoid Mn supplements without concurrent iron supplementation. (C)1999 Intox Press,
Inc.
11. Ono J, Harada K, Kodaka R, Sakurai K, Tajiri H, Takagi Y, Nagai T, Harada T, Nihei A,
Okada A and others. (1995) Manganese deposition in the brain during long-term total parenteral
nutrition. Journal of Parenteral and Enteral Nutrition 19(4):310-312.
BIOSIS COPYRIGHT: BIOL ABS. Background: Manganese deposition was suspected in a
pediatric patient who received long-term total parenteral nutrition. T1-weighted magnetic
resonance images revealed high intensity areas in the globus pallidus. This study was designed to
clarify if these abnormal findings were related to manganese deposition and clinical neurological
manifestations. Methods: Whole-blood manganese concentrations were measured during
manganese supplementation to total parenteral nutrition and after 5 months without manganese.
Magnetic resonance images were also examined on each occasion and compared with the blood
level of manganese. Results: The whole-blood manganese level during supplementation was 135
mug (normal range 14.6 | 4.7 mug/L), whereas the level was 20 mug/L after a manganese-free
period of 5 months. Accompanied with normalization of manganese level, abnormal high
intensity lesions in the globus pallidus on Tl-weighted images also disappeared. No neurological
manifestation
12. Reynolds N, Blumsohn A, Baxter JP, Houston G, Pennington CR. (1998) Manganese
requirement and toxicity in patients on home parenteral nutrition. Clinical Nutrition 17(5):227-
230.
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Two patients who were receiving home parenteral nutrition complained of vague neurological
symptoms of such severity that they underwent full clinical appraisal. The only positive finding
was that plasma manganese concentrations were greater than twice the upper 95% confidence
interval of normal (7-27 nmol/1). In the light of this result all nine patients receiving home
parenteral nutrition underwent evaluation for possible manganese toxicity. One other patient had
serum manganese concentrations exceeding twice the upper limit (127 nmol/1). The three
patients with elevated serum Mn had evidence of manganese deposition in the brain on magnetic
resonance imaging scanning. In contrast two patients with normal plasma results had negative
scans. Patient susceptibility appears very variable. We suggest that current amounts of trace
elements provided in nutrition solutions may be a potential source of nutrient activity. The fine
tuning of supply and demand may be difficult on account of a limited range of commercially
available trace element solutions.
4.1 STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
Key References (34)
1. Beuter A, Lambert G, MacGibbon B. (2004) Quantifying postural tremor in workers exposed
to low levels of manganese. Journal of Neuroscience Methods 139(2):247-255.
The aim of this study was: (1) To determine the minimum number of characteristics necessary to
discriminate between postural tremor recorded in control subjects (CO), in subjects exposed to
manganese (MN), and in patients with Parkinson's disease (PD), and (2) to examine the
continuum of changes between the three groups examined. Workers previously exposed to Mn (n
= 10), patients with PD (n = 10), and control subjects (CO) (n = 11) underwent a clinical
examination. Blood Mn was measured at the end of exposure time for the MN group and 12
months later at the beginning of the experiment for all groups. Postural tremor with visual
feedback was recorded in the index finger with a laser system. Statistical criteria were used to
reduce computed tremor characteristics to a minimal set of reliable discriminating variables.
Two variables were retained namely corrected wobble (CW), describing the morphology of the
tremor oscillations, and variability ratio (VR), describing proportional power of tremor. Both
variables had an overall correct classification rate of 77.4%. Blood Mn levels at the time of the
experiment were similar for all groups and had insignificant correlation with tremor variables.
However, blood Mn levels in workers which were also measured at the end of exposure time
(i.e., 12 months before) showed significant correlation (Spearman's rank coefficient) with both
harmonic index (p = 0.70, P = 0.03) and first maximum of the autocorrelation function (p = 0.89,
P = 0.001). We conclude that (1) the tremor of workers exposed to Mn could be adequately
described with only two variables; (2) a continuum of changes between tremor recorded in
control subjects, in subjects exposed to Mn and in patients with PD was observed, with the MN
group always found in between the control (CO) and the PD groups; (3) while blood Mn levels
in workers were back at control levels at the time of the experiment, the effect of Mn on postural
tremor was still detected. Thus our method has the potential to detect the effect of Mn on tremor
with only two variables even after Mn level in the blood is back to normal values. (C) 2004
Elsevier B.V. All rights reserved.
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2. Boojar MMA, Goodarzi F. (2002) A longitudinal follow-up of pulmonary function and
respiratory symptoms in workers exposed to manganese. Journal of Occupational and
Environmental Medicine 44(3):282-290.
The purpose of the investigation was to study the effects on the respiratory system in mine
workers with long-term exposure to manganese (Mn) in the workplace. The study included a
follow-up Of pulmonary Junction and respiratory symptoms among 145 workers employed in a
large Mn mine an 5 matched controls, and the assessment of Mn concentrations in environment
and biological samples. Lung function was measured by recording spirometric parameters. The
Mn-exposed workers reported more respiratory symptoms and a significantly higher prevalence
of all grades of pulmonary function impairment. All predicted symptoms except for asthma
increased significantly in the current smoking group compared with the non-smoking group.
There was a significant decrease in FEV1, FVC, and FEV1% values in exposed workers
compared with controls at stages 2 and 3, with an additive effect of the smoking habit. The Mn
concentrations in blood, urine, and hair were significantly higher in the exposed workers than in
the controls. The level of cumulative exposure index of workplace Mn was notable and did not
change significantly over this study. The respiratory effects found in Mn-exposed workers were
probably caused by the Mn in the workplace and the synergistic effect of smoking. These effects
indicate a need for respiratory protection and improvements in the work environment.
3. Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D. (2007) Hair manganese and
hyperactive behaviors: Pilot study of school-age children exposed through tap water.
Environmental Health Perspectives 115(1): 122-127.
BACKGROUND: Neurotoxic effects are known to occur with inhalation of manganese
particulates, but very few data are available on exposure to Mn in water. We undertook a pilot
study in a community in Quebec (Canada) where naturally occurring high Mn levels were
present in the public water system. Our objective was to test the hypothesis that greater exposure
to Mn via drinking water would be reflected in higher Mn content in hair which, in turn, would
be associated with increased level of hyperactive behaviors. METHODS: Forty-six children
participated in the study, 24 boys and 22 girls, 6-15 years of age (median, 11 years). Their homes
received water from one of two wells M with different Mn concentrations: W1: mean 6 10 mu
g/L; W2: mean 160 mu g/L. The Revised Conners' Rating Scale for parents (CPRS-R) and for
teachers (CTRS-R) were administered, providing T-scores on the following subscales:
Oppositional, Hyperactivity, Cognitive Problems/Inattention, and ADHD Index. RESULTS:
Children whose houses were supplied by W1 had higher hair Mn (MnH) than those supplied by
W2 (mean 6.2 +/- 4.7 mu g/g vs. 3.3 +/- 3.0 mu g/g, p = 0.025). MnH was significantly
associated with T-scores on the CTRS-R Oppositional (p = 0.020) and Hyperactivity (p = 0.002)
subscales, after adjustment for age, sex, and income. All children with Oppositional and
Hyperactivity T-scores >= 65 had MnH >3.0 mu g/g. CONCLUSIONS: The findings of this
pilot study are sufficiently compelling to warrant more extensive investigations into the risks of
Mn exposure in drinking water.
4. Bowler RM, Gysens S, Diamond E, Nakagawa S, Drezgic M, Roels HA. (2006) Manganese
exposure: Neuropsychological and neurological symptoms and effects in welders.
Neurotoxicology 27(3):315-326.
Manganese exposure reportedly may have an adverse effect on CNS function and mood. Sixty-
two welders with clinical histories of exposure to manganese were compared to 46 matched
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regional controls chosen at random from a telephone directory. The following tests were given:
Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III), Boston
Naming, WRAT-3, Cancellation H, Trail Making Tests A and B, Auditory Consonant Trigrams,
Stroop, Rey-Osterreith, Animal Naming, Controlled Oral Word Association (COWAT), Test of
Memory Malingering, Rey 15-item, Fingertapping, Grooved Pegboard, Dynamometer, Visual
Attention Test. Lanthony d-15 Color Vision, Vistech Contrast Sensitivity, and Schirmer strips.
The controls were administered a shorter battery of tests and the Rey-Osterreith, Animal Naming
and some of the subtests of the WAIS-III, WMS-III were not administered. Mood tests, given to
both groups, included the Symptom Checklist-40, Symptom Checklist-90-R, Profile of Mood
Scale, Beck Depression Inventory II, and Beck Anxiety Inventory. Forty-seven welders and 42
controls were retained for statistical analysis after appropriate exclusions. Results showed a high
rate of symptom prevalence and pronounced deficits in motor skills, visuomotor tracking speed
and information processing, working memory, verbal skills (COWAT), delayed memory, and
visuospatial skills. Neurological examinations compared to neuropsychological test results
suggest that neuropsychologists obtain significantly more mood symptoms overall. Odds ratios
indicate highly elevated risk for neuropsychological and neurological symptomatology of
manganism. Mood disturbances including anxiety, depression, confusion, and impaired vision
showed very high odds ratios. Neurological exams and neuropsychological tests exhibit
complementarity and differences, though neuropsychological methods may be more sensitive in
detecting early signs of manganism. The present study corroborates the findings of our previous
study in another group of welders, (c) 2005 Elsevier Inc. All rights reserved.
5. Bowler RM, Koller W, Schulz PE. (2006) Parkinsonism due to manganism in a welder:
Neurological and neuropsychological sequelae. Neurotoxicology 27(3):327-332.
A 33-year-old welder with 3 years of exposure to manganese (Mn) bearing welding fumes was
seen by neurologists for cognitive and motor complaints. He exhibited signs and symptoms of
Parkinson's disease, including tremor, bradykinesia, gait disturbance and cogwheel rigidity.
However, he was young and had significant inattention and forgetfulness, had found levodopa
unhelpful and moved with a cock-walk gait, all of which suggested manganism. His serum and
urine levels of Mn were, in fact, elevated, and his brain MRI had increased T1-weighted signal
intensities in the basal ganglia bilaterally (globus pallidus) consistent with Mn deposition. Two
years later, he underwent comprehensive neuropsychological testing. Clinical history indicated a
mild tremor and emotional dysfunction with irritability, anxiety, and depression with psychotic
features. He showed deficits in cognitive flexibility, information processing and speed, and
greatly reduced motor speed, which are consistent with a fronto-subcortical process. These
findings support a diagnosis of early onset parkinsonism from welding, (c) 2006 Elsevier Inc. All
rights reserved.
6. Bowler RM, Nakagawa S, Drezgic M, Roels HA, Park RM, Diamond E, Mergler D,
Bouchard M, Bowler RP, Koller W. (2007) Sequelae of fume exposure in confined space
welding: A neurological and neuropsychological case series. NeuroToxicology 28(2):298-311.
Welding fume contains manganese (Mn) which is known to be bio-available to and neurotoxic
for the central nervous system. Although an essential metal, Mn overexposure may cause
manganism, a parkinsonian syndrome. The present welder study sought to improve the clinical
portrait of manganism and to determine dose-effect relationships. The welders were employed in
the construction of the new Bay Bridge (San Francisco) and welded in confined spaces for up to
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2 years with minimal protection and poor ventilation. Neurological, neuropsychological,
neurophysiological, and pulmonary examinations were given to 49 welders. Clinical cases were
selected on the basis of apriori defined criteria pertaining to welding history and
neurological/neuropsychological features. Among the 43 eligible welders, 11 cases of
manganism were identified presenting with the following symptoms: sleep disturbance, mood
changes, bradykinesia, headaches, sexual dysfunction, olfaction loss, muscular rigidity, tremors,
hallucinations, slurred speech, postural instability, monotonous voice, and facial masking.
Significant associations between outcome variables and cumulative exposure index (CEI) or
blood Mn (MnB) were obtained with CEI for variables implicating attention and concentration,
working and immediate memory, cognitive flexibility, and verbal learning; and with MnB for
executive function, cognitive flexibility, visuo-spatial construction ability, and visual contrast
sensitivity. This study strongly suggests that neuropsychological features contribute in a dose-
effect related way to the portrait of manganism usually characterized by tremor, loss in balance,
diminished cognitive performance, and signs and symptoms of parkinsonism.
7. Bowler RM, Roels HA, Nakagawa S, Drezgic M, Diamond E, Park R, Koller W, Bowler RP,
Mergler D, Bouchard M and others. (2007) Dose-effect relationships between manganese
exposure and neurological, neuropsychological and pulmonary function in confined space bridge
welders. Occupational and Environmental Medicine 64(3): 167-177.
Background: Although adverse neuropsychological and neurological health effects are well
known among workers with high manganese (Mn) exposures in mining, ore-processing and
ferroalloy production, the risks among welders with lower exposures are less well understood.
Methods: Confined space welding in construction of a new span of the San Francisco-Oakland
Bay Bridge without adequate protection was studied using a multidisciplinary method to identify
the dose-effect relationship between adverse health effects and Mn in air or whole blood. Bridge
welders (n = 43) with little or no personal protection equipment and exposed to a welding fume
containing Mn, were administered neurological, neuropsychological, neurophysiological and
pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a
Cumulative Exposure Index (CEI) based on Mn-air, duration and type of welding. Welders
performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age
and had on average 12.6 years of education. Results: The mean time weighted average of Mn-air
ranged from 0.11-0.46 mg/m(3) (55% > 0.20 mg/m(3)). MnB >10 mu g/1 was found in 43% of
the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma
were normal. Forced expiratory volume at Is: forced vital capacity ratios (FEV1/FVC) were
found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge.
Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6,
respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and
University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and
88%) of the welders, respectively. Significant inverse dose-effect relationships with CEI and/or
MnB were found for IQ (p <= 0.05), executive function (p <= 0.03), sustaining concentration
and sequencing (p <= 0.04), verbal learning (p <= 0.01), working (p <= 0.04) and immediate
memory (p <= 0.02), even when adjusted for demographics and years of welding before Bay
Bridge. Symptoms reported by the welders while working were: tremors (41.9%>); numbness
(60.5%>); excessive fatigue (65.1%>); sleep disturbance (79.1%); sexual dysfunction (58.1%>);
toxic hallucinations (18.6%>); depression (53.5%); and anxiety (39.5%). Dose-effect associations
between CEI and sexual function (p < 0.05), fatigue (p < 0.05), depression (p < 0.01) and
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headache (p < 0.05) were statistically significant. Conclusions: Confined space welding was
shown to be associated with neurological, neuropsychological and pulmonary adverse health
effects. A careful enquiry of occupational histories is recommended for all welders presenting
with neurological or pulmonary complaints, and a more stringent prevention strategy should be
considered for Mn exposure due to inhalation of welding fume.
8. Cersosimo MG, Koller WC. (2006) The diagnosis of manganese-induced parkinsonism.
Neurotoxicology 27(3):340-346.
Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance
problems, in addition to various non-motor symptoms. There are many causes of parkinsonism
such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and
toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of
parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars
compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive
condition in which there is a dramatic and sustained responsiveness to levodopa therapy.
Manganese is an essential trace element that can be associated with neurotoxicity.
Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese
intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and
dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas
can also be involved. MRI scans may show globus pallidus changes during (and for a short
period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra,
dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to
be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due
to manganese may have some clinical features that occur less commonly in Parkinson's disease,
such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech
changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of
the body. Patients with manganese-induced parkinsonism may be younger at the onset of the
disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa
therapy in manganese-induced parkinsonism. In summary it may be possible to differentiate
manganese-induced parkinsonism from Parkinson's disease using clinical and imaging studies,
(c) 2005 Elsevier Inc. All rights reserved.
9. Deschamps FJ, Guillaumot A, Raux S. (2001) Neurological effects in workers exposed to
manganese. Journal of Occupational and Environmental Medicine 43(2): 127-132.
The purpose of this study was to examine the effects on the nervous system in enamels-
production workers who have low levels of and long exposure to manganese (Mn). The study
included 138 Mn-exposed workers and 137 controls who received questionnaires on symptoms,
a batter of psychological tests, and assessments of blood concentrations of metal. The exposure
levels to airborne Mn concentrations were determined by personal and stationary samplings. The
mean duration exposure to Mn was 19.87 years (SD +/- 9). The workers exposed to Mn reported
more nonspecific subjective complaints than the control group. No effect of Mn exposure was
indicated by the results of any of the neuropsychological tests. The Mn workers did not have
higher concentrations of Mn in blood than the controls. Exposures of workers currently working
with Mn averaged 57 mug/m(3) respirable (personal samplings) and 12 g/m(3) (stationary
samplings). In conclusion, long exposure to low levels of Mn (approximately 200 mug/m(3)), as
induced in our study, showed no significant disturbance of neurological performance.
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10. Finley BL, Santamaria AB. (2005) Current evidence and research needs regarding the risk of
manganese-induced neurological effects in welders. Neurotoxicology 26(2):285-289.
11. Fored CM, Fryzek JP, Brandt L, Nise G, Sjogren B, McLaughlin JK, Blot WJ, Ekbom A.
(2006) Parkinson's disease and other basal ganglia or movement disorders in a large nationwide
cohort of Swedish welders. Occupational and Environmental Medicine 63(2): 135-140.
Introduction: Although it has been hypothesised that metal welding and flame cutting are
associated with an increased risk for Parkinson's disease due to manganese released in the
welding fume, few rigorous cohort studies have evaluated this risk. Methods: The authors
examined the relation between employment as a welder and all basal ganglia and movement
disorders (ICD-10, G20-26) in Sweden using nationwide and population based registers. All men
recorded as welders or flame cutters (n=49 488) in the 1960 or 1970 Swedish National Census
were identified and their rates of specific basal ganglia and movement disorders between 1964
and 2003 were compared with those in an age and geographical area matched general population
comparison cohort of gainfully employed men (n=489 572). Results: The overall rate for basal
ganglia and movement disorders combined was similar for the welders and flame cutters
compared with the general population (adjusted rate ratio (aRR)=0.91 (95% CI 0.81 to 1.01).
Similarly, the rate ratio for PD was 0.89 (95% CI 0.79 to 0.99). Adjusted rate ratios for other
individual basal ganglia and movement disorders were also not significantly increased or
decreased. Further analyses of Parkinson's disease by attained age, time period of follow up,
geographical area of residency, and educational level revealed no significant differences between
the welders and the general population. Rates for Parkinson's disease among welders in
shipyards, where exposures to welding fumes are higher, were also similar to the general
population (aRR=0.95; 95% CI 0.70 to 1.28). Conclusion: This nationwide record linkage study
offers no support for a relation between welding and Parkinson's disease or any other specific
basal ganglia and movement disorders.
12. Fryzek JP, Hansen J, Cohen S, Bonde JP, Llambias MT, Kolstad HA, Skytthe A, Lipworth
L, Blot W, Olsen JH. (2005) A cohort study of Parkinson's disease and other neurodegenerative
disorders in Danish welders. Journal of Occupational and Environmental Medicine 47(5):466-
472.
Objective. We sought to evaluate rates of hospitalizations for neurode-generative disorders in a
cohort of Danish metal manufacturing employees. Methods: A retrospective cohort study was
conducted from 1977 to 2002 among 27,839 mate Danish metal-manufacturing employees, with
9,817 of those employed in departments engaged in mild or stainless-steel welding and 6,163
welders. Results: The standardized hospitalization ratio and 95 % confidence intervals (Q) for
Parkinson's disease were 0.9 (CI = 0.7-1.2) for men in steel-manufacturing companies, 1.0 (CI =
0.7-1.5) for men in welding departments, and 0.9 (CI = 0.4 -1.5) for welders. Observed numbers
for other neurological conditions were small and not above population expectations. Analyses
for time period worked, age, and duration of welding were unremarkable. Conclusions: This
relatively large cohort study with long-term follow-up provides no support for the hypothesis
that rates of hospitalization for Parkinson's disease or other neurological conditions are elevated
under the exposure circumstances of these Danish workers.
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13. Gibbs JP, Crump KS, Houck DP, Warren PA, Mosley WS. (1999) Focused medical
surveillance: A search for subclinical movement disorders in a cohort of U.S. workers exposed to
low levels of manganese dust. Neurotoxicology (Little Rock) 20(2-3):299-314.
BIOSIS COPYRIGHT: BIOL ABS. Seventy-five workers with recent and/or historical exposure
to manganese (Mn) at a metal producing plant in northern Mississippi were closely matched with
75 control workers who had no known history of occupational exposure to Mn. Both plants are
OSHA STAR work sites and share common medical, safety, and industrial hygiene services.
Airborne Mn levels were assessed for each of twelve job categories at the Mn facility by
collecting 63 side-by-side full-shift personal samples of both total and res n was estimated for
the preceding 30 days, preceding year, and for the worker's entire employment history. Both Mn
and control workers were administered multiple neuropsychological tests including tests of
hand-eye coordination, hand steadiness, complex reaction time, and rapidity of finger tapping. A
questionnaire was used to evaluate a worker's neuropsychological status. Performance decreased
sign)ficantly with increasing age in tests of hand-eye coordination, complex reaction
14. Hernandez EH, Discalzi G, Valentini C, Venturi F, Chio A, Carmellino C, Rossi L,
Sacchetti A, Pira E. (2006) Follow-up of patients affected by manganese-induced Parkinsonism
after treatment with CaNa(2)EDTA. Neurotoxicology 27(3):333-339.
In the period of 1998-2004, seven workers affected by manganese-induced Parkinsonism were
diagnosed, studied and treated with CaNa(2)EDTA at our Occupational Health Ward. Biological
markers, as well as magnetic resonance imaging and clinical examinations, were used to assess
the disease trend. Those workers still employed were immediately removed from exposure. Our
results seem to confirm that very good clinical, biological and neuroradiological results can be
obtained by timely removal from exposure and chelating treatment, and that amelioration can
persist in time. Manganism is, however, a severe condition that can also progress independent of
further exposure. Therefore, chelating treatment can be a great aid in overt manganism, but
particular attention must be paid to primary prevention, as this disease should now be totally
preventable and definitely merits eradication, (c) 2005 Elsevier Inc. All rights reserved.
15. Hochberg F, Miller G, Valenzuela R, McNelis S, Crump KS, Covington T, Valdivia G,
Hochberg B, Trustman JW. (1996) Late motor deficits of Chilean manganese miners: A blinded
control study. Neurology 47(3):788-795.
BIOSIS COPYRIGHT: BIOL ABS. High-level chronic manganese (Mn) exposure produces
dystonic rigidity and proximal tremor. The late effects of asymptomatic exposure are uncertain.
To evaluate hand movements of asymptomatic Chilean miners, we utilized a manual
tremormeter (EAP) and a digitizing tablet (MOVEMAP). In Andacollo, Chile, we examined 59
individuals aged > 50 years (mean age, 64.4 years). Twenty-seven exposed miners had heavy
Mn dust exposure in Mn mines for more than 5 years (mean duration, 20.25 years), ending at
least 5 years previously. Thirty-two control miners had never worked in Mn mines or had short-
term Mn employment. Tests of resting tremor (EAP Tremormeter, MOVEMAP Steady
paradigm), action tremor (MOVEMAP Square paradigm), and repetitive hand movements (EAP
Tapping Test and Orthokinesimeter) differentiated performance of exposed miners from that of
controls. Chronic asymptomatic Mn exposure results in detectable late-life abnormalities of
movement.
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16. Hudnell HK. (1999) Effects from environmental Mn exposures: A review of the evidence
from non-occupational exposure studies. Neurotoxicology 20(2-3):379-397.
Objective: The risk posed to human health by environmental manganese exposure is unknown.
Occupational-exposure outcomes may not extrapolate to environmental exposures due to the
healthy worker effect and differences in dosage parameters which may affect the biological
response. This paper attempts to combine the existing literature on non-occupational Mn
exposures with results from our current study in SW Quebec on environmental Mn exposure
(Mergler et al., this issue) within the framework of a biologically-based, dose-response (BBDR)
model. BBDR Model: The basic BBDR model consists of seven stages relating exposure to
health effects. The stages are: 1) sources, 2) applied dose, 3) absorbed dose, 4) target-site dose,
5) toxic event, 6) measurable change, and 7) health outcome. Results: Several air monitoring
programs, such as the PTEAM study (Riverside, CA, 1990, mean PM10 Mn outdoor-airborne
24h average=0.045 mu g/m(3)) provided data relevant to the estimation of Mn applied dose, but
did not include measures of body burden. Data from the SW Quebec study showed a mean total
particulate airborne Mn concentration of 0.022 mu g/m(3) with a range of 0.009 to 0.035 mu
g/m(3) across four sampling sites, whereas the EPA reference concentration (RfC) is 0.05 mu
g/m(3). EPA has considered tap water levels to be safe below 200 mu g/1 Mn, and mean Mn tap-
water (MnW) level in the participants' homes was 6.38+/-11.95 mu g/1 with a range from 0.1 to
158.9 mu g/1 Mn. A previous study of MnW exposure in Greece reported Mn levels in areas with
low, medium and high MnW ranging from 4 to 2,300 mu g/1 and a significant association with
Mn in hair but not Mn in blood (MnB). The mean absorbed dose of the SW Quebec study
participants, as indicated by MnB, was 7.5+/-2.3 mu g/1 with a range of 2.5 to 15.9 mu g/1. Our
study and others on environmental Mn exposure did not provide an estimate of target-site dose.
However, a significant correlation (r=0.65) between MnB and signal intensify in Tl-weighted
MRI images has been reported in liver-disease patients with Parkinson-like signs who had MnB
levels as low as 6.6 mu g/1. Only animal and in vitro studies ha ve provided evidence on the
mechanisms of toxicity caused by Mn in the CNS. Several studies reported measurable changes
in endpoints suggestive of a Parkinson-like syndrome in subjects with MnB levels ranging from
7.5 to 25.0 mu g/1. Among other effects on neurobehavioral function observed in the current
study was a significant relationship between MnB and the direction and speed of body-sway in
men. The effects observed in these participants are sub-clinical and no health outcomes have
been diagnosed. However, the Parkinson's disease incidence in the study area was previously
reported to be 2-5 times higher than in the rest of Quebec, and several studies indicate that 25-
35% of idiopathic Parkinson disease diagnoses are incorrect. Our study, the Greek study, and
some clinical studies suggest that the risk of a Parkinson-like syndrome diagnosis may increase
with continued Mn exposure and aging. Conclusion: The limited data available for the BBDR
model point to the need for evidence, particularly on relationships between Mn species, exposure
route, MnB with chronic environmental exposure, ageing, and susceptibility factors, to improve
human-health risk assessments for chronic, environmental Mn exposure. (C) 1999 Inter Press,
Inc.
17. Iregren A. (1999) Manganese neurotoxicity in industrial exposures: Proof of effects, critical
exposure level, and sensitive tests. Neurotoxicology 20(2-3):315-323.
Manganese neurotoxicity has been known for more than 150 years, since Couper(1837)
described a syndrome, similar to Parkinsonis disease, in Scottish workers exposed to high levels
of dust while grinding "black oxide of manganese" at a chemical industry. Since then, the
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syndrome has been described in several groups of highly exposed miners and other workers. A
thorough review of manganese neurotoxicity was provided by the WHO (1981) and a recent
update was written by Mergler and Baldwin (1997). From these reviews it is evident that the
critical effect from manganese exposure is damage to the central nervous system, and that the
effects, once established, are generally irreversible. Therefore, the early detection of symptoms
of manganese neurotoxicity in populations at risk is of the utmost importance. In spite of this
fact, only about a dozen studies of manganese exposed groups of workers have been performed
using psychological test methods. These studies are briefly presented, the preponderance of
proof for Mn neurotoxicity even in present industrial settings is demonstrated, the critical
exposure level is briefly discussed, the test methods are evaluated, and recommendations for a
test battery useful for studies of manganese neurotoxicity, are presented. (C) 1999 Inter Press,
Inc.
18. Jiang YM, Zheng W. (2005) Cardiovascular toxicities upon manganese exposure.
Cardiovascular Toxicology 5(4):345-354.
Manganese (Mn)-induced Parkinsonism has been well documented; however, little attention has
been devoted to Mn-induced cardiovascular dysfunction. This review summarizes literature data
from both animal and human studies on Mn's effect on cardiovascular function. Clinical and
epidemiological evidence suggests that the incidence of abnormal electrocardiogram (ECG) is
significantly higher in Mn-exposed workers than that in the control subjects. The main types of
abnormal ECG include sinus tachycardia, sinus bradycardia, sinus arrhythmia, sinister
megacardia, and ST-T changes. The accelerated heartbeat and shortened P-R interval appear to
be more prominent in female exposed workers than in their male counterparts. Mn-exposed
workers display a mean diastolic blood pressure that is significantly lower than that of the
control subjects, especially in the young and female exposed workers. Animal studies indicate
that Mn is capable of quickly accumulating in heart tissue, resulting in acute or sub-acute
cardiovascular disorders, such as acute cardio-depression and hypotension. These toxic outcomes
appear to be associated with Mn-induced mitochondrial damage and interaction with the calcium
channel in the cardiovascular system.
19. Kim Y, Kim KS, Yang JS, Park IJ, Kim E, Jin YW, Kwon KR, Chang KH, Kim JW, Park
SH and others. (1999) Increase in signal intensities on T1-weighted magnetic resonance images
in asymptomatic manganese-exposed workers. Neurotoxicology 20(6):901-907.
Objectives. To clarify the clinical significance of increased signal intensities on T1 weighted
magnetic resonance imaging (MRI) we performed a large-scale epidemiological study on
asymptomatic manganese (Mn)-exposed workers with its focus on MRI. Methods: We randomly
selected 121 male workers out of a total of 750 workers including Mn-exposed, non-exposed
manual, and non-exposed clerical workers in the factories. We studied environmental and
biological monitoring, neurological examination, and MRI. Results: The proportion of workers
with increased signal intensities among the exposed the non-exposed manual workers, and the
non-exposed clerical workers was 46.1%, 18.8%, and 0%, respectively. Especially, 12.5% of the
welders showed increased signal intensities. In no subject, were clinical signs of manganism
observed. The pallidal index correlated with blood Mn concentration. Conclusion: Increase in
signal intensities on the T1-weighted image reflect recent exposure to Mn, but not necessarily
manganism. At which increase of signal intensity, the progression of manganism from Mn
exposure occurs, remains to be solved. (C) 1999 Intox Press, Inc.
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20. Klos KJ, Chandler M, Kumar N, Ahlskog JE, Josephs KA. (2006) Neuropsychological
profiles of manganese neurotoxicity. European Journal of Neurology 13(10): 1139-1141.
The etiology of manganese neurotoxicity is heterogenous and includes exposure to welding
fumes, chronic liver failure, and chronic total parental nutrition (TPN). We recently reported that
cognitive impairment occurs in welders and patients with chronic liver failure who had evidence
of manganese neurotoxicity including abnormal magnetic resonance imaging (MRI) basal
ganglia T1 hyperintensity. In this study, we compared the neuropsychological profiles of patients
with manganese neurotoxicity and basal ganglia T1 hyperintensities from three different
etiologies: welding, chronic liver failure, and chronic TPN. Across all three groups, the
neuropsychological profiles suggest frontal and subcortical cognitive impairment, with more
widespread abnormalities occurring in the non-welding groups.
21. Lees-Haley PR, Greiffenstein MF, Larrabee GJ, Manning EL. (2004) Methodological
problems in the neuropsychological assessment of effects of exposure to welding fumes and
manganese. Clinical Neuropsychologist 18(3):449-464.
Recently, Kaiser (2003) raised concerns over the increase in brain damage claims reportedly due
to exposure to welding fumes. In the present article, we discuss methodological problems in
conducting neuropsychological research on the effects of welding exposure, using a recent paper
by Bowler et al. (2003) as an example to illustrate problems common in the neurotoxicity
literature. Our analysis highlights difficulties in conducting such quasi-experimental
investigations, including subject selection bias, litigation effects on symptom report and
neuropsychological test performance, response bias, and scientifically inadequate casual
reasoning.
22. Levy BS, Nassetta WJ. (2003) Neurologic effects of manganese in humans: A review.
International Journal of Occupational and Environmental Health 9(2): 153-163.
Manganese, which enters the body primarily via inhalation, can damage the nervous system and
respiratory tract, as well as have other adverse effects. Occupational exposures occur mainly in
mining, alloy production, processing, ferro-manganese operations, welding, and work with
agrochemicals. Among the neurologic effects is an irreversible parkinsonian-like syndrome. An
estimated 500,000 to 1.5 million people in the United States have Parkinson's disease, and
physicians need to consider manganese exposure in its differential diagnosis. Since 1837, there
have been many reports of cases and case series describing manganese toxicity. More recently,
there have been epidemiologic studies of its adverse effects on health. Occupational medicine
physicians can play critical roles in preventing the adverse health effects of manganese.
23. Levy LS, Aitken R, Holmes P, Hughes J, Hurley F, Rumsby PC, Searl A, Shuker LK,
Spurgeon A, Warren FC. (2004) The derivation of a health-based occupational exposure limit for
maganese using human neurobehaviour/neurotoxicity data. Toxicology 202(1-2): 133-134.
24. Lucchini R, Selis L, Folli D, Apostoli P, Mutti A, Vanoni O, Iregren A, Alessio L. (1995)
Neurobehavioral Effects of Manganese in Workers from a Ferroalloy Plant after Temporary
Cessation of Exposure. Scandinavian Journal of Work Environment & Health 21(2): 143-149.
Objectives The goal of this study was to assess long-term neurobehavioral effects associated
with low airborne concentrations of manganese in a ferroalloy plant. Methods During a period of
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forced cessation of work (1 to 42 d) neurobehavioral performance on tests of simple reaction
time, finger tapping, digit span, additions, symbol digit, and shapes comparison was evaluated
for 58 workers exposed from 1 to 28 (mean 13, SD 7) years to manganese. Airborne manganese
concentrations in total dust had been reduced in the last 10 years from 70-1590 mu g . m(-3)
(geometric means in different areas) to 27-270 mu g . m(-3). For each worker, manganese
concentrations in blood and urine were measured, and a cumulative exposure index was also
calculated. Results Blood manganese and urinary manganese ranged from 4 to 18 mu g . 1(-1)
(0.07 to 0.03 mu mol . 1(-1)) and from 0.7 to 7 mu g . 1(-1) (0.01 to 0.13 mu mol . 1(-1)),
respectively. Significant relationships were found between the blood manganese and urinary
manganese levels and between these biological measures and the cumulative exposure index.
Correlations were also found between the blood manganese level, the urinary manganese level,
and the cumulative exposure index and the following tests: finger tapping, symbol digit, digit
span, and additions. The correlation coefficients increased as the latency time after the cessation
of exposure and work seniority increased. Conclusions The results support the hypothesis that
the neurobehavioral effects observed at exposure levels well below current occupational
standards are related to manganese body burden, which is better reflected by the blood
manganese level after the cessation of exposure.
25. Myers JE, Thompson ML, Ramushu S, Young T, Jeebhay MF, London L, Esswein E,
Renton K, Spies A, Boulle A and others. (2003) The nervous system effects of occupational
exposure on workers in a South African manganese smelter. Neurotoxicology 24(6):885-894.
Five hundred and nine production workers at a manganese (Mn) smelting works comprising
eight production facilities and 67 external controls were studied cross-sectionally for Mn related
neurobehavioural effects. Exposure measures from personal sampling included Mn in inhalable
dust as cumulative exposure indices (CEI) and average intensity (INT). Biological exposure and
biological effect measures included blood (MnB), urine (MnU) manganese and serum prolactin.
Endpoints included items from the Swedish nervous system questionnaire (Q16), World Health
Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation
system (SPES), Luria-Nebraska (IN), and Danish product development (DPD) test batteries, and
a brief clinical examination. Potential confounders and effect modifiers included age,
educational level, alcohol and tobacco consumption, neurotoxic exposures in previous work, past
medical history, previous head injury and home language. Associations were evaluated by
multiple linear and logistic regression modelling. Modelling assumptions were tested. Average
exposure intensity across all jobs ranged from near 0 (0.06 mug/m(3)) for external controls to
5.08 mg/m(3) for inhalable Mn, and was greater than the ACGIH TLV for 69% of subjects.
Results from the large number of tests performed resolved into three groups. Group I shows
differences between external unexposed referents and all the exposed and/or differences between
internal low exposed referents and the rest of the exposed but no further exposure-response
relationships. It includes the Santa Ana, Benton and digit-span tests from the WHO NCTB; the
hand tapping and endurance tapping tests from the SPES; Luria-Nebraska item 2L; questionnaire
items tired, depressed, irritated, having to take notes in order to remember things, and subjects'
perception that they had sex less often than normal; a test of clinical abnormality; and increased
sway under two conditions (eyes open without foot insulation, eyes open with foot insulation).
Group 2 shows the presence of a more substantive exposure-response relationship. It consists of
only two tests: and includes the WHO digit-symbol test (although the major impact is at low
exposure and therefore counterintuitive, arguably placing this test in group 3) and the LN item
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IR which has a step to a poorer score at high exposure. Group 3 contains the overwhelming
majority of test results (almost all the questionnaire items, almost all the DPD tests including
tremor, sway and diadochokinesia, and serum prolactin) which were either null or
counterintuitive (did not make sense). The CEI was the strongest predictor of test abnormalities,
except for the clinical test which was more strongly associated with blood manganese. Despite a
comprehensive range of endpoints, and levels of exposure ranging from environmental to
industrial, this large study of Mn workers found little convincing
26. Nagatomo S, Umehara F, Hanada K, Nobuhara Y, Takenaga S, Arimura K, Osame M.
(1999) Manganese intoxication during total parenteral nutrition: report of two cases and review
of the literature. Journal of the Neurological Sciences 162(1): 102-105.
We report two cases of manganese (Mn) intoxication during total parenteral nutrition including
manganese (Mn). Both patients showed parkinsonism with psychiatric symptoms and elevated
serum Mn levels. Tl-weighted magnetic resonance images (MRI) revealed symmetrical high
intensity lesions in the globus pallidus. Discontinuation of Mn supplementation and levodopa
treatment improved the symptoms and MRI abnormalities in the both patients. Thus, careful
attention should be paid to the long-term intravenous administration of Mn. (C) 1999 Elsevier
Science B.V. All rights reserved.
27. Ohtake T, Negishi K, Okamoto K, Oka M, Maesato K, Moriya H, Kobayashi S. (2005)
Manganese-induced parkinsonism in a patient undergoing maintenance hemodialysis. American
Journal of Kidney Diseases 46(4):749-753.
We report a rare case of manganese (Mn)-induced parkinsonism in a patient on maintenance
hemodialysis therapy who complained of gait disturbance and dysarthria. His symptoms and
abnormal magnetic resonance imaging (MRI) findings of the brain were thought to be caused, at
least in part, by long-term ingestion of a health supplement (Chlorella extract) that contained 1.7
mg of Mn in the usual daily dose. Elevated serum and cerebrospinal fluid Mn levels were
detected, and brain MRI showed areas of abnormal intensity in the bilateral basal ganglia (low
intensity on Tl-weighted images and high intensity on T2-weighted images). Edetic acid
infusion therapy dramatically improved the MRI abnormalities, after which his symptoms
gradually improved 4 months later.
28. Pal PK, Samii A, Calne DB. (1999) Manganese neurotoxicity: A review of clinical features,
imaging and pathology. Neurotoxicology 20(2-3):227-238.
Manganese intoxication can result in a syndrome of parkinsonism and dystonia. If these
extrapyramidal findings are present, they are likely to be irreversible and even progress after
termination of the exposure to manganese. Clinical features are usually sufficient to distinguish
these patients from those with Parkinson's disease. The neurological syndrome does not respond
to levodopa. Imaging of the brain may reveal MRI signal changes in the globus pallidus,
striatum, and midbrain. Positron emission tomography reveals normal presynaptic and
postsynaptic nigrostriatal dopaminergic function. The primary site of neurological damage has
been shown by pathological studies to be the globus pallidus. The mechanism of toxicity is not
clear. (C) 1999 Inter Press, Inc.
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29. Roels HA, Eslava MIO, Ceulemans E, Robert A, Lison D. (1999) Prospective study on the
reversibility of neurobehavioual effects in workers exposed to manganese dioxide.
Neurotoxicology 20(2-3):255-271.
In 1987, a cross-sectional study in a dry-alkaline battery plant in Belgium revealed subclinical
neurobehavioral dysfunctions associated with inhalation exposure to manganese dioxide (Mn02)
particulate. The overall geometric mean of the time-weighted average concentration of
manganese (Mn) in "total" dust (MnT) amounted, at that time, to 1 mg Mn/m(3) and the duration
of exposure was 5.5 years on average. An 8-year longitudinal investigation was conducted in this
cohort (n = 92) in order to iind out whether early effects on eye-hand coordination (EHC), hand
steadiness (HST), and simple visual reaction time (VRT) were reversible when the airborne
manganese concentration at the workplace was abated. During the observation period from 1988
to 1995, MnT monitoring was implemented on a monthly basis producing more than 1300
personal air samples, EHC tests were given yearly to assess the precision of the hand-forearm
movement (PN1), and HST and VRT tests were carried out yearly since 1991. By the end of the
study, the cohort size had dropped to 34 subjects. The model of unbalanced repeated
measurements with unstructured covariance matrix and a time-varying covariate (log MnT) was
the most appropriate to analyze the data. Wald chi(2) statistic was used for testing time-trends.
The reduction of MnT over time was significantly associated with an improvement of the PN1
values (total cohort: Wald chi(2) = 8.5, p=0.004; beta(log MnT) = -6.098 +/- 2.096). Like in the
total cohort, time-trends were also found in the three exposure subgroups which could be
identified in the cohort (average MnT over 1987-1992 were about 400, 600, and 2000 mu g
Mn/m(3) for the low, medium, and high exposure subgroups, respectively). Only in the low
exposure subgroup the PN 1 value normalized when MnT(provisional estimates) decreased from
about 400 to 130 mu g Mn/m3 by the end of the study. Solely the reduction in MnT explained
these findings on PN1, while a "healthy-worker-effect" mechanism was unlikely to have
operated. The prognosis for the medium and high exposure subgroups remains uncertain as the
improvement of their EHC performance may have been affected by past Mn02 exposure to such
an extent that the persistence of a partial loss of EHC ability is suggested. The time courses of
the HST and VRT test results, however, indicated the absence of any improvement, suggesting
irreversible impairment of hand stability (postural tremor) and simple visual reaction time. A
separate examination in a group of 39 control subjects, re-tested 10 years alter the first test in
1987, virtually precluded age as confounding factor in this prospective study. The findings of the
longitudinal study are corroborated by the outcome of a separate follow-up study in a group of
24 ex-Mn employees, who showed in 1996 a significant improvement of eye-hand coordination
alter at least three years with no Mn02 exposure; as to HST and VRT; there was no significant
change in the deficit of these two neurobehavioral markers. (C) 1999 Inter Press, Inc.
30. Vieregge P, Heinzow B, Korf G, Teichert HM, Schleifenbaum P, Mosinger HU. (1995)
Long-Term Exposure to Manganese in Rural Well Water Has No Neurological Effects. Canadian
Journal of Neurological Sciences 22(4):286-289.
Background: There is debate on the neurological impact of chronic exposure to Manganese
(MN), Methods: MN burden from rural well water was studied cross-sectionally in two proband
cohorts from rural dwellings located in northern Germany. Both cohorts had exposure times for
up to 40 years and were separated on the basis of well water MN content, Group A (41 subjects;
mean age 57.5 years) was exposed to MN water contents of at least 0.300 mg/1 (range 0.300 to
2.160), while group B (74 subjects; mean age 56.9 years) was exposed to concentrations of less
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than 0.050 mg/1. Both proband groups were homogenous with regard to age, sex, nutritional
habits, and drug intake. Neurological assessments by clinical investigators blinded for proband's
exposure status was done using structured questionnaires, standardized neurological examination
with assessment of possible Parkinsonian signs by the Columbia University Rating Scale, and
instrumental tests of fine motor coordination. Results: No significant difference in any
neurological measure was found between groups. Results were not confounded by demographic
and dietary features. Conclusion: Exposure to high body burden of MN does not result in
detectable neurological impairment, Exposure to MN in drinking water does not seem to be a
risk factor for idiopathic Parkinson's disease.
31. Walczak, Jakubowski M, Matczak W. (2001) Neurological and neurophysiological
examinations of workers occupationally exposed to manganese. International Journal of
Occupational Medicine and Environmental Health 2001, Vol. 14, No. 4, p. 329-337. 16 ref.
To assess the effects of manganese on the functions of the nervous system in exposed workers in
the shipbuilding and electrical industries, 75 male workers, 62 welders and fitters and 13 workers
involved in battery production, were studied. The control group consisted of 62 non-exposed
men matched by age and work shift distribution. Of the 62 welding workers, 30 worked in the
area with Mn concentrations exceeding the MAC value of 0.3mg/m3. In battery production, six
subjects were subject to concentrations exceeding MAC values. Clinically, the increased
emotional irritability, dysmnesia, concentration difficulties, sleepiness and limb paresthesia
predominated among the disorders of the nervous system functions in exposed workers.
Generalized and paroxysmal changes were the most common recordings in the abnormal
electroencephalography. Visual evoked potentials examinations showed abnormalities which
could be a signal of the optic neuron disorders. The results show that manganese exposures
within the range of < 0.01-2.67mg/m3 can induce sub-clinical effects on the nervous system.
32. Wirth JJ, Rossano MG, Daly DC, Paneth N, Puscheck E, Potter RC, Diamond MP. (2007)
Ambient manganese exposure is negatively associated with human sperm motility and
concentration. Epidemiology 18(2):270-273.
Background: Occupational and experimental animal studies indicate that exposure to high levels
of manganese impairs male fertility, but the effects of ambient manganese in humans are not
known. Methods: We measured blood levels of manganese and selenium in 200 infertility clinic
clients in a cross-sectional study. Correlations between metals and semen variables were
determined, adjusting for other risk factors. Outcomes were low motility (< 50% motile), low
concentration (< 20 million/mL), or low morphology (< 4% normal). We also investigated dose-
response relationships between quartiles of manganese exposure and sperm parameters. Results:
High manganese level was associated with increased risk of low sperm motility (odds ratio = 5.4;
95% confidence interval = 1.6-17.6) and low sperm concentration (2.4; 1.2-4.9). We saw a U-
shaped dose-response pattern between quartiles of manganese exposure and all 3 sperm
parameters. Conclusion: Ambient exposure to manganese levels is associated with a reduction in
sperm motility and concentration. No adverse effects were seen for high selenium.
33. Young T, Myers JE, Thompson ML. (2005) The nervous system effects of occupational
exposure to manganese - Measured as respirable dust - in a South African manganese smelter.
Neurotoxicology 26(6):993-1000.
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Objectives: A major recent review of occupational exposure limits for manganese (Mn) has
proposed a respirable dust level of 0.1 mg/m(3). There is, however no theoretical basis for using
this exposure metric to estimate the systemic effects of Mn, and little in the way of empirical
data relating respirable Mn to neurobehavioural and other non-pulmonary effects. Cross-
sectional data from a study showing few and unconvincing neurobehavioural effects of inhalable
dust in Mn smelter workers published just prior to this review were reanalyzed here using
respirable Mn. The hypotheses tested were that respirable Mn exposure is a more appropriate
predictor of neurobehavioural effects than inhalable Mn where such effects exist, and that there
should be no observed effects at respirable dust levels below 0.1 mg/m(3). Methods: Five
hundred and nine production workers and 67 external referents were studied. Exposure measures
from personal sampling included the Mn content of respirable dust as a concentration-time
integrated cumulative exposure index (CEI) and as average intensity (INT) over a working
lifetime. Neurobehavioural endpoints included items from the Swedish nervous system
questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO
NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish
product Development (DPD) test batteries, and a brief clinical examination. Results: The median
respirable Mn exposure was 0.058 mg/m(3) (range = 0-0.51; IQR = 0.02-0.16) amongst the
exposed, with 30% having average intensities above the proposed 0.1 mg/m(3) and 44% above
the proposed supplemental limit of 0.5 mg/m(3) inhalable dust. As in the study of inhalable Mn
effects, there were few respirable Mn effects showing clear continuity of response with
increasing exposure. Conclusion: These data did not provide empirical support for a respirable,
as opposed to an inhalable, dust metric being more sensitive in the identification of Mn effects.
Neither metric showed convincing effects within the exposure range studied. Further study is
needed to determine a threshold for respirable Mn effects, if such exist, and to verify our
findings, (c) 2005 Elsevier Inc. All rights reserved.
34. Yuan H, He SC, He MW, Niu Q, Wang L, Wang S. (2006) A comprehensive study on
neurobehavior, neurotransmitters and lymphocyte subsets alteration of Chinese manganese
welding workers. Life Sciences 78(12): 1324-1328.
The neurotoxicity of manganese has been demonstrated by many researches. But few reports
have been found on its immunotoxicity in manganese-exposed workers. Here we selected
welding workers (aged 34 years) as Mn-exposed subjects. They have been exposed to
manganese for 16 years. The control group was from a flour plant. The average concentrations of
Mn, Cd, Fe andNi in work place were 138.40 +/- 11.60 mu g/m(3), 581.40 +/- 45.32 mu g/m(3),
3.84 +/- 0.53 mu g/m(3) and 12.64 +/- 2.80 ng/m(3), respectively. Blood Mn (4.84 mu g/dl) of
welding workers was higher than that of the control group (1.92 mu g/dl). Neurobehavioral core
test battery (NCTB) recommended by WHO was conducted on the subjects and found that the
scores of negative emotions, such as confusion-bewilderment, depression-dejection, fatigue-
inertia, and tension-anxiety, were higher in welding workers. Visual simple reaction time and the
fast simple reaction time were shorter than that of the control group. The numbers of digital
span, forward digital span, backward digital span and digital symbol decreased in welding
workers compared with control group. Monoamine neurotransmitters and their metabolism
substances in urine were tested by HPLC-ultraviolet. NE, E, MHPG, HVA, DA, DOPAC and 5-
HT in the urine of Mn-exposed group had no significant changes while 5-HIAA in Mn-exposed
group had significantly decreased compared with that of the control group. Lymphocyte subsets
of the subjects were determined by Flow Cytometer. CD3(+) T cell, CD4(+)CD8(-) T cell,
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CD4(-)CD8(+) T cell, CD4(+)CD45RO(-) "virgin" lymphocytes, CD4(+)CD45RO(+) "memory"
lymphocytes, and CD3(-)CD19(+) B cell had no significant changes compared with the control
group. The results showed that long-term exposure to manganese in welding might have adverse
effects on mood state, neurobehavior, and peripheral neurotransmitters. However, they had no
effects on lymphocyte subsets parameters, (c) 2005 Elsevier Inc. All rights reserved.
Supporting References (57)
1. Alves G, Thiebot J, Tracqui A, Delangre T, Lerebours E, et al. (1997) Neurologic disorders
due to brain manganese deposition in a jaundiced patient receiving long term parenteral
nutrition. JPEN J. Parenter. Enteral Nutr. 21(Jan-Feb):41-45.
2. Azin F, Raie RM, Mahmoudi MM. (1998) Correlation between the levels of certain
carcinogenic and anticarcinogenic trace elements and esophageal cancer in northern Iran.
Ecotoxicology and Environmental Safety 39(3): 179-184.
Levels of four carcinogenic (Ni, Fe, Cu, Pb) and four anticarcinogenic (Zn, Se, Mn, Mg) trace
elements were measured in hair samples from esophageal cancer patients, their unaffected family
members, and members of families with no history of cancer. Measurements were also made in
non-esophageal cancer patients, using atomic absorption spectroscopy, inductively coupled
plasma-emission spectroscopy, and neutron activation analysis. The results showed thatNi and
Cu concentrations were significantly higher and Mg and Mn concentrations were significantly
lower in all cancer cases. Levels of Zn, Fe, Se, and Pb were not significantly different in the
above-mentioned groups. In addition, the serum albumin fraction, which is reported to have
antioxidant activity, was found to be significantly lower among esophageal cancer patients. (C)
1998 Academic Press.
3. Barbee JY, Prince TS. (1999) Acute respiratory distress syndrome in a welder exposed to
metal fumes. Southern Medical Journal 92(5):510-512.
A 43-year-old man began having malaise, chills, and fever 12 hours after cutting a galvanized
steel grating with an acetylene torch at work. Over the next 72 hours, his symptoms persisted and
became worse with progressive shortness of breath. We was admitted to the hospital and begun
on antibiotics and steroids. The next day his condition had deteriorated to the point that he had to
he intubated, Chest x-ray film and computed tomography showed patchy and interstitial
infiltration bilaterally, consistent with acute respiratory distress syndrome. Open lung biopsy
showed focal mild interstitial pneumonia. Multiple laboratory studies were negative for an
infectious or an immune process. The patient remained on mechanical ventilation for 10 days
and was discharged from the hospital 2 days after extubation. He continued to improve, with
minimal symptoms and a return to normal activity levels several months after the incident with
no continued treatment. Re-creation of his exposure was done under controlled circumstances,
with air sampling revealing elevated air levels for cadmium and zinc and borderline levels of
arsenic, manganese, lead, and iron.
4. Barrington WW, Angle CR, Willcockson NK, Padula MA, Korn T. (1998) Autonomic
function in manganese alloy workers. Environmental Research 78(l):50-58.
The observation of orthostatic hypotension in an index case of manganese toxicity lead to this
prospective attempt to evaluate cardiovascular autonomic function and cognitive and emotional
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neurotoxicity in eight manganese alloy welders and machinists. The subjects consisted of a
convenience sample consisting of an index case of manganese dementia, his four co-workers in a
"frog shop" for gouging, welding, and grinding repair of high manganese railway track and a
convenience sample of three mild steel welders with lesser manganese exposure also referred
because of cognitive or autonomic symptoms. Frog shop air manganese samples 9.6-10 years
before and 1.2-3.4 years after the diagnosis of the index case exceeded 1.0 mg/m(3) in 29% and
0.2 mg/m(3) in 62%. Twenty-four-hour electrocardiographic (Holter) monitoring was used to
determine the temporal variability of the heartrate (RR' interval) and the rates of change at low
frequency (0.04-0.15Hz) and high frequency (0.15-0.40Hz). MMPI and MCMI personality
assessment and shortterm memory, figure copy, controlled oral word association, and symbol
digit tests were used. The five frog shop workers had abnormal sympathovagal balance with
decreased high frequency variability (increased In LF/ln HF). Seven of the eight workers had
symptoms of autonomic dysfunction and significantly decreased heart rate variability (rMSSD)
but these did not distinguish the relative exposure. Mood or affect was disturbed in all with
associated changes in short-term memory and attention in four of the subjects. There were no
significant correlations with serum or urine manganese. Power spectrum analysis of 24-h
ambulatory ECG indicating a decrease in parasympathetic high frequency activation of heart rate
variability may provide a sensitive index of central autonomic dysfunction reflecting increased
exposure to manganese, although the contribution of exposures to solvents and other metals
cannot be excluded. Neurotoxicity due to the gouging, melding, and grinding of mild steel and
high manganese alloys (11-25%) merits air manganese and neuropsychologic surveillance
including autonomic function by Holter monitoring of cardiovagal activation. (C) 1998
Academic Press.
5. Beath. (1996) Manganese toxicity and parenteral nutrition (vol 347, pg 1773, 1996). Lancet
348(9024):416-416.
6. Beuter A, Edwards R, De Geoffroy A, Mergler D, Hudnell K. (1999) Quantification of
neuromotor function for detection of the effects of manganese. Neurotoxicology (Little Rock)
20(2-3):355-366.
BIOSIS COPYRIGHT: BIOL ABS. The effect of low level exposure to manganese (Mn) was
examined in 297 subjects from southwest Quebec. Blood manganese (MnB) levels as well as
other possibly relevant variables were obtained. We tested equipment and analysis procedures
that we have developed to quantify aspects of motor function thought to be affected by exposure
to toxins, in particular, rapid alternating movements, rapid and precise pointing movements, and
tremor. (1) The eurythmokinesimeter measures timing and precision of co kinesimeter accurately
measures rapid rotation of the forearms (pronation/supination). Characteristics quantifying the
range, speed, period, shape and regularity of the oscillatory movements were calculated, as well
as the smoothness of the movement on a fine scale and the coordination between the two hands.
(3) Postural tremor of the arm and hand was measured using the accelerometry-based
"TREMOR" system of Danish Product Development. We used the amplitude and frequency
characte
7. Bocca B, Alimonti A, Bomboi G, Giubilei F, Forte G. (2006) Alterations in the level of trace
metals in Alzheimer's disease. Trace Elements and Electrolytes 23(4):270-276.
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In the present study, serum and blood trace elements and oxidative status in Alzheimer's disease
patients and healthy individuals were compared in order to identify possible biomarkers of the
disease. A Sector Field Inductively Coupled Plasma Mass Spectrometry (SF-ICP-MS) method
was developed for the determination of Al, Ba, Be, Bi, Cd, Co, Cr, Hg, Li, Mn, Mo, Ni, Pb, Sb,
Sn, Sr, Tl, V, W and Zr. Pre-treatment procedures based on high sample throughput, procedural
simplicity and low contamination risk were utilized. The following significant imbalances in
Alzheimer's disease were found: increment of Hg and Sri in serum (p <= 0.01), higher levels of
Co, Li, Mn and Sri and lower levels of Mo in blood (p < 0.01), increased formation of serum
oxidant species (SOS) and decreased antioxidant capacity (SAC) (p < 0.001).
8. Bouchard M, Mergler D, Baldwin M. (2005) Manganese exposure and age: neurobehavioral
performance among alloy production workers. Environmental Toxicology and Pharmacology
19(3):687-694.
Manganese (Mn) is associated with neurotoxic effects under certain conditions of exposure. A
recent study on environmental Mn exposure showed an Mn x age interaction for several
neurobehavioral functions. The objective of the present study was to examine the
neurobehavioral test results in relation to age and Mn exposure, using an existing data set on 74
workers from an Mn alloy production plant and referents pair-matched for age (&PLUSMN; 3
years), educational level (&PLUSMN; 2 years), number of children, and smoking status. The
pair differences between Mn-exposed workers and referents increased significantly with age for
scores on Delayed Word Recall, Trail Making B, Cancellation H, Nine-Hole Hand Steadiness
Test, and Vibratometer. These results suggest that for certain neurobehavioral functions, and in
particular for information processing, Mn-related deficits increase with age. This outcome could
not be explained by higher cumulative Mn exposure. © 2005 Elsevier B.V. All rights
reserved.
9. Chia SE, Gan SL, Chua LH, Foo SC, Jeyaratnam J. (1995) Postural stability among
manganese exposed workers. Neurotoxicology (Little Rock) 16(3):519-526.
BIOSIS COPYRIGHT: BIOL ABS. Postural stability was investigated by static posturography
in 32 manganese exposed workers with exposure duration of 6.6 (range 1.1-15.7) years and 53
referent subjects. The mean current urine manganese concentration for the exposed was 6.0
mug/g creatinine (range 0.6 to 53.3). There was no significant differences between both groups
for the postural sway parameters obtained during eyes open condition. However, significant
differences were observed for L - length of sway path and Vel - mean velocity of the center of
pressure along its path. The Romberg Ratios (the relationship between eyes closed/open
conditions) for the exposed's Vel, L, and Ao were also significantly different from the referent.
The study showed that manganese exposed workers had significantly poorer postural stability
compared to a referent group. We postulate that this could be a subclinical effect of manganese
on the basal ganglia (pallidus) resulting in the postural instability when the visual in
10. Crump KS, Rousseau P. (1999) Results from eleven years of neurological health
surveillance at a manganese oxide and salt producing plant. Neurotoxicology (Little Rock) 20(2-
3):273-286.
BIOSIS COPYRIGHT: BIOL ABS. In 1983, Roels et al. (1987a,b) collected blood and urine
samples and conducted neurological testing of workers at a manganese oxide and salt producing
plant in Belgium, and at a nearby chemical plant. Workers from the manganese plant performed
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significantly worse than workers from the chemical plant on tests of short-term memory
capacity, eye-hand coordination, hand steadiness, and visual reaction time. Between 1985 and
1996, workers at the manganese plant were tested routinely using the same b osed longer. Large
year-to-year differences were observed in some neurological test outcomes that could not be
explained by age or Mn exposure. Older age was significantly associated with poorer
performance on tests of short-term memory and eye-hand coordination. After controlling for age
and year of testing, reduced hand steadiness was significantly associated with blood Mn and
(marginally) urine Mn, and both reaction time and one measure of hand steadiness were
significantly as
11. Degner D, Bleich S, Riegel A, Sprung R, Poser W, Ruther E. (2000) A follow-up study in
enteral manganese intoxication: clinical, laboratory, and neuroradiological aspects. Nervenarzt
71 (5):416-419.
Manganese intoxication is an unusual, severe form of intoxication. This report deals with a
patient now 80 years old who accidentally ingested a solution of potassium permanganate for a
period of at least 4 weeks 14 years ago. Since then, the patient suffers from a mild parkinsonian
syndrome and distally accentuated polyneuropathies. Psychiatric disorders, especially demential
or depressive symptoms, were not observed. Manganese analysis of his hair still shows a clear
increase in manganese concentration. The MRI of his brain showed no pathological changes, in
particular none of those often described with symmetric signal elevation in T-l in the area of the
basal ganglia. In this study, we present clinical, laboratory, and neuroradiological findings.
Unusual in this case with a short exposition is the long duration and clinical improvement
without I-dopa treatment.
12. Ericson JE, Crinella FM, Clarke-Stewart KA, Allhusen VD, Chan T, Robertson RT. (2007)
Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicology and
Teratology 29(2): 181-187.
Although manganese (Mn) is an essential mineral, high concentrations of the metal can result in
a neurotoxic syndrome affecting dopamine balance and behavior control. We report an
exploratory study showing an association between Mn deposits in tooth enamel, dating to the
20th and 62-64th gestational weeks, and childhood behavioral outcomes. In a sample of 27
children, 20th week Mn level was significantly and positively correlated with measures of
behavioral disinhibition, specifically, play with a forbidden toy (36 months), impulsive errors on
a continuous performance and a children's Stroop test (54 months), parents' and teachers' ratings
of externalizing and attention problems on the Child Behavior Checklist (1st and 3rd grades),
and, teacher ratings on the Disruptive Behavior Disorders Scale (3rd grade). By way of contrast,
Mn level in tooth enamel formed at the 62-64th gestational week was correlated only with
teachers' reports of externalizing behavior in 1st and 3rd grades. Although the source(s) of Mn
exposure in this sample are unknown, one hypothesis, overabsorption of Mn secondary to
gestational iron-deficiency anemia, is discussed, (c) 2006 Elsevier Inc. All rights reserved.
13. Forte G, Bocca B, Senofonte O, Petrucci F, Brusa L, Stanzione P, Zannino S, Violante N,
Alimonti A, Sancesario G. (2004) Trace and major elements in whole blood, serum,
cerebrospinal fluid and urine of patients with Parkinson's disease. Journal of Neural
Transmission 111(8): 1031-1040.
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Quantifications of Al, Ca, Cu, Fe, Mg, Mn, Si and Zn were performed in urine, serum, blood and
cerebrospinal fluid (CSF) of 26 patients affected by Parkinson's disease (PD) and 13 age-
matched controls to ascertain the potential role of biological fluids as markers for this pathology.
Analyses were performed by Inductively Coupled Plasma Atomic Emission Spectrometry and
Sector Field Inductively Coupled Plasma Mass Spectrometry. The serum oxidant status (SOS)
and anti-oxidant capacity (SAC) were also determined. Results showed a decreasing trend for Al
in all the fluids of PD patients, with the strongest evidence in serum. Calcium levels in urine,
serum and blood of PD patients were significantly higher than in controls. Copper and Mg
concentrations were significantly lower in serum of PD patients. Levels of Fe in urine, blood and
CSF of patients and controls were dissimilar, with an increase in the first two matrices and a
decrease in CSF. No significant difference was found in levels of Mn between patients and
controls. Urinary excretion of Si was significantly higher in PD subjects than in controls. No
clear difference between Zn levels in the two groups was found for serum, urine or CSF, but an
increase in Zn levels in the blood of PD patients was observed. The SOS level in PD was
significantly higher while the corresponding SAC was found to be lower in patients than in
controls, in line with the hypothesis that oxidative damage is a key factor in the pathogenesis of
PD. The results on the whole indicate the involvement of Fe and Zn (increased concentration in
blood) as well as of Cu (decreased serum level) in PD. The augmented levels of Ca and Mg in
the fluids and of Si in urine of patients may suggest an involuntary intake of these elements
during therapy.
14. Fortoul TI, Mendoza ML, Avila MD, Torres AQ, Osorio LS, Espejel GM, Fernandez GO.
(2001) Manganese in lung tissue: Study of Mexico City residents' autopsy records from the
1960s and 1990s. Archives of Environmental Health 56(2): 187-190.
During the conduct of autopsies performed on residents of Mexico City during the 1960s (20
males, 19 females) and 1990s (30 males and 18 females), concentrations of manganese in lung
were studied with atomic absorption spectrometry. Concentrations of manganese were not
significantly greater in the samples obtained in the 1990s (1.87 +/- 0.8 mug/gm [mean +/-
standard deviation]) than in samples from the 1960s (1.72 +/- 1.2 mug/gm). Concentrations were
not correlated with gender, smoking habit, age, or cause of death; however, there was a
correlation with occupation. The findings suggest that manganese exposure via air does not
represent a health hazard to residents of Mexico City, given that lung concentrations of
manganese remained stable during the 30-y period studied. Investigators should monitor
concentrations of manganese in suspended particles to follow-up on these findings.
15. Fredstrom S, Rogosheske J, Gupta P, Burns LJ. (1995) Extrapyramidal Symptoms in a Bmt
Recipient with Hyperintense Basal Ganglia and Elevated Manganese. Bone Marrow
Transplantation 15(6):989-992.
Neurologic syndromes attributed to conditioning or medications have been reported in BMT
recipients. A patient is presented who developed extrapyramidal symptoms on day +56 after
allogeneic BMT. Brain magnetic resonance images of this patient demonstrated hyperintense
basal ganglia, which has been associated with manganese (Mn) toxicity. The patient had
received total parenteral nutrition (TPN) with standard trace element supplementation and had
been cholestatic. Serum Mn was elevated, and continued to be so 5 months after BMT, long after
discontinuation of TPN. Cholestatic patients and those on long-term TPN have been found to
have high blood or serum levels of Mn, but generally are asymptomatic, When other cholestatic
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BMT patients were reviewed, all had elevated serum Mn. Manganese supplementation in TPN
requires evaluation for BMT recipients.
16. Goldman SM, Quinlan PJ, Smith AR, Langston J, Tanner CM. (2004) Manganese exposure
and risk of Parkinson's disease in twins. Movement Disorders 19:S162-S162.
17. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ.
(1997) Occupational exposures to metals as risk factors for Parkinson's disease. Neurology
48(3):650-658.
In a population-based case-control study, we investigated the potential role of occupational
exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's
disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and
controls (n = 464) consisting of men and women greater than or equal to 50 years of age,
frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary
medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects
were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs
held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-
control status of subjects, rated occupational exposure to each of the metals of interest. When
adjusted for sex, race, age, and smoking status, we found in those with more than 20 years'
exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06,
5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to
combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI
= 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association
with PD than with any of these metals alone. These findings suggest that chronic exposure to
these metals is associated with PD, and that they may act alone or together over time to help
produce the disease.
18. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ.
(1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of
Parkinson's disease. Neurotoxicology 20(2-3):239-247.
A population-based case-control study was conducted in the Henry Ford Health System (HFHS)
in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron,
mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50
years of age who were receiving primary medical care at HFHS were recruited, and concurrently
enrolled cases (n = 744) and controls (n = 464) were frequency-matched for sex, race and age
(+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about
every job held by each subject for 6 months from age 18 onward, including a detailed assessment
of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to
subjects' case-control status, used these data to rate every job as exposed or not exposed to one
or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of
occupational exposure to any metal was not associated with PD. However, more than 20 years
exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83)
or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for >
20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59,17.21), lead-iron (OR =
2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 7.40, 9.71) was also
associated with the disease. No association of occupational exposure to iron, mercury or zinc
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with PD was found. A lack of statistical power precluded analyses of metal combinations for
chose with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings
suggest that chronic occupational exposure to manganese or copper, individually, or to dual
combinations of lead iron and copper, is associated with PD. (C) 1999 Infer Press, Inc.
19. Gorell JM, Rybicki BA, Johnson CC, Peterson EL. (1999) Occupational metal exposures
and the risk of Parkinson's disease. Neuroepidemiology 18(6):303-308.
Occupational exposure to specific metals (manganese, copper, lead, iron, mercury, zinc,
aluminum and others) appears to be a risk factor for Parkinson's disease (PD) in some, but not
all, case-control studies. These epidemiological studies are reviewed. Several methodological
issues that may account for the lack of unanimity of findings are discussed, and suggestions for
improved case-control methodology are offered. The study of the neurological disease outcome
of workers who have had long-term, well-defined occupational exposure to one or more metals is
also urged, with collaborative work including industrial hygienists, occupational toxicologists,
neurologists, epidemiologists and biostatisticians. Such efforts, employing state-of-the-art case
and control ascertainment and enrollment from suitable population bases, neurological
diagnostic rigor and exposure assessment, will help to further define the potentially important
roles played by metals in PD and other neurodegenerative disorders.
20. Greiffenstein MF, Lees-Haley PR. (2007) Neuropsychological correlates of manganese
exposure: A meta-analysis. Journal of Clinical and Experimental Neuropsychology 29(2): 113-
126.
The hypothesized effect of recurrent low-dose manganese (Mn) exposure on neuropsychological
function is controversial because of inconsistent findings across three decades of research. We
conducted a meta-analysis on 41 variables from nineteen neuropsychological studies of Mn-
exposed workers. The results showed: Large effect size (ES) for biological markers of Mn and
lead levels; thirteen of 26 neurocognitive measures showing a small average ES; only one of 26
tasks showed a moderate ES; and small to medium ES for confounding/competing variables such
as education and aptitude. Tasks with the highest ES included clerical substitution tasks, digit
span, tapping endurance, and Swedish Performance Evaluation System "Additions" reaction
time, but none exceeded the ES for education or aptitude. The mean ES of dose-response
relationships was zero. The data did not support a theory of preclinical ("early") neuromotor or
cognitive dysfunction. Overall, the pooled data are more consistent with covariate effect than
toxic effect, insofar as the pooled exposure group showed demographics less favorable to
neuropsychological performance than the pooled referent groups. Future consideration of
demographic and biological covariates is necessary before inferring subtle toxin-induced brain
damage because neuropsychological tests are nonspecific.
21. Ha@l/atek T, Sinczuk-Walczak H, Szymczak M, Rydzynski K. (2005) Neurological and
respiratory symptoms in shipyard welders exposed to manganese. International Journal of
Occupational Medicine and Environmental Health 3rd quarter 2005, Vol. 18, No. 3, p. 265-274.
Illus. 51 ref.
This case-control study was performed to assess the use of neurophysiological tests for the
detection of early effects of exposure to low manganese concentrations and to examine the use of
Clara cell protein (CC16) as an early pulmonary biomarker of exposure to welding fumes. The
study involved 59 shipyard welders and 23 controls, matched by age and smoking habits.
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Subjective neurological symptoms, visual evoked potentials and electroencephalography were
examined. Relationships between manganese concentrations in the air, blood and urine as well as
between cumulative exposure indices were investigated. CC16 as an early pulmonary biomarker
in welding exposure was examined by immunoassay. Findings are discussed. It was confirmed
that these sensitive tests could be used for the detection of early effect of exposure to low
manganese concentrations.
22. Hernandez EH, Discalzi G, Dassi P, Jarre L, Pira E. (2003) Manganese intoxication: The
cause of an inexplicable epileptic syndrome in a 3 year old child. Neurotoxicology 24(4-5):633-
639.
Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have
reported epileptic syndromes related to manganese intoxication. We describe an epileptic
syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was
elevated, but no other abnormal values or toxic substances were found in blood or urine. The
electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain
magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status
despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to
remove excess manganese and promptly succeeded in reverting epileptic symptoms.
Concurrently, manganese blood levels and electroencephalogram progressively normalized.
Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in
excellent conditions without any treatment. (C) 2003 Elsevier Science Inc. All rights reserved.
23. Hobbesland A, Kjuus H, Thelle DS. (1999) Study of cancer incidence among 6363 male
workers in four Norwegian ferromanganese and silicomanganese producing plants. Occupational
and Environmental Medicine 56(9):618-624.
Objectives-Little has been known about the risk of cancer associated with occupational exposure
to manganese. The objective of this study was therefore to examine the associations between
duration of specific work and cancer incidence among employees in four Norwegian
ferromanganese and silicomanganese producing plants. Methods-Among men first employed in
1933-91 and with at least 6 months in these plants, the incident cases of cancer during 1953-91
were obtained from The Cancer Registry of Norway. The numbers of various-cancers were
compared with expected figures calculated from age and calendar time specific rates for
Norwegian men during the same period. Internal comparisons of rates were performed urith
Poisson regression analysis. The final cohort comprised 6363 men. Results-A total of 607 cases
of cancer were observed against 596 cases expected (standardised incidence ratio (SIR) 1.02).
Internal comparisons of rates showed a positive trend between the rate of all cancers and
duration of furnace work, A slightly weaker trend was also found for duration of blue collar non-
furnace work when lags of 25 or 30 years were applied in the annalyses. However, several
results indicated that the incidence of all cancers among the non-furnace workers decreased
during the period of active employment. Conclusions-Furnace and non-furnace workers may
have exposures that increase the incidence of several cancers. The low incidence of cancer
among non-furnace workers during the period of ongoing exposure cannot be explained. As this
study cannot identify any causal factors, the role of exposure to manganese remains unclear.
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24. Hossny E, Mokhtar G, El-Awady M, El-Wahab AA. (1998) Serum manganese deficiency in
Egyptian children with bronchial asthma. Journal of Allergy and Clinical Immunology
101(1):S117-S117.
25. Hsieh CT, Liang JS, Peng SSF, Lee WT. (2007) Seizure associated with total parenteral
nutrition-related hypermanganesemia. Pediatric Neurology 36(3): 181-183.
The trace element manganese is usually supplied when total parenteral nutrition is used.
However, long-term parenteral administration of manganese, which bypasses the normal,
regulatory mechanism, may cause hypermanganesemia. Manganese poisoning presents clinically
with parkinsonian-like symptoms and psychological changes. Seizures are a rare presentation of
this disease. This report describes a 10-year-old female who had received total parenteral
nutrition for 3 months because of short bowel syndrome, and presented with tonic-clonic seizure,
decreased level of consciousness, and fever. The serum electrolytes, glucose and the
cerebrospinal fluid examination were normal. The blood culture grew Pantoea agglomerans. The
brain magnetic resonance imaging disclosed no evidence of central nervous system infection.
However, symmetric high-intensity signal on T-l-weighted images was documented in the basal
ganglia, especially in the globus pallidus. Her whole blood manganese level was 3.7 mu g/dL,
which was significantly higher than the normal range (0.4-1.4 mu g/dL). Diagnosis of
hypermanganesemia related to total parenteral nutrition was made, (c) 2007 by Elsevier Inc. All
rights reserved.
26. Jimenezjimenez FJ, Molina JA, Aguilar MV, Arrieta FJ, Jorgesantamaria A, Cabreravaldivia
F, Ayusoperalta L, Rabasa M, Vazquez A, Garciaalbea E and others. (1995) Serum and Urinary
Manganese Levels in Patients with Parkinsons-Disease. Acta Neurologica Scandinavica
91(5):317-320.
To elucidate the possible role of manganese in the risk of developing Parkinson's disease (PD),
we compared serum levels of manganese, and 24-h manganese excretion by urine in 29 PD
patients and in 27 matched controls. We also measured chromium and cobalt in the same
samples. All these values did not differ significantly between the groups, they were not
influenced by antiparkinsonian drugs, and they did not correlate with age, age at onset and
duration of the PD, scores of the Unified PD Rating Scale or the Hoehn and Yahr staging in the
PD group. These results might suggest that serum levels and urinary excretion of manganese are
apparently unrelated to the risk of developing PD.
27. Kenangil G, Ertan S, Sayilir I, Ozekmekci S. (2006) Progressive motor syndrome in a
welder with pallidal T1 hyperintensity on MRI: A two-year follow-up. Movement Disorders
21(12):2197-2200.
Chronic exposure to manganese (Mn) fume during welding may lead to mainly extrapyramidal
syndrome that is resistant to treatment. We present a 32-year-old patient who developed severe
postural instability, Parkinsonism, dystonia, and pyramidal signs in the 10th year of welding.
The neurological condition of the patient worsened markedly in the following 3 years, resulting
in severe disability rendering him to be assisted in all his daily activities and he did not benefit
from any dopaminergic agent. T1 sequences of the MRI of the brain showed pallidal
hyperintensity symmetrically. Welders in our country often protect their eyes but ignore to use
tools that protect them from inhalation of the fume. Since chronic Mn toxicity may cause serious
disability and irreversible neurological disturbances, we strongly believe that it is necessary to
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inform welders and their employers about this potential hazard. (C) 2006 Movement Disorder
Society.
28. Kessler KR, Wunderlich G, Hefter H, Seitz RJ. (2003) Secondary progressive chronic
manganism associated with markedly decreased striatal D2 receptor density. Movement
Disorders 18(2):216-218.
We describe a patient with chronic manganism due to intoxication 40 years ago. Whereas
previous reports on acute or subacute intoxication have shown no or only small reductions in
striatal D2 receptor density, we found markedly decreased D2 receptor density using F-18-
methylspiperone PET in this very late stage of chronic manganism, supporting the hypothesis
that manganese intoxication may trigger a neuro-degenerative disease process. (C) 2002
Movement Disorder Society.
29. Kilic E, Saraymen R, Demiroglu A, Ok E. (2004) Chromium and manganese levels in the
scalp hair of normals and patients with breast cancer. Biological Trace Element Research 102(1-
3):19-25.
The adverse health effects linked with chromium and manganese and the diverse cellular and
molecular effects of chromium and manganese make the study of chromium and manganese
carcinogenesis and toxicology very interesting and complex. Quantitative elemental analysis of
scalp hair of breast cancer patients (stage III) (n = 26) and controls (n = 27) were used to study to
find correlation and possible changes between breast cancer and healthy controls. The graphite
furnace atomic absorption analysis of quantitative method was used for the determination of
chromium and manganese element levels. Comparison of mean elemental contents of the breast
cancer patients with controls shows a significant enhancement of chromium (p < 0.05) but
declining trends for manganase (p < 0.05) in breast cancer patients. Changes in element content
in hair can serve as a guide to opening up new vistas in the treatment of breast cancer on the
basis of an overall analysis of symptoms and signs.
30. Kim JW, Kim Y, Cheong HK, Ito K. (1998) Manganese induced Parkinsonism: A case
report. Journal of Korean Medical Science 13(4):437-439.
BIOSIS COPYRIGHT: BIOL ABS. Manganese (Mn) intoxication is known to induce
parkinsonism. Mn-induced parkinsonism preferentially affect the globus pallidus in contrast to
idiopathic parkinsonism where degeneration predominantly involves the nigral pars compacta.
We describe a 51-year-old man who had been occupationally exposed to Mn. He had
parkinsonian features including masked face, resting tremor, and bradykinesia. He also had a
cock walk and a particular propensity to fall in a backward gait. There was no sustained
therapeutic response to levodopa. A fluorodopa PET scan was normal. This case indicates that
Mn-induced parkinsonism can be differentiated from idiopathic parkinsonism in that the former
has unique clinical features and a normal fluorodopa PET scan.
31. Kim Y, Kim JM, Kim JW, Yoo CI, Lee CR, Lee JH, Kim HK, Yang SO, Chung HK, Lee
DS and others. (2002) Dopamine transporter density is decreased in parkinsonian patients with a
history of manganese exposure: What does it mean? Movement Disorders 17(3):568-575.
Manganese (Mn) exposure can cause parkinsonism. Pathological changes Occur mostly in the
pallidum and striatum. Two patients with a long history of occupational Mn exposure presented
with Mn-induced parkinsonism. In I patient, magnetic resonance imaging (MRI) showed
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findings consistent with Mn exposure, and Mn concentration was increased in the blood and
urine. However, this patient's clinical features were typical of idiopathic Parkinson disease (PD).
Previous pathological and positron emission tomography Studies indicate that striatal dopamine
transporter density is normal in Mn-induced parkinsonism, whereas it is decreased in PD.
Therefore, we performed [I-123]-(le)-2beta-carboxymethoxy-3beta-(4( [I-123]-beta-CIT) single-
photon emission iodophenyl)tropane computed tomography. Severe reduction of striatal beta-
CIT bindin,, was indicated, which is consistent with PD. We propose three interpretations: (1)
the patients have PD, and Mn exposure is incidentals (2) Mn induces selective degeneration of
presynaptic dopaminergic nerve terminals, thereby causing parkinsonism or (3) Mn exposure
acts as a risk of PD in these patients. Our results and careful review of previous studies indicate
that the axiom that Mn Causes parkinsonism by pallidal lesion may be over-simplified Mn
exposure and parkinsonism may be more complex than previously thought. Further studies are
required to elucidate the relationship between Mn and various forms of parkinsonism. (C) 2002
Movement Disorder Society.
32. Kim YH, Kim JW, Ito KG, Lim HS, Cheong HK, Kim JY, Shin YC, Kim KS, Moon YH.
(1999) Idiopathic parkinsonism with superimposed manganese exposure: Utility of positron
emission tomography. Neurotoxicology 20(2-3):249-252.
It is difficult to distinguish manganism from idiopathic parkinsonism by clinical signs only. Case
history and examination: A 48-year-old welder for over 10 years complained of masked lace
right side (arm and leg) resting tremor, and bradykinesia for over one year. Magnetic resonance
imaging (MRI) findings showed symmetrical high signal intensities in the globus pallidus on T1
weighted image. These intensities disappeared almost completely six months after cessation of
exposure. F-18-6-fluorodopa (F-18-dopa) positron emission tomography (PET) findings showed
reduced F-18-dopa uptake in the left putamen, findings which appear in idiopathic parkinsonism.
A PET study is necessary to distinguish manganism from idiopathic parkinsonism, especially in
a working environment with elevated Mn concentrations, such as welding. (C) 1999 Intox Press,
Inc.
33. Kocyigit A, Zeyrek D, Keles H, Koylu A. (2004) Relationship among manganese, arginase,
and nitric oxide in childhood asthma. Biological Trace Element Research 102(1-3): 11-18.
It has been demonstrated that the lowest intakes of manganese (Mn) were associated with more
than a fivefold increased risk of bronchial reactivity. It was also known that nitric oxide (NO)
production was found to be significantly higher in asthmatics. There is a reciprocal pathway
between arginase and nitric oxide synthase (NOS) for NO production, and Mn is required for
arginase activity and stability. We investigated plasma NO, arginase, and its cofactor Mn levels
to evaluate this reciprocal pathway in patients with childhood asthma. Arginase activities and
Mn and NO levels were measured in plasma from 31 patients with childhood asthma and 22
healthy control subjects. Plasma arginase activities and Mn concentrations were found to be
significantly lower and NO levels were significantly higher in patients with childhood asthma as
compared to the control subjects. There was a significantly positive correlation between plasma
Mn and arginase and negative correlations between arginase and NO values and Mn and NO
values in patients with childhood asthma. These data indicate that the lower concentration of Mn
could cause lower arginase activity and this could also upregulate NO production by increasing
L-arginine content in patients with childhood asthma.
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34. Komaki H, Maisawa S, Sugai K, Kobayashi Y, Hashimoto T. (1999) Tremor and seizures
associated with chronic manganese intoxication. Brain & Development 21(2): 122-124.
Tremor and seizures developed in a 2-year-old girl receiving total parenteral nutrition. Tl-
weighted images on MRI revealed areas of hyperintensity in the basal ganglia, brainstem and
cerebellum. Blood manganese was elevated. The symptoms and MRT abnormalities disappeared
after withdrawal of manganese administration. The recommendation of daily parenteral
manganese intake was discussed. (C) 1999 Elsevier Science B.V. All rights reserved.
35. Kondoh H, Iwase K, Higaki J, Tanaka Y, Yoshikawa M, Hori S, Osuga K, Kamiike W.
(1999) Manganese deposition in the brain following parenteral manganese administration in
association with radical operation for esophageal cencer: Report of a case. Surgery Today-the
Japanese Journal of Surgery 29(8):773-776.
We report herein the case of a patient in whom manganese (Mn) deposition in the basal ganglia
was detected by magnetic resonance imaging (MRI) subsequent to thoracic esophagectomy,
performed following perioperative parenteral nutrition. A multi-trace-element supplement
solution which included 20 mu mol of Mn per day had been parenterally administered for 7 days
preoperatively and 21 days postoperatively. The serum level of total bilirubin reached a
maximum value of 5.1mg/dl postoperatively. The T1-weighted MRI on the 32nd postoperative
day demonstrated bilateral and symmetrical hyperintense lesions in the globus pallidus and the
whole-blood Mn level on the 34th postoperative day was 4.9 mu g/1, the normal range being 0.8-
2.5 mu g/1. This hyperintensity on Tl-weighted MRI was gradually improved following
normalization of the blood Mn level. This case report serves to demonstrate that even short-term
perioperative parenteral nutrition may result in Mn deposition in the brain following radical
surgery for esophageal cancer, especially in patients with hyperbilirubinemia.
36. Lucchini R, Bergamaschi E, Smargiassi A, Festa D, Apostoli P. (1997) Motor function,
olfactory threshold, and hematological indices in manganese-exposed ferroalloy workers.
Environmental Research 73(1-2): 175-180.
BIOSIS COPYRIGHT: BIOL ABS. A cross-sectional study was conducted in 35 male subjects
randomly selected from workers of a ferroalloy production plant and exposed to manganese
(Mn) oxides; the objective was to detect early signs of neurologic impairment. The subjects'
mean age was 39.4 years (SD, 8.4); the average exposure duration was 14.5 years (range, 5-29
years). A control group of industrial workers not exposed to neurotoxic chemicals and
comparable in age and confounding factors was recruited. The intensity of Mn exposure was
moderate, as reflected by airborne Mn concentrations in total dust averaging 93 mug/m3. Mn
levels in blood (MnB) and urine (MnU) were significantly higher in the Mn-exposed workers
than in control workers. A relationship (not found with MnU) was found between MnB and a
cumulative exposure index calculated on the basis of air concentration and exposure history for
each subject (r = 0.52; r2 = 0.27; P = 0.002). Psychomotor function scores were lower among
Mn-exposed subjec MH - CHEMISTRY, CLINICAL
37. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M,
Mihara F. (2001) Manganese intoxication during intermittent parenteral nutrition: Report of two
cases. Journal of Parenteral and Enteral Nutrition 25(2):95-99.
Background and Methods: The administration of trace elements is thought to be needed in
patients receiving long-term parenteral nutrition. Recently, manganese intoxication or deposition
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was documented in such patients. We report two cases of manganese intoxication during
intermittent parenteral nutrition including manganese. Manganese had been administered for 4
years at a frequency of one or two times per week in one case and for 5 years at a frequency of
one or two times per month in the other case. Both cases showed mild symptoms with headache
and dizziness. One case had mild hepatic dysfunction and the other did not. The whole-blood
manganese level increased in one case, but not in the other case. Tl-weighted magnetic
resonance images revealed symmetrical high-intensity areas in basal ganglia and thalamus in
both cases. After the administration of manganese was stopped, these symptoms all disappeared
and the magnetic resonance images abnormalities gradually improved in both patients. Mild
long-term manganese intoxication is thus considered to occur regardless of the frequency of
using a manganese supplement. Conclusions: Patients should be carefully monitored when
receiving long-term parenteral nutrition including manganese, even when the manganese dose is
small and the frequency of receiving a manganese supplement is low.
38. Mergler D, Baldwin M, Belanger S, Larribe F, Beuter A, Bowler R, Panisset M, Edwards R,
de Geoffroy A, Sassine MP and others. (1999) Manganese neurotoxicity, a continuum of
dysfunction: Results from a community based study. Neurotoxicology 20(2-3):327-342.
Excessive manganese (Mn) has been associated with neurobehavioral deficits and neurological
and/or neuropsychiatric illness, but the level at which this metal can cause adverse neurotoxic
effects, particularly with long-term exposure, is still unknown. The objective of the present study
was to assess nervous system functions in residents exposed to manganese from a variety of
environmental sources. A random stratified sampling procedure was used to select participants;
persons with a history of workplace exposure to Mn and other neurotoxic substances were
excluded. A self-administered questionnaire provided data on socio-demographic variables.
Blood samples were analyzed for total manganese (MnB) lead, mercury and serum iron. Nervous
system assessment included computer and hand-administered neurobehavioral tests,
computerized neuromotor tests, sensory evaluation and a neurological examination. The present
analyses include 273 persons (151 women and 122 men); MnB range: 2.5 mu g/L - 15.9 mu g/L
(median: 7.3 mu g/L). Multivariate analyses were used and neuro-outcomes were examined with
respect to MnB, laking into account potential confounders and covariables. Results were grouped
according to neurofunctional areas and MANOVA analyses revealed that higher MnB (7.5 mu
g/L) was significantly associated with changes in coordinated upper limb movements (Wilks'
lambda = 0.92; p = 0.04) and poorer learning and recall (men: Wilks' lambda = 0.77; p = 0.002;
women: Wilks' lambda = 0.86; p = 0.04). Further analyses revealed that with increasing log MnB
(Simple regression : p<0.05) performance on a pointing task was poorer, frequency dispersion of
hand-arm tremor decreased, while harmonic index increased, and the velocity of a
pronation/supination arm movement was slower. An Mn-age interaction was observed for certain
motor tasks, with the poorest performance observed among chose 50 y and in the higher MnB
category. Differences between genders suggest that men may be at greater risk than women,
although effects were also observed in women. These findings are consistent with the hypothesis
that Mn neurotoxicity can be viewed on a continuum of dysfunction, with early, subtle changes
at lower exposure levels. (C) 1999 Inter Press, Inc.
39. Molina JA, Jimenez-Jimenez FJ, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-
Munoz MJ, de Bustos F, Porta J, Orti-Pareja M, Zurdo M and others. (1998) Cerebrospinal fluid
Draft Bibliography: Manganese Lit. Search
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levels of transition metals in patients with Alzheimer's disease. Journal of Neural Transmission
105(4-5):479-488.
We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic
absorption spectrophotometry, in 26 patients patients with Alzheimer's disease (AD) without
major clinical signs of undernutrition, and 28 matched controls. CSF zinc levels were
significantly decreased in AD patients as compared with controls (p < 0.05). The serum levels of
zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly
between AD-patient and control groups. These values were not correlated with age, age at onset,
duration of the disease, and scores of the MiniMental State Examination in the AD group.
Weight and body mass index were significantly lower in AD patients than in controls. Because
serum zinc levels were normal, the possibility that low CSF zinc levels were due to a deficiency
of dietary intake seems unlikely. However, it is possible that they might be related to the
interaction of beta-amyloid and/or amyloid precursor protein with zinc, that could result in a
depletion of zinc levels.
40. Muhtaseb MS, O'Reilly D, McKee R, Anderson J, Finlay IG. (2004) Patients who have had
ileal-anal pouch surgery are at risk of manganese and vitamin B toxicity. British Journal of
Surgery 91:5-5.
41. Myers JE, teWaterNaude J, Fourie M, Zogoe HBA, Naik I, Theodorou P, Tassel H, Daya A,
Thompson ML. (2003) Nervous system effects of occupational manganese exposure on South
African manganese mineworkers. Neurotoxicology 24(4-5):649-656.
Occupational exposure to airborne manganese dust has been shown to produce adverse effects on
the central nervous system. Four hundred and eighty-nine blue and white collar manganese
mineworkers from South Africa were studied cross-sectionally to investigate the nervous system
effects of medium to low occupational manganese exposures. The different facilities included
underground mines, surface processing plants, and office locations. A job exposure matrix was
constructed using routine occupational hygiene data. Exposure variables included years of
service, a cumulative exposure index (CEI) and average intensity of exposure (AINT) across all
jobs, and blood manganese. Endpoints included items from the Q16, WHO-NCTB, SPES, and
Luria-Nebraska test batteries, and a brief clinical examination. Potential confounders and effect
modifiers included age, level of education, past medical history including previous head injury,
previous neurotoxic job exposures, tobacco use, alcohol use and home language. Associations
were evaluated by multiple linear and logistic regression modeling. Average exposure intensity
across all jobs was 0.21 mg/m(3) manganese dust. Multivariate analyses showed that none of the
symptom nor test results were associated with any measure of exposure including blood
manganese, after adjustment for confounders. This relatively large null study indicates that
manganese miners exposed on average across all jobs to Mn02 at levels near the American
Conference of Governmental Industrial Hygienists Threshold Limit Value (ACGIH TLV) are
unlikely to have a subclinical neurotoxicity problem. (C) 2003 Elsevier Science Inc. All rights
reserved
42. Park J, Yoo CI, Sim CS, Kim HK, Kim JW, Jeon BS, Kim KR, Bang OY, Lee WY, Yi Y
and others. (2005) Occupations and Parkinson's disease: A multi-center case-control study in
South Korea. Neurotoxicology 26(1):99-105.
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Objective: We performed a hospital based case-control study in South Korea (1) to clarify the
role of occupational exposure, and especially manganese (Mn) exposure in the etiology of
Parkinson's disease (PD) and (2) to discover the association between any occupations and PD.
Methods: We selected two groups, PD patient group (NI) and controls (N-2). Three hundred
sixty-seven consecutive outpatients with PD (177 men, 190 women) and 309 controls were
interviewed about life style, past history, family history, education level, and occupational
history etc. We employed a range of industrial categories as defined by section (the most broad
category) and division (sub-category) of the Korea Standard Industry Code (KSIC) Manual.
Along with KSIC, we also used the Korea Standard Classification of Occupations (KSCO) as
proxies of occupational exposure. The odds ratios (ORs) and 95% confidence intervals (CA),
adjusted for age, sex, smoking status, and education level are presented. Results: As regarding
the exposure to hazardous materials, especially Mn, more subjects in the control group than the
PD patient group 'have worked in the occupations with potential exposure to Mn (P < 0.001).
Ever having worked in 'agriculture, hunting, and forestry' section of industry was positively
associated with PD (OR 1.88), and 'agriculture production crops (OR 1.96)'division of industry
was positively associated with PD. On the other hand, ever having worked in the 'manufacturing
(OR 0.56)', 'transportation (OR 0.28)' section of industry, and 'transporting (OR 0.20)' division of
industry were negatively associated with PD. 'Drivers (OR 0.13)'division of occupation also was
negatively associated with PD. Conclusions: To our knowledge, this is the first case-control
studies to find an inverse relationship between 'transporting' or 'technicians like machinery
engineers' as his/her longest job and PD risk. Because of this unexpected finding, our work
should be replicated in various populations. (C) 2004 Elsevier Inc. All rights reserved.
43. Park J, Yoo CI, Sim CS, Kim JW, Yi Y, Shin YC, Kim DH, Kim Y. (2006) A retrospective
cohort study of Parkinson's disease in Korean shipbuilders. Neurotoxicology 27(3):445-449.
Objective: We performed a retrospective cohort study in South Korea to clarify the role of
occupational exposure, especially to welding, in the etiology of Parkinson's disease (PD).
Methods: We constructed a database of subjects classified into an exposure group (blue-collar
workers) and a non-exposure group (white-collar workers) in two shipbuilding companies. Jobs
of blue-collar workers were categorized into the first group of welding, the second group of
fitting, grinding and finishing, cutting, and the other group. To determine new cases of PD
during the follow-up period (1992-2003), we used the physician billing claims database of the
National Health Insurance Corporation. For the detected PD patients in the physician billing
claims database, a neurologist in our research team confirmed the appropriateness of each
diagnosis by reviewing medical charts. Based on the review, we confirmed the numbers of new
cases of PD and calculated the relative risk (RR) and the 95% confidence intervals (CI) by Cox
regression analysis. Results: In a backward selection procedure, 'age' was a significant
independent variable but exposure was not. Furthermore, the RR in welders (high exposure
group) was also insignificant and less than that in others (very low exposure group). Conclusion:
This longitudinal study of shipbuilding workers supports our previous case-control studies
suggesting that exposure to manganese does not increase the risk of PD. (c) 2006 Elsevier Inc.
All rights reserved.
44. Ransom-Schwaeber MM. (2007) Manganese toxicity due to oral ingestion as an acne
treatment. Neurology 68(12):A327-A327.
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45. Rodriguez-Agudelo Y, Riojas-Rodriguez H, Rios C, Rosas I, Pedraza ES, Miranda J, Siebe
C, Texcalac JL, Santos-Burgoa C. (2006) Motor alterations associated with exposure to
manganese in the environment in Mexico. Science of the Total Environment 368(2-3):542-556.
Overexposure to manganese (Mn) causes neurotoxicity (a Parkinson-like syndrome) or
psychiatric damage ("manganese madness"). Several studies have shown alterations to motor and
neural behavior associated with exposure to Mn in the workplace. However, there are few
studies on the effects of environmental exposure of whole populations. We studied the risk of
motor alterations in people living in a mining district in Mexico. We studied 288 individual
people (168 women and 120 men) from eight communities at various distances from manganese
extraction or processing facilities in the district of Molango. We measured manganese
concentrations in airborne particles, water, soil and crops and evaluated the possible routes of
Mn exposure. We also took samples of people's blood and determined their concentrations of Mn
and lead (Pb). We used "Esquema de Diagnostico Neuropsicologico" Ardila and Ostrosky-Solis's
neuropsychological battery to evaluate motor functions. Concentrations of Mn in drinking water
and maize grain were less than detection limits at most sampling sites. Manganese extractable by
DTPA in soils ranged between 6 and 280 mg kg(-l) and means were largest close to Mn
extraction or processing facilities. Air Mn concentration ranged between 0.003 and 5.86 mu
g/m(3); the mean value was 0.42 mu g/m(3) and median was 0.10 mu g/m(3), the average value
(geometric mean) resulted to be 0.13 mu g/m(3). Mean blood manganese concentration was
10.16 mu g/1, and geometric mean 9.44 mu g/1, ranged between 5.0 and 31.0 mu g/1. We found
no association between concentrations of Mn in blood and motor tests. There was a statistically
significant association between Mn concentrations in air and motor tests that assessed the
coordination of two movements (OR 3.69; 95% CI 0.9, 15.13) and position changes in hand
movements (OR 3.09; CI 95% 1.07, 8.92). An association with tests evaluating conflictive
reactions (task that explores verbal regulations of movements) was also found (OR 2.30; CI 95%
1.00, 5.28). It seems from our results that people living close to the manganese mines and
processing plants suffer from an incipient motor deficit, as a result of their inhaling manganese-
rich dust, (c) 2006 Elsevier B.V All rights reserved.
46. Ross C, O'Reilly DS, McKee R. (2006) Potentially clinically toxic concentrations of whole
blood manganese in a patient fed enterally with a high tea consumption. Annals of Clinical
Biochemistry 43:226-228.
This report describes a 37-year-old female patient who after seven years on intermittent
overnight enteral feeding supplementation was noted to have an increased whole blood
manganese concentration. Manganese toxicity is well documented after pathological absorption
through inhalation via the lungs, or after intravenous administration to patients on long-term
total parenteral nutrition. A dietary history revealed high tea consumption. The association
between high blood manganese concentrations and enteral/oral nutrition does not appear to have
previously been described.
47. Sadek AH, Rauch R, Schulz PE. (2003) Parkinsonism due to Manganism in a Welder.
International Journal of Toxicology 22(5):393-401.
A 33-year-old right-handed male presented complaining of a 2-year history of progressive
cognitive slowing, rigidity, tremors, slowing of movements, and gait instability leading to falls.
On examination, he had a Mini-Mental Status Examination (MMSE) score of 29, slowed
saccadic eye pursuit, hypomimia, cogwheel rigidity, a 3 - to 4-Hz tremor, and a "cock-walk" gait.
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His symptoms and signs were similar to idiopathic Parkinson's disease; however, he was young,
inattention and forgetfulness occurred early in the course of the disorder, levodopa was
unhelpful, and his gait was atypical. His work up for secondary causes of parkinsonism was
negative, except for increased signal intensity on T1-weighted magnetic resonance image (MRI)
in the bilateral basal ganglia. Typical etiologies for that finding were ruled-out, which led to
further inquiries into the patient's lifestyle. He was a welder, and discussion with his employer
revealed that he used a steel-manganese alloy, he often worked in a confined ship's hold, and he
did not use a respiratory mask. Because manganese toxicity can produce increased T1-weighted
signal intensities in the basal ganglia, the authors tested his serum and urine manganese, and
both were elevated. This patient emphasizes the importance of a careful occupational history in
persons presenting with atypical manifestations of a neurodegenerative disorder. It also lends
support to the hypothesis that welding can produce enough exposure to manganese to produce
neurologic impairment.
48. Sassine MP, Mergler D, Bowler R, Hudnell HK. (2002) Manganese accentuates adverse
mental health effects associated with alcohol use disorders. Biological Psychiatry 51(11):909-
921.
Background: A population-based study, on earl, v neurotoxic effects of environmental exposure
to manganese (Mn) enabled its to investigate the relation between blood Mn levels (MnB),
alcohol consumption, and risk for alcohol use disorders (AUD) on mental health. Methods:
participants were selected using a random stratified sampling procedure. Self-administered
questionnaires provided data on alcohol consumption, sociodemographics, medical history, and
lifestyle. Mood states were assessed with the Brief Symptom Inventory (BSI), and risk for AUD
was surveyed using a behavioral screening questionnaire and categorized into no, low, and high
risk. Of 297 participants, 253 current drinkers who had responded to all questions on alcohol use
were retained. Results: Psychologic distress increased with risk for AUD and alcohol
consumption greater than or equal to 420 g/week. Higher MnB levels (greater than or equal to7.5
mug/L) intensified the relation between risk for AUD and BSI settle scores. The prevalence odd
ratios for positive cases of psychologic distress with risk for AUD, 1.98 [1.13-3.46], differed
Amen divided by MnB strata: lower MnB: 1.34 [0.64-2.85]; higher MnB: 4.22 [1.65-10.77],
Conclusions: These findings suggest that higher levels of blood manganese significantly increase
neuropsychiatric symptoms associated with risk for alcohol use disorders. Biol Psychiatry
2002;51:909-921 (C) 2002 Society of Biological Psychiatry.
49. Shinotoh H, Snow BJ, Chu NS, Huang CC, Lu CS, Lee C, Takahashi H, Calne DB. (1997)
Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese
intoxication: A positron emission tomography study. Neurology 48(4): 1053-1056.
BIOSIS COPYRIGHT: BIOL ABS. We performed PET on four patients with chronic industrial
Mn intoxication; presynaptic and postsynaptic dopaminergic function were measured with
(18F)6-fluoro-L-dopa (6FD) and (1 lC)raclopride (RAC). All patients had a rigid-akinetic
syndrome; they had no sustained benefit from L-dopa. Influx constants (Ki) of 6FD were normal
in the caudate and putamen. RAC binding was mildly reduced in the caudate and normal in the
putamen. We conclude that nigrostriatal dopaminergic dysfunction is not responsible for the
parkinsonism caused by chronic Mn intoxication. The pathology is likely to be downstream of
the dopaminergic projection.
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50. Sjogren B, Iregren A, Freeh W, Hagman M, Johansson L, Tesarz M, Wennberg A. (1996)
Effects on the nervous system among welders exposed to aluminium and manganese.
Occupational and Environmental Medicine 53(l):32-40.
Objectives-The purpose was to study the effects on the nervous system in welders exposed to
aluminium and manganese. Methods-The investigation included questionnaires on symptoms,
psychological methods (simple reaction time, finger tapping speed and endurance, digit span,
vocabulary, tracking, symbol digit, cylinders, olfactory threshold, Luria-Nebraska motor scale),
neurophysiological methods (electroencephalography, event related auditory evoked potential
(P-300), brainstem auditory evoked potential, and diadochokinesometry) and assessments of
blood and urine concentrations of metals (aluminium, lead, and manganese). Results-The
welders exposed to aluminium (n = 38) reported more symptoms from the central nervous
system than the control group (n = 39). They also had a decreased motor function in five tests.
The effect was dose related in two of these five tests. The median exposure of aluminium
welders was 7065 hours and they had about seven times higher concentrations of aluminium in
urine than the controls. The welders exposed to manganese (n = 12) had a decreased motor
function in five tests. An increased latency of event related auditory evoked potential was also
found in this group. The median manganese exposure was 270 hours. These welders did not have
higher concentrations of manganese in blood than the controls. Conclusions-The neurotoxic
effects found in the groups of welders exposed to aluminium and manganese are probably caused
by the aluminium and manganese exposure, respectively. These effects indicate a need for
improvements in the work environments of these welders.
51. Staunton M, Phelan DM. (1995) Manganese Toxicity in a Patient with Cholestasis
Receiving Total Parenteral-Nutrition. Anaesthesia 50(7):665-665.
52. Wardle CA, Forbes A, Roberts NB, Jawhari AV, Shenkin A. (1999) Hypermanganesemia in
long-term intravenous nutrition and chronic liver disease. Journal of Parenteral and Enteral
Nutrition 23(6):350-355.
Background: Hypermanganesemia and cholestatic liver disease are both recognized
complications of long-term IV nutrition. Manganese is primarily excreted in bile, and recent
studies have indicated that manganese toxicity may play a role in the pathogenesis of IV
nutrition-associated cholestasis. Methods: Whole blood and plasma manganese concentrations
were measured in patients receiving long-term home IV nutrition (HIN, n = 30). Whole blood
manganese concentrations also were measured in patients with chronic liver disease (CLD, n =
10) and control subjects (n = 10). Results: Whole blood manganese concentrations of all. CLD
patients were within the reference interval (73 to 210 nmol/L) and were not different from those
of the control group (151 +/- 44 nmol/L, CLD vs 155 +/- 35 nmol/L, control; not significant),
despite the presence of cholestasis. In contrast, whole blood manganese concentration was
increased (>210 nmol/L) in 26 patients, and plasma manganese concentration increased (>23
nmol/L) in 23 of the patients receiving HIN. None of the patients exhibited neurologic signs of
manganese toxicity. There was no correlation between whole blood manganese concentrations
and markers of cholestasis, IV manganese intake, or duration of HIN. However, plasma
manganese concentration correlated both with average weekly IV manganese intake (r = .44, p =
.02) and with gamma-glutamyl transferase (r = .43, p = .02) and alkaline phosphatase activities (I
= .55, p = .003). Conclusions: Cholestatic liver disease does not appear to contribute to increased
whole blood manganese concentrations in patients not receiving HIN. Plasma manganese
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concentrations in patients receiving HIN reflect recent manganese exposure and impaired
excretion where cholestasis is present. The lack of relationship between plasma and whole blood
manganese concentrations suggests that factors other than manganese intake and excretion affect
intracellular concentrations.
53. Wasserman GA, Liu XH, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A,
Slavkovich V, Lolacono NJ and others. (2006) Water manganese exposure and children's
intellectual function in Araihazar, Bangladesh. Environmental Health Perspectives 114(1): 124-
129.
Exposure to manganese via inhalation has long been known to elicit neurotoxicity in adults, but
little is known about possible consequences of exposure via drinking water. In this study, we
report results of a cross-sectional investigation of intellectual function in 142 10-year-old
children in Araihaza, Bangladesh, who had been consuming tube-well water with an average
concentration of 793 mu g Mn/L and 3 mu g arsenic/L. Children and mothers came to our field
clinic, where children received a medical examination in which weight, height, and head
circumference were measured. Children's intellectual function was assessed on tests drawn from
the Wechsler Intelligence Scale for Children, version III, by summing weighted items across
domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine
specimens for measuring urinary As and creatinine and were asked to provide blood samples for
measuring blood lead, As, Mn, and hemoglobin concentrations. After adjustment for
sociodemographic covariates, water Mn was associated with reduced Full-Scale, Performance,
and Verbal raw scores, in a dose-response fashion; the low level of As in water had no effect. In
the United States, roughly 6% of domestic household wells have Mn concentrations that exceed
300 mu g Mn/L, the current U.S. Environmental Protection Agency, lifetime health advisory
level. We conclude that in both Bangladesh and the United States, some children are at risk for
Mn-induced neurotoxicity.
54. Woolf A, Wright R, Amarasiriwardena C, Bellinger D. (2002) A child with chronic
manganese exposure from drinking water. Environmental Health Perspectives 110(6):613-616.
The patient's family bought a home in a suburb, but the proximity of the house to wetlands and
its distance from the town water main prohibited connecting the house to town water. The family
had a well drilled and they drank the well water for 5 years, despite the fact that the water was
turbid, had a metallic taste, and left an orange-brown residue on clothes, dishes, and appliances.
When the water was tested after 5 years of residential use, the manganese concentration was
elevated (1.21 ppm; U.S. Environmental Protection Agency reference, <0.05 ppm). The family's
10-year-old son had elevated manganese concentrations in whole blood, urine, and hair. The
blood manganese level of his brother was normal, but his hair manganese level was elevated.
The patient, the 10-year-old, was in the fifth grade and had no history of learning problems;
however, teachers had noticed his inattentiveness and lack of focus in the classroom. Our results
of cognitive testing were normal, but tests of memory revealed a markedly below-average
performance: the patient's general memory index was at the 13th percentile, his verbal memory
at the 19th percentile, his visual memory at the 14th percentile, and his learning index at the 19th
percentile. The patient's free recall and cued recall tests were all 0.5-1.5 standard deviations (1
SD = 16th percentile) below normal. Psychometric testing scores showed normal IQ but
unexpectedly poor verbal and visual memory. These findings are consistent with the known toxic
effects of manganese, although a causal relationship cannot necessarily be inferred.
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55. Yanik M, Kocyigit A, Tutkun H, Vural H, Herken H. (2004) Plasma manganese, selenium,
zinc, copper, and iron concentrations in patients with schizophrenia. Biological Trace Element
Research 98(2): 109-117.
A number of essential trace elements play a major role in various metabolic pathways. Selenium
(Se), manganese (Mn), copper (Cu), zinc (Zn), and iron (Fe) are essential trace elements that
have been studied in many diseases, including autoimmune, neurological, and psychiatric
disorders. However, the findings of previous research on the status of trace elements in patients
with schizophrenia have been controversial. We studied these elements in patients with a DSM-
IV diagnosis of schizophrenia and compared them with sex- and age-matched healthy controls.
Plasma Cu concentrations were significantly higher (p < 0.01) and Mn and Fe concentrations
were lower (p < 0.05 and p < 0.05, respectively) in schizophrenic patients than in controls. Se
and Zn concentrations and protein levels did not differ between patients and healthy controls.
These observations suggest that alterations in essential trace elements Mn, Cu, and Fe may play
a role in the pathogenesis of schizophrenia. However, findings from trace element levels in
schizophrenia show a variety of results that are difficult to interpret.
56. Yiin SJ, Lin TH, Shih TS. (1996) Lipid peroxidation in workers exposed to manganese.
Scandinavian Journal of Work Environment & Health 22(5):381-386.
BIOSIS COPYRIGHT: BIOL ABS. Objectives: The following hypothesis was tested: plasma
manganese concentration is associated positively with the product of lipid peroxidation, and lipid
peroxidation is associated negatively with the activities of antioxidants in workers exposed to
manganese. Methods: The plasma manganese concentration of 22 manganese-exposed workers
and 45 referents was determined by graphite furnace atomic absorption spectrophotometry.
Malondialdehyde, the product of lipid peroxidation, was determined by high-performance liquid
chromatography, and the activities of protective enzymes were measured by ultraviolet-visible
spectrophotometry. Results: The activities of superoxide dismutase, glutathione peroxidase, and
catalase spread widely among the referents. The activity of superoxide dismutase and the
concentrations of malondialdehyde and manganese were significantly higher in the manganese
workers than in the referents. The concentration of malondialdehyde in the exposed workers wa
57. Yoshikawa K, Matsumoto M, Hamanaka M, Nakagawa M. (2003) A case of manganese
induced parkinsonism in hereditary haemorrhagic telangiectasia. Journal of Neurology
Neurosurgery and Psychiatry 74(9): 1312-1314.
A 44 year old right handed woman complained of difficulty in moving. She and her relatives had
skin telangiectasia or recurrent epistaxis. On neurological examination, she had a mask-like
facies and bradykinesia in both extremities. Laboratory examinations showed iron deficiency
anaemia and mild liver dysfunction with raised serum manganese. On T1 weighted cranial
magnetic resonance imaging there were hyperintense areas in the globus pallidus bilaterally,
suggesting manganese deposition. Abdominal angiography confirmed multiple portal-systemic
shunts in the liver, and a needle biopsy of the liver showed diffuse dilatation of the sinusoids
with fatty change. Levodopa did not improve the bradykinesia. This appears to be a case of
hereditary haemorrhagic telangiectasia with manganese induced parkinsonism, which may be a
new type of neurological disorder in such patients.
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4.2 LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
4.2.1 Less-than-lifetime and Chronic Studies
Key References (32)
1. Ahn SS, Lee KM. (1998) Neurotoxicity of chronic manganese exposure causing frontal lobe
dysfunction. Journal of Neurochemistry 70:S29-S29.
2. Chen MT, Yiin SJ, Sheu JY, Huang YL. (2002) Brain lipid peroxidation and changes of trace
metals in rats following chronic manganese chloride exposure. Journal of Toxicology and
Environmental Health-Part A 65(3-4):305-316.
The aim of this study was to investigate the effects of chronic daily, 30-d administration of
manganese chloride (MnC12) to male Sprague-Dawley rats on lipid peroxidation and changes of
trace elements (manganese, iron, copper, zinc) in various brain regions. Rats were
intraperitoneally injected with MnC2 (20 mg/kg) once daily for 30 consecutive days. The Mn
accumulated in frontal cortex, corpus callosum, hippocampus, striatum, hypothalamus, medulla,
cerebellum, and spinal cord. Malondialdehyde, an end product of lipid peroxidation, was
markedly decreased in frontal cortex and cerebellum. An increased level of Cu was observed in
frontal cortex, medulla, and a cerebellum. A decreased Fe level was found only in cerebellum,
and a decreased Zn level was observed in hippocampus and striatum. In a second group of
animals, Mn (20 mg/kg/d) and glutathione (CSH, 75 mg/kg/d) were administered ip for 30 d. In
CSH-Mn-treated rats, compared to Mn-treated rats, MDA concentrations were significantly
reduced in frontal cortex, medulla and cerebellum. The changes of trace elements in rat brain
were similar to the Mn-treated group. We suggest that Mn is an atypical antioxidant, as well as
not involved in oxidative damage in rat brain. Fe and Cu may play roles in the protective effect
of Mn against lipid peroxidation in rat brain.
3. Desole MS, Esposito G, Migheli R, Fresu L, Sircana S, Zangani D, Miele M, Miele E. (1995)
Cellular Defense-Mechanisms in the Striatum of Young and Aged Rats Sub chronically Exposed
to Manganese. Neuropharmacology 34(3):289-295.
A deficiency of striatal dopamine (DA) is generally accepted as an expression of manganese
(Mn) toxicity in experimental animals. Since compromised cellular defence mechanisms may be
involved in Mn neurotoxicity, we investigated the response of the neuronal antioxidant system
[ascorbic acid (AA) oxidation, glutathione (GSH) and uric acid levels] and neurochemical
changes in the striatum in aged rats exposed to Mn. Levels of dopamine (DA),
dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT),
5-hydroxyindoleacetic acid (5-HIAA), AA, dehydroascorbic acid (DHAA), GSH and uric acid
were determined after subchronic oral exposure to MnC12 200 mg/kg (3-month-old rats) and 30-
100-200 mg/kg (20-month-old rats). Aged rats had basal levels of striatal DA, DOPAC, HVA, 5-
HT, 5-HIAA, GSH and AA lower than those of young rats. In the striatum of aged rats, Mn
induced biphasic changes in the levels of DA, DOPAC, HVA (an increase at the lower dose and
a decrease at the higher dose) and DHAA (opposite changes). Mn decreased GSH levels and
increased uric acid levels both in the striatum and in synaptosomes in all groups of aged rats. All
of these parameters were affected to a lesser extent in young rats. In conclusion, the response of
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cellular defence mechanisms in aged rats is consistent with a Mn-induced increase in the
formation of reactive oxygen species. An age-related impairment of the neuronal antioxidant
system may play an enabling role in Mn neurotoxicity.
4. Dorman DC, McManus BE, Parkinson CU, Manuel CA, McElveen AM, Everitt JI. (2004)
Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following
subchronic (13-week) inhalation exposure. Inhalation Toxicology 16(6-7):481-488.
Growing evidence suggests that nasal deposition and transport along the olfactory nerve
represents a route by which inhaled manganese and certain other metals are delivered to the
rodent brain. The toxicological significance of olfactory transport of manganese remains poorly
defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the
olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein
(GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to
further characterize the nasal toxicity of manganese sulfate (MnS04) and manganese phosphate
(as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnS04
(0.01, 0.1, and 0.5 mg Mn/m(3)), or hureaulite (0.1 mg Mn/m(3)). Nasal pathology, brain GFAP
levels, and brain manganese concentrations were assessed immediately following the end of the
90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and
cerebellum manganese concentrations were observed following MnS04 exposure to greater than
or equal toO.Ol, greater than or equal toO. 1, and 0.5 mg Mn/m(3), respectively. Exposure to
MnS04 or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations.
Exposure to MnS04 (0.5 mg Mn/m(3)) was also associated with reversible inflammation within
the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese
inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity
(irritation) and increased delivery of manganese to the brain; however, we could not confirm that
manganese inhalation would result in altered brain GFAP concentrations.
5. Dorman DC, Struve MF, Gross EA, Wong BA, Howroyd PC. (2005) Sub-chronic inhalation
of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys.
Respiratory Research 6.
Background: Neurotoxicity and pulmonary dysfunction are well-recognized problems associated
with prolonged human exposure to high concentrations of airborne manganese. Surprisingly,
histological characterization of pulmonary responses induced by manganese remains incomplete.
The primary objective of this study was to characterize histologic changes in the monkey
respiratory tract following manganese inhalation. Methods: Subchronic (6 hr/day, 5 days/week)
inhalation exposure of young male rhesus monkeys to manganese sulfate was performed. One
cohort of monkeys (n = 4-6 animals/exposure concentration) was exposed to air or manganese
sulfate at 0.06, 0.3, or 1.5 mg Mn/m(3) for 65 exposure days. Another eight monkeys were
exposed to manganese sulfate at 1.5 mg Mn/m(3) for 65 exposure days and held for 45 or 90
days before evaluation. A second cohort (n = 4 monkeys per time point) was exposed to
manganese sulfate at 1.5 mg Mn/m(3) and evaluated after 15 or 33 exposure days. Evaluations
included measurement of lung manganese concentrations and evaluation of respiratory histologic
changes. Tissue manganese concentrations were compared for the exposure and control groups
by tests for homogeneity of variance, analysis of variance, followed by Dunnett's multiple
comparison. Histopathological findings were evaluated using a Pearson's Chi-Square test.
Results: Animals exposed to manganese sulfate at = 0.3 mg Mn/m(3) for 65 days had increased
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lung manganese concentrations. Exposure to manganese sulfate at 1.5 mg Mn/m(3) for = 15
exposure days resulted in increased lung manganese concentrations, mild subacute bronchiolitis,
alveolar duct inflammation, and proliferation of bronchus-associated lymphoid tissue.
Bronchiolitis and alveolar duct inflammatory changes were absent 45 days post-exposure,
suggesting that these lesions are reversible upon cessation of subchronic high-dose manganese
exposure. Conclusion: High-dose subchronic manganese sulfate inhalation is associated with
increased lung manganese concentrations and small airway inflammatory changes in the absence
of observable clinical signs. Subchronic exposure to manganese sulfate at exposure
concentrations (<= 0.3 mg Mn/m(3)) similar to the current 8-hr occupational threshold limit
value established for inhaled manganese was not associated with pulmonary pathology.
6. Dorman DC, Struve MF, Vitarella D, Byerly FL, Goetz J, Miller R. (2000) Neurotoxicity of
manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral
exposure. Journal of Applied Toxicology 20(3): 179-187.
The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to
manganese-induced neurotoxicity, Identical oral manganese chloride (MnC12) doses (0, 25, or 50
mg kg(-l) body wt. day(-l)) were given to neonatal rats throughout lactation (i.e. from postnatal
day (PND) 1 through 21) and to adult male rats for 21 consecutive days. The MnC12 doses
administered to neonates were ca, 100-fold higher than those resulting from the consumption of
an equivalent volume of rat's milk. Rats were assessed using similar behavioral and
neurochemical evaluations. Several statistically significant changes occurred in Mn-exposed rats
relative to control animals. Neonates given the high dose of MnC12 had reduced body weight
gain. An increased pulse-elicited acoustic startle response amplitude was observed in neonates
from both MnC12 treatment groups on PND 21. Increased striatal, hippocampal, hindbrain and
cortical Mn concentrations were observed in all Mn-exposed neonates on PND 21. Increased
hypothalamic and cerebellar Mn concentrations were also observed on PND 21 in neonates from
the high-dose group only. Increased striatal, cerebellar and brain residue Mn concentrations were
observed in adult rats from the high-dose group. Increased striatal dopamine and 3,4-
dihydroxyphenylacetic acid levels were observed only in PND 21 neonates from the high-dose
group, No treatment-related changes were observed in clinical signs, motor activity (assessed in
neonates on PND 13, 17, 21 +/- 1 and in adults), passive avoidance (assessed in neonates on
PND 20 +/- 1 and in adults) or neuropathology (assessed in PND 21 neonates only). The results
of our experiment suggest that neonates may be at greater risk for Mn-induced neurotoxicity
when compared to adults receiving similar high oral levels of Mn. Copyright (C) 2000 John
Wiley & Sons, Ltd.
7. Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde
CA, Syversen T, Decamp E and others. (2006) Nigrostriatal dopamine system dysfunction and
subtle motor deficits in manganese-exposed non-human primates. Experimental Neurology
202(2):381-390.
We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn)
exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human
primate striatum. Motor function and general activity of animals was monitored in parallel with
chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine
release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal
concentrations in whole blood and brain was obtained and post-mortem, analysis of brain tissue
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was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor
function deficits that were associated with a marked decrease of in vivo dopamine release in the
absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in
the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn
concentrations within the upper range of environmental, medical and occupational exposures in
humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor
function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide
a novel mechanism of Mn effects on the dopaminergic system, (c) 2006 Elsevier Inc. All rights
reserved.
8. Guilarte TR, McGlothan JL, Degaonkar M, Chen MK, Barker PB, Syversen T, Schneider JS.
(2006) Evidence for cortical dysfunction and widespread manganese accumulation in the
nonhuman primate brain following chronic manganese exposure: A H-l-MRS and MRI study.
Toxicological Sciences 94(2):351-358.
Exposure to high levels of manganese (Mn) is known to produce a complex neurological
syndrome with psychiatric disturbances, cognitive impairment, and parkinsonian features.
However, the neurobiological basis of chronic low-level Mn exposure is not well defined. We
now provide evidence that exposure to levels of Mn that results in blood Mn concentrations in
the upper range of environmental and occupational exposures and in certain medical conditions
produces widespread Mn accumulation in the nonhuman primate brain as visualized by T-l-
weighted magnetic resonance imaging. Analysis of regional brain Mn distribution using a
"pallidal index equivalent" indicates that this approach is not sensitive to changing levels of
brain Mn measured in postmortem tissue. Evaluation of longitudinal H-l-magnetic resonance
spectroscopy data revealed a significant decrease (p = 0.028) in the N-acetylaspartate
(NAA)/creatine (Cr) ratio in the parietal cortex and a near significant decrease (p = 0.055) in
frontal white matter (WM) at the end of the Mn exposure period relative to baseline. Choline/Cr
or myo-Inositol/Cr ratios did not change at any time during Mn exposure. This indicates that the
changes in the NAA/Cr ratio in the parietal cortex are not due to changes in Cr but in NAA
levels. In summary, these findings suggest that during chronic Mn exposure a significant amount
of the metal accumulates not only in the basal ganglia but also in WM and in cortical structures
where it is likely to produce toxic effects. This is supported by a significantly decreased, in the
parietal cortex, NAA/Cr ratio suggestive of ongoing neuronal degeneration or dysfunction.
9. Gwiazda R, Kern C, Smith D. (2005) Progression Of Neurochemical Effects In Different
Brain Regions As A Function Of The Magnitude And Duration Of Manganese Exposure.
Toxicol Sci 84(1-S): 122-123.
Manganese (Mn) is known to elicit symptoms resembling those of Parkinson's disease (PD) at
high exposure levels, but its effects at low levels of exposure are uncertain. Because of the
similarity of behavioral deficits at elevated Mn exposure to PD symptoms, earlier Mn toxicity
studies have proposed that striatal dopamine (DA) depletion, a hallmark of PD, is also produced
by Mn, despite the observation in humans that Mn accumulates in the globus pallidus. To
reconcile this, we have proposed the hypothesis that there is a progression of effects from the
globus pallidus to striatum as a function of increasing magnitude of Mn dose and treatment
duration (Gwiazda et al., NeuroToxicology, 95:1-8, 2002). To test this, we administered Mn ip 3
times/wk to Sprague-Dawley rats at nominal doses of 0, 1.2, 4.8 and 9.6 mg/Kg over 5 wks, and
0, 1.2, 4.8 mg/Kg over 15 wks. We conducted a battery of motor tests, spontaneous motor
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activity (SMA) and rotorod measurements, evaluated brain, blood, and plasma Mn levels, and
neurochemical levels in the striatum, globus pallidus, substantia nigra and motor regions of the
thalamus. Mn treatment increased DA levels in the globus pallidus in animals receiving the
highest Mn doses over both 5 and 15 wks, but had no effect on striatal or substantia nigra DA
levels. Motor deficits measured as impairment in the balance beam and in hind limb hopping,
and shorter latency to fall from the rotorod were observed at the highest dose at 5 weeks. No Mn
effects were detected on SMA. Blood and brain Mn showed similar relative increases as a
function of nominal dose at 5 and 15 wks, even though the cumulative Mn doses of 15 wks
animals were three times higher than in animals exposed for 5 wks. These results suggest that 1)
Across a wide range of Mn doses the globus pallidus is a more sensitive locus of Mn toxicity
compared to the striatum, and 2) The magnitude of the Mn nominal dose is more important than
exposure duration in bringing about an increase in Mn body burden and eliciting Mn toxicity.
10. Gwiazda R, Lucchini R, Smith D. (2007) Adequacy and consistency of animal studies to
evaluate the neurotoxicity of chronic low-level manganese exposure in humans. Journal of
Toxicology and Environmental Health-Part a-Current Issues 70(7):594-605.
The adequacy of existing animal studies to understand the effects of chronic low- level
manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent
and nonhuman primate studies was evaluated to determine whether there is a consistent dose-
response relationship among studies, whether there is a progression of effects with increasing
dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-
level manganese exposures in humans. Neurochemical and behavioral effects were compared
along the axis of estimated internal cumulative manganese dose, independent of the route of
exposure. In rodents, motor effects emerged at cumulative doses below those where
occupationally exposed humans start to show motor deficits. The main neurochemical effects in
rodents were an increase in striatal gamma- aminobutyric acid ( GAB A) concentration
throughout the internal cumulative dose range of 18 to 5300 mg Mn/ kg but a variable effect on
striatal dopamine concentration emerging at internal cumulative doses above similar to 200 mg
Mn/ kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively
low doses and consistent harmful effects on both the globus pallidus and the caudate and
putamen at higher doses (> 260 mg Mn/ kg). Internal cumulative manganese doses of animal
studies extend more than two orders of magnitude (< 1 to 5300 mg Mn/ kg) above the doses at
which occupationally exposed humans show neurological dysfunction ( 10 - 15 mg Mn/ kg).
Since the animal data indicate that manganese neurotoxicity may be different at low compared to
elevated exposures, most existing animal model studies might be of limited relevance for the risk
assessment of chronic low- level manganese exposure to humans.
11. Gwiazda RH, Lee D, Sheridan J, Smith DR. (2002) Low cumulative manganese exposure
affects striatal GABA but not dopamine. Neurotoxicology 23(l):69-76.
The introduction of the anti-knock methylcyclopentadienyl manganese (Mn) tricarbonyl (MMT)
in gasoline has raised concerns about the potential for manganese neurotoxicity. Because
subpopulations such as the elderly in the early stages of neurodegenerative disease may be at
increased risk for manganese toxicity, a pre-Parkinsonism rat model was used to evaluate
whether sub-chronic manganese exposure can aggravate the neurochemical and behavioral
dysfunctions characteristic of Parkinsonism. Sub-threshold levels of dopamine depletion of 3.5,
53 and 68% were generated via intrastriatal unilateral 6-hydroxydopamine (6-OHDA) doses. A
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sub-chronic dosing regimen of low cumulative manganese exposure (4.8 mg Mn/kg body
weight, 3 i.p. injections per week x 5 weeks) was started 4 weeks after 6-OHDA treatments.
Neurochemical and neuromotor (functional observational battery (FOB)) measures were
evaluated. Manganese produced significant (P < 0.05) reductions of 30-60% in motor function.
This effect was exacerbated in the presence of a pre-Parkinsonism condition [Neurotox, Teratol.
22 (2000) 851], Manganese did not affect striatal dopamine, but resulted in significant increases
in striatal γ-aminobutyric acid (GABA) of 16 and 22% (P < 0.01) in both striati and a
borderline non-significant 4% increase in frontal cortex (P = 0.076). Manganese treatment
produced increased aspartate (P <0.01) in the manganese and 6-OHDA treated striatum. In light
of previous studies predominantly showing dopamine depletion with elevated manganese
exposures, the significant effects of manganese on striatal GABA but not on striatal dopamine at
the low cumulative exposure administered here suggest a progression in manganese toxicity with
increasing cumulative dose, whereby GABA levels are adversely affected before striatal
dopamine levels. Because these neurochemical disruptions were accompanied by motor
dysfunction that was exacerbated in the presence of a pre-Parkinsonism condition, an increased
environmental burden of manganese may have deleterious effects on populations with sub-
threshold neurodegeneration in the basal ganglia (e.g. pre-Parkinsonism). (C) 2002 Elsevier
Science Inc. All rights reserved.
12. Hussain S, Lipe GW, Slikker W, Ali SF. (1997) The effects of chronic exposure of
manganese on antioxidant enzymes in different regions of rat brain. Neuroscience Research
Communications 21(2): 135-144.
The present study was designed to investigate if chronic exposure to manganese (Mn) produces
an effect on antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase
(GPx) activities and reduced glutathione (GSH) content in different regions of rat brain. Adult
male Sprague-Dawley (CD) rats were dosed with 0, 2.5 or 5.0 mg MnC12/kg, for 3 months (5
days/week). The activity of total superoxide dismutase did not vary significantly in any region of
the brain with either 2.5 or 5.0 mg MnC12/kg. A significant increase of Mn-superoxide
dismutase (Mn-SOD) activity was attained in hippocampus, cerebellum and brain stem. The
Cu,Zn-superoxide dismutase activity was reduced in all regions of the brain, however, reduction
was not statistically significant. No significant effect of Mn on glutathione peroxidase activity
was observed in any region of the brain. Glutathione content was significantly reduced in
cerebellum, whereas, no change was observed in other brain regions. The results show that
chronic exposure to manganese significantly increased the Mn-superoxide dismutase activity in
selected brain regions. Therefore, increased Mn-SOD may enhance the antioxidant ability of the
brain to reduce oxidative stress. (C) 1997 John Wiley & Sons, Ltd.
13. Komiskey H. (2005) Influence Of Subacute Manganese Sulfate On Dopamine And N-
Methyl-D-Aspartate Receptors. Toxicol Sci 84(1-S):122.
The potential of manganese sulfate (MnS04) to alter the dopamine (D2 + D3) and N-methyl-D-
aspartate (NMDA) receptor after fourteen days of daily gavage was studied in rats. Sprague-
Dawley male rats were randomly given, by gavage, one of six liquid mixtures (suspended in 40
%ocorn starch; 10 %osucrose, and 12 %odextrinized corn starch) of manganese sulfate (MnS04),
negative control (40 %ocorn starch, 10 %osucrose, and 12 %odextrinized corn starch), or the
positive control (6 mg/kg midazolam). The doses of the MnS04 were given to provide: 1.0, 10,
30, or 100 milligrams manganese/kg. Binding studies of the (D2 + D3) receptor with raclopride
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were preformed in the basal ganglia. Binding studies of the NMDA receptor with CGP-39653
were preformed in the cerebellum, cerebral cortex, globus pallidus, and hippocampus. The
receptor binding studies indicate that fourteen of daily gavage with 1 to 100 mg/kg MnS04 did
not alter the affinity of the NMDA receptor or the maximum number of binding sites in the three
of the brain areas examined (cerebellum, cerebral cortex, and globus pallidus). Only the affinity
of the NMDA receptor in the hippocampus was altered by the 14-day oral exposure to 10 mg/kg
MnS04. In contrast, the affinity of (D2 + D3) binding sites was not altered by any of the liquid
mixtures containing manganese relative to the negative control given for fourteen days. The
liquid mixtures containing the highest concentrations of manganese altered the maximum
number of (D2 + D3) binding sites. The receptor binding studies indicate that two weeks of daily
gavage with 10 mg/kg MnS04 altered the affinity of the NMDA receptor in only one of the four
brain regions examined, while higher oral concentrations of MnS04 altered the maximum
number of (D2 + D3) binding sites in the basal ganglia.
14. Lipe GW, Duhart H, Newport GD, Slikker W, Ali SF. (1999) Effect of manganese on the
concentration of amino acids in different regions of the rat brain. Journal of Environmental
Science and Health Part B-Pesticides Food Contaminants and Agricultural Wastes 34(1): 119-
132.
The present study was designed to determine if chronic exposure of weanlings and adult rats to
Mn produces significant alterations in amino acid concentrations in different regions of the rat
brain. Weanling (30 day old) and adult (90 day old) male rats were exposed to 10 and 20 mg
Mn/kg body weight per day, by gavage, for 30 days. Forty-eight hours after the last dose,
animals were sacrificed by decapitation and brains were dissected into different regions to
determine the concentration of amino acids by HPLC/EC. A dose dependent decrease in body
weight gain was found in the adult, but not in the weanling rats. Significant increases occurred in
concentrations of aspartate, glutamate, glutamine, taurine and gamma-aminobutyric acid
(GAB A) in the cerebellum of the adult rats dosed with 20 mg/kg per day, Mn. A significant
decrease in the concentration of glutamine was observed in caudate nucleus and hippocampus of
weanling rats dosed with 10 mg/kg, Mn. These data suggest that chronic Mn exposure can
produce a decrease in body weight gain in adult rats and alterations in amino acids in different
regions of weanling and adult rat brains.
15. Newland MC. (1999) Animal models of manganese's neurotoxicity. Neurotoxicology 20(2-
3):415-432.
Manganese's neurotoxicity continues to present a puzzling array of differences across individuals
and across published reports in the profile of effects seen in humans and nonhuman species, but
some of the sources of individual variability are becoming clear from studies of animals. The
kinetics of manganese is a critical component of any assessment of risk associated with
exposure. After inhalation, the uptake of manganese into and elimination from the central
nervous system are slow and same manganese remains in the nervous system a year after
inhalation. Comparison with other parenteral routes suggests that manganese depots in lung
prolongs exposure even after environmental exposure has ended. Manganese's neurotoxicity is
associated with its appearance in basal ganglia structures, especially the globus pallidus.
Manganese a Iso appears in the pituitary gland but the functional consequences of this are not
well understood. Other critical components in characterizing manganese's neurotoxicity appear
to be the behavioral endpoints used, the species studied, and the exposure rate. Overt
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neurological signs and excitability are associated with high exposure rates and the appearance of
manganese throughout basal ganglia and basal forebrain regions. More focused behavioral
endpoints are required to detect the subtle signs associated with slow exposure rates low
exposure levels, but when such designs are used the effect is unequivocal. At lower exposure
levels, doses of 5 mg/kg and greater, deficits in a task in which a monkey executed a rowing type
motion against a spring approximating its body weight were clearly related to manganese
exposure while other traditional measures of response patterns under schedules of reinforcement
remained intact. Excitability and other signs of emotionality have not been reported at low
exposure rates. In rodents, manganese accumulation and alterations in the function or
concentration of neurotransmitters have been reported. Investigations of behavioral effects in
these species, which usually involved locomotor activity, have resulted in less consistent results.
Manganese produces a constellation of neurotoxic signs whose appearance and detection are
influenced by dose and exposure rate. Despite investigations of manganese's neurotoxicity in
animals over a wide range of exposure levels, a NOAEL has not been identified. (C) 1998 Inter
Press, Inc.
16. Normandin L, Beaupre LA, Salehi F, St-Pierre A, Kennedy G, Mergler D, Butterworth RE,
Philippe S, Zayed J. (2004) Manganese distribution in the brain and neurobehavioral changes
following inhalation exposure of rats to three chemical forms of manganese. Neurotoxicology
25(3):433-441.
The central nervous system is an important target for manganese (Mn) intoxication in humans; it
may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted
from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are
primarily Mn phosphate, Mn sulfate, and Mn phosphate/ sulfate mixture. The purpose of this
study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb,
frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver
kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn
species. Rats (n = 15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13
consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/ sulfate mixture at about
3000 mug m(-3) and compared to controls. At the end of the exposure period, spontaneous motor
activity was measured for 36 h using a computerized autotrack system. Mn in tissues was
determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the
brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate
mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate
mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results
confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.
(C) 2003 Elsevier Inc. All rights reserved.
17. Normandin L, Carrier G, Gardiner PF, Kennedy G, Hazell AS, Mergler D, Butterworth RF,
Philippe S, Zayed J. (2002) Assessment of bioaccumulation, neuropathology, and neurobehavior
following subchronic (90 days) inhalation in Sprague-Dawley rats exposed to manganese
phosphate. Toxicology and Applied Pharmacology 183(2):135-145.
Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn)
compound added to unleaded gasoline. It has been suggested that the combustion products of
MMT containing Mn, such as manganese phosphate, could cause neurological symptoms similar
to Parkinson's disease in humans. The aim of this work was to investigate the exposure-response
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relationship of bioaccumulation, neuropathology, and neurobehavior following a subchronic
inhalation exposure to manganese phosphate in Sprague-Dawley male rats. Rats were exposed 6
h/day, 5 days/week for 13 consecutive weeks at 30, 300, or 3000 mug/m(3) Mn phosphate and
compared to controls. Some rats were implanted with chronic EMG electrodes in the
gastrocnemius muscle of the hind limb to assess tremor at the end of Mn exposure. Spontaneous
motor activity was measured for 36 h using a computerized auto-track system. Rats were then
sacrificed by exsanguination and Mn level in different brain tissues and other organs was
determined by instrumental neutron activation analysis. Neuronal cell counts were obtained by
assessing the sum of five grid areas for the caudate/putamen and the sum of two adjacent areas
for the globus pallidus. Increased manganese concentrations were observed in all tissues of the
brain and was dose-dependent in olfactory bulb and caudate/putamen. In fact, beginning with the
highest level of exposure (3000 mug/m) and ending with the control group, Mn concentrations in
the olfactory bulb were 2.47 vs 1.28 vs 0.77 vs 0.64 ppm (P < 0.05) while for the
caudate/putamen, Mn concentrations were 1.06 vs 0.73 vs 0.62 vs 0.47 ppm (P < 0.05). The Mn
concentrations in lung were also dose-dependent (10.30 vs 1.40 vs 0.42 vs 0.17 ppm; P < 0.05).
No statistical difference was observed for loss of neurons in caudate/putamen and globus
pallidus. Locomotor activity assessment and tremor assessment did not reveal in neurobehavioral
changes between the groups. Our results reinforce the hypothesis that the olfactory bulb and
caudate/putamen are the main brain tissues for Mn accumulation after subchronic inhalation
exposure. (C) 2002 Elsevier Science (USA).
18. Ponnapakkam T, Iszard M, Henry-Sam G. (2003) Effects of oral administration of
manganese on the kidneys and urinary bladder of Sprague-Dawley rats. International Journal of
Toxicology 22(3):227-232.
The purpose of this study was to investigate the effect of oral administration of manganese
acetate on the kidneys and urinary bladder of Sprague-Dawley (SD) rats. Male and female SD
rats (150 to 175 g), 6 weeks old, were administered varying doses of manganese acetate for 63
days by oral gavage. At the end of 63 days, 50% of the animals were sacrificed and kidney tissue
was isolated and fixed for histopathological studies (study A). The remaining 50% were cross-
mated and dosing ceased. Animals were sacrificed after 2 weeks (study B). Male treated animals
were noted to have viscous, gritty urine in the urinary bladder, and the high-dose groups had
urinary bladder stones (uroliths). Histopathologically, the most striking lesions were observed in
the kidneys and prostate glands of male animals. Mild-to-moderate tubulointerstitial nephritis
with tubular proteineous and glomerulosclerosis was observed in animals of all treatment groups.
Urolithiasis in the urinary bladder was confirmed in 33% to 66% of treated animals. Female
animals did not show a significant difference above controls in renal tissues. Results of this study
suggest that male rats are more sensitive to the effects of high levels of manganese given orally
than female rats and that the genitourinary structures represent target organs of toxicity.
19. Reaney SH, Bench G, Smith DR. (2006) Brain accumulation and toxicity of Mn(II) and
Mn(III) exposures. Toxicological Sciences 93(1): 114-124.
Concern over the neurotoxic effects of chronic moderate exposures to manganese has arisen due
to increased awareness of occupational exposures and to the use of methylcyclopentadienyl
manganese tricarbonyl, a manganese-containing gasoline antiknock additive. Little data exist on
how the oxidation state of manganese exposure affects toxicity. The objective of this study was
to better understand how the oxidation state of manganese exposure affects accumulation and
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subsequent toxicity of manganese. This study utilized a rat model of manganese neurotoxicity to
investigate how ip exposure to Mn(II)-chloride or Mn(III)pyrophosphate at total cumulative
doses of 0, 30, or 90 mg Mn/kg body weight affected the brain region distribution and
neurotoxicity of manganese. Results indicate that Mn(III) exposures produced significantly
higher blood manganese levels than equimolar exposures to Mn(II). Brain manganese
concentrations increased in a dose-dependent manner, with Mn(III) exposures producing
significantly higher (> 25%) levels than exposures to Mn(II) but with no measurable differences
in the accumulation of manganese across different brain regions. Gamma amino butyric acid
concentrations were increased in the globus pallidus (GP) with manganese exposure. Dopamine
(DA) levels were altered in the GP, with the highest Mn(II) and Mn(III) exposures producing
significantly different DA levels. In addition, transferrin receptor and H-ferritin protein
expression increased in the GP with manganese exposure. These data substantiate the heightened
susceptibility of the GP to manganese, and they indicate that the oxidation state of manganese
exposure may be an important determinant of tissue toxico-dynamics and subsequent
neurotoxicity.
20. Salehi F, Carrier G, Normandin L, Kennedy G, Butterworth RF, Hazell A, Therrien G,
Mergler D, Philippe S, Zayed J. (2001) Assessment of bioaccumulation and neurotoxicity in rats
with portacaval anastomosis and exposed to manganese phosphate: A pilot study. Inhalation
Toxicology 13(12): 1151-1163.
The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has
resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically,
people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn.
In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in
end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was
investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at
the end of exposure, the rats were subjected to a locomotor evaluation ( day-night activities)
using a computerized autotrack system. Then a group of 6 PCA rats ( EXP) was exposed to 3050
mug m(-3) ( Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a
control group ( CON), 7 PCA rats exposed to 0.03 mug m(-3). After exposure, the rats were
euthanized and Mn content in tissues and organs was determined by neutron activation analysis.
The manganese concentrations in blood (0.05 mug/g vs. 0.02 mug/g), lung (1.32 mug/g vs. 0.24
mug/g), cerebellum (0.85 mug/g vs. 0.64 mug/g), frontal cortex (0.87 mug/g vs. 0.61 mug/g),
and globus pallidus (3.56 mug/g vs. 1.33 mug/g) were significantly higher in the exposed group
compared to the control group (p < .05). No difference was observed in liver, kidney, testes, and
caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell
counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was
significantly higher (p < .05) for the EXP group. Assessment of the locomotor activities did not
reveal any significant difference. This study constitutes a first step toward our understanding of
the potential adverse effects of Mn in sensitive populations.
21. Salehi F, Krewski D, Mergler D, Normandin L, Kennedy G, Philippe S, Zayed J. (2003)
Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-
Dawley rats following subchronic (90 days) inhalation exposure. Toxicology and Applied
Pharmacology 191(3):264-271.
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Methylcyclopentadienyl manganese tricarbonyl (NEWT) is an organic manganese (Mn)
compound added to unleaded gasoline in Canada. The primary combustion products of MMT are
Mn phosphate, Mn sulfate, and a Mn phosphate/Mn sulfate mixture. Concerns have been raised
that the combustion products of MMT containing Mn could be neurotoxic, even at low levels of
exposure. The objective of this study is to investigate exposure-response relationships for
bioaccumulation and locomotor effects following subchronic inhalation exposure to a mixture of
manganese phosphates/sulfate mixture. A control group and three groups of 30 male Sprague-
Dawley rats were exposed in inhalation chambers for a period of 13 weeks, 5 days per week, 6 h
a day. Exposure concentrations were 3000, 300, and 30 mug/m(3). At the end of the exposure
period, locomotor activity and resting time tests were conducted for 36 h using a computerized
autotrack system. Rats were then euthanized by exsanguination and Mn concentrations in
different tissues (liver, lung, testis, and kidney) and blood and brain (caudate putamen, globus
pallidus, olfactory bulb, frontal cortex, and cerebellum) were determined by neutron activation
analysis. Increased manganese concentrations were observed in blood, kidney, lung, testis, and
in all brain sections in the highest exposure group. Mn in the lung and in the olfactory bulb were
dose dependent. Our data indicate that the olfactory bulb accumulated more Mn than other brain
regions following inhalation exposure. Locomotor activity was increased at 3000 mug/m(3), but
no difference was observed in resting time among the exposed groups. At the end of the
experiment, rats exposed to 300 and 3000 mug/m(3) exhibited significantly decreased body
weight in comparison with the control group. Biochemical profiles also revealed some
significant differences in certain parameters, specifically alkaline phospatase, urea, and chlorate.
(C) 2003 Elsevier Inc. All rights reserved.
22. Salehi F, Normandin L, Krewski D, Kennedy G, Philippe S, Zayed J. (2006)
Neuropathology, tremor and electromyogram in rats exposed to manganese phosphate/sulfate
mixture. Journal of Applied Toxicology 26(5):419-426.
In Canada, Methylcyclopentadienyl manganese tricarbonyl (MMT) replaced tetraethyl lead in
gasoline as an antiknock agent from 1976 until 2003. The combustion of MMT leads to
increased manganese (Mn) concentrations in the atmosphere, and represents one of the main
sources of human exposure to Mn. The nervous system is the major target of the toxicity of Mn
and Mn compounds. The purpose of this study was to investigate exposure-response
relationships for neuropathology and tremor, and the associated electromyogram (EMG),
following subchronic inhalation exposure of rats to a mixture of Mn phosphate/sulfate particles.
Rats were exposed 6 h per day, 5 days per week for 13 consecutive weeks at 30, 300 or 3000 mu
g m(-3) Mn phosphate/sulfate mixture and compared with controls. Half of the rats had EMG
electrodes implanted in the gastrocnemius muscle of the hind limb to assess tremor at the end of
Mn exposure. Two days after the end of Mn exposure, rats were killed by exsanguination and
Mn concentrations in the brain (caudate putamen, globus pallidus and frontal cortex) were
determined by neutron activation analysis while neuropathology was assessed by counting
neuronal cells in 2.5 mm X 2.5 nun grid areas. Increased Mn concentrations were observed in all
brain sections at the highest level of exposure. The neuronal cell loss was significantly different
in the globus pallidus and the caudate putamen at the highest level of exposure (3000 mu g m(-
3)). No sign of tremor was observed among the rats. In conclusion, exposure to a high level of
Mn phosphate/sulfate mixture brought on neuropathological changes in a specific area of the
brain; however, no sign of tremor was observed. Copyright (c) 2006 John Wiley & Sons, Ltd.
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23. Schneider JS, Decamp E, Koser AJ, Fritz S, Gonczi H, Syversen T, Guilarte TR. (2006)
Effects of chronic manganese exposure on cognitive and motor functioning in non-human
primates. Brain Research 1118:222-231.
Acute exposure to manganese is associated with complex behavioral/psychiatric signs that may
include Parkinsonian motor features. However, little is known about the behavioral
consequences of chronic manganese exposures. In this study, cynomolgus macaque monkeys
were exposed to manganese sulfate (10-15 mg/kg/week) over an exposure period lasting 272 +/-
17 days. Prior to manganese exposure, animals were trained to perform tests of cognitive and
motor functioning and overall behavior was assessed by ratings and by videotaped analyses. By
the end of the manganese exposure period, animals developed subtle deficits in spatial working
memory and had modest decreases in spontaneous activity and manual dexterity. In addition,
stereotypic or compulsive-like behaviors such as compulsive grooming increased in frequency
by the end of the manganese exposure period. Blood manganese levels measured at the end of
the manganese exposure period ranged from 29.4 to 73.7 mu g/1 (mean = 55.7 +/- 10.8
(compared to levels of 5.1-14.2 mu g/1 at baseline (mean = 9.2 +/- 2.7)), placing them within the
upper range of levels reported for human environmental, medical or occupational exposures.
These results suggest that chronic exposure to levels of manganese achieved in this study may
have detrimental effects on behavior, cognition and motor functioning, (c) 2006 Elsevier B.V.
All rights reserved.
24. Shinotoh H, Snow BJ, Hewitt KA, Pate BD, Doudet D, Nugent R, Perl DP, Olanow W,
Calne DB. (1995) MRI and PET studies of manganese-intoxicated monkeys. Neurology
45(6): 1199-1204.
BIOSIS COPYRIGHT: BIOL ABS. Using MRI and PET, we investigated the consequences of
manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys
were injected intravenously with doses of 10 to 14 mg/kg of MnC12 on seven occasions, each a
week apart. Two animals became hypoactive with abnormal extended posturing in the hind
limbs. These motor disturbances did not improve with administration of levodopa. In all three
monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum,
globus pallidus, and substantia nigra. No significant changes were found on (18F)6-fluoro-L-
dopa, (1 lC)raclopride, or (18F)fluorodeoxyglucose PET. These results are consistent with the
pathologic findings, which were primarily confined to the globus pallidus, and indicate that
manganese intoxication is associated with preservation of the nigrostriatal dopaminergic
pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may
caus
25. Spadoni F, Stefani A, Morello M, Lavaroni F, Giacomini P, Sancesario G. (2000) Selective
vulnerability of pallidal neurons in the early phases of manganese intoxication. Experimental
Brain Research 135(4):544-551.
Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder
characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-
established phase of the intoxication. The early phase of the intoxication may be characterized
by psychic, nonmotor signs, and its morphological and electrophysiological correlates are less
defined. In a rat model of manganese intoxication (20 mg/ml in drinking water for 3 months),
neither neuronal loss nor gliosis was detected in globus pallidus (GP). However, a striking
vulnerability of manganese-treated GP neurons emerged. The majority of GP neurons isolated
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from manganese-treated rats died following brief incubation in standard dissociation media. In
addition, patch-clamp recordings in the whole-cell configuration were not tolerated by surviving
GP neurons. Neither coeval but untreated GP neurons nor striatal ones manifested analogous
susceptibility. Using the perforated-patch mode of recording we attempted at identifying the
functional hallmarks of GP vulnerability: in particular, voltage-gated calcium currents and
glutamate-induced currents were examined. Manganese-treated GP neurons exhibited calcium
currents similar to control cells aside from a slight reduction in the dihydropyridine-sensitive
current facilitation. Strikingly, manganese-treated GP cells - but not striatal ones - manifested
peculiar responses to glutamate, since repeated applications of the excitatory amino acid, at
concentrations which commonly promote desensitizing responses, produced instead an
irreversible cell damage. Possible mechanisms are discussed.
26. St-Pierre A, Normandin L, Carrier G, Kennedy G, Butterworth R, Zayed J. (2001)
Bioaccumulation and locomotor effect of manganese dust in rats. Inhalation Toxicology
13(7):623-632.
The primary goal of this study is to determine the effects of Mn exposure via inhalation. The
bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters,
and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were
exposed to 3750 mug/m(3) of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and
compared to a control group of 12 rats (C) exposed to 4 mug/m(3). After exposure, neurological
evaluation was carried out for 36 h ( a night-day-night cycle) using a computerized autotrack
system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was
determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum
were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p < .01),
as well as in the kidney, frontal cortex, and globus pallidus ( 1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs.
0.55 ppm; p < .05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79
mmol/L; p < .05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p < .01). Locomotor
activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p
< .05) and lower resting time in the last 12-h period for E ( 36 326 vs. 37 393 s; p < .05). This
study is the first of several ongoing studies in our laboratory that address health concerns
associated with inhalation exposure to different Mn species and to different levels of exposure.
27. Tapin D, Kennedy G, Lambert J, Zayed J. (2006) Bioaccumulation and locomotor effects of
manganese sulfate in Sprague-Dawley rats following subchronic (90 days) inhalation exposure.
Toxicology and Applied Pharmacology 211(2): 166-174.
Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic compound that was
introduced as an antiknock additive to replace lead in unleaded fuel. The combustion of MMT
results in the emission of fine Mn particulates mainly in the form of manganese sulfate and
manganese phosphate. The objective of this study is to determine the effects of subchronic
exposure to Mn sulfate in different tissues, on locomotor activity, on neuropathology, and on
blood serum biochemical parameters. A control group and three groups of 30 male
SpragueDawley rats were exposed 6-h/day, 5 days/week for 13 consecutive weeks at 30, 300. or
3000 mu g/m(3) Mn Sulfate. Locomotor activity was measured during 36 h using an Auto-Track
System. Blood and the following tissues were collected and analyzed for manganese content by
neutron activation analysis: olfactory bulb, globus pallidus, caudate/putamen, cerebellum, frontal
cortex, liver, lung, testis, and kidney. Neuronal cell counts were obtained for the
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caudate/putamen and the globus pallidus and clinical biochemistry was assessed. Manganese
concentrations were increased in blood, kidney, lung, and testis and in all brain regions in the
3000 mu g/m(3) exposure group. Significant differences were also noted in the 300 mu g/m(3)
exposure group, Neuronal cell counts for the globus pallidus were significantly different between
the two highest exposed groups and the controls. Locomotor activity for all exposure
concentrations and resting time for the middle and highest concentrations for the two night
resting periods were significantly increased. Total ambulatory count was decreased significantly
for all exposure concentrations. Biochemical profiles also presented significant differences. No
body weight loss was observed between all groups. These results suggest that neurotoxicity
could occur at low exposure levels of Mn sulfate, one of the main combustion products of MMT.
(c) 2005 Elsevier Inc. All rights reserved.
28. Taylor MD, Erikson KM, Dobson AW, Fitsanakis VA, Dorman DC, Aschner M. (2006)
Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain. Neurotoxicology
27(5):788-797.
Manganese (Mn) is a ubiquitous and essential element that can be toxic at high doses. In
individuals exposed to high levels of this metal, Mn can accumulate in various brain regions,
leading to neurotoxicity. In particular, Mn accumulation in the mid-brain structures, such as the
globus pallidus and striatum, can lead to a Parkinson's-like movement disorder known as
manganism. While the mechanism of this toxicity is currently unknown, it has been postulated
that Mn may be involved in the generation of reactive oxygen species (ROS) through interaction
with intracellular molecules, such as superoxide and hydrogen peroxide, produced within
mitochondria. Conversely, Mn is a required component of an important antioxidant enzyme, Mn
superoxide dismutase (MnSOD), while glutamine synthetase (GS), a Mn-containing astrocyte-
specific enzyme, is exquisitely sensitive to oxidative stress. To investigate the possible role of
oxidative stress in Mn-induced neurotoxicity, a series of inhalation studies was performed in
neonatal and adult male and female rats as well as senescent male rats exposed to various levels
of airborne-Mn for periods of time ranging from 14 to 90 days. Oxidative stress was then
indirectly assessed by measuring glutathione (GSH), metallothionein (MT), and GS levels in
several brain regions. MT and GS mRNA levels and regional brain Mn concentrations were also
determined. The collective results of these studies argue against extensive involvement of ROS
in Mn neurotoxicity in rats of differing genders and ages. There are, however, instances of
changes in individual endpoints consistent with oxidative stress in certain brain tissues. (C) 2006
Elsevier Inc. All rights reserved.
29. Torrente M, Colomina MT, Domingo JL. (2005) Behavioral effects of adult rats
concurrently exposed to high doses of oral manganese and restraint stress. Toxicology 211(1-
2):59-69.
The behavioral effects Of concurrent exposure of high doses of manganese (Mn) and restraint
stress were assessed in adult rats. Male Sprague-Dawley rats (250-300 g) received 0, 275 and
550 mg/kg/day of Mn in the drinking water for 19 weeks. Each group was divided into two
subgroups. Animals in one subgroup were restrained for 2 h/day. During the treatment period,
food and water intake, and body weight were weekly recorded. At the end of the treatment
period, activity levels were monitored in an open-field. Learning was evaluated by a water-maze
task during five consecutive days. A trial probe was also conducted to assess the time spent in
the platform quadrant. Body weight and food consumption were significantly reduced in the
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group receiving 550 mg/kg/day of Mn. A two-way analysis of variance (ANOVA) revealed an
overall effect of Mn on the total distance traveled. Differences on spatial learning were observed
in the acquisition period, in which rats given 550 mg/kg/day of Mn (alone or restrained) were
impaired in comparison with the control and the restrained only groups. In the probe trial, there
was an impaired retention in the group treated with Mn at 550 mg/kg/day. The results of this
investigation in the open-field and water maze suggest that it would be plausible that restraint
stress and a high exposure to Mn interact at common neurotransmitter levels but inducing
opposite effects, (c) 2005 Elsevier Ireland Ltd. All rights reserved.
30. Vezer T, Papp A, Hoyk Z, Varga C, Naray M, Nagymajtenyi L. (2005) Behavioral and
neurotoxicological effects of subchronic manganese exposure in rats. Environmental Toxicology
and Pharmacology 19(3):797-810.
In male Wistar rats, behavioral and electrophysiological investigations, and blood and brain
manganese level determinations, were performed; during 10 weeks treatment with low-dose
manganese chloride and a 12 weeks post-treatment period. Three groups of 16 animals each
received daily doses of 14.84 and 59.36 mg/kg b.w. MnC12 (control: distilled water) via gavage.
During treatment period, Mn accumulation was seen first in the blood, then in the brain samples
of the high-dose animals. Short- and long-term spatial memory performance of the treated
animals decreased, spontaneous open field activity (OF) was reduced. The number of acoustic
startle responses (ASR), and the pre-pulse inhibition (PPI) of these, diminished. In the cortical
and hippocampal spontaneous activity, power spectrum was shifted to higher frequencies. The
latency of the sensory evoked potentials increased, and their duration, decreased. By the end of
the post-treatment period, Mn levels returned to the control in all samples. The impairment of
long-term spatial memory remained, as did the number of acoustic startle responses. Pre-pulse
inhibition, however, returned to the pre-treatment levels. The changes of the open field activity
disappeared but a residual effect could be revealed by administration Of D-amphetamine. The
electrophysiological effects were partially reversed. By applying a complex set of methods, it
was possible to obtain new data for a better-based relationship between the known effects of Mn
at neuronal level and the behavioral and electrophysiological outcomes of Mn exposure.
© 2005 Elsevier B.V. All rights reserved.
31. Witholt R, Gwiazda RH, Smith DR. (2000) The neurobehavioral effects of subchronic
manganese exposure in the presence and absence of pre-parkinsonism. Neurotoxicology and
Teratology 22(6):851-861.
Recent studies have implicated chronic elevated exposures to environmental agents, such as
metals (e.g., manganese, Mn) and pesticides, as contributors to neurological disease. In
particular, there is a concern that sensitive subpopulations such as the aged may be at increased
risk for the onset of neurologic disorders because elevated exposures to Mn is associated with
increased incidence of parkinsonism. Here, we utilized a rat model of pre-parkinsonism to
investigate the effects of Mn exposure on neurotoxicity and the exacerbation of parkinsonism. A
pre-parkinsonism state was induced using a unilateral intrastriatal injection of 6-
hydroxydopamine (6-OHDA), followed 4 weeks later by Mn exposure (4.8 mg Mn/kg x 3
intraperitoneal injections/week) for 5 weeks. Female Sprague-Dawley rats (n = 44) were divided
among the following treatments: (A) control, saline/vehicle; (B) Mn only; (C) 6-OHDA only;
and (D) 6-OHDA + Mn. Brain Mn levels were measured by ICP MS. Neurobehavioral function
was assessed following Mn exposure using a functional observational battery (FOB) consisting
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of 10 neurobehavioral tests. Unilateral O-OHDA lesions produced significant ipsilateral vs,
contralateral striatal dopamine depletions (60-70%), but no measurable impairment of
neurobehavioral function, thereby substantiating this pre-parkinsonism (i.e., subthreshold)
model. In contrast, Mn exposure resulted in significant impairment of neurobehavioral function
for eight of the 10 FOE tests. No effects of Mn exposure on striatal dopamine depletion were
detected, despite the 3.4-fold increase in brain Mn levels over controls. Notably, Mn exposure in
the presence of a pre-parkinsonism state significantly exacerbated the neurobehavioral
impairment in the reactivity to handling (P < .049) and hopping contralateral rear limb ( P <
.033) FOE tests. While the persistence and Mn dose - response relationship of these
neurobehavioral effects were not evaluated here, these results nonetheless suggest that chronic
Mn exposure may increase the risk of neurobehavioral impairment in subpopulations that are in a
pre-parkinsonism state. (C) 2000 Elsevier Science Inc. All rights reserved.
32. Yang PY, Klimis-Tavantzis DJ. (1998) Manganese deficiency alters arterial
glycosaminoglycan structure in the Sprague-Dawley rat. Journal of Nutritional Biochemistry
9(6):324-331.
This study was designed to investigate the effect of dietary manganese on rat arterial
glycosaminoglycan structure. Weanling male Sprague-Dawley rats were randomly assigned to
two groups and were fed either a manganese-deficient or a manganese-sufficient diet. After 15
weeks, proteoglycans and glycosaminoglycans were extracted from the aorta and isolated by
DEAE-Sephacel chromatography. The disaccharide composition of glycosaminoglycans was
determined by high performance liquid chromatography following chondroitinase ABC
digestion. Manganese deficiency significantly (P less than or equal to 0.01) reduced the total
amount of arterial proteoglycans. The molecular size of chrondroitin sulfate in both the
manganese-deficient and the manganese-sufficient group ranged between 3 X
104 and 6 X 104. The size of chondroitin sulfate
of the manganese-deficient groups was slightly small than that of the manganese-sufficient group
as analyzed for Sepharose CL-6B column chromatography. Results on the disaccharide
composition of glycosaminoglycans showed that Delta Di-OS, Delta Di-4S, and Delta Di-6S
accounted for 90% of the disaccharides. There was a significant increase in the ratio of Delta Di-
6S to Delta Di-4S disaccharides in chondroitin sulfate in the manganese-deficient group (Delta
Di-6S:Delta Di-4S, 2.0) compared with the manganese-sufficient group (1.2). Our results
demonstrate for the first time that dietary manganese deficiency not only reduced the total
proteoglycan content of the aorta, but also alters the molecular weight and sulfation pattern of
chrondroitin sulfate in that tissue. This alteration may change the composition of the
extracellular matrix and consequently affect the structural properties of the vascular wall. (J.
Nutr. Biochem. 9:324-331, 1998) (C) Elsevier Science Inc. 1998.
Supporting References (3)
1. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
The aim of this study was to investigate the effects of chronic, daily, 30-d administration of
manganese chloride (MnC12) to male Sprague-Dawley rats on lipid peroxidation in various
tissues. Rats were intraperitoneally injected with MnC12 (20 mg/kg) once daily for 30
consecutive days. The Mn accumulated in liver, spleen, adrenal glands, heart, kidneys, lung, and
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testes. This was associated with decreased lipid peroxidation in liver, spleen, and adrenal glands
and a decrease in the levels of Fe in these tissues. In a second group of animals, Mn (20
mg/kg/d) and glutathione (GSH, 15 mg/kg/d) were administered ip for 30 d. GSH counteracted
the Mn-induced protective fall in lipid peroxidation, but Fe levels remained lower in liver and
spleen. Mn decreases lipid peroxidation in certain tissues, which may involve lowering Fe
content, but interaction with Fe is not the sole mechanism.
2. Desole MS, Serra PA, Esposito G, Delogu MR, Migheli R, Fresu L, Rocchitta G, Miele M.
(2000) Glutathione deficiency potentiates manganese-induced increases in compounds
associated with high-energy phosphate degradation in discrete brain areas of young and aged
rats. Aging Clinical and Experimental Research 12(6):470-477.
Aging is a factor known to increase neuronal vulnerability to oxidative stress, which is widely
accepted as a mechanism of manganese-induced neuronal damage. We previously showed that
subchronic exposure to manganese induced greater energy impairment (as revealed by increases
in hypoxanthine, xanthine and uric acid levels) in the striatum and brainstem of aged rats vs
young rats. This study shows that inhibition of glutathione (GSH) synthesis, by means of
buthionine (SR) sulfoximine, decreased GSH levels and increased the ascorbic acid oxidation
status in the striatum and limbic forebrain of both young and aged rats. In addition, inhibition of
GSH synthesis greatly potentiated the manganese-induced increase in inosine, hypoxanthine,
xanthine and uric acid levels in both regions of aged rats; moreover, inhibition of GSH synthesis
significantly increased inosine, hypoxanthine, xanthine and uric acid levels in both regions of
young rats, compared with the manganese-treated group. These results suggest that an
impairment in the neuronal antioxidant system renders young rats susceptible to manganese-
induced energetic impairment, and further support the hypothesis that an impairment in this
system plays a permissive role in the increase of neuronal vulnerability that occurs with aging.
3. Husain M, Khanna VK, Roy A, Tandon R, Pradeep S, Seth PK. (2001) Platelet dopamine
receptors and oxidative stress parameters as markers of manganese toxicity. Human &
Experimental Toxicology 20(12):631-636.
The present study has been undertaken to investigate whether neurotoxic effects of manganese
(Mn) are reflected in platelets in rats to monitor the usefulness of platelet as peripheral model.
Exposure of rats to Mn (10 or 15 mg/kg bw, i.p.) for 45 days caused a significant increase in
membrane fluidity as evidenced by decrease in fluorescence polarisation in platelets (11% and
14%) and striatum (9% and 13%). These rats exhibited a significant increase in superoxide
dismutase activity both in platelets (24% and 37%) and striatum (31% and 42%), respectively, in
comparison to controls. Exposure of rats to Mn for 45 days (15 mg/kg bw, i.p.) caused a
significant decrease in reduced glutathione content (platelets 20%, striatum 24%) and catalase
activity (platelets 35%, striatum 44%) compared to control rats. Rats exposed to Mn (10 or 15
mg/kg bw, i.p.) for 15 days exhibited a significant increase in dopamine receptors both in
platelets (55% and 40%) and striatum (38% and 31%). The results suggest that exposure to Mn
may alter the membrane functions and impair the anti-oxidant defense mechanism both in
platelets and brain. The study also suggests that dopaminergic mechanisms are impaired
following Mn exposure and such changes are reflected in platelets. Interestingly, parallel
changes both in striatum and platelets, as observed in the present study, strengthen the usefulness
of platelets as a peripheral neuronal model.
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4.2.2 Cancer bioassays
Key References (0)
There were no key references identified for this section.
Supporting References (0)
There were no supporting references identified for this section.
4.3 REPRODUCTIVE AND DEVELOPMENTAL STUDIES—ORAL AND
INHALATION
Key References (12)
1. Colomina MT, Domingo JL, Llobet JM, Corbella J. (1996) Effect of day of exposure on the
developmental toxicity of manganese in mice. Veterinary and Human Toxicology 38(l):7-9.
Manganese is embryotoxic and fetotoxic in mammals. The aim of this study was to determine
whether the day of exposure would modify the developmental toxicity of manganese (II).
Pregnant Swiss mice were given single sc doses of 50 mg manganese chloride tetrahydrate/kg on
day 9, 10, ii or 12 of gestation. No maternal deaths, abortions or early deliveries were observed.
Dams were killed on gestational day 18 and the uterine contents examined. Embryotoxicity,
evidenced by significant increases in number of late resorptions and in percentage of
postimplantation loss, was especially relevant in groups dosed on gestational days 9 or 10.
Fetotoxicity (reduced fetal body weight and increased incidence of skeletal defects) was also
especially remarkable from doses on days 9 or 10 of gestation. However, no teratogenic effects
were noted in any group. Although mouse conceptus are adversely affected by sc exposure to
manganese on any of the gestational days 9-12, days 9 and 10 of gestation are the most sensitive
for manganese-induced embryo/fetal toxicity in mice.
2. Eder K, Kralik A, Kirchgessner M. (1996) The effect of manganese supply on thyroid
hormone metabolism in the offspring of manganese-depleted dams. Biological Trace Element
Research 55(1-2): 137-145.
The present study was performed to investigate the effect of manganese (Mn) supply on
metabolism of thyroid hormones in the rat. A study with rats was carried out over two
generations. Female rats were raised with a Mn-deficient diet (0.1 mg Mn/kg), and mated to
produce a second generation. The male rats of the second generation were used as subjects for
the investigation They were divided into five groups and fed diets with Mn concentrations of 0.1,
0.5, 2.2, 10, and 46 mg/kg for 40 d. For assessment of thyroid hormone metabolism,
concentrations of thyroid hormones in serum and activity of hepatic type I 5'deiodinase (5'D-I)
were measured. Feeding diets with 0.1 mg Mn/kg impaired growth and food conversion,
influenced parameters of thyroid hormone metabolism, and changed some clinical-chemical
parameters, such as concentrations of total protein, albumin, calcium (Ca) and magnesium (Mg)
as well as activity of alkaline phosphatase in serum. Regarding the thyroid hormone metabolism,
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rats fed the diet with a Mn level of 0.1 mg/kg had a higher 5'D-I activity in liver, and
consequently a higher concentration of triiodothyronine in serum than the rats fed the other diets.
Ln contrast, the concentrations of total and free thyroxine were not influenced by the Mn intake.
Growth, clinical-chemical parameters, concentrations of thyroid hormones in serum, and activity
of hepatic 5'D-I were similar in the rats fed diets with Mn concentrations between 0.5 and 46
mg/kg. The present study shows that feeding a diet with a very low Mn concentration affects
growth and thyroid hormone metabolism and that a dietary level of 0.5 mg Mn/kg is adequate for
growth and thyroid hormone metabolism in the offspring of Mn-depleted dams.
3. Garcia SJ, Syversen T, Gellein K, Aschner M. (2005) Iron Deficient And Manganese
Enhanced Diets Alter Metals And Transporters In The Developing Rat Brain. Toxicol Sci 84(1-
S):122.
Fe-deficiency is a prevalent nutritional disorder, affecting ~2 billion people, mostly pregnant and
lactating women and children. Fe and Mn share similar transport mechanisms, competing for
transport. In adults Mn toxicity leads to neurological disturbances, but little is known about
developmental Mn toxicity. To study the interactions of Fe and Mn during brain development,
pregnant Sprague-Dawley rats were fed one of four semi-purified diets from gestational day 7
until postnatal day (PN)21: control (35 Fe:10 Mn mg/kg diet), low Fe (ID; 3 Fe:10 Mn), high Mn
(Mn; 35 Fe: 100 Mn), or low Fe with high Mn (IDMn; 3 Fe: 100 Mn). Control neonates were
cross-fostered to experimental or control dams on PN4 and exposed to the diets via lactation
until PN21. Hematological measurements confirmed Fedeficiency (decreased Fe, hemoglobin;
increased transferrin (Tf), total Fe binding capacity) in dams and pups fed "ID" or "IDMn" diets,
while those fed "Mn" had some trends toward similar hematological changes. Western blot
analysis revealed that both "ID" and "IDMn" increased expression of the metal transporters, Tf
receptor and divalent metal transporter 1 (DMT1). Inductively coupled plasma mass
spectrometry (ICP-MS) showed that all three experimental diets decreased brain Fe levels, while
both Mn enhanced diets increased brain Mn levels. In addition, "ID" increased copper (Cu);
"Mn" increased chromium (Cr); and "IDMn" increased Cr, Cu, cobalt (Co), zinc (Zn), and
vanadium (V). Upregulated DMT1, a non-specific transporter, may be a route for increased
metals in the brain following dietary manipulations. Because each of the metals affected by low
Fe and/or high Mn are esessential metals for normal development and function, homeostatic
disturbances may contribute to later consequences.
4. Pappas BA, Zhang D, Davidson CM, Crowder T, Park GA, Fortin T. (1997) Perinatal
manganese exposure: Behavioral, neurochemical, and histopathological effects in the rat.
Neurotoxicology and Teratology 19(1): 17-25.
BIOSIS COPYRIGHT: BIOL ABS. Manganese chloride (Mn) was dissolved in the drinking
water (0, 2, or 10 mg/ml) of dams and their litters from conception until postnatal day (PND) 30.
Parturition was uneventful in the Mn-exposed rats and no physical abnormalities were observed.
The rats exposed to 10 mg/ml Mn showed a 2.5-fold increase in cortical Mn levels. Their weight
gain was attenuated from PND 9-24 and they were hyperactive at PND 17. Neither the 2 nor the
10 mg/ml Mn-exposed groups differed from the controls on the elevated plus apparatus or on the
Morris water maze and the radial arm maze. Brain monoamine levels and choline
acetyltransferase activity were unaffected. Tyrosine hydroxylase immunohistochemistry showed
that dopamine cells of the substantia nigra were intact. Glial fibrillary acidic protein
immunoreactivity was not increased in cortex, caudate, and hippocampus. However, both the
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January 31, 2008
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low- and high-dose Mn-exposed groups showing thinning of the cerebral cortex. This could have
resulted f
5. Ponnapakkam TP, Bailey KS, Graves KA, Iszard MB. (2003) Assessment of male
reproductive system in the CD-I mice following oral manganese exposure. Reproductive
Toxicology 17(5): 547-551.
Manganese has wide industrial applications and exposure to manganese can result in serious
health conditions. The purpose of this study was to determine the reproductive effect of oral
manganese exposure in male mice. Manganese acetate was tested at three dose levels (7.5, 15.0,
and 30.0 mg/kg/day) for 43 days. The control group (0 mg/kg/day) received distilled water.
Control negative group did not receive anything. Reproductive organ weights were recorded.
Histopathology was performed on right testis, epididymis, seminal vesicle, and the accessory
glands. Cauda epididymal, testicular sperm counts, and sperm motility was evaluated on the
organ from the left side. The results of this study suggest that exposure to manganese caused a
statistically significant (P < 0.001) decrease in sperm motility and sperm counts at 15.0 and 30.0
mg/kg/day. There were no alterations in the fertility or pathology of the testicular tissue in the
manganese-treated mice when compared with the controls. (C) 2003 Elsevier Inc. All rights
reserved.
6. Ponnapakkam TP, Henry-Sam GA, Iszard MB. (2001) A comparative study of the
reproductive toxicity of manganese in rats and mice. Faseb Journal 15(4):A585-A585.
7. Torrente M, Albina ML, Colomina MT, Corbella J, Domingo JL. (2000) Interactions in
developmental toxicology: effects of combined administration of manganese and hydrocortisone.
Trace Elements and Electrolytes 17(4): 173-179.
Objective: The maternal and embryo/fetal toxicity of concurrent administration of
hydrocortisone (HC), as a substitute of a potential "stressor", and manganese (Mn) were assessed
in pregnant mice. Methods: Animals were divided into four groups and received subcutaneous
injections of MnCl(2)x4H(2)0 at 0, 1, 2 and 4 mg/kg/day on gestation days 6-18. Each group
was subdivided into two subgroups. Mice in each subgroup received 0 or 5 mg/kg/day of HC
(s.c.) from days 6 to 18 of gestation. Cesarean sections were performed on day 18 of gestation
and all live fetuses were examined for malformations and variations. Results: In the groups
treated with MnC12 at 4 mg/kg/day, either alone or combined with HC, maternal toxicity was
evidenced by significant decreases in body weight gain during treatment, body weight at
termination, and gravid uterine weight. In turn, the most notable reproductive finding was the
dramatic number of resorptions found in the group concurrently exposed to 4 mg/kg/day of
MnC12 and 5 mg/kg/day of HC. No live fetuses were found in this group. A delayed ossification
in a number of bones was also observed at 4 mg/kg/day of MnC12 only. Conclusion: The
enhancement of Mn-induced maternal and embryo/fetal adverse effects by concurrent
administration of HC was only evident at the doses of Mn which are also toxic by themselves.
8. Torrente M, Colomina MT, Domingo JL. (2002) Effects of prenatal exposure to manganese
on postnatal development and behavior in mice: Influence of maternal restraint. Neurotoxicology
and Teratology 24(2):219-225.
Manganese (Mn) is an essential trace element whose deficiency and excess have been reported to
cause central nervous system (CNS) disturbances, On the other hand, during pregnancy,
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maternal stress has been shown to enhance the developmental toxicity of a number of metals. In
this study, the maternal toxicity and developmental effects of a concurrent exposure to Mn and
restraint stress were evaluated in mice. Pregnant animals were divided into three groups and
received subcutaneous injections of manganese chloride tetrahydrate (MnC12.4H(2)0) at 0.1 and
2 mg/kg/day on Gestation Days 6-18. Each group was divided into two subgroups. Mice in one
subgroup were subjected to restraint for 2 h/day on Days 6-18 of gestation. Pregnant mice were
allowed to deliver, and pups were evaluated for physical and neuromotor maturation.
Subsequently, adult mice were also evaluated for activity and learning. A significant increase in
perinatal mortality was observed at 2 mg/kg/day Mn. A delay in some developmental landmarks
(eye opening, testes descent) due to Mn exposure (2 mg/kg/day) was also seen in both restrained
and unrestrained animals. No differences in motor resistance and coordination, or in learning at
the passive avoidance test, were noted in adult mice. At the current Mn doses, combined
exposure to Mn and stress during the prenatal period did not produce long-lasting effects on
adult mice. (C) 2002 Elsevier Science Inc. All rights reserved.
9. Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B. (2002) Effect of high
dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine
levels, and neurodevelopmental status. Neurotoxicology 23(4-5):635-643.
Mn is an essential element, but may become neurotoxic at high levels. Recent reports of high Mn
levels in hair of children with neurodevelopmental deficits suggest that these deficits could be
due to Mn-induced neurotoxic effects on brain dopamine (DA) systems, although the mechanism
is not well understood. Infant formulas contain considerably higher concentrations of Mn than
human milk. Thus, formula-fed infants are exposed to high levels of Mn at a time when Mn
homeostasis is incompletely developed. We studied the effects of dietary Mn supplementation of
rat pups on tissue Mn accumulation, brain dopamine levels, infant neurodevelopmental status,
and behavior at maturity. Newborn rats were supplemented daily with 0, 50, 250, or 500 mug
Mn given orally from day I to day 20. Mineral analysis of small intestine and brain at day 14
showed a significant increase of tissue Mn in supplemented rats. Neurodevelopmental tests
conducted at various ages showed significant delays as a function of Mn supplementation. At
day 32, there was a significant positive relationship between passive avoidance errors and Mn
supplementation levels. Brains of animals killed on day 40 showed a significant inverse
relationship between Mn supplementation level and striatal dopamine concentration. These
observations suggest that dietary exposure to high levels of Mn during infancy can be neurotoxic
to rat pups and result in developmental deficits. (C) 2002 Elsevier Science Inc. All rights
reserved.
10. Tran TT, Kelleher SL, Lonnerdal B. (2002) Effect of high manganese intake and iron
deficiency in infant rats on DMT-1 expression and tissue mineral accumulation. Faseb Journal
16(4):A617-A617.
11. Weber S, Dorman DC, Lash LH, Erikson K, Vrana KE, Aschner M. (2002) Effects of
manganese (Mn) on the developing rat brain: Oxidative-stress related endpoints.
Neurotoxicology 23(2): 169-175.
lie evaluated biochemical endpoints related to oxidative stress in brains of neonatal rats exposed
to manganese (Mn). Oral Mn chloride (MnC12) (0, 25, or 50 mg Mn chloride kg(-l) body weight
per day) was given daily to neonatal rats throughout lactation (i.e. front postnatal day (PND) 1 to
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21). As previously reported by (J. Appl. Toxicol. 20 (2000) 179), this treatment paradigm results
in increased cerebral cortex (CTX) Mn concentrations in PND 21 rats front both Mn treatment
groups. High dose Mn exposure also results in increased cerebellar Mn concentrations. This
preliminary study determined whether this exposure paradigm also affects cerebrocortical or
cerebellar metallothionein (MT) mRNA levels, glutamine synthetase (GS) activity, GS protein
levels, as well as total glutathione (GSH) levels. High dose Mn exposure significantly increased
(P < 0.05) total cerebrocortical GSH without accompanying changes in any of the other
measured parameters. Therefore, it is unlikely that high dose Mn exposure is associated with
oxidative stress in this experimental paradigm. (C) 2002 Elsevier Science Inc. All rights
reserved.
12. Zhang BY, Chen S, Ye FL, Zhu CC, Zhang HX, Wang RB, Xiao CF, Wu TC, Zhang GG.
(2002) Effect of manganese on heat stress protein synthesis of new-born rats. World Journal of
Gastroenterology 8(1):114-118.
AIM: To study the effect of manganese (Mn) on heat stress protein 70 (HSP70) synthesis in the
brain and liver of newborn rats whose mother-rats were exposed to Mn. METHODS: 32 female
rats were randomly divided into four groups. One group was administrated with physiological
saline only as control group, the other three groups were administrated with 7.5, 15 and 30 mg .
kg(-l) manganese chloride (MnC12.) by intraperitioneal injection every two days for two weeks.
After delivery, the mother-rats received MnC12 unceasingly for a week with the same method.
Then the contents of Mn, Zn, Cu and Fe in the livers of the newborn rats were determined by
atomic absorption spectroscopy; The level of HSP70 in the brains and the livers of the new-born
rats as detected by Western-dot-blotting, and the SOD activities were measured simultaneously.
RESULTS: The contents of Mn in the livers of new-born rats of the experimental groups
(respective 1.38 +/- 0.18, 2.73 +/- 0.65, 3.44 +/- 0.89 mug . g(-l)) were significantly increased
compared with the control group (0.88 +/- 0.18mug . g(-l); P < 0.01); The contents of Fe in the
livers of new-born rats of 15 and 30 mg . kg(-l) experimental groups (426 +/- 125, 572 +/-
175μg . g(-l) respectively) were significantly increased compared with the control group
(286 +/- μg . g(-l); P < 0.05), the levels of Zn in the livers of the new-born rats of three
experimental groups(254 +/- 49, 263 +/- 47, 213 +/- 28mug . g(-l), respectively) were lower than
those of the control group (335 +/- 50mug.g(-l); respective P < 0.05, P < 0.01); and the levels of
Cu showed no significant difference among the four groups (three experimental groups: 75 +/-
21, 68 +/- 241 and 78 +/- 18mug . g(-l); control group: 83 +/- 9mug . g(-l); P > 0.05). There was
a significant increase in the levels of HSP70 in the brains of new-born rats of the 30 mg . kg(-l)
group (19.5 x 10(3) +/- 1.3 x 10(3) A; control group: 14.3 x 10(3) +/- 1.4 x 10(3)A; P < 0.01),
and the levels of HSP70 in the livers of new-born rats of three experimental groups (respective
19.6 x 10(3) +/- 3.9 x 10(3)A, 18.5 x 10(3) +/- 3.8 x 10(3)A, 22.4 x 10(3) +/- 1.9 x 10(3) A) also
increased than control group(13.3 x 10(3) +/- 1.0 x 10(3)A; P < 0.01), but the SOD activities
showed no significant difference among brains of the four groups (experimental groups: 5.04 +/-
0.43, 4.83 +/- 0.48, 4.60 +/- 0.84 ku . g(-l); control group: 4.91 +/- 0.37 ku . g(-l) P > 0.05). The
SOD activities in the livers of 15 mg . kg(-l) group(5.41 +/- 0.44 ku . g(-l)) was lower than the
control group(5.95 +/- 0.36 ku . g(-l); P < 0.05). CONCLUSION: While mother-rats were
exposed to manganese, the metabolisms of Mn,Zn and Fe of new-born rats in the livers were
Influenced and were situated in a stress status, thus HSP70 syntheses Is induced in the brains and
livers of new-born rats, but the mechanism of this effect in the developmental toxicity of Mn
remains to be further studied.
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Supporting References (93)
1. Agte V, Jahagirdar M, Chiplonkar S. (2005) Apparent absorption of eight micronutrients and
phytic acid from vegetarian meals in ileostomized human volunteers. Nutrition 21(6):678-685.
Objectives: Apparent absorption of eight micronutrients and degradation of phytic acid were
studied in human subjects who underwent ileostomy. The prominent factors affecting
micronutrient absorption from vegetarian Indian meals (n = 11) were identified. Methods: Levels
of β-carotene, ascorbic acid, riboflavin, and thiamine in food and ileostomy contents were
estimated by spectrophotometry and spectrofluorometry. Contents of zinc iron, copper, and
manganese were estimated by atomic absorption spectrometry and that of phytic acid by gradient
elution ion exchange chromatography. Statistical analyses were done with SPSS 10.0. Results:
Absorption of β-carotene,. ascorbic acid, riboflavin, and thiamine was 63% to 75.6%.
There was a negative non-significant trend in values of β-carotene absorption with
increased intake of 0-carotene (r = -0.51, P > 0.1) and iron (r = -0.67, P = 0.1) but a positive
significant trend with riboflavin intakes (r = 0.84, P = 0.018). Percentage of absorption of
ascorbic acid showed weak positive associations with intakes of riboflavin (r = 0.71) and
ascorbic acid (r = 0.5). Percentage of absorption of ascorbic acid was positively correlated, with
percentage of absorption of β-carotene (r = 0.80, P < 0.05), iron, and riboflavin (r =
0.64, P = 0.086), indicating some common influencing factors. Percentages of absorption for
zinc (20.2), iron (9.9), and copper (17.6) was comparable with those reported for soy. protein-
based, high phytate diets. Pattern of phytic acid in the meals and output indicated partial
degradation and absorption (34%). Conclusions: For vegetarian Indian meals, apparent
absorptions of β-carotene and ascorbic acid were 76% and 12.5% and of riboflavin and
thiamine was 63%. Zinc, copper, and iron showed a lower absorption (10% to 20%). ©
2005 Elsevier Inc. All rights reserved.
2. Anastassopoulou J, Theophanides T. (2002) Magnesium-DNA interactions and the possible
relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical Reviews in
Oncology Hematology 42(1):79-91.
Magnesium deficiency causes renal complications. The appearance of several diseases is related
to its depletion in the human body. In radiotherapy, as well as in chemotherapy, especially in
treatment of cancers with cis-platinum, hypomagnesaemia is observed. The site effects of
chemotherapy that are due to hypomagnesaemia are decreased using Mg supplements. The role
of magnesium in DNA stabilization is concentration dependent. At high concentrations there is
an accumulation of Mg binding, which induces conformational changes leading to Z-DNA,
while at low concentration there is deficiency and destabilization of DNA. The biological and
clinical consequences of abnormal concentrations are DNA cleavage leading to diseases and
cancer. Carcinogenesis and cell growth are also magnesium-ion concentration dependent.
Several reports point out that the interaction of magnesium in the presence of other metal ions
showed that there is synergism with Li and Mn, but there is magnesium antagonism in DNA
binding with the essential metal ions in the order: Zn > Mg > Ca. In the case of toxic metals such
as Cd, Ga and Ni there is also antagonism for DNA binding. It was found from radiolysis of
deaerated aqueous solutions of the nucleoside 5'-guanosine monophosphate (5'-GMP) in the
presence as well as in the absence of magnesium ions that, although the addition of hydroxyl
radicals ((OH)-O-.) has been increased by 2-fold, the opening of the imidazole ring of the
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guanine base was prevented. This effect was due to the binding of Mg2+ ions to N7 site of the
molecule by stabilizing the five-member ring imitating cis-platinum. It was also observed using
Fourier Transform Infrared spectroscopy, Raman spectroscopy and Fast Atom Bombardment
mass spectrometry that (OH)-O-. radicals subtract H atoms from the CI', C4' and C5' sites of the
nucleotide. Irradiation of 5'-GMP in the presence of oxygen (2.5 x 10(-4) M) shows that
magnesium is released from the complex. There is spectroscopic evidence that superoxide anions
(0-2(-.)) react with magnesium ions leading to magnesium release from the complex. From
radiolysis data it was suggested that magnesium ions can act as radiosensitizers in the absence of
oxygen, while in the presence of oxygen they act as protectors and stabilizers of DNA. (C) 2002
Elsevier Science Ireland Ltd. All rights reserved.
3. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
Iron (Fe) is an essential trace metal involved in numerous cellular processes. Iron deficiency (ID)
is reported as the most prevalent nutritional problem worldwide. Increasing evidence suggests
that ID is associated with altered neurotransmitter metabolism and a risk factor for manganese
(Mn) neurotoxicity. Though recent studies have established differences in which the female
brain responds to ID-related neurochemical alterations versus the male brain, little is known
about the interactions of dietary ID, Mn exposure, and sex on gamma-amino butyric acid
(GABA). Male and female Sprague-Dawley rats were randomly divided into four dietary
treatment groups: control (CN), control/ Mn supplemented, ID, and ID/Mn supplemented. After
6 weeks of treatment, both ID diets caused a highly significant decrease in Fe concentrations
across all brain regions compared to CN in both sexes. Both ID and Mn supplementation led to
significant accumulation of Mn across all brain regions in both sexes. There was no main effect
of sex on Fe or Mn accumulation. Striatal synaptosomes were utilized to examine the effect of
dietary intervention on H-3-GABA uptake. At 4 weeks, there was a significant correlation
between Fe concentration and H-3-GABA uptake in male rats (p < 0.05). At 6 weeks, there was
a significant inverse correlation between Mn concentration and 3H-GAB A uptake in male and
female rats and a postitive correlation between Fe concentration and H-3-GABA uptake in
female rats (p < 0.05). In conclusion, ID-associated Mn accumulation is similar in both sexes,
with Mn levels affecting GABA uptake in both sexes in a comparable fashion.
4. Anderson JG, Cooney PT, Erikson KM. (2007) Inhibition of DAT function attenuates
manganese accumulation in the globus pallidus. Environmental Toxicology and Pharmacology
23(2): 179-184.
Manganese (Mn) is an essential nutrient, though exposure to high concentrations may result in
neurotoxicity characterized by alterations in dopamine neurobiology. To date, it remains elusive
how and why Mn targets dopaminergic neurons although recently the role of the dopamine
transporter has been suggested. Our primary goal of this study was to examine the potential roles
of the monoamine transporters, dopamine transporter (DAT), serotonin transporter (SERT), and
norepinephrine transporter (NET), in neuronal Mn transport. Using striatal synaptosomes, we
found that only inhibition of DAT significantly decreased Mn accumulation. Furthermore,
weanling rats chronically exposed to Mn significantly accumulated Mn in several brain regions.
However, rats receiving the specific DAT inhibitor GBR 12909 (1 mg/kg bw, three times/week;
4 weeks) had significantly lower Mn levels only in the globus pallidus compared to saline-
Draft Bibliography: Manganese Lit. Search D-116
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treated rats (p < 0.05). Our data show that inhibition of DAT exclusively inhibits Mn
accumulation in the globus pallidus during chronic exposure, (c) 2006 Elsevier B.V. All rights
reserved.
5. Antonini JM, Santaimaria AB, Jenkins NT, Albini E, Lucchini R. (2006) Fate of manganese
associated with the inhalation of welding fumes: Potential neurological effects. Neurotoxicology
27(3):304-310.
Welding fumes are a complex mixture composed of different metals. Most welding fumes
contain a small percentage of manganese. There is an emerging concern among occupational
health officials about the potential neurological effects associated with the exposure to
manganese in welding fumes. Little is known about the fate of manganese that is complexed
with other metals in the welding particles after inhalation. Depending on the welding process and
the composition of the welding electrode, manganese may be present in different oxidation states
and have different solubility properties. These differences may affect the biological responses to
manganese after the inhalation of welding fumes. Manganese intoxication and the associated
neurological symptoms have been reported in individual cases of welders who have been
exposed to high concentrations of manganese-containing welding fumes due to work in poorly
ventilated areas. However, the question remains as to whether welders who are exposed to low
levels of welding fumes over long periods of time are at risk for the development of neurological
diseases. For the most part, questions remain unanswered. There is still paucity of adequate
scientific reports on welders who suffered significant neurotoxicity, hence there is a need for
well-designed epidemiology studies that combine complete information on the occupational
exposure of welders with both behavioral and biochemical endpoints of neurotoxicity. Published
by Elsevier Inc.
6. Aschner M. (2000) Manganese: Brain transport and emerging research needs. Environmental
Health Perspectives 108:429-432.
Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder. An
estimated 2% of the U.S. population, age 65 and older, develops IPD. The number of IPD
patients will certainly increase over the next several decades as the baby-boomers gradually step
into this high-risk age group, concomitant with the increase in the average life expectancy. While
many studies have suggested that industrial chemicals and pesticides may underlie [PD, its
etiology remains elusive. Among the toxic metals, the relationship between manganese
intoxication and IPD has long been recognized. The neurological signs of manganism have
received close attention because they resemble several clinical disorders collectively described
as extrapyramidal motor system dysfunction, and in particular, IPD and dystonia. However,
distinct dissimilarities between IPD and manganism are well established, and it remains to be
determined whether Mn plays an etiologic role in IPD. It is particularly noteworthy that as a
result of a recent court decision, methylcyclopentadienyl Mn tricarbonyl (MMT) is presently
available in the United States and Canada for use in fuel, replacing lead as an antiknock additive.
The impact of potential long-term exposure to low levels of MMT combustion products that may
be present in emissions from automobiles has yet to be fully evaluated. Nevertheless, it should
be pointed out that recent studies with Various environmental modeling approaches in the
Montreal metropolitan (where MMT has been used for more than 10 years) suggest that airborne
Mn revels were quite similar to those in areas where MMT was not used. These studies also
show that Mn is emitted from the tail pipe of motor vehicles primarily as a mixture of manganese
Draft Bibliography: Manganese Lit. Search D-117
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phosphate and manganese sulfate. This brief review characterizes the Mn speciation in the blood
and the transport kinetics of Mn into the central nervous system, a critical step in the
accumulation of Mn within the brain, outlines the potential susceptibility of selected populations
(e.g., iron-deficient) to Mn exposure, and addresses future research needs for Mn.
7. Aschner M, Lukey B, Tremblay A. (2006) The manganese health research program (MHRP):
Status report and future research needs and directions. Neurotoxicology 27(5):733-736.
The manganese (Mn) research health program (MHRP) symposium was a full day session at the
22nd International Neurotoxicology Conference. Mn is a critical metal in many defense and
defense-related private sector applications including steel making and fabrication, improved fuel
efficiency, and welding, and a vital and large component in portable power sources (batteries).
At the current time, there is much debate concerning the potential adverse health effects of the
use of manganese in these and other applications. Due to the significant use of manganese by the
Department of Defense, its contractors and its suppliers, the Manganese Health Research
Program (MHRP) seeks to use the resources of the federal government, in tandem with
manganese researchers, as well as those industries that are involved with manganese, to
determine the exact health effects of manganese, as well as to devise proper safeguard measures
for both public and private sector workers. Humans require manganese as an essential element;
however, exposure to high levels of this metal is sometimes associated with adverse health
effects, most notably within the central nervous system. Exposure scenarios vary extensively in
relation to geographical location, urban versus rural environment, lifestyles, diet, and
occupational setting. Furthermore, exposure may be brief or chronic, it may be to different types
of manganese compounds (aerosols or salts of manganese with different physical and/or
chemical properties), and it may occur at different life-stages (e.g., in utero, neonatal life,
puberty, adult life, or senescence). These factors along with diverse genetic composition that
imposes both a background and disease occurrence likely reflect on differential sensitivity of
individuals to manganese exposure. Unraveling these complexities requires a multipronged
research approach to address multiple questions about the role of manganese as an essential
metal as well as its modulation of disease processes and dysfunction. A symposium on the
Health Effects of Manganese (Mn) was held on Wednesday, September 14, 1005, to discuss
advances in the understanding on role of Mn both in health and disease. The symposium was
sponsored by the Manganese Health Research Program (MHRP). This summary provides
background on the MHRP, identifies the speakers and topics discussed at the symposium, and
identifies research needs and anticipated progress in understanding Mn health- and disease-
related issues. (C)2005 Elsevier Inc. All rights reserved.
8. Aschner M, Vrana KE, Zheng W. (1999) Manganese uptake and distribution in the central
nervous system (CNS). Neurotoxicology 20(2-3): 173-180.
Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its
transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have
focused on distribution, excretion, and accumulation of intravenous and intraperitoneal solutions
of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation
state (Mn2+) and crosses the BBB via specific carriers ata rate far slower than in other tissues.
Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn
accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme,
glutamine synthetase (GS) represents an important regulatory target of Mn. Compared to Mn2+,
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Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in
tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron
(Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential
distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in
experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn
emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to
endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying
protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and
3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the
transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.
(C) 1999 Inter Press, Inc.
9. Azin F, Raie RM, Mahmoudi MM. (1998) Correlation between the levels of certain
carcinogenic and anticarcinogenic trace elements and esophageal cancer in northern Iran.
Ecotoxicology and Environmental Safety 39(3): 179-184.
Levels of four carcinogenic (Ni, Fe, Cu, Pb) and four anticarcinogenic (Zn, Se, Mn, Mg) trace
elements were measured in hair samples from esophageal cancer patients, their unaffected family
members, and members of families with no history of cancer. Measurements were also made in
non-esophageal cancer patients, using atomic absorption spectroscopy, inductively coupled
plasma-emission spectroscopy, and neutron activation analysis. The results showed thatNi and
Cu concentrations were significantly higher and Mg and Mn concentrations were significantly
lower in all cancer cases. Levels of Zn, Fe, Se, and Pb were not significantly different in the
above-mentioned groups. In addition, the serum albumin fraction, which is reported to have
antioxidant activity, was found to be significantly lower among esophageal cancer patients. (C)
1998 Academic Press.
10. Barrington WW, Angle CR, Willcockson NK, Padula MA, Korn T. (1998) Autonomic
function in manganese alloy workers. Environmental Research 78(l):50-58.
The observation of orthostatic hypotension in an index case of manganese toxicity lead to this
prospective attempt to evaluate cardiovascular autonomic function and cognitive and emotional
neurotoxicity in eight manganese alloy welders and machinists. The subjects consisted of a
convenience sample consisting of an index case of manganese dementia, his four co-workers in a
"frog shop" for gouging, welding, and grinding repair of high manganese railway track and a
convenience sample of three mild steel welders with lesser manganese exposure also referred
because of cognitive or autonomic symptoms. Frog shop air manganese samples 9.6-10 years
before and 1.2-3.4 years after the diagnosis of the index case exceeded 1.0 mg/m(3) in 29% and
0.2 mg/m(3) in 62%. Twenty-four-hour electrocardiographic (Holter) monitoring was used to
determine the temporal variability of the heartrate (RR' interval) and the rates of change at low
frequency (0.04-0.15Hz) and high frequency (0.15-0.40Hz). MMPI and MCMI personality
assessment and shortterm memory, figure copy, controlled oral word association, and symbol
digit tests were used. The five frog shop workers had abnormal sympathovagal balance with
decreased high frequency variability (increased In LF/ln HF). Seven of the eight workers had
symptoms of autonomic dysfunction and significantly decreased heart rate variability (rMSSD)
but these did not distinguish the relative exposure. Mood or affect was disturbed in all with
associated changes in short-term memory and attention in four of the subjects. There were no
significant correlations with serum or urine manganese. Power spectrum analysis of 24-h
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ambulatory ECG indicating a decrease in parasympathetic high frequency activation of heart rate
variability may provide a sensitive index of central autonomic dysfunction reflecting increased
exposure to manganese, although the contribution of exposures to solvents and other metals
cannot be excluded. Neurotoxicity due to the gouging, melding, and grinding of mild steel and
high manganese alloys (11-25%) merits air manganese and neuropsychologic surveillance
including autonomic function by Holter monitoring of cardiovagal activation. (C) 1998
Academic Press.
11. Bizarro P, Sanchez I, Lopez I, Pasos F, Delgado V, Gonzalez-Villalva A, Colin-Barenque L,
Acevedo S, Nino-Cabrera G, Mussali-Galante P and others. (2004) Morphological Changes In
Testes. After Manganese Inhalation. Study In Mice. Toxicologist 78(1-S): 157.
Manganese (Mn) has been used as an antiknocking agent in gasoline. Its increase in the
atmosphere enhances the risk of its inhalation and the induction of systemic damage. Some
reports mention that oral administration of MnC12 induces reproductive delay in male mice.
Prostatic cancer has been identified among exposed workers. The objective of this study was to
identify in a murine inhalation model in CD-I male mice. Animals inhaled MnC12 0.02M, lh,
twice a week, for 4 weeks, sacrificed once a week and processed for light and electron
microscopy. Light changes evidenced necrosis of stem cells, binucleated spermatocytes and
dense nuclear structures. Ultrastructural changes in Leydig cells consisted in hyperplastic
endoplasmic reticulum forming whorl-like structures. As a consequence of these modifications
the function of the testes might be altered, as well as its endocrine function.
12. Blakey DH, Bayley JM. (1995) Induction of chromosomal aberrations by the fuel addictive
methylcyclopentadienyl-manganese tricarbonyl mmt in Chinese hamster ovary cells. 26th Annual
Meeting of the Environmental Mutagen Society, St. Louis, Missouri, USA, March 12-16, 1995.
Environmental and Molecular Mutagenesis 25(SUPPL. 25):6.
Biosis copyright: biol abs. rrm meeting abstract carcinogen
13. Blazak WF, Brown GL, Gray TJB, Treinen KA, Denny KH. (1996) Developmental toxicity
study of mangafodipir trisodium injection (MnDPDP) in New Zealand white rabbits.
Fundamental and Applied Toxicology 33(1): 11-15.
Mangafodipir trisodium injection (MnDPDP) is an intravenously administered manganese
chelate undergoing clinical evaluation for magnetic resonance imaging contrast enhancement of
the hepatobiliary system. The anticipated single clinical dose for adults is 5 mu mol/kg body wt.
MnDPDP, as well as the inorganic salt, MnC12, was previously shown to induce a specific
syndrome of skeletal abnormalities in rats. The syndrome malformations included angulated or
irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. The
objective of the present study was to assess the developmental toxicity of MnDPDP in a second
mammalian species, the New Zealand White rabbit. MnDPDP was intravenously administered
daily to groups of rabbits (22 per group) on Days 6 through 18 of pregnancy at doses of 0
(saline), 5, 20, 40, and 60 mu mol/kg MnDPDP. Fetuses were examined on Day 29 of pregnancy
for external, visceral, and skeletal abnormalities. Treatment with MnDPDP did not result in overt
symptoms of maternal toxicity, and there were no significant effects on maternal body weight
gains or feed consumption. The maternal no-observed-adverse-effect level (NOAEL), therefore,
was 60 mu mol/kg MnDPDP. Treatment with MnDPDP resulted in a significant increase in
postimplantation loss at 60 mu mol/kg, but there was no significant increase in external, visceral,
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or skeletal abnormalities at any dose. The developmental NOAEL for MnDPDP, therefore, was
40 mu mol/kg. These results indicate that the developmental toxicity profile of MnDPDP differs
considerably in the rat and rabbit. In the rat, this compound induces specific skeletal
abnormalities, whereas in the rabbit, embryo/fetal toxicity is the most sensitive developmental
endpoint with no evidence for the induction of specific skeletal abnormalities. (C) 1996 Society
of Toxicology
14. Bouchard M, Mergler D, Baldwin M, Sassine MP, Bowler R, MacGibbon B. (2003) Blood
manganese and alcohol consumption interact on mood states among manganese alloy production
workers. Neurotoxicology 24(4-5):641-647.
Long-term exposure to manganese (Mn) can induce neurotoxic effects including neuromotor,
neurocognitive and neuropsychiatric effects, but there is a great interpersonal variability in the
occurrence of these effects. It has recently been suggested that blood Mn (MnB) may interact
with alcohol use disorders, accentuating neuropsychiatric symptoms. The objective of the
present study was to explore a possible interaction between alcohol consumption and MnB on
mood states, using an existing data set on Mn exposed workers. Respirable Mn exposure in the
plant averaged 0.23 mg/m(3) and was correlated with MnB. All participants for whom all data on
MnB concentration and mood (assessed with the Profile of Mood States (POMS)) were available
and who reported currently drinking alcohol were included in the analyses (n = 74). Workers
were grouped according to their MnB concentration (<10 and greater than or equal to 10 mug/1)
and alcohol consumption (<400 and greater than or equal to400 g per week). Two-way ANOVAs
were performed on each POMS scale and Mann-Whitney tests were used to assess group
differences. Workers in the higher alcohol consumption group had higher scores on three POMS
scales: tension, anger and fatigue. There was no difference for POMS scale scores between MnB
subgroups. Dividing the group with respect to alcohol consumption and MnB showed that the
group with high alcohol consumption and high MnB displayed the highest scores. In the lower
MnB category, those in the higher alcohol consumption group did not have higher scores than
the others. The interaction term for alcohol consumption and MnB concentration was statistically
significant (P < 0.05) for the depression, anger fatigue and confusion POMS scales. There was a
tendency for tension (P < 0.06), and it was not significant for vigor. This study shows the first
evidence of an interaction between MnB and alcohol consumption on mood states among Mn
exposed workers and supports the results from a previous population-based study. (C) 2003
Elsevier Science Inc. All rights reserved.
15. Bowler RM, Mergler D, Sassine MP, Larribe F, Hudnell K. (1999) Neuropsychiatric effects
of manganese on mood. Neurotoxicology 20(2-3):367-378.
Adverse mood effects of overexposure to Manganese (Mn) have been described in 15 studies
which frequently report an association of Mn exposure with adverse effects in six dimensions of
mood: 1) anxiety, nervousness, irritability; 2) psychotic experiences; 3) emotional disturbance;
4) fatigue lack of vigor, sleep disturbance; 5) impulsive/compulsive behavior; 6) aggression
hostility. Only 1.15 studies used a standardized psychological measure of mood, while the
current study of environmental Mn exposure used two standardized mood scales in evaluating
low levels of Mn exposure and mood sequelae. The Profile of Moods State (POMS) and Brief
Symptom Inventory (BSI) were used, and results indicate that men who are older and have
higher Mn levels show significant disturbances on four of the six mood dimensions. Increased
scores were seen in the anxiety, nervousness, irritability; emotional disturbance; and aggression,
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hostility dimensions relative to those who had lower levels of Mn. The BSI and POMS are useful
adjuncts in the assessment of mood/Mn effects. (C) 1999 Inter Press, Inc.
16. Bredow S, Falgout MM, Divine KK. (2005) A Potential Mechanism For Pulmonary
Manganese-Toxicity: Manganese Induces Pulmonary VEGF Expression In Vitro. Toxicol Sci
84(1-S):234.
The respiratory tract constitutes a major route of entry and absorption for airborne Manganese
(Mn) dust and fume particles. Although chronic Mn-exposure causes toxic responses in lung,
little is known about the underlying mechanisms that mediate these effects. In non-pulmonary
cell lines Mn induces cellular expression of Vascular Endothelial Growth Factor (VEGF) in
vitro. VEGF is perhaps the most important positive regulator of angiogenesis, the sprouting and
growth of new blood vessels from the existing vasculature. Angiogenic activity, which is usually
low under normal physiological conditions, contributes to the pathogenesis of many diseases,
and elevated VEGF levels frequently correlate with poor prognosis and disease outcome. Here
we demonstrate that Mn increases VEGF expression in vitro in several human pulmonary
epithelial cell lines (A549, Calu-3, NCI-H292). Cells were transiently transfected with a reporter
plasmid containing the gene for firefly luciferase under the control of the VEGF wild type-
promoter. Twenty-eight hours later, MnC12 was directly added to the medium in concentrations
ranging from 50 to 1000 |iM. The cells were incubated for another 20 hours and then lyzed.
Analysis of the cell lysates for firefly activity revealed cell- and dose-dependent increases in
promoter activity between 1.5 and 3.5-fold. Interestingly in comparison to non-treated controls,
exposure to 0.25 mM MnC12 for 20 hours increases promoter activity 2-fold for up to 24 hours
after Mn is removed. Further, growing the cells in the presence of 0.25 mM MnC12 for 2 weeks
did not affect their viability. These data suggest that Mn might promote changes in pulmonary
angiogenic growth factor expression, which, over time, could affect lung vasculature
morphology, leading to enhanced susceptibility to disease. Further studies may provide an
insight into the pathogenesis of, and therapeutic targets for, lung diseases such as asthma and
other chronic inflammatory airway diseases.
17. Brurok H, Schjott J, Berg K, Karlsson JOG, Jynge P. (1997) Manganese and the heart:
Acute cardiodepression and myocardial accumulation of manganese. Acta Physiologica
Scandinavica 159(l):33-40.
The aim of study was to assess acute effects oi the divalent manganese ion (Mn2+) in an intact
bur isolated heart preparation. Rat hearts were perfused in the Langendorff mode at constant
flow rate. Left ventricular (LV) developed pressure (LVDP), LV pressure first derivatives
(LVdp/dt max and min), heart rate (HR) and aortic pressure (AoP) were recorded. Ventricular
contents of high energy phosphate compounds (HEP) and Mn metal were measured at the end of
experiment. Infusion of MnC12 for 5 min with perfusate concentrations 1-3000 mu M induced an
immediate depression of contractile function at and above 33 mu M and negative chronotropy at
and above 300 mu M. These EC(50) values were found (mu M): LVDP 250: LVdp/dt max 160.
LVdp/dp min 120, HR 1000; and increase in AoP 80. Recovery of function during a 14 min
washout period was rapid and extensive, except for Mn2+ 300 mu M. Somewhat unexpected,
Mn2+ 30-1000 mu M raised coronary vascular resistance up to about twice the control level,
whereas the vasoconstrictory response was overcome at 3000 mu M. Mn2+ 3000 mu M reduced
tissue HEP. Ventricular Mn content rose stepwise for perfusate Mn2+ above 1 mu M UP to
about 55 times the control level for perfusate Mn2+ 3000 mu M, it is concluded that: acute
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effects of Mn2+ like depression of contractility and rate is rapidly reversible: and rat hearts
accumulate and buffer large amounts of Mn2+ without affecting cardiac function or energy
metabolism in the acute stage.
18. Buchman AL, Neely M, Grossie VB, Truong L, Lykissa E, Ahn C. (2001) Organ heavy-
metal accumulation during parenteral nutrition is associated with pathologic abnormalities in
rats. Nutrition 17(7-8):600-606.
OBJECTIVES: Metabolic bone disease, hepatic abnormalities, splenic insufficiency, and
nephropathy have been associated with long-term total parenteral nutrition (TPN). We
determined the heavy-metal contamination in TPN solutions and investigated whether it was
associated with organ deposition and pathologic organ damage. METHODS: Five representative
TPN solutions (two adult standard solutions, one renal solution, and one standard pediatric
solution to reflect clinical practice) and 28 TPN components were analyzed with inductively
coupled plasma mass spectrometry. Twenty-six male Fisher 344 rats were assigned to two
groups (chow/NaCl = 8 and TPN = 18). TPN or NaCl was infused gt a rate of 50 mL/d. After 14
d, serum, femurs, spine, liver, kidneys, brain, spleen, and testes were analyzed for heavy-metal
deposition by using inductively coupled plasma mass spectrometry. Tissues were fixed in
formalin, sectioned, and stained with hematoxylin and eosin, periodic acid Schiff, and Masson's
trichrome stain. Kidneys were fixed in gluteraldehyde for ultrastructural examination with
scanning electron microscopy. RESULTS: The predominant sources of contaminants in TPN
were amino acids (Al, As, Cr, Ge, Pb, Sn), dextrose (As, Ba, Cr, Sn), Ca gluconate (Al),
K(2)P04 (Al), lipid emulsion (As, Sn), and vitamins (As). Significant variations in the level of
contamination depended on TPN formulation and brand of constituents. In the kidney, Pb, Cr,
and Mn concentrations were greater than in controls, although there was no correlation with
serum creatinine. Hepatic Cr and Pb concentrations were greater in TPN rats, although there was
no correlation with serum aspartate aminotransferase or total bilirubin. Splenic Ba, Cr, Ge, Pb,
Mn, and Sn concentrations were greater in TPN rats. Only serum Cr concentration was
significantly correlated with splenic concentration (r = 0.46, P = 0.04). Brain and serum Ba
concentrations were significantly correlated (r = 0.60, P = 0.007). No significant correlations
were observed between any other metal in serum and that metal's respective organ concentration.
No increase in heavy-metal accumulation was seen in the femur, spine, or testis. There were no
significant depositions of As, Cd, Hg, St, or V in any of the organs examined. Serum Al and Cr
concentrations were significantly increased in TPN rats, although there was no correlation with
tissue concentrations. No significant increases in heavy-metal concentrations in tissue or plasma
were observed for any of the other metals measurable by inductively coupled plasma mass
spectrometry. Histologically in the TPN group, 50% of the rats had mild to moderate hepatic
steatosis and 33% to 50% developed renal morphologic abnormalties; brains and spleens
remained histologically normal. CONCLUSIONS: We found significant heavy-metal
contamination of TPN solutions, and this contamination can lead to organ deposition and
subsequent histologic abnormalities. (C) Elsevier Science Inc. 2001.
19. Cardozo-Pelaez F, Cox DP, Bolin C. (2005) Lack of the DNA repair enzyme OGG1
sensitizes dopamine neurons to manganese toxicity during development. Gene Expression 12(4-
6):315-323.
Onset of Parkinson's disease (PD) and Parkinson-like syndromes has been associated with
exposure to diverse environmental stimuli. Epidemiological studies have demonstrated that
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exposure to elevated levels of manganese produces neuropathological changes localized to the
basal ganglia, including neuronal loss and depletions in striatal dopamine content. However,
understanding the mechanisms associated with manganese neurotoxicity has been hampered by
the lack of a good rodent model. Elevated levels of 8-hydroxy-2'-deoxyguanosine (oxo(8)dG)
have been found in brain areas affected in PD. Whether increased DNA damage is responsible
for neuronal degeneration or is a mere epiphenomena of neuronal loss remains to be elucidated.
Thus, by using mice deficient in the ability to remove oxo(8)dG we aimed to determine if
dysregulation of DNA repair coupled to manganese exposure would be detrimental to
dopaminergic neurons. Wild-type and OGG1 knockout mice were exposed to manganese from
conception to postnatal day 30; in both groups, exposure to manganese led to alterations in the
neurochemistry of the nigrostriatal system. After exposure, dopamine levels were elevated in the
caudate of wild-type mice. Dopamine was reduced in the caudate of OGG1 knockout mice, a
loss that was paralleled by an increase in the dopamine index of turnover. In addition, the
reduction of dopamine in caudate putamen correlated with the accumulation of oxo(8)dG in
midbrain. We conclude that OGG1 function is essential in maintaining neuronal stability during
development and identify DNA damage as a common pathway in neuronal loss after a
toxicological challenge.
20. Chaki H, Furuta S, Matsuda A, Yamauchi K, Yamamoto K, Kokuba Y, Fujibayashi Y.
(2000) Magnetic resonance image and blood manganese concentration as indices for manganese
content in the brain of rats. Biological Trace Element Research 74(3):245-257.
Neurological disorders similar to parkinsonian syndrome and signal hyperintensity in brain on
Tl-weighted magnetic resonance (MR) images have been reported in patients receiving long-
term total parenteral nutrition (TPN). These symptoms have been associated with manganese
(Mn) depositions in brain. Although alterations of signal intensity on T-l-weighted MR images
in brain and of Mn concentration in blood are theoretically considered good indices for
estimating Mn deposition in brain, precise correlations between these parameters have not been
demonstrated as yet. Male Sprague-Dawley rats received TPN with 10-fold the clinical dose of
the trace element preparation (TE-5) for 7 d. At 0, 2, 4, 6, and 8 wk post-TPN, the cortex,
striatum, midbrain, and cerebellum were evaluated by MR images, and Mn concentration in
blood and Mn content in these brain sites were measured by atomic absorption spectrometry.
Immediately after TPN termination, signal hyperintensity in brain sites and elevated Mn content
in blood and brain sites were observed. These values recovered at 4 wk post-TPN. A positive
correlation was observed between either the signal intensity in certain brain sites or Mn content
in blood and the relevant brain sites.
21. Chang JY, Liu LZ. (1999) Manganese potentiates nitric oxide production by microglia.
Molecular Brain Research 68(l-2):22-28.
Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are
similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive
microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9
microglial cells, the current study was designed to determine whether high levels of manganese
were associated with microglial activation. Results indicated that manganese significantly
increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity
of manganese was not shared by other transition metals tested, including iron, cobalt, nickel,
copper and zinc. Immunohistochemical staining and Western blot analysis indicated that
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manganese increased the cellular production of inducible nitric oxide synthase. Northern blot
analysis indicated that manganese Likely increased iNOS gene transcription since this agent
increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition
metals tested, manganese did not appear to be cytotoxic to microglial cells. These results
suggested that manganese could induce sustained production of neurotoxic nitric oxide by
activated microglial cells, which might cause detrimental consequences to surrounding neurons.
(C) 1999 Elsevier Science B.V. All rights reserved.
22. Chen CJ, Ou YC, Lin SY, Liao SL, Chen SY, Chen JH. (2006) Manganese modulates pro-
inflammatory gene expression in activated glia. Neurochemistry International 49(1):62-71.
Redox-active metals are of paramount importance for biological functions. Their impact and
cellular activities participate in the physiological and pathophysiological processes of the central
nervous system (CNS), including inflammatory responses. Manganese is an essential trace
element and it is required for normal biological activities and ubiquitous enzymatic reactions.
However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent
evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes,
representative CNS immune cells. In this study, we assessed the molecular basis of the effects of
manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production
in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of
microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis
factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it
potentiated iNOS and TNF-alpha gene expression by lipopol gamma-saccharide/interferon-
gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese,
generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-
KB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IKB-alpha
was one of underlying mechanisms for the increased activation of NF-KB by manganese.
However, manganese decreased iNOS enzymatic activity possibly through the depletion of
cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate
that manganese could modulate glial inflammation through variable strategies, (c) 2006 Elsevier
Ltd. All rights reserved.
23. Cheng J, Fu JL, Zhou ZC. (2003) The inhibitory effects of manganese on steroidogenesis in
rat primary Leydig cells by disrupting steroidogenic acute regulatory (StAR) protein expression.
Toxicology 187(2-3): 139-148.
Manganese is known to impede the male reproductive function, however, the mechanisms
through which the adverse effects are mediated are not clearly elucidated. In order to get insight
into those mechanisms, the effects of manganese on the biosynthesis of testosterone by primary
rat Leydig cells were examined. Primary Leydig cells were exposed to various concentrations of
manganese chloride for different periods of time. Dose and time-dependent reductions of human
chorionic gonadotropin (hCG)-stimulated testosterone level were observed in the culture
medium. The expression of Steroidogenic Acute Regulatory (StAR) protein and the activities of
P450 side-chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD)
enzymes were also detected. The expression of StAR protein stimulated by hCG was suppressed
by manganese chloride at all concentrations (0.01, 0.1, 1.0 mM) and time points (2, 4, 24, 48 h)
tested. Progesterone productions treated with 22R-hydroxycholesterol or pregnenolone were
reduced after treated by manganese chloride for 24 or 48 h, respectively. The manganese
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exposure effect on cell viability was significant at 1.0 and 1.5 mM at 24 h, while at 48 It it was
significant at every concentration tested. The decreasing effect of manganese on mitochondrial
membrane potential was significant at every concentration measured and every time point tested.
These data suggest that manganese exposure for 2 and 4 h inhibited rat primary Ley dig cell
steroidogenesis by decreasing StAR protein expression while 24 and 48 h exposure of
manganese chloride caused adverse effects on both StAR protein and P450scc and 3beta-HSD
enzyme activity to reduce steroidogenesis. Manganese may also disrupt StAR expression and/or
function secondary to mitochondrial dysfunction. (C) 2003 Elsevier Science Ireland Ltd. All
rights reserved.
24. Chua ACG, Stonell LM, Savigni DL, Morgan EH. (1996) Mechanisms of manganese
transport in rabbit erythroid cells. Journal of Physiology-London 493(1):99-112.
1. The mechanisms of manganese transport into erythroid cells were investigated using rabbit
reticulocytes and mature erythrocytes and Mn-54-labelled MnC12 and Mn-2-transferrin. In some
experiments iron uptake was also studied. 2. Three saturable manganese transport mechanisms
were identified, two for Mn2+ (high and low affinity processes) and one for transferrin-bound
manganese (Mn-Tf). 3. High affinity Mn2+ transport occurred in reticulocytes but not
erythrocytes, was active only in low ionic strength media such as isotonic sucrose and had a K-m
of 0.4 mu M. It was inhibited by metabolic inhibitors and several metal ions. 4. Low affinity
Mn2+ transport occurred in erythrocytes as well as in reticulocytes and had K-m values of
approximately 20 and 50 mu M for the two types of cells, respectively. The rate of Mn2+
transport was maximal in isotonic KC1, RbCl or CsCl, and was inhibited by NaCl and by
amiloride, valinomycin, diethylstilboestrol and other ion transport inhibitors. The direction of
Mn2+ transport was reversible, resulting in Mn2+ efflux from the cells. 5. The uptake of
transferrin-bound manganese occurred only with reticulocytes and depended on receptor-
mediated endocytosis of Mn-Tf. 6. The characteristics of the three saturable manganese transport
mechanisms were similar to corresponding mechanisms of iron uptake by erythroid cells,
suggesting that the two metals are transported by the same mechanisms. 7. It is proposed that
high affinity manganese transport is a surface representation of the process responsible for the
transport of manganese across the endosomal membrane after its release from transferrin. Low
affinity transport probably occurs by the previously described Na+ - Mg2+ antiport, and may
function in the regulation of intracellular manganese concentration by exporting manganese from
the cells.
25. Cox D, Bolin C, Cardozo-Pelaez F. (2003) Assessment of dopaminergic neurons, DNA
damage, DNA repair, and antioxidants in a model for manganese (MN) neurotoxicity. Free
Radical Biology and Medicine 35:S156-S156.
26. Crossgrove J, Zheng W. (2004) Manganese toxicity upon overexposure. Nmr in
Biomedicine 17(8):544-553.
Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent
mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by
the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging.
The administration of intravenous Mn impacts its homeostatic balance in the human body and
can lead to toxicity. Human Mn deficiency has been reported in patients oil parenteral nutrition
and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder)
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and dietary overexposure and is evidenced primarily in the central nervous system, although
lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results
from all accumulation of the metal in brain tissue and results in a progressive disorder of the
extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from
blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-
cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain
Mn accumulation and neurotoxicity. The mechanism for the neuro-degenerative damage specific
to select brain regions is not clearly understood. Disturbances in iron homeostasis and the
valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation
therapy with EDTA and supplementation with levodopa are the current treatment options, which
are mildly and transiently efficacious. In conclusion, repeated administration of Mn Or
compounds that readily release Mn. may increase the risk of Mn-induced toxicity. Copyright (C)
2004 John Wiley Soils. Ltd.
27. Davis CD, Schafer DM, Finley JW. (1998) Effect of biliary ligation on manganese
accumulation in rat brain. Biological Trace Element Research 64(l-3):61-74.
Neurologic and radiologic disorders have been reported to occur in miners inhaling manganese
(Mn)-laden dust and in humans receiving long-term parenteral nutrition. These abnormalities
have been attributed to Mn intoxication because of elevated serum Mn concentrations. Because
the liver, by way of the bile, is the major route of Mn excretion, it is possible that anything that
decreases biliary excretion could increase accumulation of Mn in the brain. The purpose of this
study was to determine whether biliary ligation would increase Mn accumulation in the brain of
rats that were exposed to deficient or adequate amounts of dietary manganese. The first
experiment had a 2 x 3 factorial design, two levels of Mn (0 or 45 mu g/g diet) and three surgical
treatments (control, sham, or bile-ligation). Animals were sacrificed 10 d after being fed Mn-54.
In experiment 2, animals that had a sham operation or bile-ligation were sacrificed at 8 time
points after being injected intraportally with 54Mn complexed to albumin. The biliary-ligated
animals had a significantly (p < 0.001) smaller percentage of the 54Mn in their brains (when
expressed as a percentage of whole animal 54Mn) than the sham-operated animals. Mn
deficiency had a similar effect. However, we did observe an increased accumulation of the
radioisotope in the brain over time. Therefore, in short-term studies, biliary-ligated rats do not
appear to be a good model for Mn accumulation in the brains of people with cholestatic liver
disease.
28. Degner D, Bleich S, Riegel A, Sprung R, Poser W, Ruther E. (2000) A follow-up study in
enteral manganese intoxication: clinical, laboratory, and neuroradiological aspects. Nervenarzt
71 (5):416-419.
Manganese intoxication is an unusual, severe form of intoxication. This report deals with a
patient now 80 years old who accidentally ingested a solution of potassium permanganate for a
period of at least 4 weeks 14 years ago. Since then, the patient suffers from a mild parkinsonian
syndrome and distally accentuated polyneuropathies. Psychiatric disorders, especially demential
or depressive symptoms, were not observed. Manganese analysis of his hair still shows a clear
increase in manganese concentration. The MRI of his brain showed no pathological changes, in
particular none of those often described with symmetric signal elevation in T-l in the area of the
basal ganglia. In this study, we present clinical, laboratory, and neuroradiological findings.
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Unusual in this case with a short exposition is the long duration and clinical improvement
without I-dopa treatment.
29. Desoize B. (2003) Metals and metal compounds in carcinogenesis. In Vivo 17(6):529-539.
Several metals and metal containing compounds are potent mutagens and carcinogens. The most
often blamed are chromium, arsenic, nickel, vanadium, iron, copper and manganese. Although
each of them has its own mechanism of action, it is believed that most of their mechanisms of
action involve reactive oxygen species (ROS). Furthermore, nickel modulates gene expression
by induction of DNA methylation and/or suppression of histone acetylation. Arsenic activity on
cell metabolism is multiple; it seems that cell transformation is induced by long-term exposure to
a low level of arsenic. The paradox of arsenic is that it has also a valuable therapeutic efficacy in
cancer treatment. Manganese is known to cause DNA damage, although it does not represent a
significant carcinogenic risk. Magnesium deficiency and iron excess,are not exactly
carcinogenetic, but certain concentrations of these metal ions are needed to prevent cancer.
30. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R. (1996) Manganese and l-methyl-4-
(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine induce apoptosis in PC12 cells. Neuroscience Letters
209(3):193-196.
Oxidative stress is thought to play a key role both in the neurotoxin MPTP- and manganese
(Mn)-induced neurotoxicity and in apoptotic cell death. In the present study, we report that Mn
and the MPTP analogue l-methyl-4-(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine (2'Et-MPTP),
which is metabolized by MAO-A to l-methyl-4-(2'-ethylphenyl)-pyridinium ion (at
concentrations of 0.5 and 1.0 mM), induced apoptosis in PC 12 cells. Apoptosis was tested by
terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate nick end
labelling (TUNEL) technique, flow cytometry and fluorescence microscopy. Both Mn and 2'Et-
MPTP induced also a time-dependent decrease in cell viability, as determined by the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Only Mn-induced
apoptosis and decrease in cell viability were inhibited by the antioxidant ascorbic acid. We
conclude that apoptosis may be an important mechanism of cell death in MPTP- and Mn-induced
parkinsonism. However, an oxidative stress mechanism may be recognized only in the Mn-
induced apoptosis.
31. DiLorenzo D, Ferrari F, Agrati P, deVos H, Apostoli P, Alessio L, Albertini A, Maggi A.
(1996) Manganese effects on the human neuroblastoma cell line SK-ER3. Toxicology and
Applied Pharmacology 140(1):51-57.
SK-ER3 cells were recently demonstrated to represent a valuable model for the study of
estrogen-inducible differentiation of neural cells in culture. This system may constitute an
important tool also for the analysis of the effects of neurotoxic drugs. The present study
demonstrates that short term exposure to Mn causes increased proliferation rate of SK-ER3 cells
regardless of their differentiation. Long term treatment causes cell death in undifferentiated cells
at concentrations of the metal as low as 100 nM. When the cells are differentiated with
estrogens, death is observed only with a Mn concentration two orders of magnitude higher.
Measurement of neurite extension and quantitation of tyrosine hydroxylase content after long-
term exposure to the metal allow the conclusion that Mn does not alter the state of differentiation
of SK-ER3 cells induced by the treatment with the hormone. The study underlines the
importance of studying the effect of Mn in proliferating neural cells and demonstrates the toxic
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role of micromolar concentrations of the metal in fully differentiated neural cells. Since other
authors produced evidence of effects of the metal on cell death and proliferation only at
millimolar concentrations, and none described its proliferative activity, the model utilized in the
present study seems to be of particular interest. (C) 1996 Academic Press, Inc.
32. Dodd CA, Ward DL, Klein BG. (2005) Basal ganglia accumulation and motor assessment
following manganese chloride exposure in the C57BL/6 mouse. International Journal of
Toxicology 24(6):389-397.
Equivocal clinical evidence for involvement of manganese in development of Parkinson's disease
necessitates experimental studies on this issue. The aged, l-methyl-4-phenyl-l,2,3,6-
tetrahyropyridine-treated C57BL/6 mouse is one of the most common models for Parkinson's
disease. However, there is little information on brain bioaccumulation of manganese, and little or
no information on clinical/behavioral manifestations of manganese neurotoxicity, in this strain.
Male C57BL/6 retired breeder mice were given a single subcutaneous injection of either 0, 50, or
100 mg/kg of MnC12 (single-dose regimen) or three injections of either of these doses over 7
days (multiple-dose regimen). Behavioral assessment was performed 24 h after final injection,
followed by sacrifice, and body weight was recorded each day. There was a 105% increase in
striatal manganese concentration 1 day after a single 100 mg/kg injection, and 421% and 647%)
increases, respectively, 1 day after multiple doses of 50 or 100 mg/kg of MnC12. One day after a
single injection, there were respective 30.9% and 38.9% decreases in horizontal movement ( grid
crossing) for the 50 and 100 mg/kg doses and a 43.2% decrease for the multiple dose of 100
mg/kg. There was no significant main effect of dose level on rearing, swimming, grip strength,
or grip fatigue. Unlike previous work with the C57BL/6 strain using smaller intraperitoneal
doses, this study established dosing regimens that produced significant increases in basal ganglia
manganese concentration reminiscent of brain increases in the CD-I mouse following
subcutaneous doses close to our lowest. A decrease in locomotor behavior, significant but not
severe in this study, has been reported following manganese exposure in other mouse strains.
These data, particularly the significant increase in basal ganglia manganese concentration,
provide guidance for designing studies of the potential role of manganese in Parkinson's disease
using the most common animal model for the disorder.
33. Dorman DC. (2000) An integrative approach to neurotoxicology. Toxicologic Pathology
28(l):37-42.
Exposure of human populations to a wide variety of chemicals has generated concern about the
potential neurotoxicity of new and existing chemicals. Experimental studies conducted in
laboratory animals remain critical to the study of neurotoxicity. An integrative approach using
pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral
methods is needed to determine whether a chemical is neurotoxic. There are a number of factors
that can affect the outcome of a neurotoxicity study, including the choice of animal species, dose
and dosage regimen, route of administration, and the intrinsic sensitivity of the nervous system
to the test chemical. The neurotoxicity of a chemical can vary at different stages of brain
development and maturity. Evidence of neurotoxicity may be highly subjective and species
specific and can be complicated by the presence of systemic disease. The aim of this paper is to
give an overview of these and other factors involved in the assessment of the neurotoxic
potential for chemicals. This article discusses the neurotoxicity of several neurotoxicants (eg,
acrylamide, trimethyltin, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, manganese, and
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ivermectin), thereby highlighting a multidisciplinary approach to the assessment of chemically
induced neurotoxicity in animals. These model chemicals produce a broad range of effects that
includes peripheral axonopathy, selective neuronal damage within the nervous system, and
impaired neuronal-glial metabolism.
34. Egyed M, Wood GC. (1996) Risk assessment for combustion products of the gasoline
additive MMT in Canada. Science of the Total Environment 190:11-20.
Methylcyclopentadienyl manganese tricarbonyl (MMT) has been used as an octane enhancer in
Canadian gasoline since 1976. The main potential health concern is from manganese oxides
produced on combustion (mainly Mn304), given the known neurotoxicity of chronic inhalation
of manganese (Mn) dust from mining and industrial use. Relevant epidemiological studies of
occupational exposure to respirable Mn are briefly reviewed; an ambient air reference value of
0.1 mu g Mn/m(3), and associated inhalation tolerable daily intake (TDI) and tolerable daily
uptake (TDU) of 0.035 and 0.021 mu g/kg b.w./day are derived. Ambient levels of PM(2.5)
(respirable) Mn in Canadian cities have remained unchanged or have decreased between 1986
and 1992, and do not reflect large changes in MMT usage during that time. Ambient levels of
PM(10) Mn in Canadian cities in 1992 were less than or equal to 0.025 mu g Mn/m(3). Mean,
90th and 98th percentiles of PM(10) Mn inhalation uptake based on ambient monitoring data
from high traffic areas and from estimates of personal exposure are below the inhalation uptake
criterion. An assessment of exposure from air, food, water and soil revealed that <1% of total
daily Mn uptake is derived from inhalation for all age groups. Therefore, based on current
information, Mn derived from the combustion of MMT-containing gasoline is unlikely to
represent a significant health risk to Canadians.
35. Elbetieha A, Bataineh H, Darmani H, Al-Hamood MH. (2001) Effects of long-term
exposure to manganese chloride on fertility of male and female mice. Toxicology Letters
119(3): 193-201.
The effect of long-term ingestion of manganese (II) chloride tetrahydrate was investigated on
fertility of male and female Swiss mice. Adult male or female mice ingested a solution of
manganese chloride along with drinking water at concentrations of 1000, 2000, 4000 and 8000
mg/1 for 12 weeks. Fertility was significantly reduced in male mice exposed to manganese
chloride solution at a concentration of 8000 mg/1, but not at the other concentrations. There were
no treatment-related effects on the number of implantation sites, viable fetuses or the number of
resorptions in female rats impregnated by males who had ingested manganese chloride. Fertility
was not significantly reduced in female mice exposed to manganese chloride solution at all
concentrations used in this study. However, the numbers of implantations and viable fetuses
were significantly reduced in females exposed to manganese chloride solution at a concentration
of 8000 mg/1. There was no significant effect on the number of resorbed fetuses in females
exposed to manganese chloride solution compared to their control counterparts. Absolute body
weight was not significantly affected in females exposed to manganese chloride solutions.
However, ovarian weight was significantly increased in females exposed to manganese chloride
solution at concentrations of 4000 and 8000 mg/1. A significant increase in the uterine weight
was also observed at all concentrations used in the study. These results indicate that ingestion of
manganese chloride by adult male and female mice causes some adverse effects on fertility and
reproduction. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
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36. EPA. 2004. Drinking Water Health Advisory for Manganese. U.S. Environmental Protection
Agency Office of Water. Report nr EPA-822-R-04-003.
37. Ericson JE, Crinella FM, Clarke-Stewart KA, Allhusen VD, Chan T, Robertson RT. (2007)
Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicology and
Teratology 29(2): 181-187.
Although manganese (Mn) is an essential mineral, high concentrations of the metal can result in
a neurotoxic syndrome affecting dopamine balance and behavior control. We report an
exploratory study showing an association between Mn deposits in tooth enamel, dating to the
20th and 62-64th gestational weeks, and childhood behavioral outcomes. In a sample of 27
children, 20th week Mn level was significantly and positively correlated with measures of
behavioral disinhibition, specifically, play with a forbidden toy (36 months), impulsive errors on
a continuous performance and a children's Stroop test (54 months), parents' and teachers' ratings
of externalizing and attention problems on the Child Behavior Checklist (1st and 3rd grades),
and, teacher ratings on the Disruptive Behavior Disorders Scale (3rd grade). By way of contrast,
Mn level in tooth enamel formed at the 62-64th gestational week was correlated only with
teachers' reports of externalizing behavior in 1st and 3rd grades. Although the source(s) of Mn
exposure in this sample are unknown, one hypothesis, overabsorption of Mn secondary to
gestational iron-deficiency anemia, is discussed, (c) 2006 Elsevier Inc. All rights reserved.
38. Erikson K, Aschner M. (2002) Manganese causes differential regulation of glutamate
transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.
Neurotoxicology 23(4-5):595-602.
Neurotoxicity due to excessive brain manganese (Mn) can occur due to environmental (air
pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). Manganese is
associated with oxidative stress, as well as alterations in neurotransmitter metabolism with
concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain
regional [Mn], it is likely that in pathological conditions it can reach 100-500 muM. Amino acid
(e.g. aspartate, glutamate, taurine), as well as divalent metal (e.g. zinc, manganese)
concentrations are regulated by astrocytes in the brain. Recently, it has been reported that
cultured rat primary astrocytes exposed to Mn displayed decreased glutamate uptake, thereby,
increasing the excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn
employs in terms of glutamate metabolism is unknown, a primary goal of this study was to link
altered glutamate uptake in Mn exposed astrocytes to alterations in glutamate transporter
message. Further we wanted to examine the gene expression of metallothionein (MT) and taurine
transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40%
in accordance with a 48% decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine
uptake was unaffected by Mn exposure even though tdu-T mRNA increased by 123%. MT
mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism,
although this was not examined. These data show that glutamate and taurine transport in Mn
exposed astrocytes are temporally different. (C) 2002 Elsevier Science Inc. All rights reserved.
39. Erikson KM, Aschner M. (2003) Manganese neurotoxicity and glutamate-GABA
interaction. Neurochemistry International 43(4-5):475-480.
Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent
metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate
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homeostasis is essential for the normal functioning of the central nervous system (CNS).
Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the
primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper
manganese levels is important for normal brain functioning. Several in vivo and in vitro studies
have linked increased manganese concentrations with alterations in the content and metabolism
of neurotransmitters, namely dopamine, gamma-antinobutyric acid, and glutamate. It has been
reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese
displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate.
Furthermore, decreased uptake of glutamate has been associated with decreased gene expression
of glutamate:aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional
studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a
consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that
excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing
a proximate mechanism for manganese-induced neurotoxicity. (C) 2003 Elsevier Science Ltd.
All rights reserved.
40. Erikson KM, Dorman DC, Fitsanakis V, Lash LH, Aschner M. (2006) Alterations of
oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.
Biological Trace Element Research 111(1-3): 199-215.
Neonatal rats were exposed to airborne manganese sulfate (MnS04) (0, 0.05, 0.5, or 1.0 mg
Mn/m(3)) during gestation (d 0-19) and postnatal days (PNDs) 1-18. On PND 19, rats were
killed, and we assessed biochemical end points indicative of oxidative stress in five brain
regions: cerebellum, hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine
synthetase (GS) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), TH and GS
mRNA levels, and reduced and oxidized glutathione (GSH and GSSG, respectively) levels were
determined for all five regions. Mn exposure (all three doses) significantly (p = 0.0021)
decreased GS protein levels in the cerebellum, and GS mRNA levels were significantly (p =
0.0008) decreased in the striatum. Both the median and high dose of Mn significantly (p =
0.0114) decreased MT mRNA in the striatum. Mn exposure had no effect on TH protein levels,
but it significantly lowered TH mRNA levels in the olfactory bulb (p = 0.0402) and in the
striatum (p = 0.0493). Mn exposure significantly lowered GSH levels at the median dose in the
olfactory bulb (p = 0.0032) and at the median and high dose in the striatum (p = 0.0346).
Significantly elevated (p = 0.0247) GSSG, which can be indicative of oxidative stress, was
observed in the cerebellum of pups exposed to the high dose of Mn. These data reveal that
alterations of oxidative stress biomarkers resulting from in utero and neonatal exposures of
airborne Mn exist. Coupled with our previous study in which similarly exposed rats were
allowed to recover from Mn exposure for 3 wk, it appears that many of these changes are
reversible. It is important to note that the doses of Mn utilized represent levels that are a
hundred- to a thousand-fold higher than the inhalation reference concentration set by the United
States Environmental Protection Agency.
41. Erikson KM, Dorman DC, Lash LH, Aschner M. (2005) Persistent alterations in biomarkers
of oxidative stress resulting from combined in utero and neonatal manganese inhalation.
Biological Trace Element Research 104(2): 151-163.
Neonatal female and male rats were exposed to airborne manganese sulfate (MnS04) during
gestation and postnatal d 1-18. Three weeks post-exposure, rats were killed and we assessed
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biochemical end points indicative of oxidative stress in five brain regions: cerebellum,
hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine synthetase (GS) protein
levels, metallothionein (MT) and GS mRNA levels, and total glutathione (GSH) levels were
determined for all five regions. Overall, there was a statistically significant effect of manganese
exposure on decreasing brain GS protein levels (p=0.0061), although only the highest dose of
manganese (1 mg Mn/m(3)) caused a significant increase in GS messenger RNA (mRNA) in
both the hypothalamus and olfactory bulb of male rats and a significant decrease in GS mRNA in
the striatum of female rats. This highest dose of manganese had no effect on MT mRNA in either
males or females; however, the lowest dose (0.05 mg Mn/m(3)) decreased MT mRNA in the
hippocampus, hypothalamus, and striatum in males. The median dose (0.5 mg Mn/m(3)) led to
decreased MT mRNA in the hippocampus and hypothalamus of the males and olfactory bulb of
the females. Overall, manganese exposure did not affect total GSH levels, a finding that is
contrary to those in our previous studies. Only the cerebellum of manganese-exposed young
male rats showed a significant reduction (p < 0.05) in total GSH levels compared to control
levels. These data reveal that alterations in biomarkers of oxidative stress resulting from in utero
and neonatal exposures of airborne manganese remain despite 3 wk of recovery; however, it is
important to note that the doses of manganese utilized represent levels that are 100-fold to a
1000-fold higher than the inhalation reference concentration set by the US Environmental
Protection Agency.
42. Erikson KM, Suber RL, Aschner M. (2002) Glutamate/aspartate transporter (GLAST),
taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes
exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology
23(3):281-288.
Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution,
soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese
levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with
concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain
regional Mn concentration, it is likely that in pathological conditions, Mn concentration can
reach between 100 and 500 muM. Environmental Mn exposure as a result of
methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate
or sulfate (MnP04, MnS04, respectively). Pharmacokinetic studies have shown that the Mn salt
will determine the rate of transport into the brain: MnC12 > MnS04 > MnP04. The salt-specific
neurotoxicity of these species is unknown. The primary goal of this study was to examine gene
expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and
metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnC12) manganese
sulfate (MnS04), and manganese phosphate (MnP04). We hypothesized that the effects of
MnP04 and MnS04 exposure on GLAST expression in astrocytes would be similar to those
induced by MnC12, since irrespective of salt species exposure, once internalized by astrocytes,
the Mn ion would be identically complexed. At the same time, we hypothesized that the
magnitude of the effect would be salt-dependent, since the chemical speciation would determine
the rate of intracellular uptake of Mn. MnC12 caused a significant overall decrease (P < 0.0001)
in astrocytic GLAST mRNA levels with MnS04 causing a moderate decrease. MnP04 exposure
did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein
and taurine transporter gene expression as markers of manganese exposure. Our findings suggest
that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA
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compared to both the sulfate and phosphate species. However astrocytic taurine transporter
mRNA was not affected by Mn exposure, irrespective of the salt species. These data are
consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent
upon its species, with solubility, and by inference, intracellular concentration, representing a
major determinant of its neurotoxicity. (C) 2002 Elsevier Science Inc. All rights reserved.
43. Erikson KM, Thompson K, Aschner J, Aschner M. (2007) Manganese neurotoxicity: A
focus on the neonate. Pharmacology & Therapeutics 113(2):369-377.
Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal
amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare
in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be
especially vulnerable. Mn neurotoxicity is most commonly associated with occupational
exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m(3)) of Mn,
consumption of contaminated well water, or parenteral nutrition therapy in patients with liver
disease or immature hepatic functioning such as the neonate. This review will focus primarily on
the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the
neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing
on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral
nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of
exposure becomes salient in this population. We will briefly review some of the mechanisms of
Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported
area of neurotoxicity, (c) 2006 Elsevier Inc. All rights reserved.
44. Finley JW. (2004) Does environmental exposure to manganese pose a health risk to healthy
adults? Nutrition Reviews 62(4): 148-153.
Manganese is an essential nutrient that also may be toxic at high concentrations. Subjects
chronically exposed to manganese-laden dust in industrial settings develop neuropsychological
changes that resemble Parkinson's disease. Manganese has been proposed as an additive to
gasoline (as a replacement for the catalytic properties of lead), which has generated increased
research interest in the possible deleterious effects of environmental exposure to manganese.
Low-level exposure to manganese has been implicated in neurologic changes, decreased learning
ability in school-aged children, and increased propensity for violence in adults. However, a
thorough review of the literature shows very weak cause-and-effect relationships that do not
justify concern about environmental exposure to manganese for most of the North American
population.
45. Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M. (2006) The use of
magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology
27(5):798-806.
Manganese (Mn), an element found in many foods, is an important and essential nutrient for
proper health and maintenance. It is toxic in high doses, however, and exposure to excessive
levels can result in the onset of a neurological disorder similar to, but distinct from, Parkinson's
disease. Historically, Mn neurotoxicity was most commonly associated with various
occupations, such as Mn mining, welding and steel production. More recently, increases in both
blood and brain Mn levels have been observed in persons with liver disease or those receiving
prolonged parenteral nutrition. Additionally, rodent data suggest that iron deficiency and anemia
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may be risk factors for Mn neurotoxicity. Clinically, brain Mn accumulation can be monitored in
vivo using non-invasive magnetic resonance imaging (MRI) due to the paramagnetic nature of
this element. Indeed, MRI has been used in a variety of settings to evaluate the brain Mn
deposition in various populations. This review focuses on the use of MRI technology in studies
related specifically to Mn neurotoxicity. Thus, we will examine reports using MRI to confirm
brain Mn accumulation in human populations, and conclude with data from non-human primate
and rodent models of Mn neurotoxicity. (C) 2006 Elsevier Inc. All rights reserved.
46. Fitzgerald K, Mikalunas V, Rubin H, McCarthy R, Vanagunas A, Craig RM. (1999)
Hypermanganesemia in patients receiving total parenteral nutrition. Journal of Parenteral and
Enteral Nutrition 23(6):333-336.
Background: Manganese is one of the trace elements that is routinely administered to total
parenteral nutrition (TPN) patients. The recommended daily IV dosage ranges from 100 to 800
mu g. We have used 500 mu g daily. Recent reports have suggested neurologic symptoms seen in
some patients receiving home parenteral nutrition (HPN) may be due to hypermanganesemia.
Therefore, HPN patients and some short-term inpatients receiving TPN were studied to ascertain
the relationship between dose and blood levels. Methods: Red blood cell manganese levels were
obtained by atomic absorptiometry. Results: The levels in 36 hospitalized, short-term patients
obtained within 48 hours of initiating TPN were all normal. The 30 patients receiving TPN from
3 to 30 days had levels that ranged from 4.8 to 28 mu g/L (normal, 11 to 23 mu g/L). Two
patients had abnormal levels, at days 14 and 18. Fifteen of the 21 patients receiving inpatient
TPN or HPN for 36 to 5075 days had elevated Mn levels. Only one patient with
hypermanganesemia, an inpatient, had abnormal biochemical liver tests (bilirubin and alkaline
phosphatase). One of the patients with a high level had some vestibular symptoms attributed to
aminoglycoside use and had increased signal density in the globus pallidus on T1-weighted
images on magnetic resonance imaging (MRI). A second patient with Mn levels twice normal
had no neurologic symptoms, but had similar MRI findings. A third had some basal ganglia
symptoms, confirmed by a neurologic evaluation, seizures, and very high Mn levels. The MRI
showed no signal enhancement, but motion artifacts limited the study technically. Conclusions:
Hypermanganesemia is seen in HPN patients receiving 500 mu g manganese daily and may have
resulted in some neurologic damage in three patients. Hypermanganesemia is sometimes seen
after a short course of TPN in inpatients, as early as 14 days. Patients should be monitored for
hypermanganesemia if they receive Mn in their TPN for >30 days. A 500 mu g/d dose of Mn is
probably excessive, and 100 mu g/d should probably never be exceeded. Mn should be
eliminated from the solution if the Mn level is elevated and should not be readministered unless
the level returns to normal or subnormal. Mn should not be supplemented if the patient has liver
disease with an elevated bilirubin.
47. Fortoul TI, Mendoza ML, Avila MD, Torres AQ, Osorio LS, Espejel GM, Fernandez GO.
(2001) Manganese in lung tissue: Study of Mexico City residents' autopsy records from the
1960s and 1990s. Archives of Environmental Health 56(2): 187-190.
During the conduct of autopsies performed on residents of Mexico City during the 1960s (20
males, 19 females) and 1990s (30 males and 18 females), concentrations of manganese in lung
were studied with atomic absorption spectrometry. Concentrations of manganese were not
significantly greater in the samples obtained in the 1990s (1.87 +/- 0.8 mug/gm [mean +/-
standard deviation]) than in samples from the 1960s (1.72 +/- 1.2 mug/gm). Concentrations were
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not correlated with gender, smoking habit, age, or cause of death; however, there was a
correlation with occupation. The findings suggest that manganese exposure via air does not
represent a health hazard to residents of Mexico City, given that lung concentrations of
manganese remained stable during the 30-y period studied. Investigators should monitor
concentrations of manganese in suspended particles to follow-up on these findings.
48. Fredstrom S, Rogosheske J, Gupta P, Burns LJ. (1995) Extrapyramidal Symptoms in a Bmt
Recipient with Hyperintense Basal Ganglia and Elevated Manganese. Bone Marrow
Transplantation 15(6):989-992.
Neurologic syndromes attributed to conditioning or medications have been reported in BMT
recipients. A patient is presented who developed extrapyramidal symptoms on day +56 after
allogeneic BMT. Brain magnetic resonance images of this patient demonstrated hyperintense
basal ganglia, which has been associated with manganese (Mn) toxicity. The patient had
received total parenteral nutrition (TPN) with standard trace element supplementation and had
been cholestatic. Serum Mn was elevated, and continued to be so 5 months after BMT, long after
discontinuation of TPN. Cholestatic patients and those on long-term TPN have been found to
have high blood or serum levels of Mn, but generally are asymptomatic, When other cholestatic
BMT patients were reviewed, all had elevated serum Mn. Manganese supplementation in TPN
requires evaluation for BMT recipients.
49. FreelandGraves JH, Turnlund JR. (1996) Deliberations and evaluations of the approaches,
endpoints and paradigms for manganese and molybdenum dietary recommendations. Journal of
Nutrition 126(9):S2435-S2440.
The background of the current dietary recommendations for manganese and molybdenum are
described. This article reviews how the previous and current estimated safe and adequate daily
dietary intakes (ESADDI) were set, shortcomings in the methods used, concerns about the
current recommendations, and brief summaries of new research reports. New approaches,
endpoints and paradigms to use for the development of useful recommendations are given.
50. Friberg L, Nordberg GF, Vouk VB. (2007) Handbook of the Toxicology of Metals. 3rd ed. :
Elsevier Science Publishing Company; pp. 476.
Handbook of the Toxicology of Metals is the standard reference work for physicians,
toxicologists and engineers in the field of environmental and occupational health. This new
edition is a comprehensive review of the effects on biological systems from metallic elements
and their compounds. An entirely new structure and illustrations represent the vast array of
advancements made since the last edition. Special emphasis has been placed on the toxic effects
in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-
to-date reference provides easy access to a broad range of basic toxicological data and also gives
a general introduction to the toxicology of metallic compounds.
51. Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N. (1997) Accumulation of manganese
in the brain of mice after intravenous injection of manganese-based contrast agents. Chemical
Research in Toxicology 10(4):360-363.
Because the manganese-based contrast agents used in magnetic resonance imaging are unstable
in vivo, some concern exists about the potential toxicity coming from the Mn2+ released by the
complexes. This potential problem arises because the manganese is known to accumulate in the
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brain of people intoxicated by this metal (manganism): this central accumulation leads to
neurological disorders (i.e., parkinsonism-like syndrome). The aim of this study was to assess
the amount of Mn found in the brain after administration of MnC12 or different chelates of Mn in
normal mice as well as in mice with impaired biliary elimination. Male NMRI mice received an
intravenous injection in a caudal vein of 5 mu mol/kg of Mn-54 compounds as MnC12,
manganese-diethylenetriaminepentaacetate (Mn-DTPA), or manganese-dipyridoxal diphosphate
(Mn-DPDP). The radiolabeled complexes (1:1) were prepared by direct chelation (Mn-DTPA) or
transchelation of preformed complex (Mn-DPDP), and the radiochemical purity was assessed by
paper chromatography. The mice were killed at various times post-exposure (0-3 months), and
the radioactivity present in the organs was determined by gamma counting. For each compound
analyzed in the present study, we observed an accumulation of Mn (0.25-0.3% of the amount
injected/g of tissue) in the mouse brain, reaching a plateau after 24 h, while the Mn content in the
liver was decreasing with time. The amount of Mn accumulated in the brain remained unchanged
1 month later, but decreased to 40% of the maximum amount 3 months after the exposure. In
mice whose bile ducts had been ligated 24 h before the administration of the manganese
compound, we observed, 1 week after the injection, an amount of manganese accumulated in the
brain 2 times higher than in normal mice.
52. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG,
Hainsworth LN, Umbreit JN, Conrad ME and others. (2003) DMT1: A mammalian transporter
for multiple metals. Biometals 16(l):41-54.
DMT1 has four names, transports as many as eight metals, may have four or more isoforms and
carries out its transport for multiple purposes. This review is a start at sorting out these
multiplicities. A G185R mutation results in diminished gastrointestinal iron uptake and
decreased endosomal iron exit in microcytic mice and Belgrade rats. Comparison of mutant to
normal rodents is one analytical tool. Ectopic expression is another. Antibodies that distinguish
the isoforms are also useful. Two mRNA isoforms differ in the 3' UTR: + IRE DMT1 has an IRE
(Iron Responsive Element) but -IRE DMT1 lacks this feature. The +/- IRE proteins differ in the
distal 18 or 25 amino acid residues after shared identity for the proximal 543 residues. A major
function is serving as the apical iron transporter in the lumen of the gut. The + IRE isoform
appears to have that role. Another role is endosomal exit of iron. Some evidence indicts the -IRE
isoform for this function. In our ectopic expression assay for metal uptake, four metals -
Fe2+,Mn2+,Ni2+ and Co2+ - respond to the normal DMT1 cDNA but not the G185 R mutant.
Two metals did not - Cd2+ and Zn2+ -andtwo -Cu2+ and Pb2+ -remain to be tested. In
competition experiments in the same assay, Cd2+,Cu2+ and Pb2+ inhibit Mn2+ uptake but Zn2+
did not. In rodent mutants, Fe and Mn appear more dependent on DMT1 than Cu and Zn.
Experiments based on ectopic expression, specific antibodies that inhibit metal uptake and
labeling data indicate that Fe3+ uptake depends on a different pathway in multiple cells. Two
isoforms localize differently in a number of cell types. Unexpectedly, the -IRE isoform is in the
nuclei of cells with neuronal properties. While the function of -IRE DMT1 in the nucleus is
speculative, one may safely infer that this localization identifies new role(s) for this
multifunctional transporter. Management of toxic challenges is another function related to metal
homeostasis. Airways represent a gateway tissue for metal entry. Preliminary evidence using
specific PCR primers and antibodies specific to the two isoforms indicates that -IRE mRNA and
protein increase in response to exposure to metal in lungs and in a cell culture model; the + IRE
form is unresponsive. Thus the -IRE form could be part of a detoxification system in which +
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IRE DMT1 does not participate. How does iron status affect other metals' toxicity? In the case of
Mn, iron deficiency may enhance cellular responses.
53. Gassmann B. (2001) Dietary reference intakes, report 4: Trace elements. Ernahrungs-
Umschau 48(4): 148-+.
Part 2 deals with a set of reference values established for chromium, copper, iodine, iron,
manganese, molybdenum, and zinc to replace Recommended Dietary Allowances (RDAs),
Estimated Safe and Adequate Daily Dietary Intakes published in 1989. In addition, the evidence
of beneficial and adverse effects of arsenic, boron, nickel, silicon, and vanadium has been
analyzed. AU RDAs, Adequate Intakes (AIs), and Tolerable Upper Intake Levels (ULs] reported
are summarized, commented and compared with the DACH reference values 2000. Many
questions that were raised about requirements for and recommended intakes of trace elements
were not answered fully because of inadequacies in the published database. Thus RDAs have
only been set for copper, iodine, iron, molybdenum, and zinc. Far most of the trace elements,
there is no direct information allowing to estimate the amounts required by children, adolescents,
the elderly, and pregnant and lactating women. Because of the lack of data to estimate average
requirements of adults, AIs have to be set for chromium and manganese based on representative
dietary intake data from healthy individuals in the United States, in the case of arsenic, boron,
nickel, silicon, and vanadium, there is evidence that they have a beneficial role in physiological
processes in some species. In some cases measurable responses of human subjects to changes in
dietary intake have been demonstrated. However, the available data are not sufficient to
determine average requirements. Nor could data available about dietary intake be used to
establish an AI. For boron, copper, iodine, iron, manganese, molybdenum, nickel, vanadium, and
zinc ULs have been established. For arsenic, chromium, and silicon data were sparse for setting
ULs, precluding reliable estimates of how much can be ingested safely. Although there are some
differences in their reference values, the Institute pf Medicine and DACH Societies used similar
models for establishing reference intakes of trace elements.
54. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
Mn2+ is sequestered by liver and brain mitochondria via the mitochondrial Ca2+ uniporter. The
mitochondrial Ca2+ uniporter is a cooperative transport mechanism possessing an external
activation site and a transport site. Ca2+ binding to the activation site greatly increases the
velocity of uptake of both Ca2+ and Mn2+. Electron paramagnetic resonance (EPR) shows that
over 97% of the Mn2+ in the mitochondrial matrix is normally bound to the membrane or to
matrix proteins. EPR measurements of manganese within living isolated mitochondria can be
repeat-ed for hours, and during this time most of the manganese remains in the Mn2+ state.
Mn2+ is transported out of mitochondria via the very slow Na+-independent efflux mechanism,
which is an active (energy-requiring) mechanism. Mn2+ is not significantly transported over the
Na+-dependent efflux mechanism, which is the dominant efflux mechanism in heart and brain
mitochondria. Mn2+ inhibits the efflux of Ca2+ through both of these efflux mechanisms, having
an apparent K-i of 7.9 nmol/mg protein on the Na+-independent efflux mechanism and an
apparent K-i of 5.1 nmol/mg on the Na+-dependent efflux mechanism. Mn2+ inhibition of Ca2+
efflux may increase the probability of the mitochondria undergoing the mitochondrial
permeability transition (MPT). Intramitochondrial Mn2+ also inhibits State 3 mitochondrial
respiration using either succinate or malate plus glutamate as substrate. The data suggest that
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Mn2+ depletes cellular energy supplies by interfering with oxidative phosphorylation at the level
of the F(l)ATPase and at much higher concentrations, at Complex I. Effects such as these could
lead to apoptosis in active neurons. (C) 1999 Inter Press, Inc.
55. Grandjean P, Landrigan PJ. (2006) Developmental neurotoxicity of industrial chemicals.
Lancet 368(9553):2167-2178.
Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and
cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly
unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls
[PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and
subclinical brain dysfunction. Exposure to these chemicals during early fetal development can
cause brain injury at doses much lower than those affecting adult brain function. Recognition of
these risks has led to evidence-based programmes of prevention, such as elimination of lead
additives in petrol. Although these prevention campaigns are highly successful, most were
initiated only after substantial delays. Another 200 chemicals are known to cause clinical
neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals
have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in
the developing human brain are not known and they are not regulated to protect children. The
two main impediments to prevention of neurodevelopmental deficits of chemical origin are the
great gaps in testing chemicals for developmental neurotoxicity and the high level of proof
required for regulation. New, precautionary approaches that recognise the unique vulnerability of
the developing brain are needed for testing and control of chemicals.
56. Halatek T, Opalska B, Rydzynski K, Bernard A. (2006) Pulmonary response to
methylcyclopentadienyl manganese tricarbonyl treatment in rats: injury and repair evaluation.
Histology and Histopathology 21(11): 1181-1192.
Methylcyclopentadienyl manganese tricarbonyl (MMT), an organometallic compound, used as
an antiknock additive in fuels, may produce alveolar inflammation and bronchiolar cell injury.
The aim of the experimental study on female rats was to determine by morphological
examination and sensitive biomarkers, the course of the injury and repair process following a
single i.p. injection of 5 mg/kg MMT. The animals were sacrificed 12, 24, 48 hours or 7 days
post-exposure (PE). The first biochemical changes 12 h PE showed an increase in GSH-S-
transferase (GST) activity in the lung parallel to the earliest observed morphological changes-
vacuolation and swollen cytoplasm in type I pneumocytes. Alterations in type I pneumocytes
were most prevalent in rat lung 24 h PE. Clara cells with dilated smooth endoplasmic reticulum
membranes and cytoplasmic vacuolation could be observed. Compared to the values found for
controls, Clara cell protein (CC16) in the bronchoalveolar lavage fluid (BALF) at 24 and 48 h
PE decreased by 58% and 55%, respectively. At the same time (at 24 and 48 h), the total protein
concentration in BALF increased 5 and 7 times, respectively. A significant rise in hyaluronic
acid (HA) level was observed 24 and 48 h PE. Divided type II pneumocyte cells and Clara cells
in their mitotic phase were observed in immunocytochemistry (detecting BrdU binding into
DNA) 48 h PE. Seven days after MMT administration, fibroblasts, macrophages, collagen and
elastin fibres could be seen in the alveolar walls as well as neutrophils, lymphocytes, and alveoli
macrophages in the alveolar lumen. We conclude that injury and repair of bronchial epithelium
cells, especially of Clara cells and type II pneumocyte cells, play an important part in MMT
toxicity, probably depending on the antioxidant status of these cells. The sensitive biomarkers of
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CC16 and hyaluronic acid in BALF and serum reflect lung injury and indicate the time course of
pulmonary damage and repair processes.
57. Hernandez EH, Discalzi G, Dassi P, Jarre L, Pira E. (2003) Manganese intoxication: The
cause of an inexplicable epileptic syndrome in a 3 year old child. Neurotoxicology 24(4-5):633-
639.
Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have
reported epileptic syndromes related to manganese intoxication. We describe an epileptic
syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was
elevated, but no other abnormal values or toxic substances were found in blood or urine. The
electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain
magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status
despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to
remove excess manganese and promptly succeeded in reverting epileptic symptoms.
Concurrently, manganese blood levels and electroencephalogram progressively normalized.
Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in
excellent conditions without any treatment. (C) 2003 Elsevier Science Inc. All rights reserved.
58. Hirata Y, Adachi E, Kiuchi K. (1998) Activation of JNK pathway and induction of apoptosis
by manganese in PC12 cells. Journal of Neurochemistry 71(4): 1607-1615.
Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine
deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning,
suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a
functional abnormality of the extrapyramidal system. However, the details have yet to be
elucidated. Here we report that manganese causes characteristic internucleosomal DNA
fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription
dependent, relatively specific for manganese, and blocked in Bcl-2-overexpressed PC12 cells,
The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated
with manganese, the first metal to be reported to induce this form of cell death. The early
biochemical events show the impairment of energy metabolism, and the process may require new
synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of
c-Jun at Ser(63) and Ser(73) and SEK1/MKK4 (c-Jun N-terminal kinase kinase) at Thr(258) and
tyrosine phosphorylation of several proteins. These results indicate that manganese activates
specific signal cascades including the c-Jun N-terminal kinase pathway
59. Hirata Y, Kiuchi K, Nagatsu T. (2001) Manganese mimics the action of l-methyl-4-
phenylpyridinium ion, a dopaminergic neurotoxin, in rat striatal tissue slices. Neuroscience
Letters 3ll(l):53-56.
Manganese and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) are known to induce
neurological pathologies similar to that of parkinsonism. Previous studies performed in rat
striatal slices have shown that MPTP and related compounds inhibit tyrosine hydroxylation, a
rate-limiting step of dopamine biosynthesis. Here, we reported that manganese inhibited tyrosine
hydroxylation in rat striatal slices. In addition, manganese caused increase in the levels of lactate
indicating that aerobic glycolysis was inhibited in striatal slices. This inhibition was unique to
manganese since other divalent cations, such as magnesium and zinc, did not increase lactate
concentrations. These results suggest that the mechanisms by which manganese produces
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dysfunction of the nervous system are similar to those of MPTP. (C) 2001 Elsevier Science
Ireland Ltd. All rights reserved.
60. Hsieh CT, Liang JS, Peng SSF, Lee WT. (2007) Seizure associated with total parenteral
nutrition-related hypermanganesemia. Pediatric Neurology 36(3): 181-183.
The trace element manganese is usually supplied when total parenteral nutrition is used.
However, long-term parenteral administration of manganese, which bypasses the normal,
regulatory mechanism, may cause hypermanganesemia. Manganese poisoning presents clinically
with parkinsonian-like symptoms and psychological changes. Seizures are a rare presentation of
this disease. This report describes a 10-year-old female who had received total parenteral
nutrition for 3 months because of short bowel syndrome, and presented with tonic-clonic seizure,
decreased level of consciousness, and fever. The serum electrolytes, glucose and the
cerebrospinal fluid examination were normal. The blood culture grew Pantoea agglomerans. The
brain magnetic resonance imaging disclosed no evidence of central nervous system infection.
However, symmetric high-intensity signal on T-l-weighted images was documented in the basal
ganglia, especially in the globus pallidus. Her whole blood manganese level was 3.7 mu g/dL,
which was significantly higher than the normal range (0.4-1.4 mu g/dL). Diagnosis of
hypermanganesemia related to total parenteral nutrition was made, (c) 2007 by Elsevier Inc. All
rights reserved.
61. Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. (1998) Long term outcome of
brain manganese deposition in patients in home parenteral nutrition. Archives of Disease in
Childhood 79(3):263-265.
BIOSIS COPYRIGHT: BIOL ABS. Manganese intoxication has been described in children on
long term parenteral nutrition presenting with liver and nervous system disorders. Cases are
reported of a brother and sister on long term parenteral nutrition with hypermanganesaemia and
basal ganglia manganese deposition, detected by magnetic resonance imaging (MRI), without
overt neurological signs. Following reduction of manganese intake, basal ganglia manganese
was monitored by repeated MRI, and neurological and developmental examinations. An MRI
intensity index of the globus pallidus declined over a three year period from 0.318 and 0.385 to
0.205 and 0.134 with concomitant falls in whole blood manganese from 323 and 516 to 226 and
209 nmol/1 (normal range, 73-210 nmol/1). Unlike adult experience these children developed
normally without neurological signs. In conclusion, deposited manganese is removed from
neural tissue over time and the prognosis is good when neurological manifestations and liver
disease ar
62. Kessler KR, Wunderlich G, Hefter H, Seitz RJ. (2003) Secondary progressive chronic
manganism associated with markedly decreased striatal D2 receptor density. Movement
Disorders 18(2):216-218.
We describe a patient with chronic manganism due to intoxication 40 years ago. Whereas
previous reports on acute or subacute intoxication have shown no or only small reductions in
striatal D2 receptor density, we found markedly decreased D2 receptor density using F-18-
methylspiperone PET in this very late stage of chronic manganism, supporting the hypothesis
that manganese intoxication may trigger a neuro-degenerative disease process. (C) 2002
Movement Disorder Society.
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63. Kim JW, Kim Y, Cheong HK, Ito K. (1998) Manganese induced Parkinsonism: A case
report. Journal of Korean Medical Science 13(4):437-439.
BIOSIS COPYRIGHT: BIOL ABS. Manganese (Mn) intoxication is known to induce
parkinsonism. Mn-induced parkinsonism preferentially affect the globus pallidus in contrast to
idiopathic parkinsonism where degeneration predominantly involves the nigral pars compacta.
We describe a 51-year-old man who had been occupationally exposed to Mn. He had
parkinsonian features including masked face, resting tremor, and bradykinesia. He also had a
cock walk and a particular propensity to fall in a backward gait. There was no sustained
therapeutic response to levodopa. A fluorodopa PET scan was normal. This case indicates that
Mn-induced parkinsonism can be differentiated from idiopathic parkinsonism in that the former
has unique clinical features and a normal fluorodopa PET scan.
64. Kondoh H, Iwase K, Higaki J, Tanaka Y, Yoshikawa M, Hori S, Osuga K, Kamiike W.
(1999) Manganese deposition in the brain following parenteral manganese administration in
association with radical operation for esophageal cencer: Report of a case. Surgery Today-the
Japanese Journal of Surgery 29(8):773-776.
We report herein the case of a patient in whom manganese (Mn) deposition in the basal ganglia
was detected by magnetic resonance imaging (MRI) subsequent to thoracic esophagectomy,
performed following perioperative parenteral nutrition. A multi-trace-element supplement
solution which included 20 mu mol of Mn per day had been parenterally administered for 7 days
preoperatively and 21 days postoperatively. The serum level of total bilirubin reached a
maximum value of 5.1mg/dl postoperatively. The T1-weighted MRI on the 32nd postoperative
day demonstrated bilateral and symmetrical hyperintense lesions in the globus pallidus and the
whole-blood Mn level on the 34th postoperative day was 4.9 mu g/1, the normal range being 0.8-
2.5 mu g/1. This hyperintensity on Tl-weighted MRI was gradually improved following
normalization of the blood Mn level. This case report serves to demonstrate that even short-term
perioperative parenteral nutrition may result in Mn deposition in the brain following radical
surgery for esophageal cancer, especially in patients with hyperbilirubinemia.
65. Kucera J, Bencko V, Sabbioni E, Vandervenne MT. (1995) Review of Trace-Elements in
Blood, Serum and Urine for the Czech and Slovak Populations and Critical-Evaluation of Their
Possible Use as Reference Values. Science of the Total Environment 166(1-3):211-234.
The availability of accurate trace element reference values in human tissues represents an
important indicator to the health status of the general population and occupational groups
exposed to trace elements. The EURO TERVIHT project (Trace Element Reference Values in
Human Tissues) aims to establish and compare trace element reference values in tissues from
inhabitants of the European countries as baseline values for clinical/toxicological assessment
studies [3], In this context, one of the first steps considered is the critical evaluation (state of the
art) of existing literature on trace element reference values in blood, serum and urine in the
general population of each European country. This paper reviews the Czech and Slovak situation
by assessing studies carried out in these countries for Al, As, Cd, Co, Cr, Cu, F, Mn, Hg, Ni, Pb,
Rb, Sc, Se, V and Zn in blood, serum and urine. These studies show that most of the data
available do not meet criteria designed recently for deriving reference intervals, especially
regarding the number of subjects, the age of population sample studies as well as the use of
appropriate sampling techniques and quality assurance procedures. Elements which present the
highest potential risk for health in Czech and Slovak populations and for which reference values
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should be urgently established are: Cd, Hg, Pb (major pollutants); As, Cr, Ni (carcinogenic
metals); Al, F, Mn, Tl, V (released into the environment by coal combustion and other industrial
activities); Pt (increasing use of Pt catalyst in petrol-driven automobiles); essential trace
elements such as I, Se and Zn for which a deficiency in Czech and Slovak populations was
detected or is suspected.
66. Lambert LB, Singer TM, Boucher SE, Douglas GR. (2005) Detailed review of transgenic
rodent mutation assays. Mutation Research-Reviews in Mutation Research 590(1-3): 1-280.
Induced chromosomal and gene mutations play a role in carcinogenesis and may be involved in
the production of birth defects and other disease conditions. While it is widely accepted that in
vivo mutation assays are more relevant to the human condition than are in vitro assays, our
ability to evaluate mutagenesis in vivo in a broad range of tissues has historically been quite
limited. The development of transgenic rodent (TGR) mutation models has given us the ability to
detect, quantify, and sequence mutations in a range of somatic and germ cells. This document
provides a comprehensive review of the TGR mutation assay literature and assesses the potential
use of these assays in a regulatory context. The information is arranged as follows. (1) TGR
mutagenicity models and their use for the analysis of gene and chromosomal mutation are fully
described. (2) The principles underlying current OECD tests for the assessment of genotoxicity
in vitro and in vivo, and also nontransgenic assays available for assessment of gene mutation, are
described. (3) All available information pertaining to the conduct of TGR assays and important
parameters of assay performance have been tabulated and analyzed. (4) The performance of TGR
assays, both in isolation and as part of a battery of in vitro and in vivo short-term genotoxicity
tests, in predicting carcinogenicity is described. (5) Recommendations are made regarding the
experimental parameters for TGR assays, and the use of TGR assays in a regulatory context. 1.
The TGR mutation assay is based on transgenic rats and mice that contain multiple copies of
chromosomally integrated plasmid and phage shuttle vectors that harbour reporter genes for
detection of mutation. Mutagenic events arising in the rodent are scored by recovering the shuttle
vector and analyzing the phenotype of the reporter gene in a bacterial host. TGR gene mutation
assays allow mutations induced in a genetically neutral transgene to be scored in any tissue of
the rodent, and therefore circumvent many of the existing limitations to the study of in vivo gene
mutation. TGR models for which sufficient data are available to permit evaluation include Muta
(TM) mouse, Big Blue (R) mouse and rat, LacZ plasmid mouse, and the gpt delta mouse.
Mutagenesis in the TGR models is normally assessed as a mutant frequency (MF); however, if
required, molecular analysis can provide additional information., 2. OECD guidelines exist for a
range of in vitro mutation assays that are capable of detecting both chromosomal and gene
mutations. In vivo assays are required components of a thorough genetic toxicity testing
programme. For somatic cells, those assays that are most commonly conducted, for which OECD
guidelines are currently available, assess induced chromosomal mutation. In addition there are
non-transgenic assays that can be used for analysis of gene mutation; none of these have an
OECD test guideline. Existing in vivo assays are limited by a range of different factors,
including cost of the assay, the number of tissues in which genotoxicity may be measured, the
state of understanding of the endpoint, and the nature of the chemicals that will be detected. 3.
As of July 2004, 163 agents have been evaluated using TGR assays. The majority of
experimental records have assessed a subset of these chemicals, most of which are strong
mutagens and carcinogens. Of the 103 agents whose carcinogenicity has been evaluated 90 are
carcinogens and only 13 are noncarcinogens. The following conclusions may be drawn from the
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existing TGR mutation data. The ability to use all routes of administration has been
demonstrated. Experiments can be tailored to use the most relevant route of administration. The
ability to examine mutation in virtually all tissues has-been demonstrated. TGR assays have most
commonly examined mutagenicity in the liver and bone marrow. The majority of the
experiments have used shorter administration times than is currently recommended by the
International Workshops on Genotoxicity Testing (IWGT); there are limited data available to
assess the effects of longer sampling time except at extremely short administration times.
Although it is recognized that a number of factors may influence the tissue specificity of
mutation, including cell turnover, DNA repair, toxicokinetics, and the nature of the genetic
target, there are currently limited experimental data specific to transgenes that are available to
inform the discussion. Limited data are available to evaluate the results of TGR assays in known
target tissues for carcinogenicity. A case-by-case analysis of instances in which discrepancies are
apparent suggests that in the majority of cases, factors such as nongenotoxic mechanism of
action, inappropriate mode of administration, or inadequate study design may account for the
observed negative result in the tissue of interest. Qualitatively similar results have been obtained
in the majority of experiments that have assayed different transgenes using similar experimental
parameters. The spontaneous mutant frequency (SMF) in most somatic tissues of TGR animals is
5-10-fold higher than observed in available endogenous loci using the same animals. Factors
such as the age of the animal, the tissue, and the animal model influence the absolute value of the
SMF. In most somatic tissues, with the exception of brain, there is an age related increase in
mutation frequency throughout the life of the animal. Most, but not all, studies suggest that the
SMF in male germline tissues remains low and constant throughout the life of the animal.
Multiple treatments of a mutagen appear to increase mutant frequencies in neutral transgenes in
an approximately additive manner. However, extremely long treatment times of 12 weeks or
longer may produce an apparent increase in MF through clonal expansion, genomic instability in
developing preneoplastic foci or tumours, or through oxidation damage of DNA resulting from
chronic induction of cytochrome P-450 monooxygenases. The time required to reach the
maximum mutant frequency is tissue-specific, and appears to be related to the turnover time of
the cell population: the optimal sampling time differs according to tissue, with liver and bone
marrow at opposite extremes among proliferating somatic tissues: in bone marrow, the mutant
frequency appears to reach a maximum at extremely short sampling times and then decreases
over 28 days following an acute treatment; in liver the induced mutation frequency increases
over the month following exposure, reaches a maximum, and remains relatively constant
thereafter. There are insufficient data available for other tissues to support any conclusion
regarding optimal sampling time. The results of studies carried out on a given chemical using
similar experimental protocols suggest that the TGR assays show good qualitative
reproducibility in both somatic and germ cells, and quantitative reproducibility over a limited
range of conditions and laboratories. The data are insufficient to draw conclusions regarding the
quantitative reproducibility of the assays over a wider range of conditions. Although there exists
a theoretical possibility that ex vivo and in vitro mutations may arise during the course of a TGR
experiment, these types of mutations are expected to be extremely rare in a properly conducted
experiment using the major TGR models. For positive selection systems, any such mutations will
not be detected. The weight of evidence suggests that transgenes and endogenous genes respond
in approximately the same manner to mutagens in the few instances where direct comparisons
are possible. Sensitivity is determined in large part by the SMF: the higher SMF in transgenes, as
compared to testable endogenous genes, appears to reduce their sensitivity, especially when
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acute treatments are used. The sensitivity of transgenes can be enhanced by increasing the
administration time. Mutagens that induce deletions are likely to be detected more easily in
certain endogenous genes than in transgenes due to phenotypic selection issues. A very high
proportion of the TGR experiments carried out to date have examined the activity of compounds
that are known to be strong mutagens. A limited number of noncarcinogens have been evaluated
with TGRs. The specificity of the TGR assay for predicting carcinogenicity is generally higher
than other assays evaluated in this paper. However, additional data from TGR assays on
noncarcinogens is required. Molecular analysis of induced mutations in transgenic targets is
possible and provides additional information in situations where high interindividual variation is
observed and clonal expansion is suspected, when weak responses are obtained, or when
mechanistic information is desired. However, DNA sequence analysis of mutants is laborious
and adds to the cost of the experiment; sequencing would not normally be required when testing
drugs or chemicals for regulatory applications, particularly where a clear positive or negative
result is obtained. 4. Analysis of the predictivity of TGR assays for carcinogenicity is hindered
somewhat by the fact that TGR data are available for only a small number of noncarcinogens. Of
the 90 carcinogens and 13 noncarcinogens that have been assessed using TGR assays, the
following conclusions can be drawn regarding the predictivity and complementarity of TGR
assays in comparison to a range of other OECD in vitro and in vivo genotoxicity tests.. The TGR
assay has high sensitivity and positive predictivity, meaning that most carcinogens have positive
results in TGR and there is a high probability that a chemical with a positive result in TGR is a
carcinogen. As is the case with most genotoxicity assays, the TGR assay exhibits low specificity
and negative predictivity, meaning that relatively few noncarcinogens were negative in TGR and
there is a low probability that a chemical with a negative result in TGR is a noncarcinogen;
however, it was no worse than the Salmonella mutagenicity assay in this regard. Considering all
the best batteries and single assays examined using the current dataset, best positive and negative
predictivity was obtained from the TGR assay alone, the Salmonella mutagenicity assay alone,
and a battery in which a positive result in TGR or Salmonella was considered positive and
negative results in both assays was considerd negative. Despite the lack of substantial increases
in predictive values of the test batteries compared with the component assays alone, the test
batteries had a much lower false negative rate. TGR and the in vivo micronucleus (MN) assay
exhibited significant complementary - i.e. they offered greater predictivity for the detection of
mutagens when combined than when alone - consistent with the fact that these two assays
measure different genotoxic endpoints. TGR was usually positive for those carcinogens that
were positive in Salmonella and the in vitro chromosomal aberration (CA) assay. In contrast, in
vivo MN had a much higher false negative rate for the same chemicals. If in vivo confirmation
of positive results from both Salmonella and in vitro CA is warranted, TGR is likely a better
choice than in vivo MN. For chemicals having positive Salmonella and negative in vitro CA
results (presumptive gene mutagens), selecting either TGR or in vivo MN as the in vivo
confirmation assay did not markedly affect the proportion of correct carcinogenicity predictions.
For chemicals having positive in vitro CA and negative Salmonella results (presumptive
clastogens), selecting in vivo MN as the in vivo confirmation assay led to a slightly higher
proportion of correct carcinogenicity predictions than did selecting TGR. For those carcinogens
with negative results in both Salmonella and in vitro CA, adding either TGR or in vivo MN to
the test battery did not improve the overall predictivity, since neither assay identified the
carcinogens missed by the in vitro assays. 5. Recommendations, based on internationally
harmonized criteria, are made regarding the proper conduct of a TGR assay. These
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recommendations relate to accepted characteristics of a transgenic rodent mutation assay,
treatment protocols, and post treatment sampling procedures. Of particular importance in
optimizing TGR protocols are two experimental variables - the administration time and the
sampling time. Based on observations that mutations accumulate with each treatment, a
repeated-dose regimen for a period of 28 days is strongly encouraged, with sampling at 3 days
following the final treatment. If slowly proliferating tissues are of particular importance, then a
longer sampling time may be more appropriate. Additional confidence in the recommended test
protocol will be provided by research that examines the following: The influence of the
administration time on the observed mutation frequency for weak mutagens. It has not
conclusively been determined if data (especially negative results) from experiments using an
administration time of less than 28 days should be discounted, if a 28 day treatment period is
sufficiently long to permit the detection of weak mutagen-induced mutations in all tissues, or if
weak mutagens could in fact be detected using treatment times shorter than 28 days. The
influence of the frequency of treatment on the observed mutation frequency. The difference
between weekly and daily administrations on mutant frequency and on the ultimate conclusions
of transgenic rodent experiments has not yet been thoroughly investigated. The influence of
sampling time following repeat administrations on the mutant frequency in both slowly and
rapidly dividing tissue, particularly when examining weak mutagens. At the current time there
are insufficient comparative data available for a range of tissues. Recommendations are made
regarding how a TGR assay might be used within a short-term test battery for assessing new
compounds. The test battery consists of various combinations of four assays - Salmonella, in
vitro CA, in vivo MN and TGR. This proposed strategy is based on the conclusions obtained
from the predictivity analysis, and the relative costs of the in vivo assays. TGR assays may also
be used to resolve conflicts between in vitro and in vivo tests that are currently components of
the standard genotoxicity test battery - Salmonella, in vitro CA and in vivo MN. In situations
where the standard test battery has been conducted and there are conflicting results -particularly
in situations where Salmonella has a positive result but in vivo MN is negative - TGR may be
conducted as an additional test to resolve the conflict. Recommended test strategies are based on
an analysis of the existing data. Confidence in these recommendations would be enhanced by
additional experimental data in the following areas. TGR data for additional non-carcinogens to
increase the proportion of non-carcinogens in the data set. Additional testing to fill data gaps for
chemicals having known TGR assay but missing data from the Salmonella, in vitro CA, or in
vivo MN assays. The testing of additional chemicals using an accepted test guideline for TGR
mutation assays. Based on the information and analyses in this review, there is sufficient
evidence to support the recommendation that the OECD undertake the development of a Test
Guideline on Transgenic Rodent Gene Mutation Assays. Accordingly, it is recommended that
the OECD establish an Expert Working Group to develop such a Test Guideline, and serve as an
international forum for undertaking any additional research that would lead to the development
of a fuller understanding of the variables surrounding the conduct of TGR mutation assays.
Crown Copyright (c) 2005 Published by Elsevier B. V. All rights reserved.
67. Laurant P, Chanut E, Bobillier-Chaumont S, Gaillard E, Jacquot C, Trouvin JH, Berthelot A.
(2003) Attenuation of the development of DOCA salt hypertension by a high Mn intake in the
rat. Trace Elements and Electrolytes 20(3): 172-180.
The effects of a high Mn intake on blood pressure, vascular reactivity and central catecholamine
levels were studied in DOCA salt-hypertensive rats. High Mn intake inhibited blood pressure
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elevation in DOCA salt rats but did not modify it in normotensive rats. The blood pressure-
lowering effect of Mn was associated with inhibited cardiac hypertrophy and increased
natriuresis. Pharmacological studies in blood vessels showed that high Mn intake normalized
vasoconstriction and sensitivity to norepinephrine of isolated and perfused mesenteric vascular
beds from DOCA salt rats. Furthermore, high Mn intake improved the endothelium- and NO-
dependent relaxation in isolated aortae from DOCA salt-hypertensive rats but not in those from
normotensive rats. Norepinephrine levels were higher in the hypothalamus of DOCA salt-
hypertensive rats than in those of normotensive rats, and high Mn intake decreased
norepinephrine levels in hypothalamus of DOCA salt rats. In conclusion, a high Mn intake
attenuated the development of hypertension with beneficial vascular and central effects.
Mechanisms related to the pathophysiological development of DOCA salt hypertension may be
involved.
68. Lee B, Hiney JK, Pine MD, Srivastava VK, Dees WL. (2007) Manganese stimulates
luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site
and mechanism of action. Journal of Physiology-London 578(3):765-772.
We have shown recently that Mn2+ stimulates gonadotropin secretion via an action at the
hypothalamic level, and a diet supplemented with a low dose of the element is capable of
advancing the time of female puberty. In this study, we used an in vitro approach to investigate
the mechanism by which Mn2+ induces luteinizing hormone-releasing hormone (LHRH)
secretion from prepubertal female rats. Themedial basal hypothalamus from 30-day-old rats was
incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with
buffer alone or buffer plus either a nitric oxide synthase ( NOS) inhibitor (N-monomethyl-L-
arginine (NMMA); 300 or 500 mu M) or a soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4]
oxadiazolo[4,3- a] quinoxalin-l-one(ODQ); 100 or 250 mu M) for another 30 min. Finally, the
incubation continued for a further 30 min, but in the presence of MnC12 (50 or 250 mu M) to
assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 mu M MnC12
stimulated LHRH release ( P < 0.05 and P < 0.01, respectively). The addition of 300-500 mu M
NMMA to the medium did not block Mn2+-stimulated release of LHRH, even with the higher
dose of MnC12. Furthermore, while 50, 100 and 250 mu M MnC12 all significantly induced
LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue,
an effect only observed with the highest dose. Taken together, these data suggest that Mn2+ is
not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn2+-
stimulated secretion of LHRH in a dose-dependent manner, indicating that GC is the site of
action of Mn2+. Additionally, we showed that Mn2+ stimulated cGMP and LHRH from the
same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 mu
M) inhibited Mn2+-induced LHRH release. These data demonstrate that the principal action of
Mn2+ within the hypothalamus is to activate sGC directly and/or as a cofactor with available
NO, hence generating cGMP and resulting in prepubertal LHRH release.
69. Lee B, Pine M, Johnson L, Rettori V, Hiney JK, Dees WL. (2006) Manganese acts centrally
to activate reproductive hormone secretion and pubertal development in male rats. Reproductive
Toxicology 22(4):580-585.
Manganese (Mn) is an important element for normal growth and reproduction. Because Mn
accumulates in the hypothalamus and is capable of stimulating puberty-related hormones in
female rats, we assessed whether this metal could cause similar effects in male rats. We have
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demonstrated that MnC12, when administered acutely into the third ventricle of the brain, acts
dose dependently to stimulate luteinizing hormone (LH) release. Furthermore, there was a dose
dependent stimulation in the secretion of LH-releasing hormone (LHRH) from the medial basal
hypothalamus in vitro, and administration of an LHRH receptor antagonist in vivo blocks Mn-
induced LH release. To assess potential chronic effects of the metal, male pups were
supplemented with 10 or 25 mg MnC12 per kg by gastric gavage from day 15 until days 48 or 55,
at which times developmental signs of spermatogenesis were assessed. Results demonstrate that
while significant effects were not observed with the 10 mg/kg dose, the animals receiving the 25
mg/kg dose showed increased LH (p < 0.05), FSH (p < 0.01) and testosterone (p < 0.01) levels at
55 days of age. Furthermore, there was a concomitant increase in both daily sperm production (p
< 0.05) and efficiency of spermatogenesis (p < 0.05), demonstrating a Mn-induced acceleration
in spermatogenesis. Our results suggest Mn is a stimulator of prepubertal LHRH/LH secretion
and may facilitate the normal onset of male puberty. These data also suggest that the metal may
contribute to male precocious pubertal development should an individual be exposed to low but
elevated levels of Mn too early in life, (c) 2006 Elsevier Inc. All rights reserved.
70. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro
L. (1999) Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal Tl-
weighted magnetic resonance signal hyperintensity. Neurotoxicology 20(4):647-652.
The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic
resonance (MR) imaging has been postulated to arise from deposition of paramagnetic
manganese(2+) (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency;
iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the
relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic
liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary
sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha 1-antitrypsin deficiency
1). Signal hyperintensity in the pallidum on axial T1 weighted images repetition time/evolution
time: 500 ms/15ms was observed in 13 of 21 subjects: four patients had mild hyperintensity,
three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were
positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005).
The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron
status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe
concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings
confirm the association of Mn with the development of pallidal hyperintensity in patients with
liver disease. We further found that iron deficiency is an exacerbating factor probably because of
increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver
disease avoid Mn supplements without concurrent iron supplementation. (C)1999 Intox Press,
Inc.
71. Malecki EA, Lo HC, Yang H, Davis CD, Ney DM, Greger JL. (1995) Tissue Manganese
Concentrations and Antioxidant Enzyme-Activities in Rats Given Total Parenteral-Nutrition
with and without Supplemental Manganese. Journal of Parenteral and Enteral Nutrition
19(3):222-226.
Background: Manganese is an essential but potentially toxic mineral. Parenteral administration
of manganese via total parenteral nutrition (TPN) bypasses homeostatic mechanisms (intestinal
absorption and presystemic hepatic elimination). Our objective in this study was to determine the
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effect of supplemental manganese in TPN solutions on manganese status in a rat model.
Methods: Male Sprague-Dawley rats underwent jugular catheterization and were given 61.0 +/-
0.4 g/d TPN solution providing 0.5 +/- 0.2 nmol manganese/g (Mn-; n = 6) or 16 +/- 3 nmol
manganese/g (Mn+; n = 7) for 7 days. Reference rats (RF; n = 8) were fed a purified diet
containing 1.3 mmol manganese/g. Results: Liver manganese decreased in both TPN groups, but
tibia, spleen, and pancreas manganese concentrations were greater in Mn+ rats than in Mn- or
RF rats. Although no treatment differences were seen in heart or liver manganese superoxide
dismutase activity, heart copper-zinc superoxide dismutase activity was lower in the Mn+ rats
than in Mn- or RF rats (p < .05). Glutathione peroxidase activity was depressed in livers of both
Mn- and Mn+ rats relative to RF rats (p < .001), which was not due to selenium deficiency.
Conclusions: Supplemental parenteral manganese is taken up to a greater extent by peripheral
tissues than the liver. In this first report of antioxidant enzyme activities in animals maintained
with TPN, we found that TPN as well as supplemental manganese can influence antioxidant
enzyme activities. We conclude that it is generally unnecessary and potentially toxic to
supplement TPN solutions with manganese during short-term usage.
72. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M,
Mihara F. (2001) Manganese intoxication during intermittent parenteral nutrition: Report of two
cases. Journal of Parenteral and Enteral Nutrition 25(2):95-99.
Background and Methods: The administration of trace elements is thought to be needed in
patients receiving long-term parenteral nutrition. Recently, manganese intoxication or deposition
was documented in such patients. We report two cases of manganese intoxication during
intermittent parenteral nutrition including manganese. Manganese had been administered for 4
years at a frequency of one or two times per week in one case and for 5 years at a frequency of
one or two times per month in the other case. Both cases showed mild symptoms with headache
and dizziness. One case had mild hepatic dysfunction and the other did not. The whole-blood
manganese level increased in one case, but not in the other case. Tl-weighted magnetic
resonance images revealed symmetrical high-intensity areas in basal ganglia and thalamus in
both cases. After the administration of manganese was stopped, these symptoms all disappeared
and the magnetic resonance images abnormalities gradually improved in both patients. Mild
long-term manganese intoxication is thus considered to occur regardless of the frequency of
using a manganese supplement. Conclusions: Patients should be carefully monitored when
receiving long-term parenteral nutrition including manganese, even when the manganese dose is
small and the frequency of receiving a manganese supplement is low.
73. Mergler D, Baldwin M. (1997) Early manifestations of manganese neurotoxicity in humans:
An update. Environmental Research 73(l-2):92-100.
BIOSIS COPYRIGHT: BIOL ABS. It is possible to detect early signs of neurotoxic dysfunction
associated with occupational and environmental exposure to manganese; neurophysiologic and
neurobehavioral tests can be used in the absence of clinical manifestations. Although outcomes
from individual studies vary, they collectively show a pattern of slowing motor functions,
increased tremor, reduced response speed, enhanced olfactory sense, possible memory and
intellectual deficits, and mood changes. This overall portrait is consistent with the action of
manganese on the central nervous system. In reports to date, there is little consistency in dose-
effect relationships between internal parameters of manganese exposure (blood manganese,
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urinary manganese, hair manganese) and external measures and neurologic outcomes. Several
studies suggest the existence of dose-effect relationships, but additional clarification is needed.
74. Miller KB, Caton JS, Finley JW. (2006) Manganese depresses rat heart muscle respiration.
Biofactors 28(l):33-46.
It has previously been reported that moderately high dietary manganese (Mn) in combination
with marginal magnesium (Mg) resulted in ultrastructural damage to heart mitochondria.
Manganese may replace Mg in biological functions, including the role of enzyme cofactor.
Manganese may accumulate and substitute for Mg during the condition of Mg-deficiency. The
objective of the current study was to determine whether high Mn alters heart muscle respiration
and Mg-enzyme activity as well as whole body Mn retention under marginal Mg. An additional
objective was to determine whether high Mn results in increased oxidative stress. In experiment
1: forty-eight rats were fed a 2 x 3 factorial arrangement of Mn (10, 100, or 1000 mg/kg) and Mg
(200 or 500 mg/kg). In experiment 2: thirty-two rats were fed one of four diets in a 2 x 2 factorial
arrangement of Mn (10 or 250 mg/kg) and Mg (200 or 500 mg/kg). In experiment 3: thirty-two
rats were fed one of four diets in a 2 x 2 factorial arrangement of Mn (10 or 650 mg/kg) and Mg
(200 or 500 mg/kg). In experiment 2, high Mn and marginal Mg reduced (P < 0.05) oxygen
consumption of left ventricle muscle. Marginal Mg, but not Mn, reduced (P < 0.05) activity of
sarcoplasmic reticulum calcium-ATPase enzyme. Dietary Mg had no affect on Mn-54 kinetics,
but high dietary Mn decreased (P < 0.01) absorption, retention, and rate of excretion of Mn-54.
Neither cellular stress, measured by Comet assay, nor antioxidant activities were increased by
high Mn. A strong interaction (P < 0.001) between increasing Mn and adequate Mg on
hematology was observed. These results confirm previous research in swine that high Mn alters
myocardial integrity as well as function, but not as a result of altered calcium transport or
oxidative stress.
75. Oikawa S, Hirosawa I, Tada-Oikawa S, Furukawa A, Nishiura K, Kawanishi S. (2006)
Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and
neuronal cell death. Free Radical Biology and Medicine 41(5):748-756.
Although the cause of dopammergic cell death in Parkinson's disease is still poorly understood,
there is accumulating evidence suggesting that metal ions can be involved in the processes. We
investigated the effect of manganese on cell death and DNA damage in Pdl2 ells treated with
dopamine. Mn(II) enhanced cell death induced by dopamine. Mn(II) also increased the 8-oxo-
7,8-dihydro-2-deoxyguanosine (8-oxodG) contents of DNA in PC12 cells treated with dopamine.
To clarify the mechanism of cellular DNA damage, we investigated DNA damage induced by
dopamine and Mn(II) using (32)p-labeled DNA fragments. Mn(II) enhanced Cu(II)-dependent
DNA damage by dopamine. The Mn(II)-enhanced DNA damage was greatly increased by
NADH. Piperidine and forrnamidopyrimidine-DNA glycosylase treatment induced cleavage sites
mainly at T and G of the 5'-TG-3' sequence, respectively. Bathocuproine, a Cu(I) chelator, and
catalase inhibited the DNA damage. Oxygen consumption and UV-visible spectroscopic
measurements showed that Mn(II) enhanced autoxidation of dopamine with H202 formation.
These results suggest that reactive species derived from the reaction of H202 with Cu(I)
participates in Mn(II)-enhanced DNA damage by dopamine plus Cu(II). Therefore, it is
concluded that oxidative DNA damage induced by dopamine in the presence of Mn(II), NADH,
and Cu(II) is possibly linked to the degeneration of dopaminergic neurons, (c) 2006 Elsevier Inc.
All rights reserved.
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76. Ostiguy C, Asselin P, Malo S. (2006) The emergence of manganese-related health problems
in Quebec: An integrated approach to evaluation, diagnosis, management and control.
Neurotoxicology 27(3):350-356.
This paper describes the strategy developed in Quebec to deal with an emerging problem:
manganism in welders. Only two cases of manganism had been reported to the Commission de la
sante et de la securite du travail (CSST, Workers Compensation Board in Quebec) before 2000.
In the fall of 200 1, the CSST was informed of a possible cluster of manganism and received 20
compensation claims from one plant. Action was rapidly taken to understand and tackle this
emerging problem. Under the leadership of the CSST, a coordinating working group
implemented medical and environmental subcommittees involving representatives of the
different partners of the prevention network. After a literature review to document the health
risks associated with manganese and the lack of some important information, a panel of
international experts was formed to try to reach agreement on the parameters to consider in the
diagnosis and management of manganism. The CSST compensation management policies would
be adjusted accordingly. Simultaneously, all the available industrial hygiene data were analyzed
to estimate where and at what levels workers were exposed to manganese. To complete these
data, the exposure of workers in more than 50 industrial plants was evaluated and existing
control measures were documented. All these data have been presented for a revision of the
Quebec permissible exposure limit (PEL). In this integrated approach, the next step targets the
formation of neurologists and neuropsychologists for a standardized medical evaluation, to
complete workplace evaluation in the high risk sectors, inform workers and employers and
recommend control measures where required, based on a revised PEL. Many strategies will be
used to inform the prevention network (about 1000 people), employers and employees of the
risks of overexposure to manganese and of the measures to control exposure in all the plants
where workers are susceptible to be exposed to manganese, (c) 2005 Elsevier Inc. All rights
reserved.
77. Park J, Yoo CI, Sim CS, Kim HK, Kim JW, Jeon BS, Kim KR, Bang OY, Lee WY, Yi Y
and others. (2005) Occupations and Parkinson's disease: A multi-center case-control study in
South Korea. Neurotoxicology 26(1):99-105.
Objective: We performed a hospital based case-control study in South Korea (1) to clarify the
role of occupational exposure, and especially manganese (Mn) exposure in the etiology of
Parkinson's disease (PD) and (2) to discover the association between any occupations and PD.
Methods: We selected two groups, PD patient group (NI) and controls (N-2). Three hundred
sixty-seven consecutive outpatients with PD (177 men, 190 women) and 309 controls were
interviewed about life style, past history, family history, education level, and occupational
history etc. We employed a range of industrial categories as defined by section (the most broad
category) and division (sub-category) of the Korea Standard Industry Code (KSIC) Manual.
Along with KSIC, we also used the Korea Standard Classification of Occupations (KSCO) as
proxies of occupational exposure. The odds ratios (ORs) and 95% confidence intervals (CA),
adjusted for age, sex, smoking status, and education level are presented. Results: As regarding
the exposure to hazardous materials, especially Mn, more subjects in the control group than the
PD patient group 'have worked in the occupations with potential exposure to Mn (P < 0.001).
Ever having worked in 'agriculture, hunting, and forestry' section of industry was positively
associated with PD (OR 1.88), and 'agriculture production crops (OR 1.96)'division of industry
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was positively associated with PD. On the other hand, ever having worked in the 'manufacturing
(OR 0.56)', 'transportation (OR 0.28)' section of industry, and 'transporting (OR 0.20)' division of
industry were negatively associated with PD. 'Drivers (OR 0.13)'division of occupation also was
negatively associated with PD. Conclusions: To our knowledge, this is the first case-control
studies to find an inverse relationship between 'transporting' or 'technicians like machinery
engineers' as his/her longest job and PD risk. Because of this unexpected finding, our work
should be replicated in various populations. (C) 2004 Elsevier Inc. All rights reserved.
78. Park RM, Bowler RM, Eggerth DE, Diamond E, Spencer KJ, Smith D, Gwiazda R. (2006)
Issues in neurological risk assessment for occupational exposures: The Bay Bridge welders.
Neurotoxicology 27(3):373-384.
The goal of occupational risk assessment is often to estimate excess lifetime risk for some
disabling or fatal health outcome in relation to a fixed workplace exposure lasting a working
lifetime. For sub-chronic or sub-clinical health effects measured as continuous variables, the
benchmark dose method can be applied, but poses issues in defining impairment and in
specifying acceptable levels of excess risk. Such risks may also exhibit a dose-rate effect and
partial reversibility such that effects depend on how the dose is distributed over time.
Neurological deficits as measured by a variety of increasingly sensitive neurobehavioral tests
represent one such outcome, and the development of a parkinsonian syndrome among welders
exposed to manganese fume presents a specific instance. Welders employed in the construction
of piers for a new San Francisco-Oakland Bay Bridge in San Francisco were previously
evaluated using a broad spectrum of tests. Results for four of those tests (Rey-Osterrieth
Complex Figure Test, Working Memory Index, Stroop Color Word Test and Auditory
Consonant Trigrams Test) were used in the benchmark dose procedure. Across the four
outcomes analyzed, benchmark dose estimates were generally within a factor of 2.0, and
decreased as the percentile of normal performance defining impairment increased. Estimated
excess prevalence of impairment, defined as performance below the 5th percentile of normal,
after 2 years of exposure at the current California standard (0.2 mg/m(3), 8 h TWA), ranged 15-
32% for the outcomes studied. Because these exposures occurred over a 1-2-year period,
generalization to lifetime excess risk requires further consideration of the form of the exposure
response and whether short-term responses can be generalized to equivalent 45-year period.
These results indicate unacceptable risks at the current OSHA PEL for manganese (5.0 mg/m(3)
15 min) and likely at the Cal OSHA PEL as well, (c) 2005 Elsevier Inc. All rights reserved.
79. Pecze L, Papp A, Nagymajtenyi L. (2004) Changes in the spontaneous and stimulus-evoked
activity in the somatosensory cortex of rats on acute manganese administration. Toxicology
Letters 148(1-2): 125-131.
In this work, acute effects of inorganic manganese exposure on nervous electrical activity of rats
were investigated. Young adult male Wistar rats were prepared for recording in anaesthesia and
spontaneous cortical as well as stimulus-evoked cortical and peripheral nervous activity was
recorded before and after i.p. administration of 25 and 50 mg/kg Mn2+. The alterations found
resulted possibly from several known neuronal effects of manganese. The frequency shift of
spontaneous cortical activity, and increased latency and decreased amplitude of the peripheral
nerve action potential, were probably due to the Mn2+-induced impairment of the mitochondria,
whereas the increased amplitude of the evoked cortical response, to the effect on glutamatergic
transmission. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
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80. Ramesh GT, Ghosh D, Gunasekar PG. (2002) Activation of early signaling transcription
factor, NF-kappaB following low-level manganese exposure. Toxicology Letters 136(2): 151-
158.
Occupational and environmental exposure to manganese (Mn2+) is an increasing problem. It
manifests neuronal degeneration characterized by dyskinesia resembling Parkinson's disease.
The study was performed to test the hypotheses whether exposure to Mn2+ alters cellular
physiology and promotes intracellular signaling mechanism in dopaminergic neuronal cell line.
Since transcription factors have been shown to play an essential role in the control of cellular
proliferation and survival, catecholaminergic rich pheochromocytoma (PC12) cells were used to
measure changes in the DNA binding activities of nuclear factor kappa B (NF-kappaB) by
electrophoretic mobility shift assay (EMSA) following Mn2+ (0.1-10 muM) exposure. Cells that
were exposed to Mn2+ produced five-fold-activation of transcription factor NF-kappaB DNA
binding activity. This remarkable increase was seen within 30-60 min period of Mn2+ exposure.
Activation of NF-kappaB DNA binding activity by Mn2+ at 1.0 muM correlated with proteolytic
degradation of the inhibitory subunit IkappaBalpha as evidenced in cytosol. Additional
experiments on NF-kappaB reporter gene assay also showed increased NF-kappaB gene
expression at 1.0 and 5.0 muM Mn2+ and this was completely blocked in the presence of NF-
kappaB translocation inhibitor, IkappaBalpha-DN supporting that NF-kappaB induction
occurred during Mn2+ exposure. In addition, Mn2+ exposure to PC 12 cells led to activation of
signal responsive mitogen activated proteinexposure. In addition, Mn2+ exposure to PC 12 cells
led to activation of signal responsive mitogen activated protein kinase kinase (MAPKK). These
results suggest that Mn2+ at a low dose appears to induce the expression of immediate early
gene, NF-kappaB through MAPKK by a mechanism in which IKBoc phosphorylation may be
involved.) (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
81. Rao KVR, Norenberg MD. (2004) Manganese induces the mitochondrial permeability
transition in cultured astrocytes. Journal of Biological Chemistry 279(31):32333-32338.
Manganese is known to cause central nervous system injury leading to parkinsonism and to
contribute to the pathogenesis of hepatic encephalopathy. Although mechanisms of manganese
neurotoxicity are not completely understood, chronic exposure of various cell types to
manganese has shown oxidative stress and mitochondrial energy failure, factors that are often
implicated in the induction of the mitochondrial permeability transition (MPT). In this study, we
examined whether exposure of cultured neurons and astrocytes to manganese induces the MPT.
Cells were treated with manganese acetate (10-100 muM), and the MPT was assessed by
changes in the mitochondrial membrane potential and in mitochondrial calcein fluorescence. In
astrocytes, manganese caused a dissipation of the mitochondrial membrane potential and
decreased the mitochondrial calcein fluorescence in a concentration- and time-dependent
manner. These changes were completely blocked by pretreatment with cyclosporin A, consistent
with induction of the MPT. On the other hand, similarly treated cultured cortical neurons had a
delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in
astrocytes was blocked by pretreatment with antioxidants, suggesting the potential involvement
of oxidative stress in this process. Induction of the MPT by manganese and associated
mitochondrial dysfunction in astrocytes may represent key mechanisms in manganese
neurotoxicity.
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82. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
Manganese (Mn) is ubiquitous in mammalian systems and is essential for proper development
and function, though it can also be toxic at elevated exposures. While essential biologic
functions of Mn depend on its oxidation state [e.g., Mn(II), Mn(III)], little is known about how
the oxidation state of elevated Mn exposures affect cellular uptake, and function/toxicity. Here
we report the dynamics of EPR measurable Mn(II) in fresh human plasma and cultured PC 12
cell lysates as a function of exposure to either manganese(II) chloride or manganese(III)
pyrophosphate, and the effects of exposure to Mn(II) versus Mn(III) on total cellular aconitase
activity and cellular Mn uptake. The results indicate that Mn(II) or Mn(III) added in vitro to
fresh human plasma or cell lysates yielded similar amounts of EPR measurable Mn(II). In
contrast, Mn added as Mn(III) was significantly more effective in inhibiting total cellular
aconitase activity, and intact PC 12 cells accumulated significantly more Mn when exposures
occurred as Mn(III)., Collectively, these data reflect the dynamic nature of Mn speciation in
simple biological systems, and the importance of Mn oxidation/speciation state in mediating
potential cellular toxicity. This study supports concern over increased environmental exposures
to Mn in different oxidation states [Mn(II), Mn(III), and Mn(IV)] that may arise from
combustion products of. the gasoline antiknock additive methycyclopentadienyl manganese
tricarbonyl (MMT).
83. Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C, Paez E, Crespo E. (2000)
Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats - A
morphometric and densitomeric study. European Journal of Obstetrics Gynecology and
Reproductive Biology 90(1):97-101.
Objective: The aim of this study was to examine the effect of manganese (Mn) alone and with
the addition of copper (Cu) in the inhibition of osteopenia induced by ovariectomy (OVX) in
rats. Study conditions: Four lots of 100-day-old female Wistar rats were divided into
experimental groups of 15 each. One group received a diet supplemented with 40 mg/kg of Mn
per kilogram of feed (OVX+Mn). The second group received the same diet as the first, but with
an additional 15 mg/kg of copper (OVX+Mn+Cu). The third group of 15 OVX and the fourth
group of 15 Sham-OVX received no supplements. At the conclusion of the 30-day experiment,
the rats were slaughtered and their femurs and fifth lumbar vertebrae were dissected. Femoral
and vertebral length were measured with caliper and bones were weighed on a precision balance.
The bone mineral content (BMC) and bone density (BMD) of the femur (F-BMC, mg and F-
BMD, mg/cm(2)) and the fifth lumbar vertebra (V-BMC, mg and V-BMD, mg/cm(2)) were
measured separately with dual energy X-ray absorptiometry. Results: The F-BMD, mg/cm(2)
was lower in the OVX than in the Sham-OVX group (P<0.0001) and in the other two groups
receiving mineral supplements (P<0.005 in both). F-BMC, mg was significantly lower in the
OVX group than in the other three (P<0.0001 in all cases), Calculations for V-BMC, mg and V-
BMD, mg/cm(2) are similar to findings in the femur. Conclusions: These data show that a Mn
supplement is an effective inhibitor of loss of bone mass after OVX, both on the axial and the
peripheral levels, although this effect is not enhanced with the addition of Cu. (C) 2000 Elsevier
Science Ireland Ltd. All rights reserved.
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84. Ross C, O'Reilly DS, McKee R. (2006) Potentially clinically toxic concentrations of whole
blood manganese in a patient fed enterally with a high tea consumption. Annals of Clinical
Biochemistry 43:226-228.
This report describes a 37-year-old female patient who after seven years on intermittent
overnight enteral feeding supplementation was noted to have an increased whole blood
manganese concentration. Manganese toxicity is well documented after pathological absorption
through inhalation via the lungs, or after intravenous administration to patients on long-term
total parenteral nutrition. A dietary history revealed high tea consumption. The association
between high blood manganese concentrations and enteral/oral nutrition does not appear to have
previously been described.
85. Seth P, Husain MM, Gupta P, Schoneboom BA, Grieder FB, Mani H, Maheshwari RK.
(2003) Early onset of virus infection and up-regulation of cytokines in mice treated with
cadmium and manganese. Biometals 16(2):359-368.
A substantial database indicates that a large number of environmental pollutants, chemicals and
therapeutic agents to which organisms are exposed cause immunotoxicity. The suppression of
immune functions may cause increased susceptibility of the host to a variety of microbial
pathogens potentially resulting in a life-threatening state. Evaluation of the immunotoxic
potential of chemical xenobiotics is of great concern and, therefore, we have investigated the
impact of exposure of inorganic metals, specifically cadmium (Cd) and manganese (Mn) on
Encephalomyocarditis virus (EMCV), Semliki Forest virus (SFV), and Venezuelan Equine
Encephalitis virus (VEEV) infection. Pretreatment with a single, oral dose of Cd or Mn increased
the susceptibility of mice to a sub-lethal infection of these viruses as observed by increased
severity of symptoms and mortality compared to untreated controls. An early onset of virus
infection was found in brains of Cd and Mn treated animals. Histopathological observations of
the brain indicate evidence of inflammation and greater tissue pathology in Cd- or Mn-exposed
mice compared to control animals. Meningitis and vascular congestion was seen in virus infected
mice in all the metal treated groups, and further, the perivascular inflammation appeared earlier
in treated mice compared to control. Encephalitis was maximum in Cd pretreated mice.
Widespread environmental contamination of metals and the potential for their exposure and
subsequent infection of humans or animals is indicative that further studies of these and all other
metals are important to understand the effect of environmental pollution on human health.
86. Sjogren B, Iregren A, Freeh W, Hagman M, Johansson L, Tesarz M, Wennberg A. (1996)
Effects on the nervous system among welders exposed to aluminium and manganese.
Occupational and Environmental Medicine 53(l):32-40.
Objectives-The purpose was to study the effects on the nervous system in welders exposed to
aluminium and manganese. Methods-The investigation included questionnaires on symptoms,
psychological methods (simple reaction time, finger tapping speed and endurance, digit span,
vocabulary, tracking, symbol digit, cylinders, olfactory threshold, Luria-Nebraska motor scale),
neurophysiological methods (electroencephalography, event related auditory evoked potential
(P-300), brainstem auditory evoked potential, and diadochokinesometry) and assessments of
blood and urine concentrations of metals (aluminium, lead, and manganese). Results-The
welders exposed to aluminium (n = 38) reported more symptoms from the central nervous
system than the control group (n = 39). They also had a decreased motor function in five tests.
The effect was dose related in two of these five tests. The median exposure of aluminium
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welders was 7065 hours and they had about seven times higher concentrations of aluminium in
urine than the controls. The welders exposed to manganese (n = 12) had a decreased motor
function in five tests. An increased latency of event related auditory evoked potential was also
found in this group. The median manganese exposure was 270 hours. These welders did not have
higher concentrations of manganese in blood than the controls. Conclusions-The neurotoxic
effects found in the groups of welders exposed to aluminium and manganese are probably caused
by the aluminium and manganese exposure, respectively. These effects indicate a need for
improvements in the work environments of these welders.
87. Sunderman FW. (2001) Review: Nasal toxicity, carcinogenicity, and olfactory uptake of
metals. Annals of Clinical and Laboratory Science 31(l):3-24.
Occupational exposures to inhalation of certain metal dusts or aerosols can cause loss of
olfactory acuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or
sinonasal cancer. Anosmia and hyposmia have been observed in workers exposed to Ni- or Cd-
containing dusts in alkaline battery factories, nickel refineries, and cadmium industries. Ulcers of
the nasal mucosa and perforated nasal septum have been reported in workers exposed to Cr(VI)
in chromate production and chrome plating, or to As(III) in arsenic smelters. Atrophy of the
olfactory epithelium has been observed in rodents following inhalation of NiS04 or alpha
Ni3S2. Cancers of the nose and nasal sinuses have been reported in workers exposed to Ni
compounds in nickel refining, cutlery factories, and alkaline battery manufacture, or to Cr(VI) in
chromate production and chrome plating. Ill animals, several metals (eg, Al, Cd, Co, Hg, Mn,
Ni, Zn) have been shown to pass via olfactory receptor neurons from the nasal lumen through the
cribriform plate to the olfactory bulb. Some metals (eg. Mn, Ni, Zn) can cross synapses in the
olfactory bulb and migrate via secondary olfactory neurons to distant nuclei of the brain. After
nasal instillation of a metal-containing solution, transport of the metal via olfactory axons can
occur rapidly within hours or a few days (eg, Mn), or slowly other days or weeks (eg, Ni). The
olfactory bulb tends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greater avidity
than other regions of the brain. The molecular mechanisms responsible for metal translocation in
olfactory neurons and deposition in the olfactory bulb are unclear, but complexation by metal-
binding molecules such as carnosine (beta -alanyl-L-histidine) may be involved.
88. Takeda A. (2004) Essential trace metals and brain function. Yakugaku Zasshi-Journal of the
Pharmaceutical Society of Japan 124(9):577-585.
Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the
brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system,
i.e., the blood-brain and blood-cerebrospinal fluid barriers. Trace metals usually serve the
function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the
presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and
manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via
the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an
inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by
manganese might mean functional and toxic aspects in the synapse. Dietary zinc deficiency
affects zinc homeostasis in the brain, followed by an enhanced susceptibility to the excitotoxicity
of glutamate in the hippocampus. Transferrin may be involved in the physiological transport of
iron and manganese into the brain and their utilization there. It is reported that the brain
transferrin concentration is decreased in neurodegenerative diseases such as Alzheimer's disease
Draft Bibliography: Manganese Lit. Search D-156
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and Parkinson's disease and that brain iron metabolism is also altered. The homeostasis of trace
metals in the brain is important for brain function and also for the prevention of brain diseases.
89. TERA. 2008. ITER Database. Concurrent Technologies Corporation and Toxicology
Excellence for Risk Assessment (TERA).
Chemical Name: Manganese CAS Registry Number: 7439-96-5
90. Wasserman GA, Liu XH, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A,
Slavkovich V, Lolacono NJ and others. (2006) Water manganese exposure and children's
intellectual function in Araihazar, Bangladesh. Environmental Health Perspectives 114(1): 124-
129.
Exposure to manganese via inhalation has long been known to elicit neurotoxicity in adults, but
little is known about possible consequences of exposure via drinking water. In this study, we
report results of a cross-sectional investigation of intellectual function in 142 10-year-old
children in Araihaza, Bangladesh, who had been consuming tube-well water with an average
concentration of 793 mu g Mn/L and 3 mu g arsenic/L. Children and mothers came to our field
clinic, where children received a medical examination in which weight, height, and head
circumference were measured. Children's intellectual function was assessed on tests drawn from
the Wechsler Intelligence Scale for Children, version III, by summing weighted items across
domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine
specimens for measuring urinary As and creatinine and were asked to provide blood samples for
measuring blood lead, As, Mn, and hemoglobin concentrations. After adjustment for
sociodemographic covariates, water Mn was associated with reduced Full-Scale, Performance,
and Verbal raw scores, in a dose-response fashion; the low level of As in water had no effect. In
the United States, roughly 6% of domestic household wells have Mn concentrations that exceed
300 mu g Mn/L, the current U.S. Environmental Protection Agency, lifetime health advisory
level. We conclude that in both Bangladesh and the United States, some children are at risk for
Mn-induced neurotoxicity.
91. Yokel RA, Lasley SM, Dorman DC. (2006) The speciation of metals in mammals influences
their toxicokinetics and toxicodynamics and therefore human health risk assessment. Journal of
Toxicology and Environmental Health-Part B-Critical Reviews 9(l):63-85.
Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should
be considered to improve human health risk assessment. Factors that influence metal speciation
(and examples) include: (1) carrier-mediated processes for specific metal species (arsenic,
chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury),
(3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum,
arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic
species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum,
arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal
toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is
reviewed to illustrate how the physicochemical characteristics of metals and their handling in the
body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury,
arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences
mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal
speciation, uptake, and toxicity are evaluated. A classification system is presented to show that
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the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics.
Essential metals, such as iron, are considered. These metals produce low oral toxicity under most
exposure conditions but become toxic when biological processes that utilize or transport them
are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should
consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because
speciation can influence a metal's fate and toxicity, different exposure standards should be
established for different metal species. Many examples are provided which consider metal
essentiality and toxicity and that illustrate how consideration of metal speciation can improve the
risk assessment process. More examples are available at a website established as a repository for
summaries of the literature on how the speciation of metals affects their toxicokinetics.
92. Yoritaka A, Hattori N, Mori H, Kato K, Mizuno Y. (1997) An immunohistochemical study
on manganese superoxide dismutase in Parkinson's disease. Journal of the Neurological Sciences
148(2): 181-186.
We report an immunohistochemical study on manganese superoxide dismutase (Mn SOD) in
Parkinson's disease (PD) patients and age-matched control subjects. Overall appearance of
immunostaining intensity of nigral neurons did not differ significantly between the PD patients
and the control subjects. However, when the immunostaining intensity of each neuron was
semi quantitatively analyzed, both very intensely stained (more than normal) neurons as well as
neurons stained only weakly were more frequently detected in the lateral part than in the medial
and the central parts of the substantia nigra in PD patients. As a result, the proportion of
normally stained neurons was significantly smaller in the lateral part of the substantia nigra in
PD patients; however, the overall distribution of the neurons among the three rating grades for
immunostaining did not differ significantly. The immunostaining intensity of the neuropils in the
medial and the central part of the substantia nigra tended to be more intense in PD patients than
in the control subjects. Our results suggest up-regulation of Mn SOD mainly in the dendritic
processes of the less involved nigral neurons. (C) 1997 Elsevier Science B.V.
93. Zheng W, Aschner M, Ghersi-Egea JF. (2003) Brain barrier systems: a new frontier in metal
neurotoxicological research. Toxicology and Applied Pharmacology 192(1): 1-11.
The concept of brain barriers or a brain barrier system embraces the blood-brain interface,
referred to as the blood-brain barrier, and the blood-cerebrospinal fluid (CSF) interface, referred
to as the blood-CSF barrier. These brain barriers protect the CNS against chemical insults, by
different complementary mechanisms. Toxic metal molecules can either bypass these
mechanisms or be sequestered in and therefore potentially deleterious to brain barriers.
Supportive evidence suggests that damage to blood-brain interfaces can lead to chemical-
induced neurotoxicities. This review article examines the unique structure, specialization, and
function of the brain barrier system, with particular emphasis on its toxicological implications.
Typical examples of metal transport and toxicity at the barriers, such as lead (Pb), mercury (Hg),
iron (Fe), and manganese (Mn), are discussed in detail with a special focus on the relevance to
their toxic neurological consequences. Based on these discussions, the emerging research needs,
such as construction of the new concept of blood-brain regional barriers, understanding of
chemical effect on aged or immature barriers, and elucidation of the susceptibility of tight
junctions to toxicants, are identified and addressed in this newly evolving field of
neurotoxicology. They represent both clear challenges and fruitful research domains not only in
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neurotoxicology, but also in neurophysiology and pharmacology. (C) 2003 Elsevier Science
(USA). All rights reserved.
4.4 OTHER ENDPOINT-SPECIFIC STUDIES [e.g., in vivo neurological,
immunological studies]
Key References (0)
There were no key references identified for this section.
Supporting References (0)
There were no supporting references identified for this section.
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE
OF ACTION
Key References (25)
1. Ali SF, Duhart HM, Newport GD, Lipe GW, Slikker W. (1995) Manganese-Induced Reactive
Oxygen Species - Comparison between Mn+2 and Mn+3. Neurodegeneration 4(3):329-334.
Manganese (Mn) is an essential element, the deficiency or excess of which is known to cause
neurotoxicity in experimental animals and man. The mechanism of action of Mn neurotoxicity is
still unclear. The present study was designed to evaluate whether in vitro or in vivo exposure to
Mn produced reactive oxygen species (ROS). We also sought to determine if a single injection of
Mn produces changes in monoamines concentration in different regions of rat brain. Adult
Sprague-Dawley rats were dosed with 0, 50 or 100 mg/kg, ip with either MnC12 (Mn+2) or
MnOAc (Mn+3) and were sacrificed 1 h after the dose was administered. Brains were quickly
removed and dissected for neurochemical analysis. ROS were measured by a molecular probe,
2',7'-dichlorofluorescein diacetate (DCFH-DA), and monoamines and their metabolites were
measured by HPLC/EC. In vitro exposure to MnC12 (1-1000 mu M) produced dose-dependent
increases of ROS in striatum whereas MnOAc produced similar increases at much lower
concentrations (1-100 mu M) In vivo exposure to MnOAc (Mn+3) produced significant
increases of ROS in caudate nucleus and hippocampus, whereas MnC12 (Mn+2) produced
significant effects only in hippocampus. Concentrations of dopamine, serotonin and their
metabolites (DOPAC, HVA and 5-HIAA) were not altered with acute injections of either MnC12
or MnOAc. These data suggest that both divalent and trivalent manganese induce ROS, however,
Mn+3 is an order of magnitude more potent than Mn+2. (C) 1995 Academic Press Limited
2. Brown S, Taylor NL. (1999) Could mitochondrial dysfunction play a role in manganese
toxicity? Environmental Toxicology and Pharmacology 7(l):49-57.
Individuals suffering from manganese toxicity exhibit several symptoms, including
mitochondrial dysfunction, which are similar to those frequently observed in cases of Parkinson's
disease. We review the literature concerning manganese toxicity and mitochondrial function, and
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propose a simple conceptual model of the aetiology of manganese toxicity which involves an
interaction between inhibition of mitochondrial energy transduction, generation of free radicals
and mutations of the mitochondrial genome. This conceptual model prompts a number of
relatively simple experiments which would provide a test of the model. (C) 1999 Elsevier
Science B.V. All rights reserved.
3. Chetty CS, Reddy GR, Suresh A, Desaiah D, Ali SF, Slikker WJ. (2001) Effects of
manganese on inositol polyphosphate receptors and nitric oxide synthase activity in rat brain.
International Journal of Toxicology 20(5):275-280.
The neurotoxic effects of excessive exposure to manganese (Mn) include degeneration of
dopaminergic neurons, impairment of energy metabolism, and perturbations in phosphoinositide
(PI) hydrolysis leading to altered calcium (Ca2+) homeostasis. This study is designed to assess
the in vitro and in vivo effects of Mn on Ca2+/calmodulin-dependent neuronal nitric oxide
synthase (nNOS) activity and on the regulation of inositol 1,4,5-trisphosphate (InsP(3)) and
inositol 1,3,4,5-tetrakisphosphate (InsP(4)) receptors involved in intracellular and extracellular
mobilization of Ca2+. In vivo Mn exposure significantly increased H-3-InsP(3) and H-3-InsP(4)
binding in the cerebellum and the cerebral cortex in a dose-dependent manner. However, in vitro
Mn decreased H-3-InsP(3) binding and increased H-3-InsP(4) binding. In vitro and in vivo
exposure of Mn inhibited nNOS activity in the cerebellum and the cerebral cortex.
Immunohistochemical studies also showed a notable decrease in nNOS immunoreactivity in the
granule cell layer of the cerebellum, whereas no significant changes were observed in the
cerebral cortex. These data suggest that Mn neurotoxicity may be due to altered calcium
homeostasis by its modulation of inositol polyphosphate receptors. Further, the inhibition of
nNOS by Mn is of considerable importance because NO regulates a number of neurotransmitter
functions.
4. Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. (1998) The influence
of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat. Proceedings
of the Society for Experimental Biology and Medicine 219(l):41-47.
Young male rats subjected to a dietary manganese (Mn) deficiency respond to the deficiency by
reducing their growth rate. The growth hormone (GH)/insulin-like growth factor (IGF) axis is
critical for linear growth; this system is exquisitely sensitive to the nutritional state of the animal,
In this study, we examined circulating GH, IGF-1, and insulin levels in Mn-deficient (-Mn; fed a
0.5 mu g Mn/g diet) and sufficient (+Mn; fed a 45 mu g Mn/g diet) male Sprague-Dawley rats.
Additionally, we examined the distribution of circulating IGF binding proteins (IGFBPs) in
animals of both dietary groups as these proteins modulate IGF-1 action in vivo and in vitro, and
have been demonstrated to be altered in a number of nutritional and physiological states. Body
weight was significantly reduced in -Mn relative to +Mn rats. Consistent with other studies,
daily food intake was not altered. However, cumulative food intake (over 3 months) was
marginally lower in -Mn versus +Mn animals. -Mn animals displayed lower circulating
concentrations of IGF-1 (66% of control levels) and insulin (60% of control levels) despite
having significant elevations in circulating GH levels relative to +Mn animals (140% of control
levels), The IGFBP profile of -Mn animals reflected their elevated GH status, as we observed
increased binding of tracer (I-125-IGF-1) to the circulating IGFBP-3 complex (120% of control
binding) using native chromatography techniques, Interestingly, the lower circulating insulin
concentrations of -Mn animals did not result in dramatic elevations in lower-molecular-weight
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binding proteins. In summary, we demonstrate that in young male rats, Mn deficiency is
associated with alterations in IGF metabolism. These alterations may contribute to the growth
and bone abnormalities observed in -Mn animals.
5. Diaz-Veliz G, Mora S, Gomez P, Dossi MT, Monti el J, Arriagada C, Aboitiz F, Segura-
Aguilar J. (2004) Behavioral effects of manganese injected in the rat substantia nigra are
potentiated by dicumarol, a DT-diaphorase inhibitor. Pharmacology Biochemistry and Behavior
77(2):245-251.
The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo
neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The
neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate
(Mn3+) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor
dicumarol into the right rat substantia nigra. The behavioral effects were compared with those
induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA).
Intranigral injection of Mn3+ and Mn3+ plus dicumarol produced significant impairment in
motor behavior compared with control animals. However, the effect seen in the Mn3+ plus
dicumarol injected group was significantly more severe than that observed in the Mn3+ alone
injected group. In motor activity and rearing behavior, the simultaneous injection of Mn3+ plus
dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition
of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance
conditioning although without affecting the motor behavior. The behavioral effects were
correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving
unilateral intranigral Mn3+ and Mn3+ plus dicumarol injections exhibited a significant reduction
in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the
contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity
of Mn3+ in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could
play a neuroprotective role in the nigrostriatal DA systems. (C) 2003 Elsevier Inc. All rights
reserved.
6. Erikson KM, Dobson AW, Dorman DC, Aschner M. (2004) Manganese exposure and
induced oxidative stress in the rat brain. Science of the Total Environment 334-35:409-416.
Neurotoxicity linked to excessive brain manganese levels can occur as a result of high level Mn
exposures and/or metabolic aberrations (liver disease and decreased biliary excretion). Increased
brain manganese levels have been reported to induce oxidative stress, as well as alterations in
neurotransmitter metabolism with concurrent neurobehavioral and motor deficits. Two putative
mechanisms in which manganese can produce oxidative stress in the brain are: (1) via its
oxidation of dopamine, and (2) interference with normal mitochondrial respiration.
Measurements of antioxidant species (e.g., glutathione and metallothionein), and the abundance
of proteins (enzymes) exquisitely sensitive to oxidation (e.g., glutamine synthetase) have been
commonly used as biomarkers of oxidative stress, particularly in rat brain tissue. This paper
examines the link between manganese neurotoxicity in the rat brain and common pathways to
oxidative stress. (C) 2004 Published by Elsevier B.V.
7. Erikson KM, Jones SR, Aschner M. (2005) Brain manganese accumulation due to toxic
exposure is mediated by the dopamine transporter. Faseb Journal 19(5):A1033-A1034.
Draft Bibliography: Manganese Lit. Search D-161
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8. Gonzalez-Reyes RE, Gutierrez-Alvarez AM, Moreno CB. (2007) Manganese and epilepsy: A
systematic review of the literature. Brain Research Reviews 53(2):332-336.
Manganese is an essential trace element for the development and function of the central nervous
system. Alterations in manganese concentrations, whether excessive or deficient, can be
accompanied by convulsions. This article represents a systematic review of available quantitative
evidence that might clarify this issue. We searched The Cochrane Library, Medline and LILACS
databases from January 1966 through June 2006 and reviewed all resulting English and Spanish
language publications, as well as those possibly relevant in other languages based on their
abstracts. The final selection included for this review comprises all investigations in humans and
animals that compared manganese levels in any tissue of a group with spontaneous or induced
convulsions (with or without antiepileptic treatment) and a convulsion-free control group. The
literature search identified thirteen publications since then relevant to the issue, four of which
failed to meet our criteria for inclusion, of the remaining nine, six were in humans and three in
rodents. At present, there is no satisfactory explanation for the relationship between low
manganese levels and the presence of convulsions. There is a documented correlation between
low blood manganese levels and the presence of convulsions in both humans and animals. The
lack of evidence indicating whether this is a cause or an effect of the convulsions clearly justifies
more detailed follow-up investigations in humans, (c) 2006 Elsevier B.V. All rights reserved.
9. HaMai D, Bondy SC. (2004) Oxidative basis of manganese neurotoxicity. Redox-Active
Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp 129-141.
Exposure to excessive levels of manganese, an essential trace element, can evoke severe
psychiatric and extrapyramidal motor dysfunction closely resembling Parkinson's disease. The
clinical manifestations of manganese toxicity arise from focal injury to the basal ganglia. This
region, characterized by intense consumption of oxygen and significant dopamine content, can
incur mitochondrial dysfunction, depletion of levels of peroxidase and catalase, and
catecholamine biochemical imbalances following manganese exposure. The site specificity of
the pathology and the nature of the cellular damage caused by manganese have been attributed to
its capacity to produce cytotoxic levels of free radicals. However, support for such a pro-oxidant
role for manganese has been largely limited to inferences drawn from histopathological
observations. More recently, research efforts into the molecular details of manganese toxicity
have provided evidence of an etiological relationship between oxidative stress and manganese-
related neurodegeneration. This review focuses on studies that evaluate the redox chemistry of
manganese during the neurodegenerative process and its molecular consequences.
10. Hussain SM, Javorina AK, Schrand AM, Duhart HM, Ali SF, Schlager JJ. (2006) The
interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion.
Toxicological Sciences 92(2):456-463.
This investigation was designed to determine whether nano-sized manganese oxide (Mn-40nm)
particles would induce dopamine (DA) depletion in a cultured neuronal phenotype, PC-12 cells,
similar to free ionic manganese (Mn2+). Cells were exposed to Mn-40nm, Mn2+ (acetate), or
known cytotoxic silver nanoparticles (Ag-15nm) for 24 h. Phase-contrast microscopy studies
show that Mn-40nm or Mn2+ exposure did not greatly change morphology of PC-12 cells.
However, Ag-15nm and AgN03 produce cell shrinkage and irregular membrane borders
compared to control cells. Further microscopic studies at higher resolution demonstrated that
Mn-40nm nanoparticles and agglomerates were effectively internalized by PC-12 cells.
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Mitochondrial reduction activity, a sensitive measure of particle and metal cytotoxicity, showed
only moderate toxicity for Mn-40nm compared to similar Ag-15nm and Mn2+ doses. Mn-40nm
and Mn2+ dose dependency depleted DA and its metabolites, dihydroxyphenylacetic acid
(DOPAC) and homovanillic acid (HVA), while Ag-15nm only significantly reduced DA and
DOPAC at concentrations of 50 mu g/ml. Therefore, the DA depletion of Mn-40nm was most
similar to Mn2+, which is known to induce concentration-dependent DA depletion. There was a
significant increase (> 10-fold) in reactive oxygen species (ROS) with Mn-40nm exposure,
suggesting that increased ROS levels may participate in DA depletion. These results clearly
demonstrate that nanoscale manganese can deplete DA, DOPAC, and HVA in a dose-dependent
manner. Further study is required to evaluate the specific intracellular distribution of Mn-40nm
nanoparticles, metal dissolution rates in cells and cellular matrices, if DA depletion is induced in
vivo, and the propensity of Mn nanoparticles to cross the blood-brain barrier or be selectively
uptaken by nasal epithelium.
11. Malecki EA, Devenyi AG, Beard JL, Connor JR. (1999) Existing and emerging mechanisms
for transport of iron and manganese to the brain. Journal of Neuroscience Research 56(2): 113-
122.
The metals iron (Fe) and manganese (Mn) are essential for normal functioning of the brain. This
review focuses on recent developments in the literature pertaining to Fe and Mn transport, These
metals are treated together because they appear to share several transport mechanisms. In
addition, several neurological diseases such as Alzheimer's Disease, Parkinson's Disease, and
Huntington's Disease are all associated with Fe mismanagement in the brain, particularly in the
striatum and basal ganglia. Similarly, Mn accumulation in brain also appears to target the same
brain regions. Therefore, stringent regulation of the concentration of these metals in the brain is
essential, The homeostatic mechanisms for these metals must be understood in order to design
neurotoxicity prevention strategies. J, Neurosci, Res. 56:113-122, 1999, (C) 1999 Wiley-Liss,
Inc.
12. Martin CJ. (2006) Manganese neurotoxicity: Connecting the dots along the continuum of
dysfunction. Neurotoxicology 27(3):347-349.
Three different manifestations of manganese neurotoxicity have been described. The first, and
historically most prominent, is often termed manganism: a dramatic extrapyramidal syndrome
following acute, overwhelming exposure. While resembling Idiopathic Parkinson's Disease
(IPD), most authorities have regarded the two conditions as clinically and pathophysiologically
distinct. The second manifestation, reported by several investigators starting in the 1980s,
consisted of subclinical and subfunctional declines in the performance of specialized
neuropsychological tests. The implication of these cross-sectional findings was that, when
superimposed upon age-related attritional effects, increased rates of clinical disease could result.
In this decade, it has been proposed that manganese exposure may play a role in the development
of IPD itself. Investigating the relationship between these three manifestations should be a
priority for future research, (c) 2005 Elsevier Inc. All rights reserved.
13. Normandin L, Hazell AS. (2002) Manganese neurotoxicity: An update of pathophysiologic
mechanisms. Metabolic Brain Disease 17(4):375-387.
The central nervous system, and the basal ganglia in particular, is an important target in
manganese neurotoxicity, a disorder producing neurological symptoms similar to that of
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Parkinson's disease. Increasing evidence suggests that astrocytes are a site of early dysfunction
and damage; chronic exposure to manganese leads to selective dopaminergic dysfunction,
neuronal loss, and gliosis in basal ganglia structures together with characteristic astrocytic
changes known as Alzheimer type II astrocytosis. Astrocytes possess a high affinity, high
capacity, specific transport system for manganese facilitating its uptake, and sequestration in
mitochondria, leading to a disruption of oxidative phosphorylation. In addition, manganese
causes a number of other functional changes in astrocytes including an impairment of glutamate
transport, alterations of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase,
production of nitric oxide, and increased densities of binding sites for the "peripheral-type"
benzodiazepine receptor (a class of receptor predominantly localized to mitochondria of
astrocytes and involved in oxidative metabolism, mitochondrial proliferation, and neurosteroid
synthesis). Such effects can lead to compromised energy metabolism, resulting in altered cellular
morphology, production of reactive oxygen species, and increased extracellular glutamate
concentration. These consequences may result in impaired astrocytic-neuronal interactions and
play a major role in the pathophysiology of manganese neurotoxicity.
14. Pamphlett R, McQuilty R, Zarkos K. (2001) Blood levels of toxic and essential metals in
motor neuron disease. Neurotoxicology 22(3):401-410.
Toxic and essential metals have been implicated in the pathogenesis of sporadic motor neuron
disease (SMND), but attempts to measure blood levels of these metals have led to contradictory
results. We, therefore, measured blood levels of various metals using paired SMND/controls. In
20 subjects with SMND (15 males, five females, mean age 56.8 years) and 20 partner controls
(15 females, five males, mean age 55.0 years) cadmium, lead, mercury, copper, zinc and
selenium levels were measured in blood, plasma and red cells with inductively coupled plasma
mass spectrometry and manganese levels with atomic absorption spectrophotometry. Results
were analysed using non-parametric tests. Hypoosmotic red blood cell fragility was estimated in
six SMND/control pairs to see if hemolysis could account for increased metal levels. The plasma
cadmium level was significantly raised in SMND cases (P = 0.005), but with considerable
overlap between SMND and controls. No other metal levels were significantly different, though
plasma lead in SMND had a tendency to be higher than controls. No difference in red cell
fragility was found between groups. In conclusion, plasma levels of cadmium were raised in this
SMND group, but the biological significant of this is uncertain. The measurement of metals in
the blood of SMND cases seems unwarranted for routine diagnostic testing. (C) 2001 Published
by Elsevier Science Inc.
15. Ranasinghe JGS, Liu MC, Sakakibara Y, Suiko M. (2000) Manganese administration
induces the increased production of dopamine sulfate and depletion of dopamine in Sprague-
Dawley rats. Journal of Biochemistry 128(3):477-480.
Sprague-Dawley rats were used as an experimental model for investigating the effects of
manganese poisoning on the serum levels of unsulfated and sulfated forms of dopamine and its
biosynthetic precursors, L-Dopa and L-p-tyrosine. Groups of rats were treated daily with Mn2+
(20 mg or 40 mg; in the form of MnS04) or Na+ (20 mg; in the form of Na2S04). High
performance liquid chromatography (HPLC) analysis of the serum samples taken after a 50-day
experimental period revealed that the serum level of dopamine sulfate increased by more than 10
times compared with untreated control rats or rats treated with sodium sulfate. In contrast, there
was a dramatic decrease (by as much as 4.8 times) in the serum level of unsulfated dopamine in
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manganese-treated rats. The serum levels of L-Dopa sulfate and L-p-tyrosine sulfate were also
markedly elevated, although not as much as those of dopamine sulfate. Meanwhile, the serum
levels of unsulfated L-Dopa and L-p-tyrosine showed no dramatic changes. Atomic absorption
spectrophotometric analysis revealed in general an accumulation of manganese in the four organ
samples taken from manganese-treated rats. Compared with liver, heart, and kidney, the highest
degree of manganese accumulation in manganese-treated rats appeared to be in brain. These
results together suggested a role for manganese in stimulating the dopamine-sulfating
sulfotransferases in brain, thereby leading to the depletion of dopamine in vivo.
16. Rovetta F, Catalani S, Steimberg N, Bonlottl J, Gilberti ME, Mariggio MA, Mazzoleni G.
(2007) Organ-specific manganese toxicity: a comparative in vitro study on five cellular models
exposed to MnC12. Toxicology in Vitro 21(2):284-292.
Manganese (Mn) is both an essential nutrient and a toxicant, with specific effects on liver and
kidney (acute exposure) and on central nervous system (CNS) (chronic exposure). Mn
neurotoxicity includes neurobehavioral disorders and extra-pyramidal motor dysfunctions
(manganism), possibly due to focal injuries to the basal ganglia. Even if widely investigated, the
molecular mechanisms responsible for Mn toxicity remain to be clarified. Aim of this study was
to identify suitable in vitro models to investigate these molecular pathways. To this purpose we
compared the effect of manganese chloride on four cell lines, representative of the main target
organs of Mn toxicity in vivo. HepG2 and MDCK cell lines were selected for liver and kidney,
respectively; glial GL15 and neuronal SHSY5Y cells were used as models of CNS components.
To complete the "motor system" model, skeletal muscle C2C12 cells were also included. Our
results demonstrate that hepatic, renal, glial and neuronal cell types differently react to Mn,
mirroring the specific in vivo response of the tissue they represent. This confirms their value as
suitable in vitro models to study Mn-related toxic events. Interestingly, also muscle C2C12 cells
showed a noticeable sensitivity to Mn, preferential targets being differentiated myotubes. (c)
2006 Elsevier Ltd. All rights reserved.
17. Sloot WN, Korf J, Koster JF, DeWit LEA, Gramsbergen JBP. (1996) Manganese-induced
hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron
chelation in vivo. Experimental Neurology 138(2):236-245.
The present studies were aimed at investigating the possible roles of dopamine (DA) and iron in
production of hydroxyl radicals ((OH)-O-.) in rat striatum after Mn2+ intoxication. For this
purpose, DA depletions were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic
acid (DHBA) formation from the reaction of salicylate with (OH)-O-., of which 2,3-DHBA is a
nonenzymatic adduct. Following intrastriatal Mn2+ injection, marked 2,3-DHBA increases were
observed in a time- and dose-dependent fashion reaching maximum levels at 6-18 h and a
plateau beyond 0.4 mu mol (fourfold increase). The delayed increase of 2,3-DHBA levels
suggests that Mn2+ induces (OH)-O-. formation in the living brain by an indirect process. The
early DA depletion (2 h) and relatively late (OH)-O-. formation (6 h) indicate independent
processes by Mn2+. In addition, depletion of DA (about 90%) by reserpine pretreatment did not
significantly alter Mn2+-induced 2,3-DHBA formation or the extent of DA depletion, suggesting
that DA or DA autoxidation are not participating in Mn2+ induced (OH)-O-. formation in vivo.
Furthermore, Mn2+ injection did not significantly alter the low molecular weight iron pool in
striatum, and co-injections of the iron-chelator deferoxamine with Mn2+ into striatum did not
significantly attenuate Mn2+-induced 2,3-DHBA formation. These findings suggest no role of
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chelatable iron in generation of Mn2+-induced (OH)-O-., but do not exclude a role for
mitochondrial heme-iron or peroxynitrite (Fe-independent) in Mn2+-induced (OH)-O-.
formation. (C) 1996 Academic Press, Inc.
18. Takeda A. (2003) Manganese action in brain function. Brain Research Reviews 41(l):79-87.
Manganese, an essential trace metal, is supplied to the brain via both the blood-brain and the
blood-cerebrospinal fluid barriers. There are some mechanisms in this process and transferrin
may be involved in manganese transport into the brain. A large portion of manganese is bound to
manganese metalloproteins, especially glutamine synthetase in astrocytes. A portion of
manganese probably exists in the synaptic vesicles in glutamatergic neurons and the manganese
is dynamically coupled to the electrophysiological activity of the neurons. Manganese released
into the synaptic cleft may influence synaptic neurotransmission. Dietary manganese deficiency,
which may enhance susceptibility to epileptic functions, appears to affect manganese
homeostasis in the brain, probably followed by alteration of neural activity. On the other hand,
manganese also acts as a toxicant to the brain because this metal has prooxidant activity.
Abnormal concentrations of manganese in the brain, especially in the basal ganglia, are
associated with neurological disorders similar to Parkinson's disease. Understanding the
movement and action of manganese in synapses may be important to clarify the function and
toxicity of manganese in the brain. (C) 2002 Elsevier Science B.V. All rights reserved.
19. Takeda A. (2004) Analysis of brain function and prevention of brain diseases: the action of
trace metals. Journal of Health Science 50(5):429-442.
Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the
brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system,
i.e., the blood-brain and blood-cerebrospinal fluid barriers. The alteration of homeostasis of trace
metals in the brain is associated with brain diseases. Trace metals usually serve the function of
metalloproteins in neurons and glial cells, while a portion of trace metals exists in the
presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and
manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via
the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an
inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by
manganese might have both functional and toxic aspects in the synapse. Dietary zinc deficiency
affects zinc homeostasis in the brain, followed by an enhanced excitotoxicity of glutamate in the
hippocampus. Transferrin may be involved in the physiologic transport of iron and manganese
into the brain and their utilization there.
20. Takeda A, Sotogaku N, Oku N. (2002) Manganese influences the levels of neurotransmitters
in synapses in rat brain. Neuroscience 114(3):669-674.
previously taken up by the amygdala is released along with known neurotransmitters into the
extracellular space during stimulation with 100 mM KC1. The possibility of manganese release
from neuron terminals in a calcium- and impulse-dependent manner was examined by using the
in vivo microdialysis method in the present study. The increase of Mn-54 release into the
amygdalar extracellular space during stimulation with high K+ was inhibited by addition of 1
muM tetrodotoxin. This increase of Mn-54 release into the extracellular space by stimulation
with high K was also observed in the hippocampus, but not in the substantia nigra. The
increment of glutamate in the extracellular space during stimulation with high K+ was highly
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correlated with that of Mn-54, suggesting that manganese is concurrently released with
glutamate from neuron terminals. The level of Mn-54 in the extracellullar space in the
hippocampus was increased with that of glutamate, but not with those of GAB A and glycine,
during stimulation with 100 mM KC1 in the presence of 30 muM kainate. This increase was
more marked than during stimulation with 30 muM kainate alone. It is likely that manganese is
released from glutamatergic neuron terminals. When the rat hippocampus was perfused with
artificial cerebrospinal fluid containing 20 or 200 nM MnC12, the levels of glutamate, aspartate
and GABA in the perfusate were dose-dependently decreased during perfusion with manganese.
The present findings demonstrate that manganese released into the synaptic cleft may influence
synaptic neurotransmission. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights
reserved.
21. Tjalkens R. (2005) Neuro-Glial Interactions In Basal Ganglia Dysfunction: Insights From
Manganese Neurotoxicity. Toxicol Sci 84(1-S):337.
During periods of stress or injury, astroglia can undergo phenotypic transformation into an
activated state whereupon expression of inflammatory mediators is dramatically increased, to the
detriment of associated neurons. Neuronal injury in several disorders of the basal ganglia,
including manganism and Parkinsons disease, is associated with regional increases in expression
of inflammatory mediators and activation of astroglia, with subsequent overproduction of nitric
oxide (NO). The present studies explore the role of astroglial activation in basal ganglia
dysfunction by examining a prototypic neurotoxicant of the basal ganglia, manganese, and its
capacity to elicit expression of inflammatory genes in astroglia. Although playing various
essential physiological roles in the central nervous system, manganese in excess is the cause of
an extrapyramidal neurodegenerative disorder in humans that produces progressive dyskinesia,
emotional lability, and certain neurological deficits resembling Parkinsons disease. It is
postulated that astroglial-derived NO mediates neuronal injury induced by manganese exposure
and that manganese potentiates the effects of pro-inflammatory cytokines on induction of nitric
oxide synthase in astroglial cells. This hypothesis is tested utilizing: 1) subchronic in vivo
exposure to manganese in mice; 2) an astroglial-neuronal co-culture system; and 3) primary
astrocyte cultures to examine molecular signaling events relevant to inflammatory gene
expression.Manganese potentiates cytokine-induced expression of nitric oxide synthase in
astrocytes that increases apoptosis in co-cultured neurons in an NFkappaB- dependent fashion.
Dysregulation of intracellular calcium and mitochondrial dysfunction in astroglia mitochondria
appear to be pivotal to induction of nitric oxide production. Thus, therapeutic strategies that
target the molecular signaling pathways regulating expression of nitric oxide synthase in
astroglia may be effective in mitigating neuronal injury in degenerative conditions of the basal
ganglia.
22. Villalobos V, Estevez J, Novo E, Bonilla E. (2001) Effects of chronic manganese treatment
on mouse brain (H-3) spiroperidol binding parameters: In vivo and in vitro studies. Revista
Cientifica-Facultad De Ciencias Veterinarias 11(4):306-313.
The in vivo and in vitro effects of Mn on the binding of (H-3) spiroperidol to mouse brain was
assessed. (H-3) spiroperidol bind ing parameters (Kd and Bmax) in striatum, hypothalamus and
olfactory bulb did not change by Mn administration (5mg/kg/day) for 9 weeks. On the other
hand, preincubation of mouse brain homogenates with increasing concentrations of Mn (0.05-10
mM) and dopamine (10 mM) resulted in a significant rise in the (H-3) spiroperidol specific
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binding with a Mn concentration of 75 muM or higher. Binding assays carried out using
homogenates preincubated with 10 mM dopamine and 75 muM Mn showed an increase in Bmax
and Kd. These studies demonstrated that Mn administration does not after the binding pattern of
(H-3) spiroperidol. The increase in Bmax and Kd observed in the in vitro assays, when dopamine
and Mn are added to the incubation medium seem to be originated from changes in cell
membranes, leading to the exposure of new and different binding sites.
23. Yavorskaya V, Pelekhova O, Grebenyuk G, Chernyshova T. (2006) Manganese toxic
encephalopathy with parkinsonism. European Journal of Neurology 13:289-290.
24. Zheng W, Ren S, Graziano JH. (1998) Manganese inhibits mitochondrial aconitase: A
mechanism of manganese neurotoxicity. Brain Research 799(2):334-342.
The symptoms of Mn-induced neurotoxicity resemble those of Parkinson's diseases. Since iron
(Fe) appears to play a pivotal role in pathophysiology of Parkinson's disease, we set out to test
the hypothesis that alterations in Fe-requiring enzymes such as aconitase contribute to Mn-
induced neurotoxicity. Mitochondrial fractions prepared from rat brain were preincubated with
MnC12 in vitro, followed by the enzyme assay. Mn treatment significantly inhibited
mitochondrial aconitase activity (24% inhibition at 625 mu M to 81% at 2.5 mM, p < 0.05). The
inhibitory effect was reversible and Mn-concentration dependent, and was reversed by the
addition of Fe (0.05-1 mM) to the reaction mixture. In an in vivo chronic Mn exposure model,
rats received intraperitoneal injection of 6 mg/kg Mn as MnC12 once daily for 30 consecutive
days. Mn exposure led to a region-specific alteration in total aconitase (i.e., mitochondrial +
cytoplasmic): 48.5% reduction of the enzyme activity in frontal cortex (p < 0.01), 33.7% in
striatum (p < 0.0963), and 20.6% in substantia nigra (p < 0.139). Chronic Mn exposure increased
Mn concentrations in serum, CSF, and brain tissues. The elevation of Mn in all selected brain
regions (range between 3.1 and 3.9 fold) was similar in magnitude to that in CSF (3.1 fold)
rather than serum (6.1 fold). The present results suggest that Mn alters brain aconitase activity,
which may lead to the disruption of mitochondrial energy production and cellular Fe metabolism
in the brain. (C) 1998 Elsevier Science B.V. All rights reserved.
25. Zwingmann C, Leibfritz D, Hazell AS. (2004) Brain energy metabolism in a sub-acute rat
model of manganese neurotoxicity: An ex vivo nuclear magnetic resonance study using [1-C-
13]glucose. Neurotoxicology 25(4):573-587.
Ex vivo high-resolution NMR spectroscopy combined with in vivo injection of [l-C-13]glucose
was applied to gain insight into the mechanism(s) leading to energy failure in manganese
neurotoxicity. In rats treated for 4 days with 50 mg/kg MnC12 (intraperitoneally, i.p.), the
concentration of C-13-labeled lactate increased to 154% compared to control rats. Changes in the
absolute amounts of lactate were much less, resulting in increased fractional C-13-enrichments
in lactate (indicating relative changes of de novo synthesis from glucose via the glycolytic
pathway) to 143% of control values (P < 0.001). Analysis of samples obtained from blood
plasma and peripheral organs demonstrate a selective increase of lactate synthesis from [1-C-
13]glucose in the brain, which is released into the circulation. In parallel, manganese treatment
resulted, in stimulation of flux through pyruvate dehydrogenase (PDH), leading to accumulation
of [4-C-13]glutamate, [4-C-13]glutamine and [2-C-13JGABA to 168, 247 and 144% of control,
respectively. The relative flux of glucose through astrocytic pyruvate carboxylase (PC), on the
other hand, was impaired by manganese, as evident from a decreased ratio of [2-C-13]/[4-C-
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13]glutamate or [2-C-13]/[4-C-13]glutamine. Consistent with stimulated glucose oxidative
metabolism, the firactional C-13-enrichment in [2-C-13]acetyl-CoA entering the tricarboxylic
acid (TCA) cycle and contributing to glutamate and glutamine synthesis increased to 138 and
156% of control, respectively (P < 0.001). In parallel, the TCA cycling ratio increased to 134%
compared to control rats, prior to the label ending up in glutamate. In contrast, glutamine is
synthesized mainly during the first TCA cycle turn. The present data provide new evidence in
support of changes in brain energy metabolism playing an important role in manganese
neurotoxicity. In particular, increased glycolytic flux and lactate synthesis may contribute to the
deleterious effects of manganese in the brain. Furthermore, stimulated astrocytic glucose
oxidation and glutamine synthesis may be associated with astrocytic pathology and altered
astrocytic-neuronal metabolic trafficking in manganese neurotoxicity. (C) 2003 Elsevier Inc. All
rights reserved.
Supporting References (146)
1. Reaney SH, Smith DR. (2005) Manganese oxidation state mediates toxicity in PC12 cells.
Toxicology and Applied Pharmacology 205(3):271-281.
The role of the manganese (Mn) oxidation state on cellular Mn uptake and toxicity is not well
understood. Therefore, undifferentiated PC12 cells were exposed to 0-200 mu M Mn(II)-chloride
or Mn(III)-pyrophosphate for 24 h, after which cellular manganese levels were measured along
with measures of cell viability, function, and cytotoxicity (trypan blue exclusion, medium lactate
dehydrogenase (LDH), 8-isoprostanes, cellular ATP, dopamine, serotonin, H-ferritin, transferrin
receptor (TfR), Mn-superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase
(CuZnSOD) protein levels). Exposures to Mn(III) >10 mu M produced 2- to 5-fold higher
cellular manganese levels than equimolar exposures to Mn(II). Cell viability and ATP levels
both decreased at the highest Mn(II) and Mn(III) exposures (150-200 mu M), while Mn(III)
exposures produced increases in LDH activity at lower exposures (>= 50 mu M) than did Mn(II)
(200 mu M only). Mn(II) reduced cellular dopamine levels more than Mn(III), especially at the
highest exposures (50% reduced at 200 mu M Mn(II)). In contrast, Mn(III) produced a > 70%
reduction in cellular serotonin at all exposures compared to Mn(II). Different cellular responses
to Mn(II) exposures compared to Mn(III) were also observed for H-ferritin, TfR, and MnSOD
protein levels. Notably, these differential effects of Mn(II) versus Mn(III) exposures on cellular
toxicity could not simply be accounted for by the different cellular levels of manganese. These
results suggest that the oxidation state of manganese exposures plays an important role in
mediating manganese cytotoxicity, (c) 2004 Elsevier Inc. All rights reserved.
2. Alcaraz-Zubeldia M, Montes S, Rios C. (2001) Participation of manganese-superoxide
dismutase in the neuroprotection exerted by copper sulfate against 1-methyl 4-phenylpyridinium
neurotoxicity. Brain Research Bulletin 55(2):277-279.
Neurodegenerative effects of l-methyl-4-phenylpyridinium (MPP+), the main metabolite of the
neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) include enhancement of lipid
peroxidation in the striatum of mice, associated to overproduction of free radicals. Copper acts as
a prosthetic group of several copper-dependent antioxidant enzymes, and we previously showed
the neuroprotective effect of CuS04 pretreatment against the MPP+-induced neurotoxicity. In
those studies, acute administration of CuS04 (2.5 mg/kg) blocked MPP+-induced striatal lipid
peroxidation, suggesting the activation of Cu-dependent proteins that defend neurons from
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damage elicited by free radicals. In the present study, we evaluated the activity of superoxide
dismutase in mice pretreated with CuS04 16 h or 24 h prior to MPP+ administration. Copper
administration produced a specific and significant increase in manganese superoxide dismutase
activity in both the CuS04/saline (fivefold increase) and the CuS04/MPP+ groups of animals
(sevenfold increase). The Na2S04/MPP+ group showed a twofold increase in manganese
superoxide dismutase activity versus control levels. The results suggest that the load of copper
activating manganese-dependent superoxide dismutase could be responsible for neuroprotection
against the MPP+ insult. (C) 2001 Elsevier Science Inc.
3. Alinovi R, Vettori MV, Mutti A, Cavazzini S, Bacchini A, Bergamaschi E. (1996) Dopamine
(DA) metabolism in PC12 cells exposed to manganese (Mn) at different oxidation states.
Neurotoxicology (Little Rock) 17(3-4):743-750.
BIOSIS COPYRIGHT: BIOL ABS. The present study was aimed at assessing the role of Mn
valency state in Mn-induced changes in DA metabolism by PC12 cells. Mn(II)C12,
Mn(III)Acetate, and Mn(V)02 were used for these experiments. PC12 cells were incubated for
3, 24 and 72 hours to Mn nominal concentrations ranging from 10-8 to 10-4 M in 24-well plates
containing 21. Supernatants and cellular materials were then separated and immediately
processed for the analysis of dopamine (DA), and its metabolite 3,4-di-hydroxyphenylacetic acid
(DOPAC). Lactate dehydrogenase (LDH) activity and MTT cleavage were measured as indices
of cell death. In parallel experiments, Mn-containing medium (10-5 M) was removed and cells
incubated for further periods with Mn-free medium to evaluate the reversibility of observed
changes. At the end of the experimental periods, none of Mn-exposed cultures showed
appreciable reduction in cell viability as compared to their respective controls. After exposure to
Mn(II) and Mn(III), irre
4. Anantharam V, Kitazawa M, Latchoumycandane C, Kanthasamy A, Kanthasamy AG. (2004)
Blockade of PKC delta proteolytic activation by loss of function mutants rescues mesencephalic
dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl (MMT)-induced
apoptotic cell death. Protective Strategies for Neurodegenerative Diseases. NEW YORK: NEW
YORK ACAD SCIENCES, pp 271-289.
The use of methytcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive has
raised health concerns and increased interest in understanding the neurotoxic effects of
manganese. Chronic exposure to inorganic manganese causes Manganism, a neurological
disorder somewhat similar to Parkinson's disease. However, the cellular mechanism by which
MMT, an organic manganese compound, induces neurotoxicity in dopaminergic neuronal cells
remains unclear. Therefore, we systematically investigated apoptotic cell-signaling events
following exposure to 3-200 mu M MMT in mesencephalic dopaminergic neuronal (N27) cells.
MMT treatment resulted in a time- and dose-dependent increase in reactive oxygen species
generation and cell death in N27 cells. The cell death was preceded by sequential activation of
mitochondrial-dependent proapoptotic events including cytochrome c release, caspase-3
activation, and DNA fragmentation, indicating that the mitochondrial-dependent apoptotic
cascade primarily triggers MMT-induced apoptotic cell death. Importantly, MMT induced
proteolytic cleavage of protein kinase C delta (PKC delta), resulting in persistently increased
kinase activity. The proteolytic activation of PKC delta was suppressed by treatment with 100
mu M Z-VAD-FMK and 100 mu M Z-DEVD-FMK, suggesting that caspase-3 mediates the
proteolytic activation of PKC delta. Pretreatment with 100 mu M Z-DEVD-FMK and 5 mu M
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rottlerin (a PKC delta inhibitor) also significantly attenuated MMT-induced DNA fragmentation.
Furthermore, overexpression of either the kinase inactive dominant negative PKC delta(K376R)
mutant or the caspase cleavage resistant PKC delta(D327A) mutant rescued N27 cells from
MMT-induced DNA fragmentation. Collectively, these results demonstrate that the
mitochondrial-dependent apoptotic cascade mediates apoptosis via proteolytic activation of PKC
delta in MMT-induced dopaminergic degeneration and suggest that PKC delta may serve as an
attractive therapeutic target in Parkinson-related neurological diseases.
5. Anantharam V, Kitazawa M, Wagner J, Kaul S, Kanthasamy AG. (2002) Caspase-3 -
dependent proteolytic cleavage of protein kinase C delta is essential for oxidative stress-
mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese
tricarbonyl. Journal of Neuroscience 22(5): 1738-1751.
In the present study, we characterized oxidative stress-dependent cellular events in dopaminergic
cells after exposure to an organic form of manganese compound, methylcyclopentadienyl
manganese tricarbonyl (MMT). In pheochromocytoma cells, MMT exposure resulted in rapid
increase in generation of reactive oxygen species (ROS) within 5-15 min, followed by release of
mitochondrial cytochrome C into cytoplasm and subsequent activation of cysteine proteases,
caspase-9 (twofold to threefold) and caspase-3 (15- to 25-fold), but not caspase-8, in a time- and
dose-dependent manner. Interestingly, we also found that MMT exposure induces a time- and
dose-dependent proteolytic cleavage of native protein kinase Cdelta (PKCdelta, 72-74 kDa) to
yield 41 kDa catalytically active and 38 kDa regulatory fragments. Pretreatment with caspase
inhibitors (Z-DEVD-FMK or Z-VAD-FMK) blocked MMT-induced proteolytic cleavage of
PKCdelta, indicating that cleavage is mediated by caspase-3. Furthermore, inhibition of
PKCdelta activity with a specific inhibitor, rottlerin, significantly inhibited caspase-3 activation
in a dose-dependent manner along with a reduction in PKCdelta cleavage products, indicating a
possible positive feedback activation of caspase-3 activity by PKCdelta. The presence of such a
positive feedback loop was also confirmed by delivering the catalytically active PKCdelta
fragment. Attenuation of ROS generation, caspase-3 activation, and PKCdelta activity before
MMT treatment almost completely suppressed DNA fragmentation. Additionally,
overexpression of catalytically inactive PKCdelta(K376R) (dominant-negative mutant)
prevented MMT-induced apoptosis in immortalized mesencephalic dopaminergic cells. For the
first time, these data demonstrate that caspase-3-dependent proteolytic activation of PKCdelta
plays a key role in oxidative stress-mediated apoptosis in dopaminergic cells after exposure to an
environmental neurotoxic agent.
6. Anastassopoulou J, Theophanides T. (2002) Magnesium-DNA interactions and the possible
relation of magnesium to carcinogenesis. Irradiation and free radicals. Critical Reviews in
Oncology Hematology 42(1):79-91.
Magnesium deficiency causes renal complications. The appearance of several diseases is related
to its depletion in the human body. In radiotherapy, as well as in chemotherapy, especially in
treatment of cancers with cis-platinum, hypomagnesaemia is observed. The site effects of
chemotherapy that are due to hypomagnesaemia are decreased using Mg supplements. The role
of magnesium in DNA stabilization is concentration dependent. At high concentrations there is
an accumulation of Mg binding, which induces conformational changes leading to Z-DNA,
while at low concentration there is deficiency and destabilization of DNA. The biological and
clinical consequences of abnormal concentrations are DNA cleavage leading to diseases and
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cancer. Carcinogenesis and cell growth are also magnesium-ion concentration dependent.
Several reports point out that the interaction of magnesium in the presence of other metal ions
showed that there is synergism with Li and Mn, but there is magnesium antagonism in DNA
binding with the essential metal ions in the order: Zn > Mg > Ca. In the case of toxic metals such
as Cd, Ga and Ni there is also antagonism for DNA binding. It was found from radiolysis of
deaerated aqueous solutions of the nucleoside 5'-guanosine monophosphate (5'-GMP) in the
presence as well as in the absence of magnesium ions that, although the addition of hydroxyl
radicals ((OH)-O-.) has been increased by 2-fold, the opening of the imidazole ring of the
guanine base was prevented. This effect was due to the binding of Mg2+ ions to N7 site of the
molecule by stabilizing the five-member ring imitating cis-platinum. It was also observed using
Fourier Transform Infrared spectroscopy, Raman spectroscopy and Fast Atom Bombardment
mass spectrometry that (OH)-O-. radicals subtract H atoms from the CI', C4' and C5' sites of the
nucleotide. Irradiation of 5'-GMP in the presence of oxygen (2.5 x 10(-4) M) shows that
magnesium is released from the complex. There is spectroscopic evidence that superoxide anions
(0-2(-.)) react with magnesium ions leading to magnesium release from the complex. From
radiolysis data it was suggested that magnesium ions can act as radiosensitizers in the absence of
oxygen, while in the presence of oxygen they act as protectors and stabilizers of DNA. (C) 2002
Elsevier Science Ireland Ltd. All rights reserved.
7. Anderson JG, Cooney PT, Erikson KM. (2007) Brain manganese accumulation is inversely
related to gamma-amino butyric acid uptake in male and female rats. Toxicological Sciences
95(1):188-195.
Iron (Fe) is an essential trace metal involved in numerous cellular processes. Iron deficiency (ID)
is reported as the most prevalent nutritional problem worldwide. Increasing evidence suggests
that ID is associated with altered neurotransmitter metabolism and a risk factor for manganese
(Mn) neurotoxicity. Though recent studies have established differences in which the female
brain responds to ID-related neurochemical alterations versus the male brain, little is known
about the interactions of dietary ID, Mn exposure, and sex on gamma-amino butyric acid
(GABA). Male and female Sprague-Dawley rats were randomly divided into four dietary
treatment groups: control (CN), control/ Mn supplemented, ID, and ID/Mn supplemented. After
6 weeks of treatment, both ID diets caused a highly significant decrease in Fe concentrations
across all brain regions compared to CN in both sexes. Both ID and Mn supplementation led to
significant accumulation of Mn across all brain regions in both sexes. There was no main effect
of sex on Fe or Mn accumulation. Striatal synaptosomes were utilized to examine the effect of
dietary intervention on H-3-GABA uptake. At 4 weeks, there was a significant correlation
between Fe concentration and H-3-GABA uptake in male rats (p < 0.05). At 6 weeks, there was
a significant inverse correlation between Mn concentration and 3H-GAB A uptake in male and
female rats and a postitive correlation between Fe concentration and H-3-GABA uptake in
female rats (p < 0.05). In conclusion, ID-associated Mn accumulation is similar in both sexes,
with Mn levels affecting GABA uptake in both sexes in a comparable fashion.
8. Anderson JG, Fordahl SC, Cooney PT, Erikson KM. (2007) Iron deficiency and manganese
exposure are associated with decreases in neurotransmitter uptake. Faseb Journal 21(6):A1065-
A1065.
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9. Antonini JM, Santaimaria AB, Jenkins NT, Albini E, Lucchini R. (2006) Fate of manganese
associated with the inhalation of welding fumes: Potential neurological effects. Neurotoxicology
27(3):304-310.
Welding fumes are a complex mixture composed of different metals. Most welding fumes
contain a small percentage of manganese. There is an emerging concern among occupational
health officials about the potential neurological effects associated with the exposure to
manganese in welding fumes. Little is known about the fate of manganese that is complexed
with other metals in the welding particles after inhalation. Depending on the welding process and
the composition of the welding electrode, manganese may be present in different oxidation states
and have different solubility properties. These differences may affect the biological responses to
manganese after the inhalation of welding fumes. Manganese intoxication and the associated
neurological symptoms have been reported in individual cases of welders who have been
exposed to high concentrations of manganese-containing welding fumes due to work in poorly
ventilated areas. However, the question remains as to whether welders who are exposed to low
levels of welding fumes over long periods of time are at risk for the development of neurological
diseases. For the most part, questions remain unanswered. There is still paucity of adequate
scientific reports on welders who suffered significant neurotoxicity, hence there is a need for
well-designed epidemiology studies that combine complete information on the occupational
exposure of welders with both behavioral and biochemical endpoints of neurotoxicity. Published
by Elsevier Inc.
10. Baek SY, Kim YH, Oh SO, Lee CR, Yoo CI, Lee JH, Lee H, Sim CS, Park J, Kim JW and
others. (2007) Manganese does not alter the severe neurotoxicity of MPTP. Human &
Experimental Toxicology 26(3):203-211.
We utilized a mice model of Parkinsonism: (1) to evaluate l-methyl-4-phenyl-l,2,3,6-
tetrahydropyridine (MPTP)-induced neurotoxicity; and (2) to evaluate whether manganese (Mn)
exposure can affect MPTP-induced neurotoxicity. A 2 X 3 experimental design (MPTP x +/-
Mn) was as follows: SS, MPTP(-) x Mn(-); SLMn, MPTP(-) x low Mn(+); SHMn, MPTP(-) x
high Mn(+); MpS, MPTP(+) x Mn(-); MpLMn, MPTP(+) x low Mn(+); MpHMn, MPTP(+) x
high Mn(+). We administered MPTP (30 mg/kg per day) to male C57BL/6 mice
intraperitoneally, once a day for 5 days. Subsequently, mice were treated with either 2 or 8 mg/
kg of MnC12 center dot 4H(2)0 intraperitoneally, once a day for 3 weeks. Blood and striatal Mn
levels were elevated in the Mn-exposed groups. The number of tyrosine hydroxylase (TH)-
immunoreactive (ir) neurons in the substantia nigra pars compacta were decreased significantly
in the MPTP-exposed groups. The densities of TH-ir axon terminals in caudate-putamen (CPU)
were significantly decreased in the MPTP-treated groups. However, Mn treatment did not affect
MPTP neurotoxicity. The densities of glial fibrillary acidic protein (GFAP)-ir astrocytes in the
CPU or globus pallidus were significantly increased in the MPTP-treated groups. Concentrations
of dopamine in the striatum were decreased significantly in the MPTP-exposed groups only, but
Mn had no effect.
11. Baek SY, Lee MJ, Jung HS, Kim HJ, Lee CR, Yoo C, Lee JH, Lee H, Yoon CS, Kim YH
and others. (2003) Effect of manganese exposure on MPTP neurotoxicities. Neurotoxicology
24(4-5):657-665.
We used a l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated mice model to evaluate
whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. We randomly
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assigned adult male C57BL/6 mice (n = 5-7 per group) the following treatments: SO, Mn(-)
MPTP(-); MO, Mn(+) MPTP(-); SM, Mn(-) MPTP(+); MM, Mn(+) MPTP(+). Mn
(MnCl(2)4H(2)0) was administered intraperitoneally at a dose of 2 mg/kg daily for 3 weeks.
MPTP was then administered intraperitoneally at a dose of 30 mg/kg daily for 5 days in the SM
and MM groups. Seven days after the last MPTP injection, the animals were sacrificed. Blood
Mn levels were elevated in the Mn-exposed groups. Striatal Mn levels were not influenced by
Mn treatment alone, however they were decreased following MPTR Tyrosine hydroxylase (TH)-
immunoreactive (ir) neurons in the substantia nigra pars compacta (SNpc) were decreased
significantly in the MPTP-exposed groups. Densities of TH- and dopamine transporter (DAT)-ir
axon terminals in the caudate-putamen (CPU) were also decreased in the MPTP-treated groups.
Furthermore, glial fibrillary acidic protein (GFAP)-ir astrocytes increased in the CPU with
MPTP treatment. However no effects were observed with Mn exposure. Concentrations of
dopamine (DA), 3,4-dihydrophenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the
corpus striatum were also decreased significantly with MPTP treatment alone, but Mn had no
effect. Thus, decreased dopaminergic activities with MPTP led to decreased DA and its
metabolites. Significant hypertrophies of GFAP-ir astrocytes in the globus pallidus (GP) were
observed in Mn-exposed groups, especially in the MM group. MPTP targeted dopaminergic
systems whereas Mn neurotoxicities occurred in the GP In conclusion, our data suggest that Mn
does not potentiate the neurotoxicity of MPTP. (C) 2003 Elsevier Science Inc. All rights
reserved.
12. Bairati C, Goi G, Bollini D, Roggi C, Luca M, Apostoli P, Lombardo A. (1997) Effects of
lead and manganese on the release of lysosomal enzymes in vitro and in vivo. Clinica Chimica
Acta 261(1):91-101.
BIOSIS COPYRIGHT: BIOL ABS. In this study we evaluated the effects of two heavy metals,
lead and manganese, on the release of some glycohydrolases of lysosomal origin, N-acetyl-beta-
D-glucosaminidase and its major isoenzymes, beta-D-glucuronidase and alpha-D-galactosidase.
We have studied release of these enzymes in vitro from peripheral mitogen-activated
lymphocytes from healthy subjects after addition of Pb or Mn to the medium and their plasma
levels in individuals exposed at work to Pb (31 subjects) or to manganese (36 subjects), versus
matched controls. We also determined the plasma levels in a general population (417 subjects).
The enzymatic activities were assayed fluorimetrically with 4-methylumbelliferyl-glycosides as
substrates. Particular attention was given to some technical aspects: enzymatic activity was
preserved by addition of ethylene glycol and stable liquid material was employed for calibration
purposes. N-acetyl-beta-D-glucosaminidase isoenzymes were separated by a routine chrom
13. Blakey DH, Bayley JM. (1995) Induction of chromosomal aberrations by the fuel addictive
methylcyclopentadienyl-manganese tricarbonyl mmt in Chinese hamster ovary cells. 26th Annual
Meeting of the Environmental Mutagen Society, St. Louis, Missouri, USA, March 12-16, 1995.
Environmental and Molecular Mutagenesis 25(SUPPL. 25):6.
Biosis copyright: biol abs. rrm meeting abstract carcinogen
14. Bredow S, Falgout MM, Divine KK. (2005) A Potential Mechanism For Pulmonary
Manganese-Toxicity: Manganese Induces Pulmonary VEGF Expression In Vitro. Toxicol Sci
84(1-S):234.
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The respiratory tract constitutes a major route of entry and absorption for airborne Manganese
(Mn) dust and fume particles. Although chronic Mn-exposure causes toxic responses in lung,
little is known about the underlying mechanisms that mediate these effects. In non-pulmonary
cell lines Mn induces cellular expression of Vascular Endothelial Growth Factor (VEGF) in
vitro. VEGF is perhaps the most important positive regulator of angiogenesis, the sprouting and
growth of new blood vessels from the existing vasculature. Angiogenic activity, which is usually
low under normal physiological conditions, contributes to the pathogenesis of many diseases,
and elevated VEGF levels frequently correlate with poor prognosis and disease outcome. Here
we demonstrate that Mn increases VEGF expression in vitro in several human pulmonary
epithelial cell lines (A549, Calu-3, NCI-H292). Cells were transiently transfected with a reporter
plasmid containing the gene for firefly luciferase under the control of the VEGF wild type-
promoter. Twenty-eight hours later, MnC12 was directly added to the medium in concentrations
ranging from 50 to 1000 |iM. The cells were incubated for another 20 hours and then lyzed.
Analysis of the cell lysates for firefly activity revealed cell- and dose-dependent increases in
promoter activity between 1.5 and 3.5-fold. Interestingly in comparison to non-treated controls,
exposure to 0.25 mM MnC12 for 20 hours increases promoter activity 2-fold for up to 24 hours
after Mn is removed. Further, growing the cells in the presence of 0.25 mM MnC12 for 2 weeks
did not affect their viability. These data suggest that Mn might promote changes in pulmonary
angiogenic growth factor expression, which, over time, could affect lung vasculature
morphology, leading to enhanced susceptibility to disease. Further studies may provide an
insight into the pathogenesis of, and therapeutic targets for, lung diseases such as asthma and
other chronic inflammatory airway diseases.
15. Brurok H, Schjott J, Berg K, Karlsson JOG, Jynge P. (1997) Manganese and the heart:
Acute cardiodepression and myocardial accumulation of manganese. Acta Physiologica
Scandinavica 159(l):33-40.
The aim of study was to assess acute effects oi the divalent manganese ion (Mn2+) in an intact
bur isolated heart preparation. Rat hearts were perfused in the Langendorff mode at constant
flow rate. Left ventricular (LV) developed pressure (LVDP), LV pressure first derivatives
(LVdp/dt max and min), heart rate (HR) and aortic pressure (AoP) were recorded. Ventricular
contents of high energy phosphate compounds (HEP) and Mn metal were measured at the end of
experiment. Infusion of MnC12 for 5 min with perfusate concentrations 1-3000 mu M induced an
immediate depression of contractile function at and above 33 mu M and negative chronotropy at
and above 300 mu M. These EC(50) values were found (mu M): LVDP 250: LVdp/dt max 160.
LVdp/dp min 120, HR 1000; and increase in AoP 80. Recovery of function during a 14 min
washout period was rapid and extensive, except for Mn2+ 300 mu M. Somewhat unexpected,
Mn2+ 30-1000 mu M raised coronary vascular resistance up to about twice the control level,
whereas the vasoconstrictory response was overcome at 3000 mu M. Mn2+ 3000 mu M reduced
tissue HEP. Ventricular Mn content rose stepwise for perfusate Mn2+ above 1 mu M UP to
about 55 times the control level for perfusate Mn2+ 3000 mu M, it is concluded that: acute
effects of Mn2+ like depression of contractility and rate is rapidly reversible: and rat hearts
accumulate and buffer large amounts of Mn2+ without affecting cardiac function or energy
metabolism in the acute stage.
16. Btaiche IF, Khalidi N. (2004) Metabolic complications of parenteral nutrition in adults, part
1. American Journal of Health-System Pharmacy 61(18): 1938-1949.
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Purpose. Common metabolic complications associated with parenteral nutrition (PN) are
reviewed, and the consequences of overfeeding and variables for patient monitoring are
discussed. Summary. Although PN is a lifesaving therapy in patients with gastrointestinal
failure, its use may be associated with metabolic, infectious, and technical complications. The
metabolic complications associated with PN in adult patients include hyperglycemia,
hypoglycemia, hyperlipidemia, hypercapnia, refeeding syndrome, acid-base disturbances, liver
complications, manganese toxicity, and metabolic bone disease. These complications may occur
in the acute care or chronic care patient. The frequency and severity of these complications
depend on patient- and PN-specific factors. Proper assessment of the patient's nutritional status;
tailoring the macronutrient, micronutrient, fluid, and electrolyte requirements on the basis of the
patient's underlying diseases, clinical status, and drug therapy; and monitoring the patient's
tolerance of and response to nutritional support are essential in avoiding these complications.
Early recognition of the signs and symptoms of complications and knowledge of the available
pharmacologic and nonpharmacologic therapies are essential to proper management. PN should
be used for the shortest period possible, and oral or enteral feeding should be initiated as soon as
is clinically feasible. The gastrointestinal route remains the most physiologically appropriate and
cost-effective way of providing nutritional support. Conclusion. PN can lead to serious
complications, many of which are associated with overfeeding. Close management is necessary
to recognize and manage these complications.
17. Btaiche IF, Khalidi N. (2004) Metabolic complications of parenteral nutrition in adults, part
2. American Journal of Health-System Pharmacy 61(19):2050-2057.
Purpose. Common metabolic complications associated with parenteral nutrition (PN) are
reviewed, and the consequences of overfeeding and variables for patient monitoring are
discussed. Summary. Although PN is a lifesaving therapy in patients with gastrointestinal
failure, its use may be associated with metabolic, infectious, and technical complications. The
metabolic complications associated with PN in adult patients include hyperglycemia,
hypoglycemia, hyperlipidemia, hypercapnia, refeeding syndrome, acid-base disturbances, liver
complications, manganese toxicity, and metabolic bone disease. These complications may occur
in the acute care or chronic care patient. The frequency and severity of these complications
depend on patient- and PN-specific factors. Proper assessment of the patient's nutritional status;
tailoring the macronutrient, micronutrient, fluid, and electrolyte requirements on the basis of the
patient's underlying diseases, clinical status, and drug therapy; and monitoring the patient's
tolerance of and response to nutritional support are essential in avoiding these complications.
Early recognition of the signs and symptoms of complications and knowledge of the available
pharmacologic and,nonpharmacologic therapies are essential to proper management. PN should
be used for the shortest period possible, and oral or enteral feeding should be initiated as soon as
is clinically feasible. The gastrointestinal route remains the most physiologically appropriate and
cost-effective way of providing nutritional support. Conclusion. PN can lead to serious
complications, many of which are associated with overfeeding. Close management is necessary
to recognize and manage these complications..
18. Butterworth RF, Spahr L, Fontaine S, Layrargues GP. (1995) Manganese toxicity,
dopaminergic dysfunction and hepatic encephalopathy. Metabolic Brain Disease 10(4):259-267.
Patients with chronic liver disease manifest a high incidence (>75%) of pallidal signal
hyperintensity on T-l-weighted Magnetic Resonance Imaging (MRI), the intensity of which
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correlates with blood manganese levels and the presence of extrapyramidal symptoms. A major
cause of pallidal hyperintensity on T-l-weighted MRI is manganese deposition; chronic
manganese intoxication in the absence of liver disease results in pallidal MR signal
hyperintensity, in extrapyramidal symptoms and in selective effects on the dopaminergic
neurotransmitter system in basal ganglia. Direct measurements in globus pallidus obtained at
autopsy from patients with chronic liver disease who died in hepatic coma reveal 2 to 7-fold
increases of pallidal manganese and a concomitant loss of dopamine D-2 binding sites. Liver
transplantation results in normalization of pallidal MR signals and of blood manganese levels.
These findings suggest that (1) pallidal MR signal hyperintensity in patients with chronic liver
disease is the result of manganese deposition and (2) alterations of dopaminergic function due to
the toxic effects of manganese may contribute to the extrapyramidal symptoms in these patients.
19. Cano G, SuarezRoca H, Bonilla E. (1997) Alterations of excitatory amino acid receptors in
the brain of manganese-treated mice. Molecular and Chemical Neuropathology 30(l-2):41-52.
An excessive activation of excitatory amino acid (EAA) receptors has been associated with
oxidative stress, which is considered the primary cause of manganese (Mn) poisoning
neurotoxicity. Therefore, the EAA receptor distribution was analyzed by autoradiographic
methods in several brain regions during Mn intoxication. We found that chronic treatment of
mice with MnC12, during 8 wk significantly alters the L-[H-3]glutamate (L-[H-3]Glu) binding to
total glutamate (Glu) receptors, as well as to N-methyl-D-aspartate (NMDA) and quisqualate
(QA) receptor subtypes. A generalized decrease of 16-24% of the L-[H-3]Glu binding to total
Glu receptors was found in all cortex, hippocampus, basal ganglia (except globus pallidus), and
cerebellum. Saturation studies showed a significant reduction of the maximal number of
receptors (B-max) in Mn-treated mice, whereas the affinity (K-d) was not altered. L-[H-3]Glu
binding to NMD A sites was mainly decreased (10-21%) in a few cortical regions, basal ganglia
(except globus pallidus), and hippocampus, whereas binding to QA receptor subtype was
diminished (16-30%) in cortex, hippocampus, and cerebellum. The decrease of Glu receptor
binding sites during Mn poisoning could reflect a receptor downregulation more than neuronal
loss, since these reductions are moderate and diffuse. Thus, this downregulation might mean a
protection mechanism against an excitotoxic process associated with Mn toxicity.
20. Cardozo-Pelaez F, Cox DP, Bolin C. (2005) Lack of the DNA repair enzyme OGG1
sensitizes dopamine neurons to manganese toxicity during development. Gene Expression 12(4-
6):315-323.
Onset of Parkinson's disease (PD) and Parkinson-like syndromes has been associated with
exposure to diverse environmental stimuli. Epidemiological studies have demonstrated that
exposure to elevated levels of manganese produces neuropathological changes localized to the
basal ganglia, including neuronal loss and depletions in striatal dopamine content. However,
understanding the mechanisms associated with manganese neurotoxicity has been hampered by
the lack of a good rodent model. Elevated levels of 8-hydroxy-2'-deoxyguanosine (oxo(8)dG)
have been found in brain areas affected in PD. Whether increased DNA damage is responsible
for neuronal degeneration or is a mere epiphenomena of neuronal loss remains to be elucidated.
Thus, by using mice deficient in the ability to remove oxo(8)dG we aimed to determine if
dysregulation of DNA repair coupled to manganese exposure would be detrimental to
dopaminergic neurons. Wild-type and OGG1 knockout mice were exposed to manganese from
conception to postnatal day 30; in both groups, exposure to manganese led to alterations in the
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neurochemistry of the nigrostriatal system. After exposure, dopamine levels were elevated in the
caudate of wild-type mice. Dopamine was reduced in the caudate of OGG1 knockout mice, a
loss that was paralleled by an increase in the dopamine index of turnover. In addition, the
reduction of dopamine in caudate putamen correlated with the accumulation of oxo(8)dG in
midbrain. We conclude that OGG1 function is essential in maintaining neuronal stability during
development and identify DNA damage as a common pathway in neuronal loss after a
toxicological challenge.
21. Centonze D, Gubellini P, Bernardi G, Calabresi P. (2001) Impaired excitatory transmission
in the striatum of rats chronically intoxicated with manganese. Experimental Neurology
172(2):469-476.
Chronic exposure to manganese (Mn) is known to produce a parkinsonian or dystonic state in
humans caused by a rather selective involvement of the basal ganglia. Experimental observations
suggest that secondary excitotoxic mechanisms play a crucial role in the development of Mn-
induced neurodegeneration in the striatum, although the site of interference of Mn with
glutamatergic transmission in this brain area is still unknown. To answer this question, in the
present in vitro study, we investigated the physiological characteristics of striatal excitatory
synaptic transmission in a rat model of Mn intoxication. We found that chronic Mn greatly
increased both frequency and amplitude of spontaneous excitatory postsynaptic potentials, in the
absence of appreciable changes of intrinsic membrane properties of striatal cells. The sensitivity
of striatal neurons to glutamate AMPA and NMDA receptor stimulation was unaffected by Mn
poisoning, as demonstrated by comparing the membrane responses produced in control and
treated rats to the application of selective agonists of these receptors and to the direct activation
of corticostriatal glutamatergic fibers. In addition, also paired-pulse facilitation was unaltered by
Mn treatment, indicating that this toxin does not affect the pre- and postsynaptic mechanisms
responsible for the appearance of this short-term form of synaptic plasticity at corticostriatal
synapses. It is concluded, therefore, that hyperactivity of corticostriatal neurons, rather than
increased postsynaptic sensitivity to glutamate, accounts for the abnormal excitation of striatal
neurons in the course of Mn intoxication. (C) 2001 Elsevier Science.
22. Chang JY, Liu LZ. (1999) Manganese potentiates nitric oxide production by microglia.
Molecular Brain Research 68(l-2):22-28.
Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are
similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive
microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9
microglial cells, the current study was designed to determine whether high levels of manganese
were associated with microglial activation. Results indicated that manganese significantly
increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity
of manganese was not shared by other transition metals tested, including iron, cobalt, nickel,
copper and zinc. Immunohistochemical staining and Western blot analysis indicated that
manganese increased the cellular production of inducible nitric oxide synthase. Northern blot
analysis indicated that manganese Likely increased iNOS gene transcription since this agent
increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition
metals tested, manganese did not appear to be cytotoxic to microglial cells. These results
suggested that manganese could induce sustained production of neurotoxic nitric oxide by
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activated microglial cells, which might cause detrimental consequences to surrounding neurons.
(C) 1999 Elsevier Science B.V. All rights reserved.
23. Chen CJ, Liao SL. (2002) Oxidative stress involves in astrocytic alterations induced by
manganese. Experimental Neurology 175(l):216-225.
It is hypothesized that manganese neurotoxicity could be secondary to a diminuition of cellular
protective and scavenger mechanisms. Since manganese is known to be sequestered in glial
cells, we investigated possible neurotoxic mechanisms involving astrocytes in vitro. Astrocytes
differentiated into process-bearing stellate cells in response to manganese treatment. Manganese
concentration dependently decreased cellular DNA synthesis, glial fibrillary acidic protein
expression, energy production, antioxidant capacity, and glutamate transporter activity. In
contrast, manganese increased glutamine synthetase protein expression and cytokine-stimulated
interleukin 6 mRNA expression. Under the concentration of 0.1 mM manganese chloride caused
no significant astrocyte death even up to 48 h after treatment. That is, these astrocytic alterations
proceeded before the onset of cell demise. As a possible mediator of manganese-derived
alterations, we determined intracellular redox state in astrocytes. Manganese time-dependently
changed intracellular redox potential into oxidized state. The influx of manganese and its
resultant oxidative stress was essential to most of the alterations, except for the action on
stellation. Astrocytes are central component of the brain's antioxidant defense. Therefore, the
observations suggest that dysfunction of astrocytes possibly involved in neurotoxic action of
Manganese. (C) 2002 Elsevier Science (USA).
24. Chen CJ, Ou YC, Lin SY, Liao SL, Chen SY, Chen JH. (2006) Manganese modulates pro-
inflammatory gene expression in activated glia. Neurochemistry International 49(1):62-71.
Redox-active metals are of paramount importance for biological functions. Their impact and
cellular activities participate in the physiological and pathophysiological processes of the central
nervous system (CNS), including inflammatory responses. Manganese is an essential trace
element and it is required for normal biological activities and ubiquitous enzymatic reactions.
However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent
evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes,
representative CNS immune cells. In this study, we assessed the molecular basis of the effects of
manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production
in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of
microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis
factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it
potentiated iNOS and TNF-alpha gene expression by lipopol gamma-saccharide/interferon-
gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese,
generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-
KB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IKB-alpha
was one of underlying mechanisms for the increased activation of NF-KB by manganese.
However, manganese decreased iNOS enzymatic activity possibly through the depletion of
cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate
that manganese could modulate glial inflammation through variable strategies, (c) 2006 Elsevier
Ltd. All rights reserved.
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25. Chen JY, Tsao GC, Zhao QQ, Zheng W. (2001) Differential cytotoxicity of Mn(II) and
Mn(III): Special reference mitochondrial [Fe-S] containing enzymes. Toxicology and Applied
Pharmacology 175(2): 160-168.
Manganese (Mn)-induced neurodegenerative toxicity has been associated with a distorted iron
(Fe) metabolism at both systemic and cellular levels. In the current study, we examined whether
the oxidation states of Mn produced differential effects on certain mitochondrial [Fe-S]
containing enzymes in vitro. When mitochondrial aconitase, which possesses a [4Fe-4S] cluster,
was incubated with either Mn(II) or Mn(III), both Mn species inhibited the activities of
aconitase. However, the IC10 (concentration to cause a 10% enzyme inhibition) for Mn(HI) was
ninefold lower than that for Mn(II). Following exposure of mitochondrial fractions with Mn(II)
or Mn(III), there was a significant inhibition by either Mn species in activities of Complex I
whose active site contains five to eight [Fe-S] clusters. The dose-time response curves reveal that
Mn(III) was more effective in blocking Complex I activity than Mn(II). Northern blotting was
used to examine the expression of mRNAs encoding transferrin receptor (TfR), which is
regulated by cytosolic aconitase. Treatment of cultured PC 12 cells with Mn(II) and Mn(III) at
100 muM for 3 days resulted in 21 and 58% increases, respectively, in the expression of TfR
mRNA. Further studies on cell growth dynamics after exposure to 25-50 muM Mn in culture
media demonstrated that the cell numbers were much reduced in Mn(III)- treated groups
compared to Mn(II)-treated groups, suggesting that Mn(III) is more effective than Mn(II) in cell
killing. In cells exposed to Mn(II) and Mn(IH), mitochondrial DNA (mtDNA) was significantly
decreased by 24 and 16%, respectively. In contrast, rotenone and MPP+ did not seem to alter
mtDNA levels. These in vitro results suggest that Mn(IH) species appears to be more cytotoxic
than Mn(II) species, possibly due to higher oxidative reactivity and closer radius resemblance to
Fe. (C) 2001 Academic Press.
26. Chen MT, Sheu JY, Lin TH. (2000) Protective effects of manganese against lipid
peroxidation. Journal of Toxicology and Environmental Health-Part A 61(7):569-577.
The aim of this study was to investigate the effects of chronic, daily, 30-d administration of
manganese chloride (MnC12) to male Sprague-Dawley rats on lipid peroxidation in various
tissues. Rats were intraperitoneally injected with MnC12 (20 mg/kg) once daily for 30
consecutive days. The Mn accumulated in liver, spleen, adrenal glands, heart, kidneys, lung, and
testes. This was associated with decreased lipid peroxidation in liver, spleen, and adrenal glands
and a decrease in the levels of Fe in these tissues. In a second group of animals, Mn (20
mg/kg/d) and glutathione (GSH, 15 mg/kg/d) were administered ip for 30 d. GSH counteracted
the Mn-induced protective fall in lipid peroxidation, but Fe levels remained lower in liver and
spleen. Mn decreases lipid peroxidation in certain tissues, which may involve lowering Fe
content, but interaction with Fe is not the sole mechanism.
27. Cheng J, Fu JL, Zhou ZC. (2003) The inhibitory effects of manganese on steroidogenesis in
rat primary Leydig cells by disrupting steroidogenic acute regulatory (StAR) protein expression.
Toxicology 187(2-3): 139-148.
Manganese is known to impede the male reproductive function, however, the mechanisms
through which the adverse effects are mediated are not clearly elucidated. In order to get insight
into those mechanisms, the effects of manganese on the biosynthesis of testosterone by primary
rat Leydig cells were examined. Primary Leydig cells were exposed to various concentrations of
manganese chloride for different periods of time. Dose and time-dependent reductions of human
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chorionic gonadotropin (hCG)-stimulated testosterone level were observed in the culture
medium. The expression of Steroidogenic Acute Regulatory (StAR) protein and the activities of
P450 side-chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD)
enzymes were also detected. The expression of StAR protein stimulated by hCG was suppressed
by manganese chloride at all concentrations (0.01, 0.1, 1.0 mM) and time points (2, 4, 24, 48 h)
tested. Progesterone productions treated with 22R-hydroxycholesterol or pregnenolone were
reduced after treated by manganese chloride for 24 or 48 h, respectively. The manganese
exposure effect on cell viability was significant at 1.0 and 1.5 mM at 24 h, while at 48 It it was
significant at every concentration tested. The decreasing effect of manganese on mitochondrial
membrane potential was significant at every concentration measured and every time point tested.
These data suggest that manganese exposure for 2 and 4 h inhibited rat primary Ley dig cell
steroidogenesis by decreasing StAR protein expression while 24 and 48 h exposure of
manganese chloride caused adverse effects on both StAR protein and P450scc and 3beta-HSD
enzyme activity to reduce steroidogenesis. Manganese may also disrupt StAR expression and/or
function secondary to mitochondrial dysfunction. (C) 2003 Elsevier Science Ireland Ltd. All
rights reserved.
28. Cheng J, Fu JL, Zhou ZC. (2005) The mechanism of manganese-induced inhibition of
steroidogenesis in rat primary Leydig cells. Toxicology 211(1-2): 1-11.
In previous studies in cultured primary rat Leydig cells, manganese was shown to inhibit hCG-
stimulated steroidogenesis of Leydig cells, and the data showed that while the inhibition of StAR
protein expression and/or function and mitochondrial dysfunction contribute to the acute
reduction of steroidogenesis (2 and 4h manganese treatment), the enzyme activities of P450scc
and 3 beta-HSD were only reduced after 24 h manganese treatment, we hypothesize that there
were different mechanisms for its effect at later stage (24 and 48 h manganese treatment). We
further our study by examining StAR mRNA level in cultured primary rat Leydig cells to
understand if inhibition of StAR protein expression occurs at the level of transcription of StAR
mRNA. The cellular ATP content was measured to determine the extent that manganese altered
mitochondrial function. Since mitochondria are regulators of Ca2+ homeostasis, and there are
indications that manganese affects intracellular Ca2+ levels, [Ca2+]i was also tested. The effects
of manganese on Leydig cell apoptosis and cell cycle distribution were studied to see whether
these effects contribute to the reduction of steroidogenesis by manganese at later stage of
manganese treatment. In the present study, we demonstrated that manganese could increase
[Ca2+] i and reduced ATP contents in primary Leydig cells after 4 h treatment, while the effects
on StAR mRNA level appeared later (24 h). Manganese could also induce arrest at the G(0)/G(1)
phase cell cycle after 24 It manganese treatment and subsequently increased in the sub-G(l)
phase DNA contents, indicating induction of apoptosis. Combined with our previous studies, the
results indicate that inhibition of StAR protein expression and/or function, mitochondrial
dysfunction and disturbance of calcium homeostasis contribute to the adverse effects of
manganese on the Leydig cells at the early/immediate stage after treatment (2 and 4 h). However,
at later stages (24 and 48 h) manganese could arrest the cell cycle and induce apoptosis of
primary Leydig cells, StAR mRNA and enzyme activities of P450scc and 3 beta-HSD were also
reduced, leading to reduced level of steroidogenesis in Cultured primary Leydig cells, (c) 2005
Elsevier Ireland Ltd. All rights reserved.
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29. Choi C, Anantharam V, Kanthasamy A, Kanthasamy A. (2006) Effect of prion proteins on
manganese-induced oxidative insult and mitochondrial dysfunction. Neurotoxicology 27(5):917-
917.
30. Chukhlovin AB, Tokalov SV, Yagunov AS, Zharskaya VD. (1996) Acute effects of copper,
chromium and manganese upon immature blood cells and macrophages. Trace Elements and
Electrolytes 13(1):37-41.
BIOSIS COPYRIGHT: BIOL ABS. Cell survival and phagocytic capacity of rat thymocytes,
bone marrow cells and bronchoalveolar macrophages have been tested after short-term
incubations with different amounts of Cu(II), Cr(III) and Mn(II) ions (as chloride salts), and with
aqueous farm soil extracts, containing excessive amounts of these metals. Copper ions (10-100
muM) exerted lethal effects upon all 3 cell populations tested. Cr caused apoptosis of
thymocytes and marrow cells. Mn ions induced DNA autolysis of thymocytes and decrease in
adherent macrophage numbers, though increasing relative amounts of phagocytes in the latter
population. Copper and chromium ions caused loss of myeloid marrow cells in suspensions
under study. Cytotoxic effects of metal-rich soil extracts included a variety of above mentioned
cell alterations, several of them coinciding with effects obtained with pure metal salts, i.e. the
loss of marrow myeloid cells expressed direct correlations with increased soil contents of copper
31. Chun HS, Lee H, Son JH. (2001) Manganese induces endoplasmic reticulum (ER) stress and
activates multiple caspases in nigral dopaminergic neuronal cells, SN4741. Neuroscience Letters
316(l):5-8.
Chronic exposure to manganese causes Parkinson's disease (PD)-like clinical symptoms
(Neurotoxicology 5 (1984) 13; Arch. Neurol. 46 (1989) 1104; Neurology 56 (2001) 4).
Occupational exposure to manganese is proposed as a risk factor in specific cases of idiopathic
PD (Neurology 56 (2001) 8). We have investigated the mechanism of manganese neurotoxicity
in nigral dopaminergic (DA) neurons using the DA cell line, SN4741 (J. Neurosci. 19 (1999)
10). Manganese treatment elicited endoplasmic reticulum (ER) stress responses, such as an
increased level of the ER chaperone BiP, and simultaneously activated the ER resident caspase-
12. Peak activation of other major initiator caspases-like activities, such as caspase-1, -8 and -9,
ensued, resulting in activation of caspase-3-like activity during manganese-induced DA cell
death. The neurotoxic cell death induced by manganese was significantly reduced in the Bcl-2-
overexpressing DA cell lines. Our findings suggest that manganese-induced neurotoxicity is
mediated in part by ER stress and considerably ameliorated by Bcl-2 overexpression in DA cells.
(C) 2001 Published by Elsevier Science Ireland Ltd.
32. Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. (1996) Manganese
deficiency effects circulating growth hormone (GH), IGF-I, and IGFBPS in the male rat. Faseb
Journal 10(3):4539-4539.
33. Cox D, Bolin C, Cardozo-Pelaez F. (2003) Assessment of dopaminergic neurons, DNA
damage, DNA repair, and antioxidants in a model for manganese (MN) neurotoxicity. Free
Radical Biology and Medicine 35:S156-S156.
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34. Crittenden PL, Filipov NM. (2004) Enhanced Proinflammatory Cytokine Production By
Activated Microglial And Macrophage Cell Lines Exposed To Manganese In Vitro. Toxicologist
78(1-S): 180.
Activated microglia and/or astrocytes have been proposed to play a role in the mechanism of
manganese (Mn) neurotoxicity such that neurons adjacent to activated microglia could be injured
by proinflammatory cytokines and reactive oxygen species elaborated from the microglia.
Recently, we demonstrated that Mn greatly potentiated the LPS (lipopolysaccharide)-induced
proinflammatory cytokine (IL- lbeta, IL-6, and TNF-alpha) production by the microglial cell
line, N9. Because (i) Mn exposure may also potentiate proinflammatory cytokine production in
the periphery, (ii) there are functional differences between brain microglia and peripheral
macrophages, and (iii) peripheral inflammation contributes to/modulates the inflammatory
response in the brain, our objective was to compare the influence of Mn on proinflammatory
cytokine production by N9 microglia and J774 macrophage cell lines. Cells were exposed in
vitro to increasing concentrations (up to 500 |iM) of Mn (as MnC12) in the presence or absence
of LPS (up to 1000 ng/ml). Following 24 h incubation, supernatants were collected and IL-lbeta,
IL-6, and TNF-alpha concentrations were determined by ELISA. Similar to the effects already
observed in N9 microglia, LPS-induced proinflammatory cytokine production was potentiated
dose-dependently by Mn in the J774 macrophage cell line. This finding suggests that Mn
augments proinflammatory cytokine production through a common mechanism which is now the
subject of investigation. Considering that Mn exposure is not confined to the nervous system,
increased inflammatory response in the periphery may be contributory to the mechanism of Mn
neuro- and, possibly, systemic toxicity.
35. Crittenden PL, Filipov NM. (2005) Manganese-Induced Alterations In Nf-kappaB-related
Gene Expression By Activated Microglia. Toxicol Sci 84(1-S):126.
The central nervous system is uniquely sensitive to inflammation and the brain microglia are a
primary source of proinflammatory cytokines. In previous work we demonstrated that
manganese and lipopolysaccharide in combination (Mn+LPS) potentiate microglial production
of proinflammatory cytokines such as IL-lbeta, IL- 6, and TNF-alpha. Microglial cells (N9)
were exposed to up to 500|iM MnC12 either by itself or combined with LPS (lOOng/ml). The
Mn+LPS combination elicited dose-dependent cytokine production that was substantially greater
than that induced by Mn or LPS alone. To determine the mechanism of Mn-induced potentiation
of cytokine production, the early NF-kappaB-signaling pathway genes were examined by
utilizing a pathway-specific gene array. N9 cells were exposed to Mn, LPS, or Mn+LPS for
various time periods. At the end of exposure, RNA was isolated and cDNA synthesized to probe
the gene array. In comparison to control cells, 1 hour exposure to Mn (250|iM) and LPS (100
ng/ml) increased the mRNA expression for the TNF-receptor associated factor-1 (TRAF1) and
GM-CSF. Both GM-CSF and TRAF-1 are known to promote cell growth while TRAF-1 may
also induce proinflammatory cytokine synthesis by a NF-kappaB-dependent mechanism.
Expression of the proinflammatory molecule complement component 3 (C3) was also increased
following Mn+LPS exposure. By examining the time-dependent expression of these (and other)
growth and inflammatory factors, we hope to elucidate the possible mechanism(s) for the Mn-
induced proinflammatory cytokine production.
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36. Davis CD, Feng Y. (1999) Dietary copper, manganese and iron affect the formation of
aberrant crypts in colon of rats administered 3,2 '-dimethyl-4-aminobiphenyl. Journal of
Nutrition 129(5): 1060-1067.
Aberrant crypt foci (ACF) are preneoplastic lesions for colon cancer. Altered amounts of copper-
zinc (CuZnSOD) and manganese (MnSOD) superoxide clismutases have been implicated in
multistage carcinogesis of both rodents and humans. Dietary factors are potential modulators of
both CuZnSOD and MnSOD activity. The purpose of this study was to investigate the interactive
effects of dietary copper,manganese, and iron on 3,2'-dimethyl-4-aminobiphenyl (DMABP)-
induced ACF and superoxide dismutase activities in weanling rats fed low or adequate copper
(0.8 or 5.1 mu g Cu/g diet), low or adequate manganese (0.6 or 17 mu g Mn/g diet), and
adequate or high iron (37 or 140 mu g Fe/g diet). Twelve rats were allowed free access to each of
these eight diets for 3.5 wk prior to DMABP administration and for an additional 8 wk after the
first: DMABP injection. Rats fed low dietary copper had 105% (P < 0.0001) higher formation of
DMABP-induced ACF than those fed adequate dietary copper. Rats ingesting low rather than
adequate dietary manganese had 23% higher formation of ACF, and rats ingesting high rather
than adequate dietary iron had 18% higher formation of ACF. Heart total superoxide dismutase
activity was significantly correlated with the number of ACF (r = -0.43, P < 0.0001) in rats
administered DMABP. These results suggest that dietary alterations that affect superoxide
dismutase activity may affect cancer susceptibility.
37. Dedizio MCC, Gomez G, Bonilla E, Suarezroca H. (1995) Autoreceptor Presynaptic Control
of Dopamine Release from Striatum Is Lost at Early Stages of Manganese Poisoning. Life
Sciences 56(22): 1857-1864.
Manganese (Mn) poisoning in man produces an early psychotic disorder that is later followed by
a Parkinson-like syndrome. Since alterations in the brain DA system are thought to be involved,
we assessed the presynaptic autoreceptor regulation of K+-evoked H-3-DA release from
superfused striatal slices of mice treated i.p. with 5 mg Mn/kg weight/day for 2 and 8 weeks. Mn
poisoning did not change basal and evoked DA release. In controls, 1 mu M apomorphine
(APO), a D-2-like DA receptor agonist, produced an inhibition of K+-evoked H-3-DA release
that was blocked by the D-2-like DA receptor antagonist, S(-)-sulpiride (1 mu M). Yet, APO lost
its capacity to inhibit the K+-evoked H-3-DA release after 2 weeks of Mn poisoning. After 8
weeks of Mn poisoning, APO was again able to reduce K+-evoked H-3-DA release. MK-801
(0.3 mu M), a NMDA-glutamate receptor antagonist, could restore APO inhibitory control on
DA release lost at week 2 of Mn poisoning. These findings suggest a NMDA-glutamate-
receptor-mediated loss of autoreceptor presynaptic control of striatal DA release at early Mn
poisoning.
38. Defazio G, Soleo L, Zefferino R, Livrea P. (1996) Manganese toxicity in serumless
dissociated mesencephalic and striatal primary culture. Brain Research Bulletin 40(4):257-262.
Exposure to elevated levels of Manganese (Mn) can result in an irreversible brain disease
characterized by extrapyramidal signs and symptoms resembling Parkinson's disease, To identify
the neuronal target of Mn neurotoxicity, MnC12 was added to serumless dissociated
mesencephalic-striatal cultures from rat embryo on day 4 in vitro. High affinity H-3-dopamine
(DA) and C-14-GABA uptakes were assessed as specific functional markers of DAergic and
GABAergic cell viability, respectively. After 60-min exposure, MnC12 at 0-200 mu M did not
modify the morphologic appearance of the cultures, specific DA and GABA uptakes, or the
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number of DA neurons visualized by immuno-cytochemical staining with tyrosine hydroxylase,
In contrast, culture exposure to 20 mu M MnC12 for 24 h selectively reduced specific GABA
uptake without affecting specific DA uptake or the number of DA neurons. The exposure to a
higher MnC12 concentration was accompanied by signs of general toxicity, Striatal GABA
neurons seemed to be more susceptible to Mn toxicity than mesencephalic GABA neurons.
Overall, our data suggest that striatal neurons rather than mesencephalic DA neurons may be the
main target of Mn neurotoxicity.
39. Desjardins P, Bandeira P, Hazell AS, Buu NT, Ledoux S, Butterworth RF. (1997) Increased
peripheral-type benzodiazepine receptor ptbr gene expression in brain and kidney in hepatic
encephalopathy he results from exposure to ammonia or manganese. 48th Annual Meeting of the
American Association for the Study of Liver Diseases, Chicago, Illinois, USA, November 7-11,
1997. Hepatology 26(4 PART 2):249A.
Biosis copyright: biol abs. rrm meeting abstract rat peripheral-type benzodiazepine receptor ptbr
gene expression brain kidney hepatic encephalopathy ammonia manganese digestive system
toxicology genetics nervous system excretory system nervous system disease digestive system
disease
40. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R. (1996) Manganese and l-methyl-4-
(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine induce apoptosis in PC12 cells. Neuroscience Letters
209(3):193-196.
Oxidative stress is thought to play a key role both in the neurotoxin MPTP- and manganese
(Mn)-induced neurotoxicity and in apoptotic cell death. In the present study, we report that Mn
and the MPTP analogue l-methyl-4-(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine (2'Et-MPTP),
which is metabolized by MAO-A to l-methyl-4-(2'-ethylphenyl)-pyridinium ion (at
concentrations of 0.5 and 1.0 mM), induced apoptosis in PC 12 cells. Apoptosis was tested by
terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate nick end
labelling (TUNEL) technique, flow cytometry and fluorescence microscopy. Both Mn and 2'Et-
MPTP induced also a time-dependent decrease in cell viability, as determined by the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Only Mn-induced
apoptosis and decrease in cell viability were inhibited by the antioxidant ascorbic acid. We
conclude that apoptosis may be an important mechanism of cell death in MPTP- and Mn-induced
parkinsonism. However, an oxidative stress mechanism may be recognized only in the Mn-
induced apoptosis.
41. Desole MS, Sciola L, Delogu MR, Sircana S, Migheli R, Miele E. (1997) Role of oxidative
stress in the manganese and l-methyl-4-(2'-ethylphenyl)-l,2,3,6-tetrahydropyridine-induced
apoptosis in PC12 cells. Neurochemistry International 31(2): 169-176.
Oxidative stress is thought to play a key role in the apoptotic death of several cellular systems,
including neurons. Oxidative stress is proposed also as a mechanism of the neurotoxin 1-methyl-
4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)- and manganese (Mn)-induced neuronal death. We
have recently shown that Mn and the MPTP analogue l-methyl-4-(2'-ethylphenyl)-l,2,3,6-
tetrahydropyridine (2'Et-MPTP), which is metabolized by MAO-A to l-methyl-4-(2'-
ethylphenyl)-pyridinium ion, induce apoptosis in PC12 cells. In the present study, we evaluated
the effects of deprenyl and the antioxidant drugs N-acetylcysteine (NAC) and ascorbic acid (AA)
on Mn- and 2'Et-MPTP-induced apoptosis in PC 12 cells. Apoptosis was tested by terminal
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deoxynucleotidyl transferase-mediated 2'-deoxy-uridine-5'-triphosphate nick end labelling
(TUNEL) technique, flow cytometry and fluorescence microscopy. Cell viability was determined
by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Mn-induced
apoptosis and decrease in cell viability was inhibited by the antioxidants NAC and AA. Deprenyl
failed to inhibit the above Mn effects. Neither NAC, AA nor deprenyl were able to inhibit both
2'Et-MPTP-induced apoptosis and decrease in cell viability. These results confirm that apoptosis
may be an important mechanism of cell death in MPTP- and Mn-induced parkinsonism.
However, an oxidative stress mechanism may be recognized, at least in vitro, only in the Mn-
induced apoptosis. (C) 1997 Elsevier Science Ltd.
42. Desole MS, Serra PA, Esposito G, Delogu MR, Migheli R, Fresu L, Rocchitta G, Miele M.
(2000) Glutathione deficiency potentiates manganese-induced increases in compounds
associated with high-energy phosphate degradation in discrete brain areas of young and aged
rats. Aging Clinical and Experimental Research 12(6):470-477.
Aging is a factor known to increase neuronal vulnerability to oxidative stress, which is widely
accepted as a mechanism of manganese-induced neuronal damage. We previously showed that
subchronic exposure to manganese induced greater energy impairment (as revealed by increases
in hypoxanthine, xanthine and uric acid levels) in the striatum and brainstem of aged rats vs
young rats. This study shows that inhibition of glutathione (GSH) synthesis, by means of
buthionine (SR) sulfoximine, decreased GSH levels and increased the ascorbic acid oxidation
status in the striatum and limbic forebrain of both young and aged rats. In addition, inhibition of
GSH synthesis greatly potentiated the manganese-induced increase in inosine, hypoxanthine,
xanthine and uric acid levels in both regions of aged rats; moreover, inhibition of GSH synthesis
significantly increased inosine, hypoxanthine, xanthine and uric acid levels in both regions of
young rats, compared with the manganese-treated group. These results suggest that an
impairment in the neuronal antioxidant system renders young rats susceptible to manganese-
induced energetic impairment, and further support the hypothesis that an impairment in this
system plays a permissive role in the increase of neuronal vulnerability that occurs with aging.
43. DiLorenzo D, Ferrari F, Agrati P, deVos H, Apostoli P, Alessio L, Albertini A, Maggi A.
(1996) Manganese effects on the human neuroblastoma cell line SK-ER3. Toxicology and
Applied Pharmacology 140(1):51-57.
SK-ER3 cells were recently demonstrated to represent a valuable model for the study of
estrogen-inducible differentiation of neural cells in culture. This system may constitute an
important tool also for the analysis of the effects of neurotoxic drugs. The present study
demonstrates that short term exposure to Mn causes increased proliferation rate of SK-ER3 cells
regardless of their differentiation. Long term treatment causes cell death in undifferentiated cells
at concentrations of the metal as low as 100 nM. When the cells are differentiated with
estrogens, death is observed only with a Mn concentration two orders of magnitude higher.
Measurement of neurite extension and quantitation of tyrosine hydroxylase content after long-
term exposure to the metal allow the conclusion that Mn does not alter the state of differentiation
of SK-ER3 cells induced by the treatment with the hormone. The study underlines the
importance of studying the effect of Mn in proliferating neural cells and demonstrates the toxic
role of micromolar concentrations of the metal in fully differentiated neural cells. Since other
authors produced evidence of effects of the metal on cell death and proliferation only at
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millimolar concentrations, and none described its proliferative activity, the model utilized in the
present study seems to be of particular interest. (C) 1996 Academic Press, Inc.
44. Dodd CA, Ward DL, Klein BG. (2005) Basal ganglia accumulation and motor assessment
following manganese chloride exposure in the C57BL/6 mouse. International Journal of
Toxicology 24(6):389-397.
Equivocal clinical evidence for involvement of manganese in development of Parkinson's disease
necessitates experimental studies on this issue. The aged, l-methyl-4-phenyl-l,2,3,6-
tetrahyropyridine-treated C57BL/6 mouse is one of the most common models for Parkinson's
disease. However, there is little information on brain bioaccumulation of manganese, and little or
no information on clinical/behavioral manifestations of manganese neurotoxicity, in this strain.
Male C57BL/6 retired breeder mice were given a single subcutaneous injection of either 0, 50, or
100 mg/kg of MnC12 (single-dose regimen) or three injections of either of these doses over 7
days (multiple-dose regimen). Behavioral assessment was performed 24 h after final injection,
followed by sacrifice, and body weight was recorded each day. There was a 105% increase in
striatal manganese concentration 1 day after a single 100 mg/kg injection, and 421% and 647%)
increases, respectively, 1 day after multiple doses of 50 or 100 mg/kg of MnC12. One day after a
single injection, there were respective 30.9% and 38.9% decreases in horizontal movement ( grid
crossing) for the 50 and 100 mg/kg doses and a 43.2% decrease for the multiple dose of 100
mg/kg. There was no significant main effect of dose level on rearing, swimming, grip strength,
or grip fatigue. Unlike previous work with the C57BL/6 strain using smaller intraperitoneal
doses, this study established dosing regimens that produced significant increases in basal ganglia
manganese concentration reminiscent of brain increases in the CD-I mouse following
subcutaneous doses close to our lowest. A decrease in locomotor behavior, significant but not
severe in this study, has been reported following manganese exposure in other mouse strains.
These data, particularly the significant increase in basal ganglia manganese concentration,
provide guidance for designing studies of the potential role of manganese in Parkinson's disease
using the most common animal model for the disorder.
45. Dorman DC. (2000) An integrative approach to neurotoxicology. Toxicologic Pathology
28(l):37-42.
Exposure of human populations to a wide variety of chemicals has generated concern about the
potential neurotoxicity of new and existing chemicals. Experimental studies conducted in
laboratory animals remain critical to the study of neurotoxicity. An integrative approach using
pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral
methods is needed to determine whether a chemical is neurotoxic. There are a number of factors
that can affect the outcome of a neurotoxicity study, including the choice of animal species, dose
and dosage regimen, route of administration, and the intrinsic sensitivity of the nervous system
to the test chemical. The neurotoxicity of a chemical can vary at different stages of brain
development and maturity. Evidence of neurotoxicity may be highly subjective and species
specific and can be complicated by the presence of systemic disease. The aim of this paper is to
give an overview of these and other factors involved in the assessment of the neurotoxic
potential for chemicals. This article discusses the neurotoxicity of several neurotoxicants (eg,
acrylamide, trimethyltin, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, manganese, and
ivermectin), thereby highlighting a multidisciplinary approach to the assessment of chemically
induced neurotoxicity in animals. These model chemicals produce a broad range of effects that
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includes peripheral axonopathy, selective neuronal damage within the nervous system, and
impaired neuronal-glial metabolism.
46. Dukhande VV, Malthankar-Phatak GH, Hugus JJ, Daniels CK, Lai JCK. (2006) Manganese-
induced neurotoxicity is differentially enhanced by glutathione depletion in astrocytoma and
neuroblastoma cells. Neurochemical Research 31(11): 1349-1357.
Manganese (Mn) is neurotoxic: the underlying mechanisms have not been fully elucidated. L-
Buthionine-(S,R)-sulfoximine (BSO) is an irreversible inhibitor of gamma-glutamylcysteine
synthetase, an important enzyme in glutathione (GSH) synthesis. To test the hypothesis that BSO
modulates Mn toxicity, we investigated the effects of treatment of U-87 or SK-N-SH cells with
MnC12, BSO, or MnC12 plus BSO. We monitored cell viability using MTT assay, staining with
HO-33342 to assess live and/or apoptotic cells, and staining with propidium iodide (PI) to assess
necrotic cells; we also measured cellular glutathione. Our results indicate decreased viability in
both cell types when treated with MnC12 or BSO: Mn was more toxic to SK-N-SH cells, whereas
BSO was more toxic to U-87 cells. Because BSO treatment accentuated Mn toxicity in both cell
lines, GSH may act to combat Mn toxicity. Thus, further investigation in oxidative stress
mediated by glutathione depletion will unravel new Mn toxicity mechanism(s).
47. Eder K, Kirchgessner M, Kralik A. (1996) The effect of trace element deficiency (iron,
copper, zinc, manganese, and selenium) on hepatic fatty acid composition in the rat. Trace
Elements and Electrolytes 13(1): 1-6.
The present study has been performed to investigate comparatively the effect of iron-, copper-,
manganese-, selenium-, and zinc deficiency on fatty acid metabolism in rats. The experiment
included 7 groups of 12 rats each (control group, iron-deficient group, copper-deficient group,
manganese-deficient group, selenium-deficient group, zinc-deficient group, and a control group
pair-fed to zinc-deficient group). In order to asses the fatty acid metabolism, fatty acid
composition of liver total lipids was determined. The most pronounced changes of fatty acid
composition compared with control rats occurred in iron- and copper-deficient rats. The changes
in iron-deficient rats indicate impaired desaturation of saturated fatty acids and linoleic acid by
Delta 9, Delta 6 and Delta 5 desaturase. The changes in copper-deficient rats indicate impaired
Delta 9 desaturation of saturated fatty acids. Manganese-deficient rats had slightly decreased
levels of mono-unsaturated fatty acids indicating also decreased Delta 9 desaturation. Selenium
deficiency did not influence the fatty acid composition of liver total lipids. The fatty acid
composition of both zinc-deficient rats and pair-fed control rats was quite different from ad
libitum control rats demonstrating the effect of low food intake. In comparison with pair-fed
control rats, zinc-deficient rats had increased levels of (n - 3) poly-unsaturated fatty acids
whereas neither Delta 5 and Delta 6 desaturation nor Delta 9 desaturation was influenced by zinc
deficiency. In conclusion, the data of the study show that several trace elements influence fatty
acid metabolism.
48. Ensunsa JL, Symons JD, Lanoue L, Schrader HR, Keen CL. (2004) Reducing arginase
activity via dietary manganese deficiency enhances endothelium-dependent vasorelaxation of rat
aorta. Experimental Biology and Medicine 229(11): 1143-1153.
L-Arginine is a common substrate for the enzymes arginase and nitric oxide synthase (NOS).
Acute inhibition of arginase enzyme activity improves endothelium-dependent vasorelaxation,
presumably by increasing availability of substrate for NOS. Arginase is activated by manganese
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(Mn), and the consumption of a Mn-deficient (Mn-) diet can result in low arginase activity. We
hypothesize that endothelium-dependent vasorelaxation is greater in rats fed Mn- versus Mn
sufficient (Mn+) diets. Newly weaned rats fed Mn- diets (0.5 mug Mn/g; n = 12) versus Mn+
diets (45 mug Mn/g; n = 12) for 44 +/- 3 days had (i) lower liver and kidney Mn and arginase
activity (P less than or equal to 0.05), (ii) higher plasma L-arginine (P less than or equal to 0.05),
(iii) similar plasma and urine nitrate + nitrite, and (iv) similar staining for endothelial nitric oxide
synthase in thoracic aorta. Vascular reactivity of thoracic aorta (similar to720 mum i.d.) and
small coronary arteries (similar tol 10 mum i.d.) was evaluated using wire myographs.
Acetylcholine (ACh; 10(-8)-10(-4) M) produced greater (P less than or equal to 0.05)
vasorelaxation in thoracic aorta from Mn- rats (e.g., maximal percent relaxation, 79 +/- 7%)
versus Mn+ rats (e.g., maximal percent relaxation, 54 +/- 9%) at 5 of 7 evaluated doses. Tension
produced by NOS inhibition using N-G monomethyl-L-arginine (L-NMMA; 10(-3) M) and
vasorelaxation evoked by (i) arginase inhibition using difluoromethylornithine (DFMO; 10(-7)
M), (ii) ACh (10(-8)-10(-4) M) in the presence of DFMO, and (iii) sodium nitroprusside (10(-9)-
10(-4) M) were unaffected by diet. No differences existed between groups concerning these
responses in small coronary arteries. These findings support our hypothesis that endothelium-
dependent vasorelaxation is greater in aortic segments from rats that consume Mn- versus Mn+
diets; however, responses from small coronary arteries were unaffected.
49. Erikson K, Aschner M. (2002) Manganese causes differential regulation of glutamate
transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.
Neurotoxicology 23(4-5):595-602.
Neurotoxicity due to excessive brain manganese (Mn) can occur due to environmental (air
pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). Manganese is
associated with oxidative stress, as well as alterations in neurotransmitter metabolism with
concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain
regional [Mn], it is likely that in pathological conditions it can reach 100-500 muM. Amino acid
(e.g. aspartate, glutamate, taurine), as well as divalent metal (e.g. zinc, manganese)
concentrations are regulated by astrocytes in the brain. Recently, it has been reported that
cultured rat primary astrocytes exposed to Mn displayed decreased glutamate uptake, thereby,
increasing the excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn
employs in terms of glutamate metabolism is unknown, a primary goal of this study was to link
altered glutamate uptake in Mn exposed astrocytes to alterations in glutamate transporter
message. Further we wanted to examine the gene expression of metallothionein (MT) and taurine
transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40%
in accordance with a 48% decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine
uptake was unaffected by Mn exposure even though tdu-T mRNA increased by 123%. MT
mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism,
although this was not examined. These data show that glutamate and taurine transport in Mn
exposed astrocytes are temporally different. (C) 2002 Elsevier Science Inc. All rights reserved.
50. Erikson KM, Dorman DC, Fitsanakis V, Lash LH, Aschner M. (2006) Alterations of
oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.
Biological Trace Element Research 111(1-3): 199-215.
Neonatal rats were exposed to airborne manganese sulfate (MnS04) (0, 0.05, 0.5, or 1.0 mg
Mn/m(3)) during gestation (d 0-19) and postnatal days (PNDs) 1-18. On PND 19, rats were
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killed, and we assessed biochemical end points indicative of oxidative stress in five brain
regions: cerebellum, hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine
synthetase (GS) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), TH and GS
mRNA levels, and reduced and oxidized glutathione (GSH and GSSG, respectively) levels were
determined for all five regions. Mn exposure (all three doses) significantly (p = 0.0021)
decreased GS protein levels in the cerebellum, and GS mRNA levels were significantly (p =
0.0008) decreased in the striatum. Both the median and high dose of Mn significantly (p =
0.0114) decreased MT mRNA in the striatum. Mn exposure had no effect on TH protein levels,
but it significantly lowered TH mRNA levels in the olfactory bulb (p = 0.0402) and in the
striatum (p = 0.0493). Mn exposure significantly lowered GSH levels at the median dose in the
olfactory bulb (p = 0.0032) and at the median and high dose in the striatum (p = 0.0346).
Significantly elevated (p = 0.0247) GSSG, which can be indicative of oxidative stress, was
observed in the cerebellum of pups exposed to the high dose of Mn. These data reveal that
alterations of oxidative stress biomarkers resulting from in utero and neonatal exposures of
airborne Mn exist. Coupled with our previous study in which similarly exposed rats were
allowed to recover from Mn exposure for 3 wk, it appears that many of these changes are
reversible. It is important to note that the doses of Mn utilized represent levels that are a
hundred- to a thousand-fold higher than the inhalation reference concentration set by the United
States Environmental Protection Agency.
51. Erikson KM, Dorman DC, Lash LH, Aschner M. (2005) Persistent alterations in biomarkers
of oxidative stress resulting from combined in utero and neonatal manganese inhalation.
Biological Trace Element Research 104(2): 151-163.
Neonatal female and male rats were exposed to airborne manganese sulfate (MnS04) during
gestation and postnatal d 1-18. Three weeks post-exposure, rats were killed and we assessed
biochemical end points indicative of oxidative stress in five brain regions: cerebellum,
hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine synthetase (GS) protein
levels, metallothionein (MT) and GS mRNA levels, and total glutathione (GSH) levels were
determined for all five regions. Overall, there was a statistically significant effect of manganese
exposure on decreasing brain GS protein levels (p=0.0061), although only the highest dose of
manganese (1 mg Mn/m(3)) caused a significant increase in GS messenger RNA (mRNA) in
both the hypothalamus and olfactory bulb of male rats and a significant decrease in GS mRNA in
the striatum of female rats. This highest dose of manganese had no effect on MT mRNA in either
males or females; however, the lowest dose (0.05 mg Mn/m(3)) decreased MT mRNA in the
hippocampus, hypothalamus, and striatum in males. The median dose (0.5 mg Mn/m(3)) led to
decreased MT mRNA in the hippocampus and hypothalamus of the males and olfactory bulb of
the females. Overall, manganese exposure did not affect total GSH levels, a finding that is
contrary to those in our previous studies. Only the cerebellum of manganese-exposed young
male rats showed a significant reduction (p < 0.05) in total GSH levels compared to control
levels. These data reveal that alterations in biomarkers of oxidative stress resulting from in utero
and neonatal exposures of airborne manganese remain despite 3 wk of recovery; however, it is
important to note that the doses of manganese utilized represent levels that are 100-fold to a
1000-fold higher than the inhalation reference concentration set by the US Environmental
Protection Agency.
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52. Erikson KM, Dorman DC, Lash LH, Dobson AW, Aschner M. (2004) Airborne manganese
exposure differentially affects end points of oxidative stress in an age and sex-dependent
manner. Biological Trace Element Research 100(l):49-62.
Juvenile female and male (young) and 16-mo-old male (old) rats inhaled manganese in the form
of manganese sulfate (MnS04) at 0, 0.01, 0.1, and 0.5 mg Mn/m(3) or manganese phosphate at
0.1 mg Mn/m(3) in exposures of 6 h/d, 5 d/wk for 13 wk. We assessed biochemical end points
indicative of oxidative stress in five brain regions: cerebellum, hippocampus, hypothalamus,
olfactory bulb, and striatum. Glutamine synthetase (GS) protein levels, metallothionein (MT)
and GS mRNA levels, and total glutathione (GSH) levels were determined for all five regions.
Although most brain regions in the three groups of animals were unaffected by manganese
exposure in terms of GS protein levels, there was significantly increased protein (p<0.05) in the
hippocampus and decreased protein in the hypothalamus of young male rats exposed to
manganese phosphate as well as in the aged rats exposed to 0.1 mg/m(3) MnS04. Conversely,
GS protein was elevated in the olfactory bulb of females exposed to the high dose of MnS04.
Statistically significant decreases (p<0.05) in NIT and GS mRNA as a result of manganese
exposure were observed in the cerebellum, olfactory bulb, and hippocampus in the young male
rats, in the hypothalamus in the young female rats, and in the hippocampus in the senescent
males. Total GSH levels significantly (p<0.05) decreased in the olfactory bulb of manganese
exposed young male rats and increased in the olfactory bulb of female rats exposed to
manganese. Both the aged and young female rats had significantly decreased (p<0.05) GSH in
the striatum resulting from manganese inhalation. The old male rats also had depleted GSH
levels in the cerebellum and hypothalamus as a result of the 0.1-mg/m(3) manganese phosphate
exposure. These results demonstrate that age and sex are variables that must be considered when
assessing the neurotoxicity of manganese.
53. Erikson KM, Suber RL, Aschner M. (2002) Glutamate/aspartate transporter (GLAST),
taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes
exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology
23(3):281-288.
Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution,
soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese
levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with
concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain
regional Mn concentration, it is likely that in pathological conditions, Mn concentration can
reach between 100 and 500 muM. Environmental Mn exposure as a result of
methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate
or sulfate (MnP04, MnS04, respectively). Pharmacokinetic studies have shown that the Mn salt
will determine the rate of transport into the brain: MnC12 > MnS04 > MnP04. The salt-specific
neurotoxicity of these species is unknown. The primary goal of this study was to examine gene
expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and
metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnC12) manganese
sulfate (MnS04), and manganese phosphate (MnP04). We hypothesized that the effects of
MnP04 and MnS04 exposure on GLAST expression in astrocytes would be similar to those
induced by MnC12, since irrespective of salt species exposure, once internalized by astrocytes,
the Mn ion would be identically complexed. At the same time, we hypothesized that the
magnitude of the effect would be salt-dependent, since the chemical speciation would determine
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the rate of intracellular uptake of Mn. MnC12 caused a significant overall decrease (P < 0.0001)
in astrocytic GLAST mRNA levels with MnS04 causing a moderate decrease. MnP04 exposure
did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein
and taurine transporter gene expression as markers of manganese exposure. Our findings suggest
that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA
compared to both the sulfate and phosphate species. However astrocytic taurine transporter
mRNA was not affected by Mn exposure, irrespective of the salt species. These data are
consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent
upon its species, with solubility, and by inference, intracellular concentration, representing a
major determinant of its neurotoxicity. (C) 2002 Elsevier Science Inc. All rights reserved.
54. Fernandes A, Ferreira JG, de Oliveira E, Ponzoni S. (2004) L-Deprenyl (selegiline)
neuroprotective failure in a manganese neurotoxicity model. Movement Disorders 19:S41-S41.
55. Filipov NM, Seegal RF, Lawrence DA. (2005) Manganese potentiates in vitro production of
proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa In-
dependent mechanism. Toxicological Sciences 84(1): 139-148.
Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity involves
activation of microglia and/or astrocytes; as a consequence, neurons adjacent to the activated
microglia may be injured. Mn modulation of proinflammatory cytokine expression by microglia
has not been investigated. Therefore, the objectives of this research were to (1) assess whether
Mn induces proinflammatory cytokine expression and/or modulates lipopolysaccharide (LPS)-
induced expression of proinflammatory cytokines and (2) investigate possible mechanisms for
such an induction. N9 microglia were exposed in vitro to increasing concentrations (50-1000
muM) of Mn in the presence or absence of LPS (10, 100, or 500 ng/ml). After various incubation
times (up to 48 h), media levels of several cytokines and nitric oxide (NO) were determined, as
was the expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase (LDH)
release into the medium and the cellular uptake of Neutral Red were used as general measures
for cytotoxicity. In the absence of LPS, Mn moderately increased interleukin-6 and tumor
necrosis factor alpha (TNF-a) production only at higher Mn concentrations, which were
cytotoxic. At all LPS doses, however, proinflammatory cytokine production was dose-
dependently increased by Mn. Similarly, LPS-induced NO production and iNOS expression were
substantially enhanced by Mn. Pharmacological manipulations indicated that nuclear factor
kappa B (NFkappaB) activation is critical for the observed enhancement of cytokine and NO
production. Within the context of inflammation, increased production of proinflammatory
cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its
neurotoxicity.
56. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2005) Manganese transport by rat brain
endothelial (RBE4) cell-based transwell model in the presence of astrocyte conditioned media.
Journal of Neuroscience Research 81(2):235-243.
Manganese (Mn), an essential nutrient, is neurotoxic at high levels and has been associated with
the development of a parkinsonian syndrome termed manganism. Currently, the mechanisms
responsible for transporting Mn across the blood-brain barrier (BBB) are unknown. By using rat
brain endothelial 4 (RBE4) cell monolayers cultured in astrocyte-conditioned media (ACM), we
examine the effects of temperature, energy, proton (pH), iron (Fe), and sodium (Na+)
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dependence on Mn transport. Our results suggest that Mn transport is temperature, energy, and
pH dependent, but not Fe or Na+-dependent. These data suggest that Mn transport across the
BBB is an active process, but they also demonstrate that the presence of ACM in endothelial cell
cultures decreases the permeability of these cells to Mn, reinforcing the use of ACM or astrocyte
cocultures in studies examining metal transport across the BBB. (c) 2005 Wiley-Liss, Inc.
57. Fitsanakis VA, Piccola G, Aschner JL, Aschner M. (2006) Characteristics of manganese
(Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier.
Neurotoxicology 27(l):60-70.
Manganese (Mn), an essential elemental nutrient, is known to be neurotoxic at high occupational
levels. We examined the transport of Mn across a monolayer of rat brain endothelial cell (RBE4)
to evaluate whether an electromotive permeability mechanism is responsible for Mn transport
across the blood-brain barrier (BBB). The Mn-54(2+) apparent permeability and flux showed
significant temperature-, energy- and pH-dependence, as well as partial sodium-dependence.
Additionally, iron (Fe)-rich and Fe-deficient media significantly increased the apparent
permeability of Mn-54(2+). Finally, Mn flux and permeability decreased when RBE4 cells were
grown in astrocyte-conditioned media (ACM), compared to standard alpha-media. These data
reinforce observations that transport of Mn across the BBB occurs in part through active
transport process. (C) 2005 Elsevier Inc. All rights reserved.
58. Fitsanakis VA, Piccola G, dos Santos AP, Aschner JL, Aschner M. (2007) Putative proteins
involved in manganese transport across the blood-brain barrier. Human & Experimental
Toxicology 26(4):295-302.
Manganese (Mn) is an essential nutrient required for proper growth and maintenance of
numerous biological systems. At high levels it is known to be neurotoxic. While focused
research concerning the transport of Mn across the blood-brain barrier (BBB) is on-going, the
exact identity of the transporteds) responsible is still debated. The transferrin receptor (TfR) and
the divalent metal transporter-1 (DMT-1) have long been thought to play a role in brain Mn
deposition. However, evidence suggests that Mn may also be transported by other proteins. One
model system of the BBB, rat brain endothelial (RBE4) cells, are known to express many
proteins suspected to be involved in metal transport. This review will discuss the biological
importance of Mn, and then briefly describe several proteins that may be involved in transport of
this metal across the BBB. The latter section will examine the potential usefulness of RBE4 cells
in characterizing various aspects of Mn transport, and basic culture techniques involved in
working with these cells. It is hoped that ideas put forth in this article will stimulate further
investigations into the complex nature of Mn transport, and address the importance as well as the
limitation of in vitro models in answering these questions.
59. Fong CS, Wu RM, Shieh JC, Chao YT, Fu YP, Kuao CL, Cheng CW. (2007) Pesticide
exposure on southwestern Taiwanese with MnSOD and NQOl polymorphisms is associated with
increased risk of Parkinson's disease. Clinica Chimica Acta 378(1-2): 136-141.
Background: Hypothetic mechanism of the individual vulnerability to oxidative stress through
metabolism of environmental xenobiotics and genotypic polymorphisms has been considered to
promote the development of Parkinson's disease (PD). In this case-control study, we determined
the role of manganese-containing superoxide dismutase (MnSOD) and NAD(P)H: quinone
oxidoreductase I (NQOl) genes in PD risk in a population with high prevalence of pesticide
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exposure. Methods: From southwestern region of Taiwan, we enrolled 153 patients with
idiopathic PD and 155 healthy control subjects matched for age, sex and origin. Detailed
questionnaires of face-to-face interviews among these subjects were collected. PCR-based
restriction fragment length polymorphism (RFLP) assays were used to determine the genotypes
of MnSOD (-9 T > C) and NQOl (609 C > T) genes. Results: Exposure to pesticides associated
with PD was significant among patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07-
2.65), and this association remained significant after adjustment for age, sex, and cigarette
smoking (aOR=1.68, 95%CI, 1.03-2.76, P=0.023). Considering genetic factors, there were no
significant differences in frequencies of both genotypes of MnSOD and NQOl polymorphisms
between PD patients and the control subjects (P > 0.05). However, this difference in genotype
distribution was significant among subjects who had been exposed to pesticide, with aOR of 2.49
(95%CI, 1.18-5.26, P=0.0072) for MnSOD C allele and aOR of 2.42 (95%C1, 1.16-4.76,
P=0.0089) for NQOl T allele, respectively. Moreover, among subjects exposed to pesticide, the
combined MnSOD/NQOl variant genotype was significantly associated with a 4.09-fold
increased risk of PD (95%C1, 1.34-10.64, P=0.0052). Conclusion: Susceptible variants of
MnSOD and NQOl genes may interact with occupational pesticide exposure to increase PD risk
in southwestern Taiwanese, (c) 2006 Elsevier B.V. All rights reserved.
60. Galvani P, Fumagalli P, Santagostino A. (1995) Vulnerability of Mitochondrial Complex-I
in Pcl2 Cells Exposed to Manganese. European Journal of Pharmacology-Environmental
Toxicology and Pharmacology Section 293(4):377-383.
The present findings provide experimental evidence for the hypothesis that an impairment of
mitochondrial function may be involved in manganese neurotoxicity. Specifically, the treatment
of dopaminergic neuronal-derived cell line (PC 12) with MnC12 produced a significant inhibition
of some mitochondrial complexes of the respiratory chain, while in the glial-derived cell line
(C6) this effect was not observed. In PC 12 the decrease in complex I activity was more
pronounced than in other mitochondrial complexes. However treatment of cells with ZnS04
exerted no significant variations in enzymatic activities. A direct exposure of mitochondrial
fraction to MnC12 reduced enzymatic activities of mitochondria in both cell lines adding further
support to the proposed theory that the different sensitivity of the cells to manganese may be
explained by a difference in uptake or intracellular storage. These data indicate that manganese
neurotoxicity could be the result of a direct effect just on complex I activity or due to a
secondary effect of oxidative stress induced by an excess of this transition metal.
61. Gavin CE, Gunter KK, Gunter TE. (1999) Manganese and calcium transport in
mitochondria: Implications for manganese toxicity. Neurotoxicology 20(2-3):445-453.
Mn2+ is sequestered by liver and brain mitochondria via the mitochondrial Ca2+ uniporter. The
mitochondrial Ca2+ uniporter is a cooperative transport mechanism possessing an external
activation site and a transport site. Ca2+ binding to the activation site greatly increases the
velocity of uptake of both Ca2+ and Mn2+. Electron paramagnetic resonance (EPR) shows that
over 97% of the Mn2+ in the mitochondrial matrix is normally bound to the membrane or to
matrix proteins. EPR measurements of manganese within living isolated mitochondria can be
repeat-ed for hours, and during this time most of the manganese remains in the Mn2+ state.
Mn2+ is transported out of mitochondria via the very slow Na+-independent efflux mechanism,
which is an active (energy-requiring) mechanism. Mn2+ is not significantly transported over the
Na+-dependent efflux mechanism, which is the dominant efflux mechanism in heart and brain
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mitochondria. Mn2+ inhibits the efflux of Ca2+ through both of these efflux mechanisms, having
an apparent K-i of 7.9 nmol/mg protein on the Na+-independent efflux mechanism and an
apparent K-i of 5.1 nmol/mg on the Na+-dependent efflux mechanism. Mn2+ inhibition of Ca2+
efflux may increase the probability of the mitochondria undergoing the mitochondrial
permeability transition (MPT). Intramitochondrial Mn2+ also inhibits State 3 mitochondrial
respiration using either succinate or malate plus glutamate as substrate. The data suggest that
Mn2+ depletes cellular energy supplies by interfering with oxidative phosphorylation at the level
of the F(l)ATPase and at much higher concentrations, at Complex I. Effects such as these could
lead to apoptosis in active neurons. (C) 1999 Inter Press, Inc.
62. Gong HQ, Amemiya T. (1996) Ultrastructure of retina of manganese-deficient rats.
Investigative Ophthalmology & Visual Science 37(10): 1967-1974.
Purpose. To elucidate some biologic functions of manganese in the retina. Methods. Three-week-
old weanling Wistar Kyoto rats were used. Manganese-deficient rats were fed a manganese-
deficient solid diet containing 0.23 mg manganese/100 g diet and all other nutrients. Control rats
were fed a solid diet with 2.9 mg manganese/100 g diet. The retinas were examined by electron
microscopy in the 12th, 18th, and 30th months of experimentation. Results, There was a
statistically significant decrease in the plasma manganese levels in manganese-deficient animals
compared to controls. In rats fed a manganese-deficient diet for 12 months, photoreceptor cells
showed karyopyknosis-like changes of nuclei and a decrease in size and number of outer
segments. Rats fed a manganese-deficient diet for 18 months showed a complete loss of
photoreceptor cells, and the inner nuclear layer nuclei came in direct contact with the retinal
pigment epithelium. Rats with manganese deficiency of 30 months showed invasion by
capillaries and processes of Muller-like cells from the sensory retina into the retinal pigment
epithelium. In the sensory retina, Muller-like cells proliferated, and neural cells disappeared.
Conclusions. Because manganese is related to Mn superoxide in the mitochondrial matrix and to
protein and glycogen metabolism, manganese deficiency may disturb the renewal of
photoreceptor outer segment discs, and the decrease in antioxidant action caused by a lower level
of Mn superoxide dismutase may accelerate the damage to photoreceptor cells. After neural cell
loss, Mailer-like cells may proliferate. Manganese appears to be essential for maintaining
photoreceptor cells.
63. Gong HQ, Amemiya T. (1999) Corneal changes in manganese-deficient rats. Cornea
18(4):472-482.
Purpose. This study was undertaken to examine the changes in the cornea due to dietary
manganese (Mn) deficiency in Wistar-Kyoto rats, because there is a lack of information on the
significance of manganese in the cornea. Methods, Mature female Wistar-Kyoto albino rats were
mated with males. All pregnant females were divided into Mn-deficient and control groups. The
offspring were fed a Mn-deficient diet. When they reached age 3 months, Mn-deficient females
were mated with Mn-deficient males. The offspring of this second generation of Mn-deficient
rats continued to be fed on the Mn-deficient diet and were used for the experiment. The corneas
were examined at age 2 months. After 3 months on a Mn-deficient diet, the rats were given a
normal diet for a 3-month recovery experiment. The corneas were examined by transmission
electron microscopy (TEM) and scanning electron microscopy (SEM). Results. TEM revealed
very few microvilli and bundles of tonofibrils and abnormal mitochondria in the corneal
epithelium of Mn-deficient rats. The stroma was thin, and collagen fibers were decreased
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prominently in diameter. Descemet's membrane was thinner than in the control group. SEM
showed many fewer microvilli in the Mn-deficient rats and more dark cells in the most
superficial layer of epithelium. SEM also showed endothelial cells with a pentagonal instead of a
hexagonal shape in Mn-deficient rats. Rats fed a normal diet for 3 months after Mn deficiency
showed a normal serum Mn level and almost normal corneal structure. Conclusion. This study
suggested that the cornea needs Mn for the maintenance of its cell structure.
64. Gong HQ, Amemiya T. (1999) Optic nerve changes in manganese-deficient rats.
Experimental Eye Research 68(3):313-320.
In the present study the changes in the optic nerve due to dietary manganese (Mn) deficiency has
examined in Wistar Kyoto rats, since there is a lack of information on the significance of
manganese in the optic nerve. After 5 months on a Mn-deficient diet, the optic nerve was
examined by light and transmission electron microscopy. The serum manganese level of the
deficient rats was significantly lower than that of the controls. The light microscopic findings
showed significantly fewer myelinated axons in the Mn-deficient rats and Mn-recovery rats than
in the control group, and there were obviously more oligodendrocytes in the recovery rats.
Ultrastructural findings were: significantly decreased diameters and lamellae of myelinated
axons in the optic nerves of the Mn-deficient rats and abnormal mitochondria in the axons. Rats
fed a normal diet for 3 months after 5 months on a Mn deficient diet had a normal serum
manganese level, but no change in the abnormal morphology of the myelinated axons. Tt is
concluded that the optic nerve needs manganese for the maintenance of its cell structure. (C)
1999 Academic Press.
65. Gunter TE, Gunter KK, Aschner M. (2006) Mn2+ interference with ca(2+) activation of
ATP production by mitochondria: A novel hypothesis of Mn neurotoxicity. Neurotoxicology
27(5):901-902.
66. Halatek T, Opalska B, Rydzynski K, Bernard A. (2006) Pulmonary response to
methylcyclopentadienyl manganese tricarbonyl treatment in rats: injury and repair evaluation.
Histology and Histopathology 21(11): 1181-1192.
Methylcyclopentadienyl manganese tricarbonyl (MMT), an organometallic compound, used as
an antiknock additive in fuels, may produce alveolar inflammation and bronchiolar cell injury.
The aim of the experimental study on female rats was to determine by morphological
examination and sensitive biomarkers, the course of the injury and repair process following a
single i.p. injection of 5 mg/kg MMT. The animals were sacrificed 12, 24, 48 hours or 7 days
post-exposure (PE). The first biochemical changes 12 h PE showed an increase in GSH-S-
transferase (GST) activity in the lung parallel to the earliest observed morphological changes-
vacuolation and swollen cytoplasm in type I pneumocytes. Alterations in type I pneumocytes
were most prevalent in rat lung 24 h PE. Clara cells with dilated smooth endoplasmic reticulum
membranes and cytoplasmic vacuolation could be observed. Compared to the values found for
controls, Clara cell protein (CC16) in the bronchoalveolar lavage fluid (BALF) at 24 and 48 h
PE decreased by 58% and 55%, respectively. At the same time (at 24 and 48 h), the total protein
concentration in BALF increased 5 and 7 times, respectively. A significant rise in hyaluronic
acid (HA) level was observed 24 and 48 h PE. Divided type II pneumocyte cells and Clara cells
in their mitotic phase were observed in immunocytochemistry (detecting BrdU binding into
DNA) 48 h PE. Seven days after MMT administration, fibroblasts, macrophages, collagen and
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elastin fibres could be seen in the alveolar walls as well as neutrophils, lymphocytes, and alveoli
macrophages in the alveolar lumen. We conclude that injury and repair of bronchial epithelium
cells, especially of Clara cells and type II pneumocyte cells, play an important part in MMT
toxicity, probably depending on the antioxidant status of these cells. The sensitive biomarkers of
CC16 and hyaluronic acid in BALF and serum reflect lung injury and indicate the time course of
pulmonary damage and repair processes.
67. HaMai D, Campbell A, Bondy SC. (2001) Modulation of oxidative events by multivalent
manganese complexes in brain tissue. Free Radical Biology and Medicine 31(6):763-768.
Manganese toxicity can evoke neuropsychiatric and neuromotor symptoms, which have
frequently been attributed to profound oxidative stress in the dopaminergic system. However, the
characterization of manganese as a pro-oxidant remains controversial because antioxidant
properties also have been associated with this metal. The current study was designed to address
these disparate findings concerning the oxidative properties of manganese. The apparent ability
of manganese in its divalent form to promote formation of reactive oxygen species (ROS) within
a cortical mitochondrial-synaptosomal (P2) fraction was completely abolished by the addition of
one five hundredth of its molarity of desferroxamine (DFO), a trivalent metal chelator. This large
ratio and the high specificity of DFO for trivalent metal ions discounted the possibility of
inhibition of ROS generation by direct sequestration of divalent manganese, and implied the
trace presence of a trivalent metal. Further analysis suggested that this trace metal was manganic
rather than ferric ion. Ferric ion was able to dampen the reactive oxygen species-generating
capacity of manganous chloride, whereas manganic ion markedly promoted this property
attributed to manganous ion. Such findings of the potent effects of trace amounts of trivalent
cations upon Mn2+-related free radical generation offer resolution of earlier disparate findings
concerning the oxidative character of manganese. (C) 2001 Elsevier Science Inc.
68. HaMai D, Rinderknecht AL, Guo-Sharman K, Kleinman MT, Bondy SC. (2006) Decreased
expression of inflammation-related genes following inhalation exposure to manganese.
Neurotoxicology 27(3):395-401.
Excessive exposure to manganese (Mn) by inhalation can induce psychosis and Parkinsonism.
The clinical manifestations of Mn neurotoxicity have been related to numerous physiological and
cellular processes, most notably dopamine depletion. However, few studies have explored the
molecular events that are triggered in response to exposure to Mn by inhalation. In this current
study, the transcriptional patterns of genes related to oxidative stress or inflammation were
examined in the brain rats of exposed to inhaled Mn during either gestation or early adulthood.
The expression of genes encoding for proteins critical to an inflammatory response and/or
possessing pro-oxidant properties, including TGF beta and nNOS, were slightly depressed by
prenatal exposure, whereas inhalation exposure to Mn during adulthood markedly down-
regulated their transcription. However, when exposures to manganese occurred during gestation,
the extent of altered gene expression induced by subsequent exposure to Mn in adulthood was
reduced. This suggests that prior exposure to Mn may have attenuated the effects of inhalation
exposure to Mn in adulthood, in which the expression of inflammation-related genes were
suppressed, (c) 2005 Elsevier Inc. All rights reserved.
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69. Hazell AS, Gros P, Normandin L, Yi JH. (2005) Focal accumulation of manganese is
correlated with levels of the divalent metal transporter-1 in manganese neurotoxicity. Journal of
Neurochemistry 94:100-100.
70. Hazell AS, Norenberg MD, Yi JH. (2004) Involvement of oxidative stress in astrocytic
changes in experimental sub-acute manganese neurotoxicity. Journal of Neurochemistry 90:15-
15.
71. Hazell AS, Normandin L. (2002) Up-regulation of'peripheral-type' benzodiazepine
receptors in the globus pallidus in manganese neurotoxicity. Journal of Neurochemistry 81:104-
104.
72. Higashi Y, Asanuma M, Miyazaki I, Hattori N, Mizuno Y, Ogawa N. (2004) Parkin
attenuates manganese-induced dopaminergic cell death. Journal of Neurochemistry 89(6): 1490-
1497.
Manganese as environmental factor is considered to cause parkinsonism and induce endoplasmic
reticulum stress-mediated dopaminergic cell death. We examined the effects of manganese on
parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin
in manganese-induced neuronal cell death. Manganese dose-dependently induced cell death of
dopaminergic SH-SY5Y and CATH.a cells and cholinergic Neuro-2a cells, and that the former
two cell types were more sensitive to manganese toxicity than Neuro-2a cells. Moreover,
manganese increased the expression of endoplasmic reticulum stress-associated genes, including
parkin, in SH-SY5Y cells and CATH.a cells, but not in Neuro-2a cells. Treatment with
manganese resulted in accumulation of parkin protein in SH-SY5Y cells and its redistribution to
the perinuclear region, especially aggregated Golgi complex, while in Neuro-2a cells neither
expression nor redistribution of parkin was noted. Manganese showed no changes in proteasome
activities in either cell. Transient transfection of parkin gene inhibited manganese- or manganese
plus dopamine-induced cell death of SH-SY5Y cells, but not of Neuro-2a cells. Our results
suggest that the attenuating effects of parkin against manganese- or manganese plus dopamine-
induced cell death are dopaminergic cell-specific compensatory reactions associated with its
accumulation and redistribution to perinuclear regions but not with proteasome system.
73. Hirata Y. (2002) Manganese-induced apoptosis in PC12 cells. Neurotoxicology and
Teratology 24(5):639-653.
Manganese has been known to induce neurological disorders similar to parkinsonisms for a long
time. Dopamine deficiency has been demonstrated in Parkinson's disease and in chronic
manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the
metal ion are related to dysfunction of the extrapyramidal system. However, the details of the
mechanisms have yet to be elucidated. In an effort to learn more about the toxicity of
manganese, we have employed an in vitro model that uses the PC 12 catecholaminergic cell line.
In this model, manganese induces apoptosis in PC12 cells. In this paper, experiments conducted
with this model, the cellular biochemical changes, and the mechanism of the cell death are
reviewed. (C) 2002 Elsevier Science Inc. All rights reserved.
74. Hirata Y, Adachi E, Kiuchi K. (1998) Activation of JNK pathway and induction of apoptosis
by manganese in PC12 cells. Journal of Neurochemistry 71(4): 1607-1615.
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Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine
deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning,
suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a
functional abnormality of the extrapyramidal system. However, the details have yet to be
elucidated. Here we report that manganese causes characteristic internucleosomal DNA
fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription
dependent, relatively specific for manganese, and blocked in Bcl-2-overexpressed PC12 cells,
The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated
with manganese, the first metal to be reported to induce this form of cell death. The early
biochemical events show the impairment of energy metabolism, and the process may require new
synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of
c-Jun at Ser(63) and Ser(73) and SEK1/MKK4 (c-Jun N-terminal kinase kinase) at Thr(258) and
tyrosine phosphorylation of several proteins. These results indicate that manganese activates
specific signal cascades including the c-Jun N-terminal kinase pathway
75. Hirata Y, Furuta K, Miyazaki S, Suzuki M, Kiuchi K. (2004) Anti-apoptotic and pro-
apoptotic effect of NEPP11 on manganese-induced apoptosis and JNK pathway activation in
PC12 cells. Brain Research 1021(2):241-247.
Neurite outgrowth-promoting prostaglandins (NEPPs), cyclopentenone prostaglandin
derivatives, are found to be neurotrophic. These small organic compounds promote neurite
outgrowth of PC 12 cells and dorsal root ganglion explants in the presence of nerve growth
factor, and prevent neuronal cell death of HT22 cells and cortical neurons induced by various
stimuli. In this study, we examined whether NEPP11 prevents manganese-induced apoptosis of
PC 12 cells. NEPP11 (5 muM) attenuated manganese-induced DNA fragmentation by
approximately 50%. In addition, NEPP 11 partially prevented manganese-induced c-Jun
phosphorylation and c-Jun N-terminal kinase (JNK) phosphorylation determined by Western
blotting. Inhibition of the JNK signaling pathway by NEPP 11 appeared to be selective, because
NEPP 11 did not inhibit manganese-induced activation of p38 mitogen-activated protein kinase
(p38 MAPK), extracellular signal-regulated kinasel/2 (ERK1/2), MEK1/2 and p70 S6 kinase
(p70S6K) in PC 12 cells. In contrast, NEPP11 alone was toxic at higher concentrations (>10
muM) producing DNA fragmentation and activation of the JNK pathway. Molecular
modifications of NEPP 11 may strengthen its inhibitory effects on the JNK pathway while
preventing its cytotoxicity, and thus may become a useful small molecule reagent for the
treatment of manganese toxicity and other similar neurodegenerative processes. (C) 2004
Elsevier B.V. All rights reserved.
76. Hirata Y, Kiuchi K, Nagatsu T. (2001) Manganese mimics the action of l-methyl-4-
phenylpyridinium ion, a dopaminergic neurotoxin, in rat striatal tissue slices. Neuroscience
Letters 3ll(l):53-56.
Manganese and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) are known to induce
neurological pathologies similar to that of parkinsonism. Previous studies performed in rat
striatal slices have shown that MPTP and related compounds inhibit tyrosine hydroxylation, a
rate-limiting step of dopamine biosynthesis. Here, we reported that manganese inhibited tyrosine
hydroxylation in rat striatal slices. In addition, manganese caused increase in the levels of lactate
indicating that aerobic glycolysis was inhibited in striatal slices. This inhibition was unique to
manganese since other divalent cations, such as magnesium and zinc, did not increase lactate
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concentrations. These results suggest that the mechanisms by which manganese produces
dysfunction of the nervous system are similar to those of MPTP. (C) 2001 Elsevier Science
Ireland Ltd. All rights reserved.
77. Hojo Y, Asano Y, Tonan Y. (1999) Manganese(II)-induced brain toxicity and paramagnetic
species. Japanese Journal of Toxicology and Environmental Health 45(1):P34-P34.
78. Hsiao WL, Mendosa G, Kothari NH, Fan H. (1996) Comparison of transformation by
manganese sulfate and 5-azacytidine in rat 6 cells overexpressing the c-myc oncogene.
Carcinogenesis 17(12):2771-2777
79. Huang CC, Weng YH, Lu CS, Chu NS, Yen TC. (2003) Dopamine transporter binding in
chronic manganese intoxication. Journal of Neurology 250(11): 1335-1339.
Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinson's
disease (PD). However, clinical manifestations of manganism also have some features different
from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. Tc-
99m-TRODAT-l is a cocaine analogue that can bind to the dopamine transporter (DAT) site
reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to
evaluate DAT function using Tc-99m-TRODAT-l to investigate the integrity of the presynaptic
dopaminergic terminals in manganese-induced parkinsonism. Brain Tc-99m-TRODAT-l single
photon emission computed tomography was performed in 4 patients with chronic manganese
intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy
volunteers served as abnormal and normal controls, respectively. Clinically, all manganism
patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinson's Disease Rating
Scale ranged between 19 and 64. The uptake values of the Tc-99m-TRODAT-l were 0.868+/-
0.136 in the right corpus striatum and 0.865+/-0.118 in the left, as compared with 0.951+/-0.059
and 0.956+/-0.058, respectively for the normal controls. The data were significantly higher than
0.250+/-0.070 and 0.317+/-0.066 respectively for the PD patients. Interestingly, there was a mild
decrease in the uptake of Tc-99m-TRODAT-l in the putamen and the ratio of putamen and
caudate when compared with the normal controls. Although the DAT shows a slight decrease in
the putamen of manganism patients as compared with that of the normal controls, the data
indicate that the presynaptic dopaminergic terminals are not the main target of chronic
manganese intoxication. In addition Tc-99m-TRODAT-l SPECT can provide a useful,
convenient and inexpensive tool for differentiation between chronic manganism and PD.
80. Husain M, Khanna VK, Roy A, Tandon R, Pradeep S, Seth PK. (2001) Platelet dopamine
receptors and oxidative stress parameters as markers of manganese toxicity. Human &
Experimental Toxicology 20(12):631-636.
The present study has been undertaken to investigate whether neurotoxic effects of manganese
(Mn) are reflected in platelets in rats to monitor the usefulness of platelet as peripheral model.
Exposure of rats to Mn (10 or 15 mg/kg bw, i.p.) for 45 days caused a significant increase in
membrane fluidity as evidenced by decrease in fluorescence polarisation in platelets (11% and
14%) and striatum (9% and 13%). These rats exhibited a significant increase in superoxide
dismutase activity both in platelets (24% and 37%) and striatum (31% and 42%), respectively, in
comparison to controls. Exposure of rats to Mn for 45 days (15 mg/kg bw, i.p.) caused a
significant decrease in reduced glutathione content (platelets 20%, striatum 24%) and catalase
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activity (platelets 35%, striatum 44%) compared to control rats. Rats exposed to Mn (10 or 15
mg/kg bw, i.p.) for 15 days exhibited a significant increase in dopamine receptors both in
platelets (55% and 40%) and striatum (38% and 31%). The results suggest that exposure to Mn
may alter the membrane functions and impair the anti-oxidant defense mechanism both in
platelets and brain. The study also suggests that dopaminergic mechanisms are impaired
following Mn exposure and such changes are reflected in platelets. Interestingly, parallel
changes both in striatum and platelets, as observed in the present study, strengthen the usefulness
of platelets as a peripheral neuronal model.
81. Isaac AO, Kawikova I, Bothwell ALM, Daniels CK, Lai JCK. (2006) Manganese treatment
modulates the expression of peroxisome proliferator-activated receptors in astrocytoma and
neuroblastoma cells. Neurochemical Research 31(11): 1305-1316.
Peroxisome proliferator-activated receptors (PPARs) play roles in neural cells by regulating
energy balance, cell proliferation and anti-oxidant responses although the molecular mechanisms
underlying such roles are unclear. Chronic exposure to excess manganese (Mn) leads to
neurotoxicity, although Mn-induced neurotoxic mechanisms have not been fully elucidated. We
hypothesized Mn neurotoxicity differentially alters the expression of PPARs. We investigated
the effects of manganese chloride treatment (0.01-4 mM) on protein expression of PPAR
isoforms (alpha, beta, and gamma) in human astrocytoma (U87) and neuroblastoma (SK-NSH)
cells. The two cell types expressed the 3 PPAR isoforms differentially: their expression of the
PPARs was altered by Mn-treatment. Furthermore, nuclear and cytosolic fractions derived from
the 2 cell types, with and without Mn-treatment, exhibited marked differences in the protein
content of PPARs. Our results constitute the first demonstration that the PPAR signaling
pathway may assume pathophysiological importance in Mn neurotoxicity.
82. Javorina A, Duhart H, Ali SF, Schlager JJ, Hussain SM. (2006) Assessment Of Manganese
Nanoparticle (Mn-40nm) In PC12 Cells. Toxicol Sci 90(1-S):319.
This study was designed to investigate whether manganese nanosize 40nm particles induce
dopamine (DA) depletion in PC12 cells. The cells were exposed to various (0-100 ug/ml)
concentrations of Mn-40nm, Mn-acetate and Ag-15nm for 24 hours. After exposure, MTT and
neurotransmitters such as DOPAC, HVA, 5HIAA, 5HT and DA were measured to examine the
toxicity and changes in levels of neurotransmitters. The MTT assay results demonstrated that
Ag-15nm displayed a significant toxicity at the 25 ug/ml dose, whereas Mn-40 nm displayed a
more moderate toxicity. However, Mn-40nm induced potent dose-dependent depletion of
dopamine. The dopamine depletion was compared with bulk manganese material that is known
to induce dopamine depletion. Mn-acetate induced dopamine depletion but the level of Mn-40nm
induced depletion was relatively higher. Ag-15nm did not show significant depletion of
dopamine although significant toxicity was evident as per the MTT assay. The results clearly
demonstrated that Mn-40nm induced dopamine depletion in a dose dependent manner when
compared to other nanomaterials. To better characterize the effects of the Mn- 40nm particles,
the cells were examined via an advanced optical illumination system, CytoViva. Mn-40nm
particles were observed to be internalized by the cells as well as attach to the cell surface.
Additionally, cells were grown in the presence of nerve growth factor (NGF) to determine the
effects of Mn-40nm on cell differentiation. These results indicate qualitative changes in the NGF
treated cells in response to Mn-40nm exposure.
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83. Kalea AZ, Harris PD, Klimis-Zacas DJ. (2005) Dietary manganese suppresses alpha(l)
adrenergic receptor-mediated vascular contraction. Journal of Nutritional Biochemistry 16(1):44-
49.
We examined the effect of dietary manganese (Mn) on the vascular contractile machinery in rat
thoracic aortas. Weanling male SpragueDawley rats were fed either an Mn-deficient (MnD), Mn-
adequate (MnA) or Mn-supplemented (MnS) diet (< 1, 10-15 and 45-50 ppm Mn, respectively).
After 15 weeks on the diets the rats were sacrificed and 3-min aortic rings were contracted in six
cumulative doses of the alpha(l), adrenergic receptor agonist L-phenylephrine (L-Phe, 10(-8) to
3 X 10(-6) M) under 1.5-g preload and relaxed with one dose of acetylcholine (3 x 10(-6) M) to
assess intact endothelium. The maximal force (F-max) of contraction and relaxation, as well as
the vessel sensitivity (pD(2)) were determined. Manganese deficiency, assessed by hepatic Mn
content, significantly lowered the rate of animal growth. A two-way analysis of variance
revealed that MnS animals developed lower F-max when contracted with L-Phe compared with
the MnD and MnA animals (Pless than or equal toOOl). Thus, dietary Mn at levels of 45-50 ppm
affects the contractile machinery by reducing maximal vessel contraction to an alpha(l)
adrenergic agonist. The observed pD(2) was significantly greater in the MnD group compared
with the MnA and MnS animals (Pless than or equal to.001). Thus, restriction of dietary Mn
affects vascular sensitivity to the alpha(l) adrenergic receptor. Our results demonstrate for the
first time that dietary Mn influences the receptor signaling pathways and contractile machinery
of vascular smooth muscle cells in response to an a, adrenergic receptor. (C) 2005 Elsevier Inc.
All rights reserved.
84. Kalea AZ, Schuschke DA, Harris PD, Klimis-Zacas DJ. (2006) Cyclooxygenase inhibition
restores endothelium-mediated vasodilation in manganese deficiency. Faseb Journal 20(4):A729-
A729.
85. Kanthasamy A, Choi C, Anantharam V, Kanthasamy A. (2006) Manganese upregulates
cellular prion proteins and inhibits the rate of proteinase-K dependent proteolysis in cell culture
models of prion diseases. Neurotoxicology 27(6): 1163-1164.
86. Keller J, Owens CT, Lai JCK, Devaud LL. (2005) The effects of 17 beta-estradiol and
ethanol on zinc- or manganese-induced toxicity in SK-N-SH cells. Neurochemistry International
46(4):293-303.
Serious neurodegenerative disorders are increasingly prevalent in our society and excessive
oxidative stress may be a key mediator of neuronal cell death in many of these conditions. A
variety of metals, such as manganese and zinc, are essential trace elements but can reach
localized toxic concentrations through various disease processes or environmental exposures and
have been implicated as having a role in neurodegeneration. Both manganese and zinc exist as
bivalent cations and are essential cofactors/activators for numerous enzymes. Evidence suggests
one action of these metals, when concentrated beyond physiological levels, may be to inhibit
cellular energy production, ultimately leading to increased radical formation. Our studies were
undertaken to directly investigate the toxic effects of manganese and zinc in an immortalized
neuronal-like cell line (SK-N-SH) by testing interactions with the antioxidant, 17beta-estradiol,
and the neurotoxin, ethanol. Employing undifferentiated SK-N-SH cells, we found that these
metals caused biphasic effects, enhancing cell proliferation at low doses and inducing cell death
at higher doses. Zinc was both more efficacious and more potent than manganese in enhancing
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growth and in causing cell death. 17beta-Estradiol and ethanol enhanced the proliferative actions
of zinc and manganese across a wide concentration range. Furthermore, co-treatment with either
17beta-estradiol or ethanol afforded protection against manganese-, but not zinc-induced
toxicity. Finally, combined administration of 17beta-estradiol and ethanol to SK-N-SH cells
resulted in both a loss of growth enhancement and protective properties that were observed when
these substances were administered individually. We also noted that the toxic effects occurred
more rapidly from zinc than manganese exposure. Taken together, these data suggest that
oxidative stress likely has a role in cell death resulting from toxic exposure to either zinc or
manganese, but there is a difference in the precise mechanism of their effects. (C) 2004 Elsevier
Ltd. All rights reserved.
87. Khan KN, Andress JM, Smith PF. (1997) Toxicity of subacute intravenous manganese
chloride administration in beagle dogs. Toxicologic Pathology 25(4):344-350.
Manganese (Mn), a naturally occurring essential trace element, is currently being used as a metal
complex for pharmaceutical and magnetic resonance imaging agents. Despite its popularity in
these practices, minimal attention has focused on possible toxicity of released free Mn ions,
which could occur if these agents decomplexed. There is especially limited information available
regarding acute toxicity of Mn in dogs. In this study, we performed an in-depth evaluation of
acute toxicologic potential of manganese chloride (MnC12) when administered as a 4-hr/day
intravenous infusion to male beagle dogs. The dose of MnC12 used (16 mg/kg/day) was
equivalent to approximately 3-5 times the daily dose of Mn typically administered in some of the
Mn-complexed agents. All routine toxicologic endpoints were evaluated, including
cardiovascular parameters. This dosing regimen resulted in the death or moribund sacrifice of all
the animals within 4 days of initiation of treatment. Clinical evidence of toxicity included loss of
appetite, reduction in blood pressure with reflex tachycardia, and a marked increase in liver
enzymes, beginning with the first dose and increasing in severity with successive doses. Gross
and histopathologic evaluations confirmed severe hepatotoxicity, which was characterized by
massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperplasia.
These results indicate that acute treatment of beagle dogs with MnC12 causes severe
hepatotoxicity and hypotension with reflex tachycardia and suggest that dogs are very sensitive
to toxic effects of Mn.
88. Kim Y, Park JK, Choi Y, Yoo CI, Lee CR, Lee H, Lee JH, Kim SR, Jeong TH, Yoon CS
and others. (2005) Blood manganese concentration is elevated in iron deficiency anemia patients,
whereas globus pallidus signal intensity is minimally affected. Neurotoxicology 26(1): 107-111.
Objectives: To determine whether blood manganese (Mn) concentration is elevated in patients
with iron deficiency anemia (IDA), and whether this affects signal intensities in the globus
pallidus. Methods: Twenty-seven patients with IDA and 10 control subjects were tested for
blood Mn, and brain magnetic resonance images (MRI) were also examined. Seventeen of the 27
patients were followed-up after iron therapy. Results: IDA patients had a mean blood Mn
concentration of 2.05 +/- 0.44 mug/dl, which was higher than controls. The mean pallidal index
(PI) of anemic patients was not different from that of controls. There was a correlation between
log blood Mn and PI (p = 0.384, P = 0.048; n = 27) in IDA patients. None of the patients showed
increased signals in the globus pallidus in Tl-weighted MRI Blood Mn levels decreased and
hemoglobin levels increased after iron therapy (P < 0.05). Conclusion: Although blood Mn is
elevated in IDA patients, there is no increase in globus pallidus MRI signal intensity. These
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findings stand in contrast to those of our other studies showing patients with chronic liver
disease or occupational Mn exposure have elevated signal intensities remarkably. (C) 2004
Elsevier Inc. All rights reserved.
89. Kralik A, Kirchgessner M, Eder K. (1995) The Effect of Manganese Deficiency on
Parameters of Thyroid-Hormone Metabolism in Rats. Journal of Animal Physiology and Animal
Nutrition-Zeitschrift Fur Tierphysiologie Tierernahrung Und Futtermittelkunde 73(5):269-275.
The effect of manganese deficiency on parameters of thyroid-hormone metabolism in rats The
effect of manganese deficiency on parameters of thyroid-hormone metabolism was examined in
two experiments with 24 male, weanling, Sprague Dawley rats per experiment. The animals
were fed a semisynthetic casein-based diet containing either 0.2 mg Mn/kg (manganese deficient
diet) or 40 mg Mn/kg (control diet). The activity of arginase in liver was chosen as the criterion
for determining the manganese status of the rats, and was clearly lowered in both experiments by
manganese deficiency. While being unchanged in experiment 1, the live weight of the
manganese-deficient animals at the end of experiment 2 was significantly reduced in contrast to
control. The concentration of T-3 in the serum of the deficient animals was decreased in
experiment 1, while tending to be increased in experiment 2. The concentration of T-4 in the
serum of the manganese-deficient rats was significantly decreased in both experiments
(experiment 1: -18 %; experiment 2: -31 %). The concentration of free T-4 in serum was not
changed by manganese deficiency. The activity of hepatic deiodinase was increased in both
experiments in manganese-deficient rats (experiment 1: 35 %, ns; experiment 2: 48 %). The
results of this investigation show a potential role for manganese in thyroid-hormone metabolism.
90. Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H. (1995) Manganese
and Chronic Hepatic-Encephalopathy. Lancet 346(8970):270-274.
Clinical observations and animal studies have raised the hypothesis that increased concentrations
of manganese (Mn) in whole blood might lead to accumulation of this metal within the basal
ganglia in patients with end-stage liver disease. We studied ten patients with liver failure (and
ten controls) by magnetic resonance imaging (MRI) and measurement of Mn in brain tissue of
three patients who died of progressive liver failure (and three controls) was also done. Whole
blood Mn concentrations in patients with liver cirrhosis were significantly increased (median
34.4 mu g/L vs 10.3 mu g/L in controls; p=0.0004) and pallidal signal intensity indices
correlated with blood Mn (R(s)=0.8, p=0.0058). Brain tissue samples reveal highest Mn
concentrations in the caudate nucleus, followed by the quadrigeminal plate and globus pallidus.
Mn accumulates within the basal ganglia in liver cirrhosis. Similarities between Mn
neurotoxicity and chronic hepatic encephalopathy suggest that this metal may have a role in the
pathogenesis of chronic hepatic encephalopathy. Further studies are warranted because the use of
chelating agents could prove to be a new therapeutic option to prevent or reverse this
neuropsychiatric syndrome.
91. KulkarniNarla A, Getchell TV, Schmitt FA, Getchell ML. (1996) Manganese and copper-
zinc superoxide dismutases in the human olfactory mucosa: Increased immunoreactivity in
Alzheimer's disease. Experimental Neurology 140(2): 115-125.
Superoxide dismutases are the cell's major enzymatic defenses against cytotoxic reactive oxygen
species and oxidative stress. Reactive oxygen species, which induce the expression of these
enzymes, leave been implicated in the neurodegeneration associated with Alzheimer's disease
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(AD), and individuals with AD exhibit early, severe deficits in olfactory ability. We used
immunohistochemistry to examine the cellular localization of manganese and copper-zinc
superoxide dismutases in the olfactory mucosae of nondemented young/middle-aged and old
subjects as well as age- and postmortem-interval matched nondemented elderly individuals and
those with AD. Tissues were obtained at autopsy from individuals ranging in age from 19 to 98
years old. Immunoreactivity for both enzymes was localized in olfactory receptor neurons,
sustentacular and basal cells in the olfactory epithelium, and in olfactory and extrinsic nerves,
Bowman's glands, and vascular endothelium in the lamina propria. Computer-assisted
quantitative analysis demonstrated that very intense immunoreactivity for both manganese and
copper-zinc superoxide dismutases occupied significantly more area, particularly near the
surface and in the basal region, of the olfactory epithelium from subjects with AD than from the
age- and postmortem interval-matched nondemented elderly subjects. The pronounced increase
in superoxide dismutase immunoreactivity in the olfactory epithelium of AD subjects suggests
that oxidative stress may be responsible, at least in part, for the olfactory deficits in subjects with
AD. (C) 1996 Academic Press, Inc.
92. Kumar R, Srivastava S, Agrawal AK, Seth PK. (1996) Alteration in some membrane
properties in rat brain following exposure to manganese. Pharmacology & Toxicology 79(1):47-
48.
Biosis copyright: biol abs. rrm research article rat toxicology manganese neurotoxins brain
membrane alteration manganese-induced central nervous system dysfunction membranes
toxicity nervous system disease
93. Lai JCK, Chan AWK, Minski MJ, Lim L. (1995) Trace-Metals in Brain Mitochondria and
Synaptosomes - Modulation by Manganese Toxicity. Faseb Journal 9(3):A446-A446.
94. Laurant P, Chanut E, Bobillier-Chaumont S, Gaillard E, Jacquot C, Trouvin JH, Berthelot A.
(2003) Attenuation of the development of DOCA salt hypertension by a high Mn intake in the
rat. Trace Elements and Electrolytes 20(3): 172-180.
The effects of a high Mn intake on blood pressure, vascular reactivity and central catecholamine
levels were studied in DOCA salt-hypertensive rats. High Mn intake inhibited blood pressure
elevation in DOCA salt rats but did not modify it in normotensive rats. The blood pressure-
lowering effect of Mn was associated with inhibited cardiac hypertrophy and increased
natriuresis. Pharmacological studies in blood vessels showed that high Mn intake normalized
vasoconstriction and sensitivity to norepinephrine of isolated and perfused mesenteric vascular
beds from DOCA salt rats. Furthermore, high Mn intake improved the endothelium- and NO-
dependent relaxation in isolated aortae from DOCA salt-hypertensive rats but not in those from
normotensive rats. Norepinephrine levels were higher in the hypothalamus of DOCA salt-
hypertensive rats than in those of normotensive rats, and high Mn intake decreased
norepinephrine levels in hypothalamus of DOCA salt rats. In conclusion, a high Mn intake
attenuated the development of hypertension with beneficial vascular and central effects.
Mechanisms related to the pathophysiological development of DOCA salt hypertension may be
involved.
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95. Layrargues GP, Rose C, Spahr L, Zayed J, Normandin L, Butterworth RF. (1998) Role of
manganese in the pathogenesis of portal-systemic encephalopathy. Metabolic Brain Disease
13(4):311-317.
Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy,
manganese emerges as a new candidate. In patients with chronic liver diseases, manganese
accumulates in blood and brain leading to pallidal signal hyperintensity on T-l-weighted
Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy
from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese
concentration. The intensity of pallidal MR images correlates with blood manganese and with
the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver
transplantation results in normalization of pallidal MR signals and disappearance of
extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an
increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction.
These findings suggest that the toxic effects of manganese contribute to extrapyramidal
symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity
are still speculative, but there is evidence to suggest that manganese deposition in the pallidum
may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects
of manganese chelation and/or of treatment of the dopaminergic deficit on neurological
symptomatology in these patients.
96. Ledig M, Copin JC, Tholey G, Leroy M, Rastegar F, Wedler F. (1995) Effect of manganese
on the development of glial cells cultured from prenatally alcohol exposed rats. Neurochemical
Research 20(4):435-441.
BIOSIS COPYRIGHT: BIOL ABS. Maternal alcohol abuse is known to produce retardation in
brain maturation and brain functions. Using cultured glial cells as a model system to study these
effects of alcohol we found an alcohol antagonizing property for manganese (Mn). Mn was
added to the alcohol diet (MnC12, 25 mg/1 of 20% v/v ethanol) of pregnant rats. Glial cells were
cultured during 4 weeks from cortical brain cells of pups born to these mothers. Several
biochemical parameters were examined: protein levels, enzymatic markers of glial cell
maturation (enolase and glutamine synthetase), superoxide dismutase a scavenger of free radicals
produced during alcohol degradation. The results were compared to appropriate controls. A
beneficent effect of Mn was observed for the pups weight which was no more significantly
different from the control values. Protein levels, enolase and glutamine synthetase activities were
increased mainly during the proliferative period when Mn was added to the alcohol diet compa
97. Lee B, Hiney JK, Pine MD, Srivastava VK, Dees WL. (2007) Manganese stimulates
luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site
and mechanism of action. Journal of Physiology-London 578(3):765-772.
We have shown recently that Mn2+ stimulates gonadotropin secretion via an action at the
hypothalamic level, and a diet supplemented with a low dose of the element is capable of
advancing the time of female puberty. In this study, we used an in vitro approach to investigate
the mechanism by which Mn2+ induces luteinizing hormone-releasing hormone (LHRH)
secretion from prepubertal female rats. Themedial basal hypothalamus from 30-day-old rats was
incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with
buffer alone or buffer plus either a nitric oxide synthase ( NOS) inhibitor (N-monomethyl-L-
arginine (NMMA); 300 or 500 mu M) or a soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4]
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oxadiazolo[4,3- a] quinoxalin-l-one(ODQ); 100 or 250 mu M) for another 30 min. Finally, the
incubation continued for a further 30 min, but in the presence of MnC12 (50 or 250 mu M) to
assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 mu M MnC12
stimulated LHRH release ( P < 0.05 and P < 0.01, respectively). The addition of 300-500 mu M
NMMA to the medium did not block Mn2+-stimulated release of LHRH, even with the higher
dose of MnC12. Furthermore, while 50, 100 and 250 mu M MnC12 all significantly induced
LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue,
an effect only observed with the highest dose. Taken together, these data suggest that Mn2+ is
not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn2+-
stimulated secretion of LHRH in a dose-dependent manner, indicating that GC is the site of
action of Mn2+. Additionally, we showed that Mn2+ stimulated cGMP and LHRH from the
same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 mu
M) inhibited Mn2+-induced LHRH release. These data demonstrate that the principal action of
Mn2+ within the hypothalamus is to activate sGC directly and/or as a cofactor with available
NO, hence generating cGMP and resulting in prepubertal LHRH release.
98. Lison D, Lardot C, Huaux F, Zanetti G, Fubini B. (1997) Influence of particle surface area
on the toxicity of insoluble manganese dioxide dusts. Archives of Toxicology 71(12):725-729.
The objective of this study was to examine the influence of specific surface area on the
biological activity of insoluble manganese dioxide (Mn02) particles. The biological responses to
various Mn02 dusts with different specific surface area (0.16, 0.5, 17 and 62 m(2)/g) were
compared in vitro and in vivo. A mouse peritoneal macrophage model was used to evaluate the
in vitro cytotoxic potential of the particles via lactate dehydrogenase (LDH) release. In vivo, the
lung inflammatory response was assessed by analysis of bronchoalveolar lavage after
intratracheal instillation in mice (LDH activity, protein concentration and cellular recruitment).
In both systems, the results show that the amplitude of the response is dependent on the total
surface area which is in contact with the biological system, indicating that surface chemistry
phenomena are involved in the biological reactivity. Freshly ground particles with a specific
surface area of 5 m(2)/g were also examined in vitro. These particles exhibited an enhanced
cytotoxic activity, which was almost equivalent to that of 62 m(2)/g particles, indicating that
undefined reactive sites produced at the particle surface by mechanical cleavage may also con
tribute to the toxicity of insoluble particles. We conclude that, when conducting studies to
elucidate the effect of particles on the lung, it is important for insoluble particles such as
manganese dioxide to consider the administered dose in terms of surface area (e.g. m(2)/kg)
rather than in gravimetric terms (e.g. mg/kg).
99. Liu XH, Buffington JA, Tjalkens RB. (2005) NF-kappa B-dependent production of nitric
oxide by astrocytes mediates apoptosis in differentiated PC12 neurons following exposure to
manganese and cytokines. Molecular Brain Research 14l(l):39-47.
Neuronal injury in manganisin is accompanied by activation of astroglia within the basal ganglia
that is thought to increase production of inflammatory mediators such as nitric oxide (NO). The
present studies Postulated that astroglial-derived NO mediates neuronal apoptosis induced by
manganese (Mn) and pro-inflammatory cytokines. Pheochromocytoma (PC12) cells
differentiated with nerve growth factor (NGF) were co-cultured with primary astrocytes and
exposed to Mn and tumor necrosis factor-alpha (TNF-alpha.) plus interferon-gamma (IFN-
gamma). Mn enhanced cytokine-indu[ced expression of inducible nitric oxide synthase (NOS2,
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EC 1.14.13.39) and production of NO in astrocytes that correlated with apoptosis in co-cultured
neurons, as determined by caspase activity, terminal deoxynucleotidyl transferase-mediated
dUTP-biotin nick-end labeling (TUNEL), and nuclear morphology. Apoptosis in PC12 neurons
required the presence of astrocytes and was blocked by overexpression of a phosphorylation-
deficient mutant Of I kappa B alpha (S32/36A) in astrocytes that prevented induction of NOS2.
Pharmacologic inhibition of NOS2 with (+/-)-2-amino-5,6-dihydro-6-methyl-4H-l,3-thiazine
(AMT) significantly reduced neuronal apoptosis, and the addition of low concentrations of the
NO donor, S-nitroso-N-acetylpenicillamine (SNAP), to neurons Cultured without astrocytes was
sufficient to recover the apoptotic phenotype following exposure to Mn and TNF-alpha/IFN-
gamma. It is concluded that Mn- and cytokine-dependent apoptosis in PC12 neurons requires
astroglial-derived NO and NF-kappa B-dependent expression of NOS2. (c) 2005 Elsevier B.V.
All rights reserved.
100. Malecki EA. (2001) Manganese toxicity is associated with mitochondrial dysfunction and
DNA fragmentation in rat primary striatal neurons. Brain Research Bulletin 55(2):225-228.
Manganese (Mn) in excess is toxic to neurons of the globus pallidus, leading to a Parkinsonian-
like syndrome. We used rat primary neuron cultures to examine the cellular events following
manganese exposure. Following exposure to Mn2+ for 48 h, striatal neurons showed dose-
dependent losses of mitochondrial membrane potential and complex II activity. The Mn
exposure effect on mitochondrial membrane potential was significant at every concentration
measured (5, 50, and 500 muM), and the manganese exposure effect on complex II activity was
significant at 50 and 500 muM. Exposure of striatal neurons to both Mn2+ and the complex II
inhibitor 3-nitropropionic acid resulted in additive toxicity. Striatal neurons exposed to 5 muM
Mn2+ for 48 h exhibited DNA fragmentation and decreases in the immunohistochemically
detectable microtubule-associated protein MAP-2. These results indicate that manganese may
trigger apoptotic-like neuronal death secondary to mitochondrial dysfunction. Rescue of neurons
by apoptosis inhibitors may be helpful in treating manganese toxicity and similar
neurodegenerative processes. (C) 2001 Elsevier Science Inc.
101. Malecki EA, Connor JR. (2000) Manganese (Mn) is toxic to rat striatal neurons in primary
culture. Journal of Neurochemistry 74:S76-S76.
102. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro
L. (1999) Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal Tl-
weighted magnetic resonance signal hyperintensity. Neurotoxicology 20(4):647-652.
The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic
resonance (MR) imaging has been postulated to arise from deposition of paramagnetic
manganese(2+) (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency;
iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the
relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic
liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary
sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha 1-antitrypsin deficiency
1). Signal hyperintensity in the pallidum on axial T1 weighted images repetition time/evolution
time: 500 ms/15ms was observed in 13 of 21 subjects: four patients had mild hyperintensity,
three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were
positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005).
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The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron
status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe
concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings
confirm the association of Mn with the development of pallidal hyperintensity in patients with
liver disease. We further found that iron deficiency is an exacerbating factor probably because of
increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver
disease avoid Mn supplements without concurrent iron supplementation. (C)1999 Intox Press,
Inc.
103. Malecki EA, Greger JL. (1996) Manganese protects against heart mitochondrial lipid
peroxidation in rats fed high levels of polyunsaturated fatty acids. Journal of Nutrition
126(l):27-33.
We demonstrated previously that dietary manganese (Mn) deficiency depressed Mn
concentrations in most tissues and consistently depressed Mn superoxide dismutase (MnSOD)
levels in heart. To examine the functional consequences of these effects, we fed weanling male
Sprague-Dawley rats (n = 12/diet) diets containing 20% (wt/wt) corn oil or 19% menhaden oil +
1% corn oil by weight and 0.75 or 82 mg Mn/kg diet for 2 mo (the fish oil mixture was
supplemented with +-(mixed)-alpha-tocopherol to the level in corn oil). Heart and liver Mn
concentrations in the Mn-deficient rats were 56% of those in Mn-adequate rats (P < 0.0001),
confirming Mn deficiency. The Mn-deficient rats had more conjugated dienes in heart
mitochondria than Mn-adequate rats (P < 0.001); rats fed fish oil had more conjugated dienes
than those fed corn oil (P < 0.001). The MnSOD activity was inversely correlated with
conjugated dienes (r = -0.71, P < 0.005), and Mn-deficient rats had 37% less MnSOD activity in
the heart than did Mn-adequate rats (P < 0.0001). The dietary treatments did not affect heart
microsomal conjugated diene formation, possibly because of compensation by copper-zinc
(CuZn) SOD activity; CuZnSOD activities were 35% greater in the hearts of Mn-deficient
animals (P < 0.01). Liver was less sensitive to Mn deficiency than was the heart as judged by
MnSOD activity and conjugated diene formation. This work is the first to demonstrate that
dietary Mn protects against in vivo oxidation of heart mitochondrial membranes.
104. Malecki EA, Lo HC, Yang H, Davis CD, Ney DM, Greger JL. (1995) Tissue Manganese
Concentrations and Antioxidant Enzyme-Activities in Rats Given Total Parenteral-Nutrition
with and without Supplemental Manganese. Journal of Parenteral and Enteral Nutrition
19(3):222-226.
Background: Manganese is an essential but potentially toxic mineral. Parenteral administration
of manganese via total parenteral nutrition (TPN) bypasses homeostatic mechanisms (intestinal
absorption and presystemic hepatic elimination). Our objective in this study was to determine the
effect of supplemental manganese in TPN solutions on manganese status in a rat model.
Methods: Male Sprague-Dawley rats underwent jugular catheterization and were given 61.0 +/-
0.4 g/d TPN solution providing 0.5 +/- 0.2 nmol manganese/g (Mn-; n = 6) or 16 +/- 3 nmol
manganese/g (Mn+; n = 7) for 7 days. Reference rats (RF; n = 8) were fed a purified diet
containing 1.3 mmol manganese/g. Results: Liver manganese decreased in both TPN groups, but
tibia, spleen, and pancreas manganese concentrations were greater in Mn+ rats than in Mn- or
RF rats. Although no treatment differences were seen in heart or liver manganese superoxide
dismutase activity, heart copper-zinc superoxide dismutase activity was lower in the Mn+ rats
than in Mn- or RF rats (p < .05). Glutathione peroxidase activity was depressed in livers of both
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Mn- and Mn+ rats relative to RF rats (p < .001), which was not due to selenium deficiency.
Conclusions: Supplemental parenteral manganese is taken up to a greater extent by peripheral
tissues than the liver. In this first report of antioxidant enzyme activities in animals maintained
with TPN, we found that TPN as well as supplemental manganese can influence antioxidant
enzyme activities. We conclude that it is generally unnecessary and potentially toxic to
supplement TPN solutions with manganese during short-term usage.
105. Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, Lai JCK. (2004)
Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid
(TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with
manganese-induced cell death. Neurochemical Research 29(4):709-717.
Manganese (Mn) is a trace metal required for normal growth and development. Manganese
neurotoxicity is rare and usually associated with occupational exposures. However, the cellular
and molecular mechanisms underlying Mn toxicity are still elusive. In rats chronically exposed
to Mn, their brain regional Mn levels increase in a dose-related manner. Brain Mn preferentially
accumulates in mitochondria; this accumulation is further enhanced with Mn treatment in vivo.
Exposure of mitochondria to Mn in vitro leads to uncoupling of oxidative phosphorylation.
These observations prompted us to investigate the hypothesis that Mn induces alterations in
energy metabolism in neural cells by interfering with the activities of various glycolytic and
TCA cycle enzymes using human neuroblastoma (SK-N-SH) and astrocytoma (U87) cells.
Treatments of SK-N-SH and U87 cells with MnC12 induced cell death in these cells, in a
concentration- and time-dependent manner, as determined by MTT assays. In parallel with the
Mn-induced, dose-dependent decrease in cell survival, treatment of these cells with 0.01 to 4.0
mM MnC12 for 48 h also induced dose-related decreases in their activities of hexokinase,
pyruvate kinase, lactate dehydrogenase, citrate synthase, and malate dehydrogenase. Hexokinase
in SK-N-SH cells was the most affected by Mn treatments, even at the lower range of
concentrations. Mn treatment of SK-N-SH cells affected pyruvate kinase and citrate synthase to
a lesser extent as compared to its effect on other enzymes investigated. However, citrate synthase
and pyruvate kinase in U87 cells were more vulnerable than other enzymes investigated to the
effects of Mn. The results suggest the two cell types exhibited differential susceptibility toward
the Mn-induced effects. Additionally, the results may have significant implications in flux
control because HK is the first and highly regulated enzyme in brain glycolysis. Thus these
results are consistent with our hypothesis and may have pathophysiological implications in the
mechanisms underlying Mn neurotoxicity.
106. Migheli R, Godani C, Sciola L, Delogu MR, Serra PA, Zangani D, De Natale G, Miele E,
Desole MS. (1999) Enhancing effect of manganese on L-DOPA-induced apoptosis in PC12
cells: Role of oxidative stress. Journal of Neurochemistry 73(3): 1155-1163.
L-DOPA and manganese both induce oxidative stress-mediated apoptosis in catecholaminergic
PC12 cells, in this study, exposure of PC12 cells to 0.2 mM MnC12 or 10-20 mu M L-DOPA
neither affected cell viability, determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay, nor induced apoptosis, tested by flow cytometry,
fluorescence microscopy, and the TUNEL technique. L-DOPA (50 mu M) induced decreases in
both cell viability and apoptosis. When 0.2 mM MnC12 was associated with 10, 20, or 50 mu M
L-DOPA, a concentration-dependent decrease in cell viability was observed, Apoptotic cell
death also occurred. In addition, manganese inhibited L-DOPA effects on dopamine (DA)
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metabolism (i.e., increases in DA and its acidic metabolite levels in both cell lysate and
incubation medium). The antioxidant N-acetyl-L-cysteine significantly inhibited decreases in
cell viability, apoptosis, and changes in DA metabolism induced by the manganese association
with L-DOPA, An increase in autoxidation of L-DOPA and of newly formed DA is suggested as
a mechanism of manganese action. These data show that agents that induce oxidative stress-
mediated apoptosis in catecholaminergic cells may act synergistically.
107. Miller KB, Caton JS, Finley JW. (2006) Manganese depresses rat heart muscle respiration.
Biofactors 28(l):33-46.
It has previously been reported that moderately high dietary manganese (Mn) in combination
with marginal magnesium (Mg) resulted in ultrastructural damage to heart mitochondria.
Manganese may replace Mg in biological functions, including the role of enzyme cofactor.
Manganese may accumulate and substitute for Mg during the condition of Mg-deficiency. The
objective of the current study was to determine whether high Mn alters heart muscle respiration
and Mg-enzyme activity as well as whole body Mn retention under marginal Mg. An additional
objective was to determine whether high Mn results in increased oxidative stress. In experiment
1: forty-eight rats were fed a 2 x 3 factorial arrangement of Mn (10, 100, or 1000 mg/kg) and Mg
(200 or 500 mg/kg). In experiment 2: thirty-two rats were fed one of four diets in a 2 x 2 factorial
arrangement of Mn (10 or 250 mg/kg) and Mg (200 or 500 mg/kg). In experiment 3: thirty-two
rats were fed one of four diets in a 2 x 2 factorial arrangement of Mn (10 or 650 mg/kg) and Mg
(200 or 500 mg/kg). In experiment 2, high Mn and marginal Mg reduced (P < 0.05) oxygen
consumption of left ventricle muscle. Marginal Mg, but not Mn, reduced (P < 0.05) activity of
sarcoplasmic reticulum calcium-ATPase enzyme. Dietary Mg had no affect on Mn-54 kinetics,
but high dietary Mn decreased (P < 0.01) absorption, retention, and rate of excretion of Mn-54.
Neither cellular stress, measured by Comet assay, nor antioxidant activities were increased by
high Mn. A strong interaction (P < 0.001) between increasing Mn and adequate Mg on
hematology was observed. These results confirm previous research in swine that high Mn alters
myocardial integrity as well as function, but not as a result of altered calcium transport or
oxidative stress.
108. Molina JA, Jimenez-Jimenez FJ, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-
Munoz MJ, de Bustos F, Porta J, Orti-Pareja M, Zurdo M and others. (1998) Cerebrospinal fluid
levels of transition metals in patients with Alzheimer's disease. Journal of Neural Transmission
105(4-5):479-488.
We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic
absorption spectrophotometry, in 26 patients patients with Alzheimer's disease (AD) without
major clinical signs of undernutrition, and 28 matched controls. CSF zinc levels were
significantly decreased in AD patients as compared with controls (p < 0.05). The serum levels of
zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly
between AD-patient and control groups. These values were not correlated with age, age at onset,
duration of the disease, and scores of the MiniMental State Examination in the AD group.
Weight and body mass index were significantly lower in AD patients than in controls. Because
serum zinc levels were normal, the possibility that low CSF zinc levels were due to a deficiency
of dietary intake seems unlikely. However, it is possible that they might be related to the
interaction of beta-amyloid and/or amyloid precursor protein with zinc, that could result in a
depletion of zinc levels.
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109. Montes S, Alcaraz-Zubeldia M, Muriel P, Rios C. (2001) Striatal manganese accumulation
induces changes in dopamine metabolism in the cirrhotic rat. Brain Research 891(1-2): 123-129.
Manganese (Mn) is an essential metal that, in excess, causes an extrapyramidal syndrome
consisting in tremor, rigidity and akinesia. Recently, Mn was found to accumulate in brains of
cirrhotic patients who also present motor abnormalities. Manganese alters dopaminegic
transmission promoting an increase in the turnover of dopamine (DA). In this study, we studied
the changes in dopamine and its main metabolite homovanillic acid (HVA) to evaluate DA
turnover following administration of manganese to bile-duct obstructed rats. Some groups of rats
were treated with manganese chloride in two concentrations: 0.5 and 1 mg/ml of Mn2+ in their
drinking water. Four weeks after surgery and treatment with manganese, striatal Mn, DA and
HVA were assessed. Marked increases (P<0.05) of striatal manganese content were observed in
cirrhotic rats treated and untreated with manganese, these augments were dependent on the Mn
concentration in water. Striatal contents of DA in cirrhotic rats diminished by 30% (P<0.05),
administration of 0.5 mg/ml of manganese in drinking water to these rats returned dopamine to
the basal level and 1 mg/ml of manganese increased dopamine content by 27%. The relationship
of Mn content and DA turnover (HVA:DA) in the same animal showed a positive and statically
significant correlation (P<0.05), with differences in slope for sham (b(l) = 0.1528) and cirrhotic
rats (b(l) = 0.0174). These results suggest that manganese brain accumulation observed in liver
failure could be a key element to understand dopamine metabolism in cirrhotic condition of
humans. (C) 2001 Elsevier Science B.V. All rights reserved.
110. Mutkus L, Aschner JL, Fitsanakis V, Aschner M. (2005) The in vitro uptake of glutamate
in GLAST and GLT-1 transfected mutant CHO-K1 cells is inhibited by manganese. Biological
Trace Element Research 107(3):221-230.
In the central nervous system (CNS), extracellular concentrations of amino acids (e.g., aspartate,
glutamate) and divalent metals (e.g., zinc, copper, manganese) are primarily regulated by
astrocytes. Adequate glutamate homeostasis and control over extracellular concentrations of
these excitotoxic amino acids are essential for the normal functioning of the brain. Not only is
glutamate of central importance for nitrogen metabolism but, along with aspartate, it is the
primary mediator of excitatory pathways in the brain. Similarly, the maintenance of proper Mn
levels is important for normal brain function. Brain glutamate is removed from the extracellular
fluid mainly by astrocytes via high affinity astroglial Na+-dependent excitatory amino acid
transporters, glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The
effects of Mn on specific glutamate transporters have yet to be determined. As a first step in this
process, we examined the effects of Mn on the transport of [D-2, 3-H-3]D-aspartate, a non-
metabolizable glutamate analog, in Chinese hamster ovary cells (CHO) transfected with two
glutamate transporter subtypes, GLAST (EAAT1) or GLT-1 (EAAT2). Mn-mediated inhibition
of glutamate transport in the CHO-K1 cell line DdB7 was pronounced in both the GLT-1 and
GLAST transfected cells. This resulted in a statistically significant inhibition (p < 0.05) of
glutamate uptake compared with transfected control in the absence of Mn treatment. These
studies suggest that Mn accumulation in the CNS might contribute to dysregulation of glutamate
homeostasis.
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111. Oikawa S, Hirosawa I, Tada-Oikawa S, Furukawa A, Nishiura K, Kawanishi S. (2006)
Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and
neuronal cell death. Free Radical Biology and Medicine 41(5):748-756.
Although the cause of dopammergic cell death in Parkinson's disease is still poorly understood,
there is accumulating evidence suggesting that metal ions can be involved in the processes. We
investigated the effect of manganese on cell death and DNA damage in Pdl2 ells treated with
dopamine. Mn(II) enhanced cell death induced by dopamine. Mn(II) also increased the 8-oxo-
7,8-dihydro-2-deoxyguanosine (8-oxodG) contents of DNA in PC12 cells treated with dopamine.
To clarify the mechanism of cellular DNA damage, we investigated DNA damage induced by
dopamine and Mn(II) using (32)p-labeled DNA fragments. Mn(II) enhanced Cu(II)-dependent
DNA damage by dopamine. The Mn(II)-enhanced DNA damage was greatly increased by
NADH. Piperidine and forrnamidopyrimidine-DNA glycosylase treatment induced cleavage sites
mainly at T and G of the 5'-TG-3' sequence, respectively. Bathocuproine, a Cu(I) chelator, and
catalase inhibited the DNA damage. Oxygen consumption and UV-visible spectroscopic
measurements showed that Mn(II) enhanced autoxidation of dopamine with H202 formation.
These results suggest that reactive species derived from the reaction of H202 with Cu(I)
participates in Mn(II)-enhanced DNA damage by dopamine plus Cu(II). Therefore, it is
concluded that oxidative DNA damage induced by dopamine in the presence of Mn(II), NADH,
and Cu(II) is possibly linked to the degeneration of dopaminergic neurons, (c) 2006 Elsevier Inc.
All rights reserved.
112. Oner G, Senturk UK. (1995) Reversibility of Manganese-Induced Learning Defect in Rats.
Food and Chemical Toxicology 33(7):559-563.
In this study the mechanism by which manganese (Mn) induces learning defect and its
reversibility has been investigated in rats. Female albino rats were dosed orally with 357 mu g
Mn/kg body weight for 15 or 30 days. Attempts were made to correct the Mn-induced learning
defect by (1) co-administration of mevinolin and Mn for 30 days;(2) administration of mevinolin
for 15 days after 15 days of dosing with Mn, and (3) by withdrawal of Mn treatment (15 days
dosing with Mn followed by 15 days without Mn). Mevinolin was given orally at 235.7 mu g/kg
body weight. Significant increases in the Mn and cholesterol levels in the hippocampus were
accompanied by an obvious slowness in learning of rats exposed to Mn. After one training
period (day 29) the time required to reach the exit of a T-maze was 104.5 +/- 13.8 sec for rats
dosed with Mn for 30 days, whereas that of the controls was 28.7 +/- 11.4 sec on day 30. This
delay was completely corrected (to 30.7 +/- 6.0 sec) in rats co-administered mevinolin (an
inhibitor of cholesterol biosynthesis) with Mn. Withdrawal of Mn, with or without inhibiting the
cholesterol biosynthesis, also corrected the Mn-induced learning defect. These results suggest
that Mn toxicity produces learning disability by increasing cholesterol biosynthesis and this
reversible disability in learning can be corrected by withdrawal of Mn exposure.
113. Papp A, Pecze L, Szabo A, Vezer T. (2006) Effects on the central and peripheral nervous
activity in rats elicited by acute administration of lead, mercury and manganese, and their
combinations. Journal of Applied Toxicology 26(4):374-380.
Adult male Wistar rats were treated with inorganic lead, mercury and manganese, and their
double combinations, in acute application. The aim was to study the effects on spontaneous and
stimulus-evoked cortical, and evoked peripheral, nervous activity, to detect any interaction of the
metals and any correlation between the changes caused in the spontaneous and stimulus-evoked
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electrical activity of the primary somatosensory cortical area, and the compound action potential
of the tail nerve. In the frequency distribution of the spontaneous cortical activity, a shift to
lower frequencies was seen. The cortical responses evoked by whisker or tail stimulation showed
an increase of the peak-to-peak amplitude and peak latency on administration of the metals and
metal combinations. With the metal combinations, synergism was observed. Correlations found
between alterations of the spontaneous and evoked, or between cortical and peripheral, activity
were evaluated in terms of mechanism. According to the results, combined exposure to the three
heavy metals studied might lead to synergistic action, indicating an increased health risk in
settings with exposure to several heavy metals. Copyright (c) 2006 John Wiley & Sons, Ltd.
114. Pascal LE, Tessier DM. (2004) Cytotoxicity of chromium and manganese to lung epithelial
cells in vitro. Toxicology Letters 147(2): 143-151.
Chromium, nickel and manganese are the predominant metals in welding fumes and are
associated through epidemiological studies with an increased risk for developing occupational
asthma due to welding activities. Here, we show that chromium(VI) and manganese, but not
nickel, are cytotoxic to normal human lung epithelial cells in vitro (SAEC and BEAS-2B), at
concentration ranges of 0.2-200 muM. The toxic effect was associated with increased levels of
intracellular phosphoprotein and subsequent release of inflammatory cytokines IL-6 and IL-8,
while no release of TNF-alpha was observed. Changes in intracellular phosphoprotein levels
occurred at concentrations below the cytotoxic effect. IL-6 and IL-8 production increased up to
4.4-fold relative to controls. IL-6 and IL-8 are released from lung epithelium to recruit cells of
the immune system to sites of tissue damage. Therefore, the observed effects of chromium(VI)
and manganese in lung epithelial cells demonstrate a mechanism through which the toxicity of
these metals to epithelial cells can result in recruitment of cells of the immune system. (C) 2003
Elsevier Ireland Ltd. All rights reserved.
115. Pecze L, Papp A, Nagymajtenyi L. (2004) Changes in the spontaneous and stimulus-
evoked activity in the somatosensory cortex of rats on acute manganese administration.
Toxicology Letters 148(1-2): 125-131.
In this work, acute effects of inorganic manganese exposure on nervous electrical activity of rats
were investigated. Young adult male Wistar rats were prepared for recording in anaesthesia and
spontaneous cortical as well as stimulus-evoked cortical and peripheral nervous activity was
recorded before and after i.p. administration of 25 and 50 mg/kg Mn2+. The alterations found
resulted possibly from several known neuronal effects of manganese. The frequency shift of
spontaneous cortical activity, and increased latency and decreased amplitude of the peripheral
nerve action potential, were probably due to the Mn2+-induced impairment of the mitochondria,
whereas the increased amplitude of the evoked cortical response, to the effect on glutamatergic
transmission. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
116. Puli S, Lai JCK, Edgley KL, Daniels CK, Bhushan A. (2006) Signaling pathways
mediating manganese-induced toxicity in human glioblastoma cells (U87). Neurochemical
Research 31(10): 1211-1218.
Although essential, manganese (Mn) intake in excess leads to neurotoxicity. Mn neurotoxicity
induces impairment of energy metabolism and ultimately cell death. Nevertheless, the signaling
mechanisms underlying Mn toxicity are unknown. Employing human glioblastoma (U87) cells,
we investigated several signaling pathways (ones promoting cellular proliferation and invasion)
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underlying Mn toxicity. Mn-treatment of U87 cells induced a down-regulation of MAPK
pathway but the AKT pathway was not markedly affected. Mn-treatment of these cells induced
decreases in their levels of c-Jun and c-Fos transcription factors and extracellular matrix
degrading enzymes like MMP-2, which are associated with glioblastoma invasiveness. Mn-
treatment also induced apoptosis in U87 cells. Thus, our results indicate that other than inducing
apoptosis in U87 cells, Mn exerts differential effects on several signaling pathways promoting
glioblastoma proliferation and invasion. Consequently, Mn may have pathophysiological roles in
inducing apoptosis and in blocking glioblastoma invasion. Our results may thus have therapeutic
implications.
117. Ramesh GT, Ghosh D, Gunasekar PG. (2002) Activation of early signaling transcription
factor, NF-kappaB following low-level manganese exposure. Toxicology Letters 136(2): 151-
158.
Occupational and environmental exposure to manganese (Mn2+) is an increasing problem. It
manifests neuronal degeneration characterized by dyskinesia resembling Parkinson's disease.
The study was performed to test the hypotheses whether exposure to Mn2+ alters cellular
physiology and promotes intracellular signaling mechanism in dopaminergic neuronal cell line.
Since transcription factors have been shown to play an essential role in the control of cellular
proliferation and survival, catecholaminergic rich pheochromocytoma (PC12) cells were used to
measure changes in the DNA binding activities of nuclear factor kappa B (NF-kappaB) by
electrophoretic mobility shift assay (EMSA) following Mn2+ (0.1-10 muM) exposure. Cells that
were exposed to Mn2+ produced five-fold-activation of transcription factor NF-kappaB DNA
binding activity. This remarkable increase was seen within 30-60 min period of Mn2+ exposure.
Activation of NF-kappaB DNA binding activity by Mn2+ at 1.0 muM correlated with proteolytic
degradation of the inhibitory subunit IkappaBalpha as evidenced in cytosol. Additional
experiments on NF-kappaB reporter gene assay also showed increased NF-kappaB gene
expression at 1.0 and 5.0 muM Mn2+ and this was completely blocked in the presence of NF-
kappaB translocation inhibitor, IkappaBalpha-DN supporting that NF-kappaB induction
occurred during Mn2+ exposure. In addition, Mn2+ exposure to PC 12 cells led to activation of
signal responsive mitogen activated proteinexposure. In addition, Mn2+ exposure to PC 12 cells
led to activation of signal responsive mitogen activated protein kinase kinase (MAPKK). These
results suggest that Mn2+ at a low dose appears to induce the expression of immediate early
gene, NF-kappaB through MAPKK by a mechanism in which IKBoc phosphorylation may be
involved.) (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
118. Rao KVR, Norenberg MD. (2004) Manganese induces the mitochondrial permeability
transition in cultured astrocytes. Journal of Biological Chemistry 279(31):32333-32338.
Manganese is known to cause central nervous system injury leading to parkinsonism and to
contribute to the pathogenesis of hepatic encephalopathy. Although mechanisms of manganese
neurotoxicity are not completely understood, chronic exposure of various cell types to
manganese has shown oxidative stress and mitochondrial energy failure, factors that are often
implicated in the induction of the mitochondrial permeability transition (MPT). In this study, we
examined whether exposure of cultured neurons and astrocytes to manganese induces the MPT.
Cells were treated with manganese acetate (10-100 muM), and the MPT was assessed by
changes in the mitochondrial membrane potential and in mitochondrial calcein fluorescence. In
astrocytes, manganese caused a dissipation of the mitochondrial membrane potential and
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decreased the mitochondrial calcein fluorescence in a concentration- and time-dependent
manner. These changes were completely blocked by pretreatment with cyclosporin A, consistent
with induction of the MPT. On the other hand, similarly treated cultured cortical neurons had a
delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in
astrocytes was blocked by pretreatment with antioxidants, suggesting the potential involvement
of oxidative stress in this process. Induction of the MPT by manganese and associated
mitochondrial dysfunction in astrocytes may represent key mechanisms in manganese
neurotoxicity.
119. Rao KVR, Pichili VB, Bellam N, Norenberg MD. (2006) Manganese upregulates
aquaporin-4 in cultured astrocytes: role of oxidative stress. Journal of Neurochemistry 96:129-
129.
120. Reaney SH, Kwik-Uribe CL, Smith DR. (2002) Manganese oxidation state and its
implications for toxicity. Chemical Research in Toxicology 15(9): 1119-1126.
Manganese (Mn) is ubiquitous in mammalian systems and is essential for proper development
and function, though it can also be toxic at elevated exposures. While essential biologic
functions of Mn depend on its oxidation state [e.g., Mn(II), Mn(III)], little is known about how
the oxidation state of elevated Mn exposures affect cellular uptake, and function/toxicity. Here
we report the dynamics of EPR measurable Mn(II) in fresh human plasma and cultured PC 12
cell lysates as a function of exposure to either manganese(II) chloride or manganese(III)
pyrophosphate, and the effects of exposure to Mn(II) versus Mn(III) on total cellular aconitase
activity and cellular Mn uptake. The results indicate that Mn(II) or Mn(III) added in vitro to
fresh human plasma or cell lysates yielded similar amounts of EPR measurable Mn(II). In
contrast, Mn added as Mn(III) was significantly more effective in inhibiting total cellular
aconitase activity, and intact PC 12 cells accumulated significantly more Mn when exposures
occurred as Mn(III)., Collectively, these data reflect the dynamic nature of Mn speciation in
simple biological systems, and the importance of Mn oxidation/speciation state in mediating
potential cellular toxicity. This study supports concern over increased environmental exposures
to Mn in different oxidation states [Mn(II), Mn(III), and Mn(IV)] that may arise from
combustion products of. the gasoline antiknock additive methycyclopentadienyl manganese
tricarbonyl (MMT).
121. Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C, Paez E, Crespo E. (2000)
Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats - A
morphometric and densitomeric study. European Journal of Obstetrics Gynecology and
Reproductive Biology 90(1):97-101.
Objective: The aim of this study was to examine the effect of manganese (Mn) alone and with
the addition of copper (Cu) in the inhibition of osteopenia induced by ovariectomy (OVX) in
rats. Study conditions: Four lots of 100-day-old female Wistar rats were divided into
experimental groups of 15 each. One group received a diet supplemented with 40 mg/kg of Mn
per kilogram of feed (OVX+Mn). The second group received the same diet as the first, but with
an additional 15 mg/kg of copper (OVX+Mn+Cu). The third group of 15 OVX and the fourth
group of 15 Sham-OVX received no supplements. At the conclusion of the 30-day experiment,
the rats were slaughtered and their femurs and fifth lumbar vertebrae were dissected. Femoral
and vertebral length were measured with caliper and bones were weighed on a precision balance.
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The bone mineral content (BMC) and bone density (BMD) of the femur (F-BMC, mg and F-
BMD, mg/cm(2)) and the fifth lumbar vertebra (V-BMC, mg and V-BMD, mg/cm(2)) were
measured separately with dual energy X-ray absorptiometry. Results: The F-BMD, mg/cm(2)
was lower in the OVX than in the Sham-OVX group (P<0.0001) and in the other two groups
receiving mineral supplements (P<0.005 in both). F-BMC, mg was significantly lower in the
OVX group than in the other three (P<0.0001 in all cases), Calculations for V-BMC, mg and V-
BMD, mg/cm(2) are similar to findings in the femur. Conclusions: These data show that a Mn
supplement is an effective inhibitor of loss of bone mass after OVX, both on the axial and the
peripheral levels, although this effect is not enhanced with the addition of Cu. (C) 2000 Elsevier
Science Ireland Ltd. All rights reserved.
122. Rojas P, Rios C. (1995) Short-term manganese pretreatment partially protects against 1-
methyl-4-phenyl-l,2,3,6-tetrahydropyridine neurotoxicity. Neurochemical Research
20(10):1217-1223.
l-Methyl-4-phenyl-l,2,3,6-tetrahydropyrine (MPTP) is a neurotoxin that induces parkinsonism
in human and non-human primates. Its mechanism of action is not fully elucidated. Recently, the
participation of trace metals, such as manganese, on its neurotoxic action has been postulated. In
this work, we studied the effect of manganese administration on the neurochemical consequences
of MPTP neurotoxic action. Male Swiss albino mice were treated with manganese chloride
(MnC12 . 4H(2)0; 0.5 mg/ml or 1.0 mg/ml of drinking water) for 7 days, followed by three
MPTP administrations (30 mg/Kg, intraperitoneally). Seven days after the last MPTP
administration, mice were sacrificed and dopamine and homovanillic acid contents in corpus
striatum were analyzed. Striatal concentration of dopamine was found increased by 60% in mice
pretreated with 0.5 mg/ml and 52% in the group treated of 1.0 mg/ml as compared versus
animals treated with MPTP only. Homovanillic acid content in both groups treated with
manganese was the same as those in control animals. The results indicate that manganese may
interact with MPTP, producing an enhancement of striatal dopamine turnover as the protective
effect of manganese was more pronounced in the metabolite than in the neurotransmitter.
123. Roth JA, Horbinski C, Higgins D, Lein P, Garrick MD. (2002) Mechanisms of manganese-
induced rat pheochromocytoma (PC 12) cell death and cell differentiation. Neurotoxicology
23(2): 147-157.
Mn is a neurotoxin that leads to a syndrome resembling Parkinson's disease after prolonged
exposure to high concentrations. Our laboratory has been investigating the mechanism by which
Mn induces neuronal cell death. To accomplish this, ire have utilized rat pheochromocytoma
(PC12) cells as a model since they possess much of the biochemical machinery associated with
dopaminergic neurons. Mn, like nerve growth factor (NGF), can induce neuronal differentiation
of PC 12 cells but Mn-induced cell differentiation is dependent on its interaction with the cell
surface integrin receptors and basement membrane proteins, vitronectin or fibronectin. Similar to
NGF Mn-induced neurtite outgrowth is dependent on the phosphorylation and activation of the
MAP kinases, ERKI and 2 (p44/42). Unlike NGF, Mn is also cytotoxic having an IC50 value of
similar to600 muM. Although many apoptotic signals are turned on by Mn, cell death is caused
ultimately by disruption of mitochondrial function leading to loss of ATP. RT-PCR and
immunoblotting studies suggest that some uptake of Mn into PC12 cells depends on the divalent
metal transporter 1 (DMTI). DMTI exists in trio isoforms resulting from alternate splicing of a
single gene product with one of the two mRNA species containing an iron response clement
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(IRE) motif downstream from the stop codon. The presence of the IRE provides a binding site
for the iron response proteins (IRPI and 2); binding of either of these proteins could stabilize
DMTI mRNA and would increase expression of the +IRE form of the transporter. Iron and Mn
compete for transport into PC 12 cells via DMTI, so removal of iron from the culture media
enhances Mn toxicity. The two isoforms of DMTI ( IRE) are distributed in different subcellular
compartments with the (+/-IRE) species selectively present in the nucleus of neuronal and
neuronal-like cells. (C) 2002 Elsevier Science Inc. All rights reserved.
124. Roth JA, Walowitz J. (1999) Mechanism of manganese-induced neurotoxicity and neurite
outgrowth in ratPC12 cells. Faseb Journal 13(4):A237-A237.
125. Seth K, Agrawal AK, Date I, Seth PK. (2002) The role of dopamine in manganese-induced
oxidative injury in rat pheochromocytoma cells. Human & Experimental Toxicology 21(3): 165-
170.
Reactive dopamine (DA) metabolites have been implicated in both Parkinson's disease and
manganese (Mn) neurotoxicity. RatPC12 and genetically modified PC12 (PC12M) cells capable
of producing higher DA content, on exposure to MnC12 (10(-6) M) for 72 hours, exhibited a
significant decrease in glutathione content. Activity of antioxidant enzyme catalase was also
inhibited following 24- and 72-hour MnC12 exposure. MnC12 caused a concentration-dependent
(10(-7) to 10(-3) M) loss in mitochondrial activity after 24 and 72 hours and an impaired DNA
synthesis after 72 hours with changes being more marked in PC12M cells. The results indicate
that the free-radical-mediated toxicity of Mn at cellular level involves down-regulation of
antioxidants in normal and DA-rich PC12 cells. PC12M cells appeared to be more sensitive than
PC12 cells.
126. Seth P, Husain MM, Gupta P, Schoneboom BA, Grieder FB, Mani H, Maheshwari RK.
(2003) Early onset of virus infection and up-regulation of cytokines in mice treated with
cadmium and manganese. Biometals 16(2):359-368.
A substantial database indicates that a large number of environmental pollutants, chemicals and
therapeutic agents to which organisms are exposed cause immunotoxicity. The suppression of
immune functions may cause increased susceptibility of the host to a variety of microbial
pathogens potentially resulting in a life-threatening state. Evaluation of the immunotoxic
potential of chemical xenobiotics is of great concern and, therefore, we have investigated the
impact of exposure of inorganic metals, specifically cadmium (Cd) and manganese (Mn) on
Encephalomyocarditis virus (EMCV), Semliki Forest virus (SFV), and Venezuelan Equine
Encephalitis virus (VEEV) infection. Pretreatment with a single, oral dose of Cd or Mn increased
the susceptibility of mice to a sub-lethal infection of these viruses as observed by increased
severity of symptoms and mortality compared to untreated controls. An early onset of virus
infection was found in brains of Cd and Mn treated animals. Histopathological observations of
the brain indicate evidence of inflammation and greater tissue pathology in Cd- or Mn-exposed
mice compared to control animals. Meningitis and vascular congestion was seen in virus infected
mice in all the metal treated groups, and further, the perivascular inflammation appeared earlier
in treated mice compared to control. Encephalitis was maximum in Cd pretreated mice.
Widespread environmental contamination of metals and the potential for their exposure and
subsequent infection of humans or animals is indicative that further studies of these and all other
metals are important to understand the effect of environmental pollution on human health.
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127. Smith DR, Whitman S, Reaney S, Kwik-Uribe C, Arnold C, Gwiazda R, Holman T. (2003)
2-D DIGE proteomic analsyes of mn exposure in dopamine and GABA producing cell lines:
Implications for Mn neurotoxicity. Toxicological Sciences 72:20-21.
128. Soliman EF, Slikker W, Ali SF. (1995) Manganese-Induced Oxidative Stress as Measured
by a Fluorescent-Probe - an in-Vitro Study. Neuroscience Research Communications 17(3): 185-
193.
The fluorescent probe, 2',7'dichlorofluorescein-diacetate (DCFH-DA) was used to quantitate the
formation of reactive oxygen species (ROS) in brain tissue. Sprague-Dawley rats were sacrificed
at different ages, postnatal day (PND) 1, 24, 41 and 4 and 18 months, and brains were dissected
into caudate nucleus (CN) and cerebellum (CE). In vitro exposure to Mn (0.2-2.0 mM) increased
the formation of ROS in brain synaptosomes at all ages. Age-related differences were found in
the formation of ROS between CN and CE. In PND 1 brain synaptosomes, Mn induced dose
dependent (0.2-2.0 mM) increases in the formation of ROS. This effect was also observed at
other ages in CN and CE, but at higher concentrations (0.8-2.0 mM). It may be concluded that
oxidative stress, as measured by ROS, may be a potential mechanism underlying the
neurotoxicity induced by Mn and that the neonatal rat brain may be more susceptible than the
adult rat brain.
129. Spranger M, Schwab S, Desiderato S, Bonmann E, Krieger D, Fandrey J. (1998)
Manganese augments nitric oxide synthesis in murine astrocytes: A new pathogenetic
mechanism in manganism? Experimental Neurology 149(l):277-283.
Since manganese (Mn2+) is known to be sequestered in glial cells, we investigated possible
neurotoxic mechanisms involving astrocytes in vitro. Low concentrations of Mn2+ were toxic
only in astrocyte-neuronal cocultures but not in pure astrocyte or neuronal cultures. As a possible
mediator of manganese-derived neurotoxicity, we measured the production of nitric oxide in
astrocytes. Manganese, but not other transition metals, dose dependently increased iNOS mRNA
and protein levels and the release of nitric oxide in activated astrocytes. This effect was specific
for astrocytes, since we observed no stimulation in microglial cells. The observations suggest
that besides the known inhibition of mitochondrial function the neurotoxic effect of manganese
in low concentrations might be mediated by the increased production of nitric oxide in
astrocytes. (C) 1998 Academic Press.
130. Stredrick DL, Stokes AH, Worst TJ, Freeman WM, Johnson EA, Lash LH, Aschner M,
Vrana KE. (2004) Manganese-induced cytotoxicity in dopamine-producing cells.
Neurotoxicology 25(4):543-553.
Manganese (Mn) is an essential metal that, at excessive levels in the brain, produces
extrapyramidal symptoms similar to those in patients with Parkinson's disease (PD). In the
present study, Mn toxicity was characterized in a human neuroblastoma (SK-N-SH) cell line and
in a mouse catecholaminergic (CATH.a) cell line. Mn was demonstrated to be more toxic in the
catecholamine-producing CATH.a cells (EC50 = 60 muM) than in non-catecholaminergic SK-N-
SH cells (EC50 = 200 muM). To test the hypothesis that the sensitivity of CATH.a cells to Mn is
associated with their dopamine (DA) content, DA concentrations were suppressed in these cells
by pretreatment with a-methyl-para-tyrosine (AMPT). Treatment for 24 h with 100 muM AMPT
decreased intracellular DA, but offered no significant protection from Mn exposure (EC50 = 60
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muM). Additional studies were carried out to assess if Mn toxicity was dependent on glutathione
(GSH) levels. CATH.a cells were significantly protected by the addition of 5 mM GSH (Mn
EC50 = 200 muM) and 10 mM N-acetyl cysteine (NAC) (Mn EC50 = 300 muM), therefore,
indirectly identifying intracellular ROS formation as a mechanism for Mn neurotoxicity. Finally,
apoptotic markers of Mn-induced cell death were investigated. DNA fragmentation, caspase-3
activation, and apoptosis-related gene expression were studied in CATH.a cells. No
internucleosomal fragmentation or caspase activation was evident, even in the presence of
supraphysiological Mn concentrations. cDNA hydridization array analysis with two differing Mn
concentrations and time points, identified no noteworthy mRAA inductions of genes associated
with programmed cell death. In conclusion, DA content was not responsible for the enhanced
sensitivity of CATH.a cells to Mn toxicity, but oxidative stress was implicated as a probable
mechanism of cytotoxicity. (C) 2003 Published by Elsevier Inc.
131. Suarez N, Walum E, Eriksson H. (1995) Cellular Neurotoxicity of Trivalent Manganese
Bound to Transferrin or Pyrophosphate Studied in Human Neuroblastoma (Sh-Sy5y) Cell-
Cultures. Toxicology in Vitro 9(5):717-721.
Previous studies have shown that cellular uptake of manganese is related to its binding to
transferrin. However, it is not known how transferrin binding influences manganese toxicity.
Therefore, the cytotoxic activity of manganese bound as manganic ion to either transferrin or
pyrophosphate was investigated in the cloned human neuroblastoma cell line SH-SY5Y. The
toxicity of the two compounds was studied as changes in cell growth and survival by lipid and
protein determinations. There was a significant difference in the toxicity between the two
complexes after 72 hr of exposure. The toxicity of the manganic-pyrophosphate (MnPPi)
complex differed from that of the manganic-transferrin (MnTf) complex by a factor of 2(IC50:
26 +/- 2.6 and 65 +/- 2.4 mu M, respectively). After 3 days of exposure to MnPPi and MnTf, the
mitochondrial integrity was monitored by the mitochondrial dehydrogenase activity. The two
manganese complexes reduced the enzyme activity to the same extent. Measurements of
membrane integrity, using (3)[H]-2-deoxy-D-glucose as a probe, showed an increase in the
membrane permeability of cells exposed to MnPPi for 60 min. Exposure to MnTf did not result
in any significant change in membrane permeability. These findings suggest that transferrin not
only mediates manganese transport into the neurone, but also protects the cell from damage
caused by the manganic ion. The increase in cell membrane permeability after MnPPi exposure
indicates that this complex may enter the cell. Furthermore, the results show that inhibited
mitochondrial function is part of the mechanism of manganese neurotoxicity.
132. Tomas-Camardiel M, Herrera AJ, Venero JL, Sanchez-Hidalgo MC, Cano J, Machado A.
(2002) Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase
mRNA expression in the aged manganese-treated rats. Molecular Brain Research 103(1-2): 116-
129.
Recent studies have implicated chronic elevated exposures to environmental agents, such as
metals (e.g. manganese, Mn) and pesticides, as contributors to neurological disease. Eighteen-
month-old rats received intraperitoneal injections of manganese chloride (6 mg Mn/kg/day) or
equal volume of saline for 30 days in order to study the effect of manganese on the dopamine-
and GABA-neurons. The structures studied were substantia nigra, striatum, ventral tegmental
area, nucleus accumbens and globus pallidus. First, we studied the enzymatic activity of
mitochondrial complex 11 succinate dehydrogenase (SDH). We found an overall decrease of
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SDH in the different brain areas analyzed. We then studied the mRNA levels for tyrosine
hydroxylase (TH) and the dopamine transporter (DAT) by in situ hybridization. TH mRNA but
not DAT mRNA was significantly induced in substantia nigra and ventral tegmental area
following Mn treatment. Correspondingly, TH immunoreactivity was increased in substantia
nigra and ventral tegmental area. Manganese treatment significantly decreased GAD mRNA
levels in individual GABAergic neurons in globus pallidus but not in striatum. We also
quantified the density of glial fibrillary acidic protein (GFAP)-labeled astrocytes and OX-42
positive cells. Reactive gliosis in response to Mn treatment occurred only in striatum and
substantia nigra and the morphology of the astrocytes was different than in control animals.
These results suggest that the nigrostriatal system could be specifically damaged by manganese
toxicity. Thus, changes produced by manganese treatment on 18-month-old rats could play a role
in the etiology of Parkinson's disease. (C) 2002 Elsevier Science B.V. All rights reserved.
133. Vettori MV, Gatti R, Orlandini G, Belletti S, Alinovi R, Smargiassi A, Mutti A. (1999) An
in vitro model for the assessment of manganese neurotoxicity. Toxicology in Vitro 13(6):931-
938.
PC12 (undifferentiated and differentiated) and C6 cells have been used to investigate kinetics,
morphological and functional endpoints following exposure to MnC12 and manganic transferrin
(Mn-Tf). [Mn](i) in undifferentiated (non-differentiated cells) exposed to both free (MnC12) and
bound Mn (Mn-Tf), was three- to fivefold lower as compared to differentiated (differentiated)
PC12 cells and higher by one order of magnitude as compared to glial C6 cells. Exposure to both
MnC12 and Mn-Tf was followed by time- and dose-dependent morphological changes
characteristic of apoptosis, which was never observed in Mn-exposed C6 glial cells. Results
from cell viability assays were consistent with apoptotic response rates quantified by cell count.
Threshold concentrations for undifferentiated and differentiated PC12 cells were 10(-6) and 10(-
5) M, respectively. Thus, despite their greater ability to accumulate Mn, differentiated PC 12
cells are less sensitive to Mn-induced apoptosis. This model might be relevant to neuronal
degeneration induced by Mn occurring in the developing brain and possibly in clinical
manganism. Such critical doses at the cellular level seem to be consistent with Mn levels (5 x
10(-6) M) recorded in the basal ganglia of monkeys chronically exposed to Mn and developing
clinical signs of manganism. (C) 1999 Elsevier Science Ltd. All rights reserved.
134. Vidal L, Alfonso M, Campos F, Faro LRF, Cervantes RC, Duran R. (2005) Effects of
manganese on extracellular levels of dopamine in rat striatum: An analysis in vivo by brain
microdialysis. Neurochemical Research 30(9): 1147-1154.
The aim of this study is to determine the effects of intrastriatal administration of MnC12, on the
extracellular levels of dopamine (DA) and metabolites dihydroxyphenylacetic acid (DOPAC)
and homovanillic acid (HVA) in basal conditions and stimulated by depolarization with KC1 and
pargyline administration. Also, we studied the effect of MnC12 on extracellular levels of 1-Dopa
in the presence of aromatic amino acid decarboxylase (AADC) inhibitor 3-
hydroxybencilhydracine-HCl (NSD 1015). This study concluded that MnC12, reduced the basal
and K+-stimulated DA-release in striatum, without notably affecting the DOPAC and HVA
levels. Intraperitoneal injection of pargyline increased striatal DA levels, decreasing DOPAC
and HVA levels. The infusion of MnC12 removed the increase in DA levels, without affecting
DOPAC and HVA levels. Perfusion of NSD 1015 increased the extracellular levels of L-DOPA
in striatum, and MnC12 increased the effect of NSD1015 on L-Dopa.
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135. Wang RG, Zhu XZ. (2003) Subtoxic concentration of manganese synergistically
potentiates l-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells. Brain Research
961(1): 131-138.
Endogenous or exogenous substances that are toxic to dopaminergic cells have been proposed as
possible cause of idiopathic Parkinson's disease (PD). l-Methyl-4-phenylpyridinium (MPP+)
and manganese are dopaminergic neurotoxins causing a parkinsonism-like syndrome. Here, we
studied the possible synergistic reaction between these two neurotoxins using rat PC12
pheochromocytoma cells. MPP+ induced a delayed neurotoxicity in PC12 cells. Although low
concentration of manganese did not cause cell damage, it markedly enhanced MPP+-induced
neurotoxicity with characteristics of apoptosis, such as DNA laddering and activation of caspase-
3. To understand the mechanism of enhancement of subtoxic concentration of manganese on
MPP+-induced neurotoxicity, we investigated the reactive oxygen species (ROS) generation
using a molecular probe, 2',7'-dichlorofluorescein diacetate. Although subtoxic concentration of
manganese alone did not induce ROS increase, it significantly enhanced the ROS generation
induced by MPP+. We also determined the intracellular MPP, content. A time- and
concentration-dependent increase of MPP+ levels was found in PC12 cells treated with MPP+.
The accumulation of MPP+ by PC12 cells was not affected by manganese. Taken together, these
studies suggest that co-treatment with MPP+ and manganese may induce synergistic
neurotoxicity in PC12 cells and that subtoxic concentration of manganese may potentiate the
effect of MPP+ by an ROS-dependent pathway. (C) 2002 Elsevier Science B.V. All rights
reserved.
136. Yang HJ, Wang TN, Li JY, Gu L, Zheng XX. (2006) Decreasing expression of alpha(lc)
calcium L-type channel subunit mRNA in rat ventricular myocytes upon manganese exposure.
Journal of Biochemical and Molecular Toxicology 20(4): 159-166.
Manganese is an essential trace element found in many enzymes. As it is the case of many
essential trace elements, excessive level of manganese is toxic. It has been proven that excessive
manganese could cause heart problems. In order to understand the mechanism of manganese
toxicity in the heart, the effects of manganese on isolated rat ventricular myocytes were studied.
The L-type calcium channel current was measured by whole-cell patch clamp recording mode. In
the electrophysiology experiments, both 50 mu M Mn2+ and 100 mu M Mn2+ could effectively
decrease the channel current amplitude density by 35.7% and 68.2%, respectively. Moreover,
Mn2+ shifted the steady-state activation curve toward more positive potential and the steady-
state inactivation curve toward more negative potential. Investigation by RT-PCR showed that
the mRNA expression of alpha(lC)/Cavl.2 treated with manganese was decreased depending on
its concentration, while the mRNA expression of alpha(lD)/Cavl.3 was almost unchanged.
Fluo-3/AM was utilized for real-time free calcium scanning with laser scanning confocal
microscopy (LSCM), and the results showed that Mn2+ could elicit a slow and continuous
increase of [Ca2+](i) in a concentration-dependent manner. These results have suggested that
manganese could interfere with the function of the L-type calcium channel, downregulate the
mRNA expression of alpha(lC)/Cavl.2, and thus causing long-lasting molecular changes of L-
type calcium channel which have probably been triggered by overloading of calcium in
myocytes, (c) 2006 Wiley Periodicals, Inc.
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137. Yazbeck C, Moreau T, Sahuquillo J, Takser L, Huel G. (2006) Effect of maternal
manganese blood levels on erythrocyte calcium-pump activity in newborns. Science of the Total
Environment 354(l):28-34.
Manganese (Mn) is widely distributed in the biosphere but occurs in only trace amounts in
animal tissues. Although Mn deficiency and toxicity both have pathological consequences, the
underlying biochemical lesions have not been well defined. In vitro studies suggest that transport
proteins are affected by Mn, lead (Pb), and selenium (Se). Among these transport proteins, the
calmodulin-regulated calcium pump (Ca(2+)Mg(2+)ATPase) could be inhibited by Mn. In order
to understand Mn biochemical pathways, we examined the relationships between Mn blood
levels and red blood cell Ca-pump activity among 248 mothers and newborns, environmentally
exposed to Mn, Pb, and Se. Population and methods: 248 mother-newborn pairs were recruited at
Robert Debre University Hospital (Paris). Blood Mn and Pb concentrations were measured by
absorption spectrophotometry. Se was measured by fluorometric method. Red blood cell
membrane suspensions were obtained for Ca-pump activity measurements. Linear and quadratic
regression models and Pearson correlation were performed. Results: A non-linear parabolic
relationship between maternal Mn blood levels and newborn Ca-pump activity was discovered
from the analysis of the observed data. The peak level of maternal Mn that corresponded to a
maximal activity of the newborn Ca-pump was estimated at 23.9 mu g/1 with a 95% confidence
interval of 17.6 to 32.4 mu g/1. An inhibition of this enzyme was observed at low and high levels
of maternal Mn. The relationships between the newborn Ca-pump activity and maternal Se and
Pb levels became non-significant after adjustment on all the co-factors included in the final
model. Conclusion: Maternal environmental exposure to Mn, as reflected by maternal blood
levels of this metal, is associated with a reduced activity of newborn erythrocyte Ca-pump in a
non-linear pattern. Mn levels between 17.6 and 32.4 mu g/1 in maternal blood probably
correspond to the optimal physiological concentration for the metabolism of this enzyme in
newborns, (c) 2004 Elsevier B. V. All rights reserved.
138. Yoritaka A, Hattori N, Mori H, Kato K, Mizuno Y. (1997) An immunohistochemical study
on manganese superoxide dismutase in Parkinson's disease. Journal of the Neurological Sciences
148(2): 181-186.
We report an immunohistochemical study on manganese superoxide dismutase (Mn SOD) in
Parkinson's disease (PD) patients and age-matched control subjects. Overall appearance of
immunostaining intensity of nigral neurons did not differ significantly between the PD patients
and the control subjects. However, when the immunostaining intensity of each neuron was
semi quantitatively analyzed, both very intensely stained (more than normal) neurons as well as
neurons stained only weakly were more frequently detected in the lateral part than in the medial
and the central parts of the substantia nigra in PD patients. As a result, the proportion of
normally stained neurons was significantly smaller in the lateral part of the substantia nigra in
PD patients; however, the overall distribution of the neurons among the three rating grades for
immunostaining did not differ significantly. The immunostaining intensity of the neuropils in the
medial and the central part of the substantia nigra tended to be more intense in PD patients than
in the control subjects. Our results suggest up-regulation of Mn SOD mainly in the dendritic
processes of the less involved nigral neurons. (C) 1997 Elsevier Science B.V.
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139. Zaidi S, Patel A, Mehta N, Patel K, Takiar R, Saiyed H. (2005) Early biochemical
alterations in manganese toxicity: Ameliorating effects of magnesium nitrate and vitamins.
Industrial Health 43(4):663-668.
Manganese-induced early biochemical changes and effects of supplementation of magnesium
nitrate (Mg(N03)(2)) and antioxidant vitamins (A, C, D and E) were studied in rats intoxicated
with manganese. Significant elevation in the level of chlorides in plasma, erythrocytes, liver and
cerebellum, and a decrease in plasma inorganic phosphate (pi) with an increase in liver pi were
observed in animals exposed to manganese as compared to controls. The level of erythrocyte-
acid labile phosphate (ALP), nicotinamide adeninedinucleotide (NAD(+)) and plasma sialic acid
(N-acetyneuraminic acid, NANA) also increased significantly. Elevated levels of chlorides in
plasma, erythrocytes and cerebellum reversed to normal control values whereas liver chlorides
restored partially by the supplementation of Mg(N03)(2). Vitamins supplementation was
effective to reverse chlorides level in erythrocytes, liver and cerebellum. Decreased level of pi in
plasma and the highly elevated level of erythrocyte ALP were also recovered in animals received
Mg(N03)(2) in addition to MnS04. However, such effect of Mg(N03)(2) was not seen in
lowering the elevated level of NANA that restored by the administration of vitamins. Thus, the
early alterations in plasma levels of chlorides, pi, and NANA and erythrocyte-ALP seem to be an
indicative of early manganese toxicity while Mg(N03)(2) and vitamins supplementation appear
to provide, at least in part, protection against manganese toxicity.
140. Zaloglu N, Koc E, Yildirim G, Bastug M, Ficicilar H. (2003) How does chronic manganese
chloride application affect the rat isolated ileal contractility? Trace Elements and Electrolytes
20(3):154-159.
In this study, we investigated the effects of chronic manganese chloride (MnC12) application at
high dosage on the mechanical responses evoked by acetylcholine (2.7 x 10(-7) M) on isolated
rat ileum in standard and calcium-free tyrode perfusion solutions with diltiazem (5.5 x 10(-7) M)
and non-diltiazem mediums. In the experimental group (n = 10), MnC12 (50 mg/kg/day) was
injected for 50 days intraperitoneally. Acetylcholine-induced contraction amplitude increased
significantly with respect to that of the control in standard tyrode perfusion medium. When ileal
segments were pre-incubated with diltiazem, the amplitude of acetylcholine-induced contractions
decreased in experimental and control groups with respect to those of the standard mediums. In
calcium-free medium, pretreatment with diltiazem did not cause any change in acetylcholine-
induced contractions. Our data suggested that manganese (Mn2+) might have penetrated through
cell membrane and accumulated in the cell when, manganese was applied chronically and
overdose. Increase in plasma manganese level might have induced the increase in manganese
influx whereas calcium influx might have been induced by manganese itself The increase in
contraction amplitude maybe attributed to this phenomenon.
141. Zhang SR, Fu JL, Zhou ZC. (2004) In vitro effect of manganese chloride exposure on
reactive oxygen species generation and respiratory chain complexes activities of mitochondria
isolated from rat brain. Toxicology in Vitro 18(l):71-77.
Manganese (Mn) is known to induce mitochondrial dysfunction in excessive dose; however the
mechanisms underlying its action are not elucidated clearly. To determine if Mn2+ can act
directly on mitochondria or indirectly by producing reactive oxygen species (ROS), isolated
mitochondria were exposed to different concentration of Mn 21 (5, 50, 500, 1000 muM). ROS
generation, respiratory control ratio (RCR), mitochondrial membrane potential (MMP) and
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respiratory chain complexes activities were investigated. Dose-dependent inhibition of
respiratory chain complexes and induction of ROS were observed; these changes were paralleled
by decreasing of respiratory control ratio (RCR) both with succinate or glutamate + malate.
Further investigation indicated that the membrane potential determined by Rhodaminel23
release decreased after MnC12 exposure at 1000 muM. In addition, effects of the antioxidants
NAC (500 muM), GSH (500 muM) and Vitamin C (500 muM) were studied at 500 muM Mn2+.
The results indicate that the effect of Mn2+ exposure on respiratory chain is not site-specific,
and antioxidants can protect the mitochondria function by reducing the formation of free
radicals. (C) 2003 Elsevier Ltd. All rights reserved.
142. Zhang SR, Zhou ZC, Fu JL. (2003) Effect of manganese chloride exposure on liver and
brain mitochondria function in rats. Environmental Research 93(2): 149-157.
Manganese (Mn) is an essential trace element found in many enzymes. As is the case for many
essential trace elements, excessive Mn is toxic. Individuals suffering from manganese toxicity
exhibit several symptoms, which are similar to those frequently observed in cases of Parkinson's
disease. In this investigation, we studied the effect of manganese chloride (7.5, 15.0, and 30.0
mg/kg body weight) on mitochondrial function and attempted to ascertain the mechanism of
manganese-induced mitochondrial dysfunction. The production of reactive oxygen species in
mitochondria of rat liver and brain was assayed using 2,7'-dichlorofluorescin diacetate, and the
activities of respiratory chain enzymes were examined spectrophotometrically. Monoamine
oxidase (MAO) activity was assayed by measuring reduction of benzylamine. Manganese and
calcium content in mitochondria were determined by atomic absorption spectrophotometry.
These results indicate that manganese chloride (MnC12) can decrease MAO activity and inhibit
the respiratory chain. Manganese can accumulate in mitochondria and inhibit efflux of calcium.
There is a significant inverse correlation between the amount of superoxide radicals and the
specific activities of the mitochondria enzymes. Mitochondrial function was significantly
affected in both males and females. (C) 2003 Elsevier Inc. All rights reserved.
143. Zheng W, Zhao QQ. (2001) Iron overload following manganese exposure in cultured
neuronal, but not neuroglial cells. Brain Research 897(1-2): 175-179.
Our previous studies show that manganese (Mn) exposure inhibits aconitase, an enzyme
regulating the proteins responsible for cellular iron (Fe) equilibrium. This study was performed
to investigate whether Mn intoxication leads to an altered cellular Fe homeostasis in cultured
neuronal or neuroglial cells as a result of disrupted Fe regulation. Our results reveal a significant
increase in the expression of transferrin receptor (TfR) mRNAs and a corresponding increase in
cellular Fe-59 net uptake by PC 12 cells, but not astrocytes, following Mn exposure. These
findings suggest that alteration by Mn of cellular Fe homeostasis may contribute to Mn-induced
neuronal cytotoxicity. (C) 2001 Elsevier Science B.V. All rights reserved.
144. Zhong WX, Yan T, Webber MM, Oberley TD. (2004) Alteration of cellular phenotype and
responses to oxidative stress by manganese superoxide dismutase and a superoxide dismutase
mimic in RWPE-2 human prostate adenocarcinoma cells. Antioxidants & Redox Signaling
6(3):513-522.
To study biologic effects of increased manganese superoxide dismutase (MnSOD) on cell
behavior, we overexpressed MnSOD in a human prostate cancer cell line RWPE-2 by cDNA
transfection. Stable transfectants of MnSOD showed a two- to threefold increase in MnSOD
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protein and enzymatic activity and a decrease in growth rate with prolonged cell population
doubling times. Western blot analysis showed a 1.5- to twofold increase in the cyclin-dependent
kinase inhibitor p21(Wafl) in MnSOD transfectants. Overexpression of MnSOD resulted in a
seven- to eightfold increase in reduced glutathione (GSH), 18- to 26-fold increase in oxidized
glutathione (GSSG), and a two- to threefold decrease in the ratio of GSH to GSSG. MnSOD-
overexpressing cells showed an increase in sensitivity to the cytotoxicity of buthionine
sulfoximine, a glutathione-depleting agent, and vitamin C, but a decrease in sensitivity to sodium
selenite. Treatment with a superoxide dismutase (SOD) mimic MnTMPyP resulted in similar
effects of MnSOD overexpression on cell responses to vitamin C and selenium. These data
demonstrate that overexpression of MnSOD or treatment with SOD mimics can result in
antioxidant or prooxidant effects in cells, depending on the presence of other antioxidants and
prooxidants. MnSOD also has redox regulatory effects on cell growth and gene expression.
These findings suggest that MnSOD and SOD mimics have the potential for cancer prevention or
treatment.
145. Zwingmann C, Leibfritz D, Hazell AS. (2003) Altered metabolic trafficking via glutamine-
glutamate-cycle between astrocytes and neurons in manganese neurotoxicity. Journal of
Neurochemistry 87:142-142.
146. Zwingmann C, Leibfritz D, Hazell AS. (2003) Energy metabolism in astrocytes and
neurons treated with manganese: Relation among cell-specific energy failure, glucose
metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis.
Journal of Cerebral Blood Flow and Metabolism 23(6):756-771.
A central question in manganese neurotoxicity concerns mitochondrial dysfunction leading to
cerebral energy failure. To obtain insight into the underlying mechanism(s), the authors
investigated cell-specific pathways of [l-C-13] glucose metabolism by high-resolution
multinuclear NMR-spectroscopy. Five-day treatment of neurons with 100-mumol/L MnC12 led
to 50% and 70% decreases of ATP/ADP and phosphocreatine-creatine ratios, respectively. An
impaired flux of [113 CJglucose through pyruvate dehydrogenase, which was associated with
Krebs cycle inhibition and hence depletion of [l-C-13Jglutamate, [2-C-13JGABA, and [C-
13]glutathione, hindered the ability of neurons to compensate for mitochondrial dysfunction by
oxidative glucose metabolism and further aggravated neuronal energy failure. Stimulated
glycolysis and oxidative glucose metabolism protected astrocytes against energy failure and
oxidative stress, leading to twofold increased de novo synthesis of [3-C-13] lactate and fourfold
elevated [4-C-13] glutamate and [C-13] glutathione levels. Manganese, however, inhibited the
synthesis and release of glutamine. Comparative NMR data obtained from cocultures showed
disturbed astrocytic function and a failure of astrocytes to provide neurons with substrates for
energy and neurotransmitter metabolism, leading to deterioration of neuronal antioxidant
capacity (decreased glutathione levels) and energy metabolism. The results suggest that,
concomitant to impaired neuronal glucose oxidation, changes in astrocytic metabolism may
cause a loss of intercellular homeostatic equilibrium, contributing to neuronal dysfunction in
manganese neurotoxicity.
4.6 REVIEW ARTICLES
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Key References (18)
1. Anonymous. (1997) Manganese. RAIS Toxicity Profiles (1997).
Manganese is an essential trace element in humans that can elicit a variety of serious toxic
responses upon prolonged exposure to elevated concentrations either orally or by inhalation. The
central nervous system is the primary target. Initial symptoms are headache, insomnia,
disorientation, anxiety, lethargy, and memory loss. These symptoms progress with continued
exposure and eventually include motor disturbances, tremors, and difficulty in walking,
symptoms similar to those seen with Parkinsonism. These motor difficulties are often
irreversible. Based on human epidemiological studies, 0.8 mg/kg/day for drinking water
exposure and 0.34 mg/m3 in air for inhalation exposure have been estimated as lowest-observed-
adverse-effect levels (LOAELs) for central nervous system effects. Effects on reproduction
(decreased fertility, impotence) have been observed in humans with inhalation exposure and in
animals with oral exposure at the same or similar doses that initiate the central nervous system
effects. An increased incidence of coughs, colds, dyspnea during exercise, bronchitis, and altered
lung ventilatory parameters have also been seen in humans and animals with inhalation
exposure. A possible effect on the immune system may account for some of these respiratory
symptoms. Because of the greater bioavailability of manganese from water, separate reference
doses (RfD) for water and diet were calculated. A chronic (EPA 1995) and subchronic RfD
(EPA 1994) for drinking water of 0.005 mg/kg/day has been calculated by EPA from a human
noobservedadverse-effect level (NOAEL) of 0.005 mg/kg/day; the NOAEL was determined
from an epidemiological study of human populations exposed for a lifetime to manganese
concentrations in drinking water ranging from 3.6-2300 |ig/L (Kondakis et al. 1989). A chronic
(EPA 1995) and subchronic RfD (EPA 1994) of 0.14 mg/kg/day for dietary exposure has been
calculated by EPA from a human NOAEL of 0.14 mg/kg/day, which was determined from a
series of epidemiological studies (Schroeder et al. 1966, WHO 1973, NRC 1989). Large
populations with different concentrations of manganese in their diets were examined. No adverse
effects that were attributable to manganese were seen in any of these groups. For both the
drinking water and dietary values, the RfD was derived from these studies without uncertainty
factors since manganese is essential in human nutrition and the exposure of the most sensitive
groups was included in the populations examined. EPA (1995) indicates that the chronic RfD
values are pending change. A reference concentration (RfC) of 0.05 |ig/m3 (EPA 1995) for
chronic inhalation exposure was calculated from a human LOAEL of 0.05 mg/m3 for
impairment of neurobehavioral function from an epidemiological study by Roels et al. (1992).
The study population was occupationally exposed to airborne manganese dust with a median
concentration of 0.948 mg/m3 for 0.2 to 17.7 years with a mean duration of 5.3 years.
Neurological examinations, psychomotor tests, lung function tests, blood tests, and urine tests
were used to determine the possible effects of exposure. The LOAEL was derived from an
occupational-lifetime integrated respirable dust concentration of manganese dioxide expressed as
mg manganese/m3 x years. Confidence in the inhalation RfC is rated medium by the EPA. Some
conflicting data exist on possible carcinogenesis following injections of manganese chloride and
manganese sulfate in mice. However, the EPA weight-of-evidence classification is: D, not
classifiable as to human carcinogenicity based on no evidence in humans and inadequate
evidence in animals (EPA 1995).
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2. Anonymous. (2001) Manganese and inorganic compounds. ACGIH. Documentation of the
threshold limit values and biological exposure indices Vol:7th Ed (2001) 6 p.
A TLV-TWA of 0.2 mg/m3, as Mn, is recommended for occupational exposure to elemental
manganese and its inorganic compounds. This value is intended to minimize the potential for
pre-clinical adverse effects in the lungs and CNS and adverse effects on the fertility of male
workers exposed to manganese. The lowest exposure concentration of manganese at which early
effects on the CNS and the lungs may occur is still unknown. However, once neurological signs
are present, they tend to continue and worsen after exposure ends. Additional data are needed to
more accurately determine the exposure doses necessary to protect nearly all workers. Sufficient
data were not available to recommend Skin, SEN, or carcinogenicity notations or a TLV-STEL.
3. Anonymous. (2001) Manganese Cyclopentadienyl Tricarbonyl. ACGIH. Documentation of
the threshold limit values and biological exposure indices Vol:7th Ed (2001) 2 p.
A TLV-TWA of 0.1 mg/m3, measured as manganese, is recommended for occupational exposure
to manganese cyclopentadienyl tricarbonyl (MCT). This value is intended to minimize the
potential for skin irritation, neuropathic effects that include tremor and convulsion, and
pulmonary edema reported from studies with experimental animals. Systemic toxicity, including
mortality, in rats treated by tail immersion in MCT warrants assignment of the Skin notation.
The toxicity of MCT appears to be twice as potent as that of the organomanganese compound 2-
methylcyclopentadienyl manganese tricarbonyl (see the current TLV Documentation for 2-
methylcyclopentadienyl manganese tricarbonyl). Sufficient data were not available to
recommend SEN or carcinogenicity notations or a TLV-STEL.
4. Anonymous. (2003) Methylcyclopentadienyl Manganese Tricarbonyl (MMT). NICNAS:
Priority existing chemical assessment report Vol:24 (2003) 149 p.
Health hazards. In fuel, MMT is combusted and converted to a mixture of Mn oxides such as
Mn304 and salts including Mn phosphate (Mn3[P04]2) and Mn sulphate (MnS04). A
proportion of those inorganic derivatives are released in association with particulate material in
vehicle exhaust. The balance (around 80%) is accumulated in engines or exhaust systems.
Therefore, the health hazards associated with the use of MMT also include those associated with
inorganic Mn compounds. MMT is acutely toxic by all routes of exposure. The critical effects
from acute exposure to MMT are neurological and pulmonary dysfunction. In humans,
giddiness, headache, nausea, chest tightness, dyspnea and paresthesia are reported in anecdotal
cases of acute occupational exposure. Acute lethal exposure to MMT in animals is associated
with lomage to the lungs, kidney, liver and spleen effects, tremors, convulsions, dyspnea and
weakness. In both animals and humans, slight skin and eye irritation results from dermal and
ocular exposure respectively. Limited data show that repeated inhalation exposure to MMT in
animals results in degenerative changes in liver and kidneys. ANOAEL of 0.0062 mg/L for
inhalation exposure was reported. Manganese has been the subject of several extensive reviews
and the summary of Mn toxicity for this present report is based predominantly on the WHO
Concise International Chemical Assessment Document - Manganese and Its Compounds. In
humans, Mn is an essential element. In animal studies, the critical effect following acute
exposure to inorganic Mn compounds is neurological dysfunction. Decreased activity, alertness,
muscle tone, touch response and respiration have been reported with oral administration.
Pulmonary effects are also reported in inhalation studies, but these may at least in part reflect an
inflammatory effect following inhalation of particulate matter rather than a result of pulmonary
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toxicity of Mn. In repeated dose animal studies of Mn toxicity, the critical effect is also
neurological dysfunction, and effects range from decreased motor activity to increased activity,
aggression and movement tremors. In humans, chronic occupational exposure to respirable Mn
dusts is associated with subclinical nervous system toxicity through to overt manganism, a
progressive neurological disorder. Reproductive effects including impotence and loss of libido in
male workers have also been associated with high Mn exposures. It is generally agreed that the
critical study for neurological effects due to Mn exposure is Roels et al., (1992). This principal
neuroepidemiological study of occupational inhalation exposure to Mn was used by WHO
(1999) to determine a dose-response relationship for neurological effects. A lower 95%
confidence limit was estimated for the level of Mn exposure expected to result in a 5% response
rate. This value (30 [ug/M3) was considered a surrogate for a NOAEL for neurological effects in
the present assessment. MMT (as Mn) is currently listed in the NOHSC List of Designated
Hazardous Substances (NOHSC, 1999b) with no classification. In accordance with the NOHSC
Approved Criteria for Classifying Hazardous Substances (NOHSC, 1999a), It is recommended
that MMT is classified "Hazardous" with the following risk phrases: R26 - Very Toxic by
Inhalation; R28 - Very Toxic if Swallowed; R24 - Toxic in Contact with Skin; R48/23 - Toxic:
Danger of Serious Damage to Health by Prolonged Exposure Through Inhalation. As a result of
this classification, the following additional safety phrases are also recommended: S36 - Wear
Suitable Protective Clothing; There is currently no environmental hazard classification system in
Australia. In accordance with the OECD Globally Harmonized System of Classification and
Labelling of Chemicals, MMT would be classified Chronic 1 Very Toxic to Aquatic Life with
Long-Jasting Effects (OECD, 2002). Occupational health and safety risks. Occupational
exposure to MMT mainly via the dermal route may be envisaged for refinery and formulater
workers during blending of LRP or aftermarket fuel additives. Occupational exposure to MMT is
possible also for those workers in downstream processes that handle fuel, fuel additives and
automotive fuel system components e.g. petrol station and automotive maintenance workers. In
addition, occupational exposure to Mn, mainly via inhalation, is possible for these and other
workers associated with or in the vicinity of automotive usage e.g, service station attendants,
professional drivers, car park and road maintenance personnel. Although MMT is toxic by oral,
dermal and inhalation routes, the enclosed processes used predominantly for blending of fuel or
fuel additives where concentrates are handled renders the possibility of exposure low. Mild
irritation is possible upon contact with fuels or fuel additives containing MMT but given the
significant dilution of MMT with petroleum distillates, irritation is likely due to the irritant
properties of the petroleum distillates more tian the MMT itself. Exposure to MMT is possible
during handling of additived fuels, fuel additives and automotive fuel system components but is
expected to be infrequent, minor and of short duration and limited due to its dilution with
solvents and other additives in the fuel and fuel additives. Overall, the risks to workers posed by
MMT during formulation and during handling of fuels, fuel additives containing MMT and
automotive fuel system components contaminated with MMT is low. The main route of exposure
to Mn particulates is inhalation and in occupations where automotive usage is ubiquitous, Chonic
inhalation of inorganic Mn species may result. A worst-case scenario was considered for Mn
exposure of Australian auto mechanics from the use of MMT. Using overseas personal
inhalational exposure estimates, a Margin of Exposure of 203 for local mechanics was derived.
This is considered a sufficient Margin of Exposure given the conservative exposure estimates
derived from data from Canada where MMT is used widely as an octane enhancer in fuels and
ambient air levels of Mn are higher and calculations assuming 100% market share for MMT.
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Therefore, the occupational health risks associated with Mn exposure from MMT combustion
are assessed as low. MSDS and labels for imported MMT concentrates and formulated
aftermarket additives were assessed qualitatively against the NOHSC MSDS and Labelling
Codes. In general, labels were lacking ingredient information and although sonve relevant hazard
warnings were present, the recommended risk and safety phrases from this assessment were
missing. Signal words and disclosure of the presence of MMT were also missing from sonve
labels. Local contact details were absent from labels of imported concentrates. MSDS in general
contained relevant health effect information but also did not include recommended risk and
safety phrases. Most also had other important elements missing such as correct hazard statements
and emergency telephone numbers. A sample MSDS for MMT is included in Appendix 3. S38 -
In Case of Insufficient Ventilation Wear Suitable Respiratory Equipment. Based on a toxicity
profile from animal experiments, MMT meets the criteria of the ADG Code (FORS, 1998) for
classification as a toxic substance Class 6.1, Packing Group I. MMT can be ascribed a Proper
Shipping Name using the General Entry "Toxic Liquid, Organic, NOS" or Specific Entry "Metal
Carbonyls, NOS". MMT is currently not listed in the SUSDP. However, according to the
Guidelines for the National Drugs and Poisons Schedule Cbmmittee, its domestic use and
toxicity profile are alio consistent with a Schedule 7 entry in the SUSDP. Consequently, this
report will be referred for consideration of scheduling by the NDPSC. Environmental hazards
and risks. MMT is highly toxic to aquatic organisms and spill incidents and leaks to water bodies
and land should be managed through existing Federal, State and Territory legislative frameworks
and protocols to mitigate adverse effects to the aquatic envirownent. Such incidents may
potentially occur during shipment into Australia, bulk handling and storage and leakage of
underground storage tanks. All States and Territories have general environment protection
legislativn pertaining to pollution and contaminated land. However, there are currently no
existing leak prevention or leak detection requirements for operators of underground fuel storage
tanks in NSW, and probably other States and Territories, to detect and control leakages from
UST facilities. UST leak detection systems are implemented on a voluntary basis by industry,
particularly by major petroleum suppliers. Use of MMT in internal combustion engines as a fuel
additive and subsequent degradation through combustion, and its short persistence in the
environment, indicate that aquatic and terrestrial organisms are unlikely to be exposed to MMT
at or above levels of concern through existing use as an AVSR. A low environmental risk is
predicted. Manganese, the principle degradation by-product from combustion of MMT, is
naturally occurring and ubiquitous in the environment. It is an essential nutrient of plants and
animals. Environmental exposure to Mn compounds will mostly anse through the gaseous phase.
Eventually, these will deposit to land and waters. The emission of Mn into the environment from
use of fuels containing MMT is unlikely to develop to levels of concern and therefore poses a
low risk for terrestrial or aquatic environments. The findings of this assessment highlight the
potential for leaking USTs to pose an unacceptable risk to the environment. Such leakages
represent localised, point source discharge, but have the potential to detrimentally affect
significant areas of the environment. Although a large number of USTs have been replaced or
have bad leak detection systems or other measures installed, most USTs do not have leak
detection systems, and many that are currently in service are old and have the potential to leak in
the future if not decommissioned or replaced. Although there is potential for risk to the
environment from leakage of fuel (which may or may not contain MMT) from USTs, the risk
would be site Specific. MMT (as Mn) is listed in the NOHSC Exposure Standards for
Atmospheric Contaminants in the Occupational Environment with an exposure standard of 0.2
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mg/m~, (8 h TWA), skin notation (NOHSC 1995b). Public health risks. Direct public exposure
to MMT is likely to occur primarily via the dermal route as a result of spills and splashes of LRP
and aftermarket products. In LRP, MMT is not expected to be a skin irritant at present
concentrations. Estimated dermal doses of MMT to be received under a worst case scenario of
LRP spillage were several orders of magnitude below comparable animal dermal LD50s.
Therefore, there is a low risk of acute health effects for the general public as a result of dermal
exposure to MMT in LRP. Similarly, in aftermarket products, MMT at concentrations presently
reported is not expected to be a skin irritant. A comparison of dermal LD50 values with exposure
estimates suggests some potential for acute toxicity resulting from dermal exposure to MMT in
aftermarket products. However, LD50 values in rats were obtained after a constant 24-hour
exposure to MMT and in contrast, much shorter exposures are expected following spillage.
Overall, the risk of acute dermal effects in consumers is low given the small amounts of additive
to which people are likely to be exposed, the low concentration of MMT present with the fuel
additive and that any spill on the skin is unlikely to reside untreated for long periods. The risk of
acute health effects as a result of accidental ocular exposure to MMT in LRP and aftermarket
products is also considered to be low since exposure to very small amounts of product is
expected to occur only infrequently and MMT is not expected to cause eye irritation at low
concentrations present in these products. Acute health effects could occur as a result of
accidental ingestion of MMT by a child or by adults when siphoning fuel. The health risk to
adults from accidental ingestion of LRP containing MMT during siphoning or to children
following ingestion of LRP stored inappropriately around the home is considered low, given the
low level of MMT ( < 0.01% w/w) in LRP. However, assuming comparable toxicokinetics of
MMT in rats and humans after oral exposure and using the lowest rat LD50 for MMT of
approximately 10 mg/kg bw, a child (IOkg) ingesting about one mL of an aftermarket product
containing 10% w/w MMT could receive a potentially lethal dose. Children between one and a
quarter and three and a half years of age can swallow approximately 4.5 mL of liquid, giving a
potential dose several times higher than the lowest oral LD50 observed in laboratory animals.
The potential risk associated with accidental ingestion of aftermarket products containing MMT
is lessened by the likely storage of aftermarket products in garages, products being generally not
"attractive" for ingestion by a child and products as assessed packaged with child resistant
closures. However, since very small volumes provide a potentially lethal dose, products
containing MMT represent a significant acute health risk for children. Manganese is a ubiquitous
element and chronic Mn exposures (from all sources combined) are unlikely to be significantly
changed by the use of MMT. Exposure via food and water forms, by far, the greatest proportion
of the total human Mn dose, and are not expected to change significantly as a result of the
estimated use of MMT. However, MMT used according to the Present Use scenario of
maintained LRP inarket share or the 2004 scenario of diminished LRP inarket share will
potentially significantly increase the Mn dose received by inhalation (excluding smoking). Based
on the study of Roels et al (1992), the NOAEL for neurological effects in humans was
established at 30 ug/m3 and Margins of Exposure were calculated in this report converting
intermittent Mn exposures (5 days/week, 24 hours/day) to continuous exposures. For the Present
Use scenario, where current LRP inarket share is maintained with a calculated ambient air
concentration for Mn of 4.9 ng/m3, the Margin of Exposure was calculated at 1458. For the 2004
scenario, where the LRP market share declines with a calculated ambient air concentration for
Mn of 20 ng/m3, the Margin of Exposure was calculated at 3571. These Margins of Exposure are
considered sufficient, taking into account the conservative exposure estimates used. It is noted
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that the estimated ambient air concentration of Mn due to MMT combustion is at the lower end
of a range of overseas inhalation health standards and guidance values. However, a number of
conservative assumptions were used in this present exposure assessment. Consequently, the risk
to public health as a result of the use of MMT as an AVSR is expected to be low. However, there
are uncertainties associated with this risk assessment and there are likely to be sub-populations
that have higher exposures and hence are at greater risk than the general population. For
example, although the measured ambient air concentration of respirable Mn is probably
unrelated to the use of MMT, exposure of people in Launceston is of potential concern since the
ambient air concentration of total (but not respirable) Mn in that city is higher than some of the
ambient air standards developed overseas. The use of MMT would add potentially to
environmental Mn levels in this region.
5. ATSDR. 2000. Public Health Statement Manganese. In: CDC, editor: ATSDR.
6. Clewell HJ, Lawrence GA, Calne DB, Crump KS. (2003) Determination of an occupational
exposure guideline for manganese using the benchmark method. Risk Analysis 23(5): 1031-1046.
An occupational risk assessment for manganese (Mn) was performed based on benchmark dose
analysis of data from two epidemiological studies providing dose-response information
regarding the potential neurological effects of exposure to airborne Mn below the current
Occupational Safety and Health Administration (OSHA) Permissible Exposure Level (PEL) of 5
mg Mn/m(3). Based on a review of the scientific evidence regarding the toxicity of Mn, it was
determined that the most appropriate measure of exposure to airborne Mn for the subclinical
effects measured in these studies is recent (rather than historical or cumulative) concentration of
Mn in respirable (rather than total) particulate. For each of the studies analyzed, the individual
exposure and response data from the original study had been made available by the investigators.
From these two studies benchmark concentrations calculated for eight endpoints ranged from
0.09 to 0.27 mg Mn/m(3). From our evaluation of these results, and considering the fact that the
subtle, subclinical effects represented by the neurological endpoints tested in these studies do not
represent material impairment, we believe an appropriate occupational exposure guideline for
manganese would be in the range of 0.1 to 0.3 mg Mn/m(3), based on the respirable particulate
fraction only, and expressed as an 8-hour time-weighted average.
7. EPA. 2003. Health Effects Support Document for Manganese. Supersedes PB2002-108377.
Sponsored by Environmental Protection Agency, Washington, DC. Health and Ecological
Criteria Div.
The U.S. Environmental Protection Agency (EPA) has prepared this Health Effects Support
Document to assist in determining whether to establish a National Primary Drinking Water
Regulation (NPDWR) for manganese. At high doses by inhalation, manganese is very toxic, as
seen by occupational exposure in miners. On the other hand, manganese is essential for normal
physiological function of animals and humans. The Food and Nutrition Board of the National
Academy of Science (NAS) sets an adequate intake for manganese at 2.3 mg/day for men and
1.8 mg/day for women, and an upper limit for daily intake at 11 mg for adults (IOM, 2002).
Manganese has a low aesthetic threshold in water. Based on staining and taste, EPA has set a
secondary level for manganese at 0.05 mg/L which is below the level that may present a health
concern. Available data suggest that regulation of manganese in public water does not present a
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meaningful basis for health risk reduction. EPA will present a determination and further analysis
in the Federal Register Notice covering the Contaminant Candidate List proposals.
8. Gerber GB, Leonard A, Hantson P. (2002) Carcinogenicity, mutagenicity and teratogenicity
of manganese compounds. Critical Reviews in Oncology Hematology 42(l):25-34.
Manganese, an essential trace element, is one of the most used metals in the industry. Recently,
several new manganese compounds have been introduced as fungicide, as antiknock agent in
petrol and as contrasting agent in nuclear magnetic resonance tomography. Manganese displays
a somewhat unique behaviour with regard to its toxicity. It is relatively non-toxic to the adult
organism except to the brain where it causes Parkinson-like symptoms when inhaled even at
moderate amounts over longer periods of time. Relatively high doses of manganese affect DNA
replication and repair in bacteria and causes mutations in microorganism and mammalian cells
although the Ames test does not appear to be particularly responsive to manganese. In
mammalian cells, manganese causes DNA damage and chromosome aberrations. Information on
organic manganese derivatives is still insufficient. Large amounts of manganese affect fertility in
mammals and are toxic to the embryo and foetus. The fungicide MANEB and the contrasting
agent MnDPDP also can be embryotoxic, but the latter only at doses much higher than those
clinically employed, Information on the anti-knock agent MMT is inadequate. On the other hand,
manganese deficiency can also affect fertility and be teratogenic. Information on cancer due to
manganese is scanty but the results available do not indicate that inorganic manganese is
carcinogenic. More information is desirable with regard to the organic manganese derivatives. It
may surprise that an agent that causes mutations is not also carcinogenic. The experience with
manganese shows that conclusions with regard to carcinogenicity of an agent based on the
observation of mutations are subject to uncertainties. Altogether, it appears that, because of the
very high doses at which positive effects hake been found, manganese would not represent a
significant carcinogenic risk to the population and workers. Care must, however, be exercised
with respect to central-nervous symptoms after chronic exposure and with respect to effects on
the embryo. Pregnant women should not be exposed to manganese at the work place. (C) 2002
Elsevier Science Ireland Ltd. All rights reserved.
9. Goldhaber SB. (2003) Trace element risk assessment: essentiality vs. toxicity. Regulatory
Toxicology and Pharmacology 38(2):232-242.
Risk assessment of essential trace elements examines high intakes resulting in toxicity and low
intakes resulting in nutritional deficiencies. This paper analyzes the risk assessments carried out
by several U.S. governmental and private organizations for eight essential trace elements:
chromium, copper, iodine, iron, manganese, molybdenum, selenium, and zinc. The compatibility
of the toxicity values with the nutritionally essential values is examined, in light of recently
derived values, termed Dietary Reference Intakes, set by the U.S. Food and Nutrition Board of
the Institute of Medicine. The results show that although there are differences in the values set
by the different organizations, increased coordination has resulted in values that are more
compatible than revealed in past evaluations. (C) 2003 Elsevier Inc. All rights reserved.
10. Greger JL. (1998) Dietary standards for manganese: Overlap between nutritional and
toxicological studies. Journal of Nutrition 128(2):368S-371S.
The Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for adults for manganese is 2-
5 mg Mn/d, The LOAEL (lowest-observable-adverse-effect level) for manganese in water is 0.06
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mg Mn/(kg.d) or 4.2 mg Mn/d for a 70-kg individual. The inconsistency in these standards
reflects limitations in the available data as well as differences in the way in which the standards
are calculated, Manganese balance and excretion data are not useful biomarkers of manganese
exposure but do demonstrate that the body is protected against manganese toxicity primarily by
low absorption and/or rapid presystemic elimination of manganese by the liver. Serum
manganese concentrations in combination with lymphocyte manganese-dependent superoxide
dismutase (MnSOD) activity, and perhaps blood arginase activity, seem to be the best way to
monitor ingestion of insufficient manganese, Serum manganese concentrations in combination
with brain magnetic resonance imaging (MRI) scans, and perhaps a battery of neurofunctional
tests, seem to be the best way to monitor excessive exposure to manganese.
11. Greger JL. (1999) Nutrition versus toxicology of manganese in humans: Evaluation of
potential biomarkers. Neurotoxicology 20(2-3):205-212.
Manganese intake can vary greatly with food choices, water composition, and supplement use.
Thus, individuals consuming Western diets consume from <1 to >10 mg Mn/d. The levels of
manganese intake associated with adverse effects (both deficient and toxic) are debatable.
Moreover, many of the symptoms of manganese deficiency (growth retardation, changes in
circulating HDL cholesterol and glucose levels, reproductive failure) and manganese toxicity
(growth depression, anemia) are nonspecific. The bone deformities observed in manganese-
deficient animals and neurological symptoms of individuals who have inhaled excess manganese
are permanent and illustrate the need to identify sensitive biomarkers of manganese status that
appear before these symptoms. Manganese balance and excretion data are not useful biomarkers
of manganese exposure but demonstrate that the body is protected against manganese toxicity
primarily by low absorption and/or rapid presystemic elimination of manganese by the liver.
Serum manganese concentrations in combination with lymphocyte manganese-dependent
superoxide dismutase (MnSOD) activity and perhaps blood arginase activity, appear to be the
best ways to monitor ingestion of insufficient manganese. Serum manganese concentrations in
combination with brain MRI (magnetic resonance imaging) scans, and perhaps a battery of
neurofunctional tests, appear to be the best ways to monitor excessive exposure to manganese.
(C) 1999 Inter Press, Inc.
12. Gwiazda R, Lucchini R, Smith D. (2007) Adequacy and consistency of animal studies to
evaluate the neurotoxicity of chronic low-level manganese exposure in humans. Journal of
Toxicology and Environmental Health-Part a-Current Issues 70(7):594-605.
The adequacy of existing animal studies to understand the effects of chronic low- level
manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent
and nonhuman primate studies was evaluated to determine whether there is a consistent dose-
response relationship among studies, whether there is a progression of effects with increasing
dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-
level manganese exposures in humans. Neurochemical and behavioral effects were compared
along the axis of estimated internal cumulative manganese dose, independent of the route of
exposure. In rodents, motor effects emerged at cumulative doses below those where
occupationally exposed humans start to show motor deficits. The main neurochemical effects in
rodents were an increase in striatal gamma- aminobutyric acid ( GAB A) concentration
throughout the internal cumulative dose range of 18 to 5300 mg Mn/ kg but a variable effect on
striatal dopamine concentration emerging at internal cumulative doses above similar to 200 mg
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Mn/ kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively
low doses and consistent harmful effects on both the globus pallidus and the caudate and
putamen at higher doses (> 260 mg Mn/ kg). Internal cumulative manganese doses of animal
studies extend more than two orders of magnitude (< 1 to 5300 mg Mn/ kg) above the doses at
which occupationally exposed humans show neurological dysfunction ( 10 - 15 mg Mn/ kg).
Since the animal data indicate that manganese neurotoxicity may be different at low compared to
elevated exposures, most existing animal model studies might be of limited relevance for the risk
assessment of chronic low- level manganese exposure to humans.
13. Jankovic J. (2005) Searching for a relationship between manganese and welding and
Parkinson's disease. Neurology 64(12):2021-2028.
Research into the causes of Parkinson disease (PD) has accelerated recently with the discovery
of novel gene mutations. The majority of PD cases, however, remain idiopathic and in those
cases environmental causes should be considered. Several recent reports have focused on
welding and manganese toxicity as potential risk factors for parkinsonism and some have even
proposed that welding is a risk factor for PD. The controversy has stimulated this review, the
primary aim of which is to critically and objectively examine the evidence or lack of evidence
for a relationship among welding, manganese, parkinsonism, and PD.
14. Newland MC. (1999) Animal models of manganese's neurotoxicity. Neurotoxicology 20(2-
3):415-432.
Manganese's neurotoxicity continues to present a puzzling array of differences across individuals
and across published reports in the profile of effects seen in humans and nonhuman species, but
some of the sources of individual variability are becoming clear from studies of animals. The
kinetics of manganese is a critical component of any assessment of risk associated with
exposure. After inhalation, the uptake of manganese into and elimination from the central
nervous system are slow and same manganese remains in the nervous system a year after
inhalation. Comparison with other parenteral routes suggests that manganese depots in lung
prolongs exposure even after environmental exposure has ended. Manganese's neurotoxicity is
associated with its appearance in basal ganglia structures, especially the globus pallidus.
Manganese a Iso appears in the pituitary gland but the functional consequences of this are not
well understood. Other critical components in characterizing manganese's neurotoxicity appear
to be the behavioral endpoints used, the species studied, and the exposure rate. Overt
neurological signs and excitability are associated with high exposure rates and the appearance of
manganese throughout basal ganglia and basal forebrain regions. More focused behavioral
endpoints are required to detect the subtle signs associated with slow exposure rates low
exposure levels, but when such designs are used the effect is unequivocal. At lower exposure
levels, doses of 5 mg/kg and greater, deficits in a task in which a monkey executed a rowing type
motion against a spring approximating its body weight were clearly related to manganese
exposure while other traditional measures of response patterns under schedules of reinforcement
remained intact. Excitability and other signs of emotionality have not been reported at low
exposure rates. In rodents, manganese accumulation and alterations in the function or
concentration of neurotransmitters have been reported. Investigations of behavioral effects in
these species, which usually involved locomotor activity, have resulted in less consistent results.
Manganese produces a constellation of neurotoxic signs whose appearance and detection are
influenced by dose and exposure rate. Despite investigations of manganese's neurotoxicity in
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animals over a wide range of exposure levels, a NOAEL has not been identified. (C) 1998 Inter
Press, Inc.
15. OEHHA. 2004. Chronic Toxicity Summary Managenese and Compounds. In: Assessment
OoEHH, editor: California Environmental Protection Agency (Cal/EPA).
CHRONIC TOXICITY SUMMARY MANGANESE AND COMPOUNDS Molecular Formula
Synonyms Molecular Weight CAS Reg. No. Mn elemental manganese; colloidal manganese;
cutaval 54.94 g/mol 7439-96-5 MnO manganese oxide; manganese monoxide; manganosite 70.
16. Olanow CW. (2004) Manganese-induced parkinsonism and Parkinson's disease. Redox-
Active Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp
209-223.
It has long been appreciated that manganese exposure can cause neurotoxicity and a neurologic
syndrome that resembles Parkinson's disease (PD). Current evidence indicates that manganese-
induced parkinsonism can be differentiated from PD because of its predilection to accumulate in
and damage the pallidum and striatum rather than the SNc. The clinical syndrome, response to
levodopa, imaging studies with MRI and PET, and pathologic features all help to distinguish
these two conditions and permit the correct diagnosis to be established. This is of particular
relevance in differentiating patients with parkinsonism due to manganese intoxication from
patients with idiopathic PD who have incidental manganese exposure.
17. Roth JA, Garrick MD. (2003) Iron interactions and other biological reactions mediating the
physiological and toxic actions of manganese. Biochemical Pharmacology 66(1): 1-13.
Chronic exposure to the divalent heavy metals, such as iron, lead, manganese (Mn), and
chromium, has been linked to the development of severe, often irreversible neurological
disorders and increased vulnerability to developing Parkinson's disease. Although the
mechanisms by which these metals elicit or facilitate neuronal cell death are not well defined,
neurotoxicity is limited by the extent to which they are transported across the blood-brain barrier
and their subsequent uptake within targeted neurons. Once inside the neuron, these heavy metals
provoke a series of biochemical and molecular events leading to cell death induced by either
apoptosis and/or necrosis. The toxicological properties of Mn have been studied extensively in
recent years because of the potential health risk created by increased atmospheric levels owing to
the impending use of the gas additive methylcyclopentadienyl manganese tricarbonyl.
Individuals exposed to high environmental levels of Mn, which include miners, welders, and
those living near ferroalloy processing plants, display a syndrome known as manganism, best
characterized by debilitating symptoms resembling those of Parkinson's disease. Mn disposition
in vivo is influenced by dietary iron intake and stores within the body since the two metals
compete for the same binding protein in serum (transferrin) and subsequent transport systems
(divalent metal transporter, DMTI). There appear to be two distinct carrier-mediated transport
systems for Mn and ferrous ion: a transferrin-dependent and a transferrin-independent pathway,
both of which utilize DMTI as the transport protein. Accordingly, this commentary focuses on
the biochemical and molecular processes responsible for the cytotoxic actions of Mn and the role
that cellular transport plays in mediating the physiological as well as the toxicological actions of
this metal. (C) 2003 Elsevier Science Inc. All rights reserved.
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18. Santamaria A, Cushing C, Antonini J, Finley B, Mowat F. (2007) State-of-the-Science
Review: Does Manganese Exposure During Welding Pose a Neurological Risk? Journal of
Toxicology and Environmental Health Part B: Critical Reviews 10(6):416-475(449).
Recent studies report that exposure to manganese (Mn), an essential component of welding
electrodes and some steels, results in neurotoxicity and/or Parkinson's disease (PD) in welders.
This "state-of-the-science" review presents a critical analysis of the published studies that were
conducted on a variety of Mn-exposed occupational cohorts during the last 100 yr, as well as the
regulatory history of Mn and welding fumes. Welders often perform a variety of different tasks
with varying degrees of duration and ventilation, and hence, to accurately assess Mn exposures
that occurred in occupational settings, some specific information on the historical work patterns
of welders is desirable. This review includes a discussion of the types of exposures that occur
during the welding process - for which limited information relating airborne Mn levels with
specific welding activities exists - and the human health studies evaluating neurological effects
in welders and other Mn-exposed cohorts, including miners, millers, and battery workers.
Findings and implications of studies specifically conducted to evaluate neurobehavioral effects
and the prevalence of PD in welders are also discussed. Existing exposure data indicate that, in
general, Mn exposures in welders are less than those associated with the reports of clinical
neurotoxicity (e.g., "manganism") in miners and smelter workers. It was also found that although
manganism was observed in highly exposed workers, the scant exposure-response data available
for welders do not support a conclusion that welding is associated with clinical neurotoxicity.
The available data might support the development of reasonable "worst-case" exposure estimates
for most welding activities, and suggest that exposure simulation studies would significantly
refine such estimates. Our review ends with a discussion of the data gaps and areas for future
research.
Supporting References (71)
1. (1998) Is airborne manganese a hazard? Environmental Health Perspectives 106(2):A57-A58.
2. anon. (1997) Manganese toxicity: hazard of intravenous food. Drugs Q. l(l):31-32. IPA
COPYRIGHT: ASHP.
A high incidence of toxic blood manganese levels in children receiving prolonged intravenous
(IV) nutrition is discussed. Precautionary annual imaging of the basal ganglia is recommended
for children who need IV feeding indefinitely, and immediate reduction of some 50 fold in the
manganese content of some proprietary trace element solutions are suggested.
3. Antonini JM, Taylor MD, Zimmer AT, Roberts JR. (2004) Pulmonary responses to welding
fumes: Role of metal constituents. Journal of Toxicology and Environmental Health-Part a -
Current Issues 67(3):233-249.
It is estimated that more than 1 million workers worldwide perform some type of welding as part
of their work duties. Epidemiology studies have shown that a large number of welders
experience some type of respiratory illness. Respiratory effects seen in full-time welders have
included bronchitis, siderosis, asthma, and a possible increase in the incidence of lung cancer.
Pulmonary infections are increased in terms of severity, duration, and frequency among welders.
Inhalation exposure to welding fumes may vary due to differences in the materials used and
methods employed. The chemical properties of welding fumes can be quite complex. Most
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welding materials are alloy mixtures of metals characterized by different steels that may contain
iron, manganese, chromium, and nickel. Animal studies have indicated that the presence and
combination of different metal constituents is an important determinant in the potential
pneumotoxic responses associated with welding fumes. Animal models have demonstrated that
stainless steel (SS) welding fumes, which contain significant levels of nickel and chromium,
induce more lung injury and inflammation, and are retained in the longs longer than mild steel
(MS) welding fumes, which contain mostly iron. In addition, SS fumes generated from welding
processes using fluxes to protect the resulting weld contain elevated levels of soluble metals,
which may affect respiratory health. Recent animal studies have indicated that the lung injury
and inflammation induced by SS welding fumes that contain water-soluble metals are dependent
on both the soluble and insoluble fractions of the fume. This article reviews the role that metals
play in the pulmonary effects associated with welding fume exposure in workers and laboratory
animals.
4. Aschner M, Erikson KM. (2003) Manganese and iron deficiency in neurodegeneration.
Journal of Neurochemistry 87:129-129.
5. Aschner M, Lukey B, Tremblay A. (2006) The manganese health research program (MHRP):
Status report and future research needs and directions. Neurotoxicology 27(5):733-736.
The manganese (Mn) research health program (MHRP) symposium was a full day session at the
22nd International Neurotoxicology Conference. Mn is a critical metal in many defense and
defense-related private sector applications including steel making and fabrication, improved fuel
efficiency, and welding, and a vital and large component in portable power sources (batteries).
At the current time, there is much debate concerning the potential adverse health effects of the
use of manganese in these and other applications. Due to the significant use of manganese by the
Department of Defense, its contractors and its suppliers, the Manganese Health Research
Program (MHRP) seeks to use the resources of the federal government, in tandem with
manganese researchers, as well as those industries that are involved with manganese, to
determine the exact health effects of manganese, as well as to devise proper safeguard measures
for both public and private sector workers. Humans require manganese as an essential element;
however, exposure to high levels of this metal is sometimes associated with adverse health
effects, most notably within the central nervous system. Exposure scenarios vary extensively in
relation to geographical location, urban versus rural environment, lifestyles, diet, and
occupational setting. Furthermore, exposure may be brief or chronic, it may be to different types
of manganese compounds (aerosols or salts of manganese with different physical and/or
chemical properties), and it may occur at different life-stages (e.g., in utero, neonatal life,
puberty, adult life, or senescence). These factors along with diverse genetic composition that
imposes both a background and disease occurrence likely reflect on differential sensitivity of
individuals to manganese exposure. Unraveling these complexities requires a multipronged
research approach to address multiple questions about the role of manganese as an essential
metal as well as its modulation of disease processes and dysfunction. A symposium on the
Health Effects of Manganese (Mn) was held on Wednesday, September 14, 1005, to discuss
advances in the understanding on role of Mn both in health and disease. The symposium was
sponsored by the Manganese Health Research Program (MHRP). This summary provides
background on the MHRP, identifies the speakers and topics discussed at the symposium, and
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identifies research needs and anticipated progress in understanding Mn health- and disease-
related issues. (C)2005 Elsevier Inc. All rights reserved.
6. ATSDR. 2001. AT SDR - ToxFAQs": Manganese.
Manganese is a trace element and eating a small amount from food or water is needed to stay
healthy. Exposure to excess levels of manganese may occur from breathing air, particularly
where manganese is used in manufacturing, and from drinking water and eating food. At high
levels, it can cause
7. ATSDR. 2004. Interaction Profile: Lead, Manganese, Zinc, and Copper.
Agency for Toxic Substances and Disease Registry (ATSDR). 2004. Interaction profile for lead,
manganese, zinc, copper. Atlanta, GA: U.S. Department of Health and Human Services, Public
Health Service. Disclaimer
8. Barceloux DG. (1999) Manganese. Journal of Toxicology-Clinical Toxicology 37(2):293-
307.
Manganese is a very hard, brittle metal, which is used to increase the strength of steel alloys,
Absorption from the gastrointestinal tract occurs in the divalent and tetravalent forms.
Permanganates, which are strong oxidizing agents, have a +7 valence. The principal
organomanganese compound is the anti-knock additive, methylcyclopentadienyl manganese
tricarbonyl. Manganese is a ubiquitous constituent of the environment comprising about 0.1% of
the earth's crust. For the general population, food is the most important source of manganese
with daily intake ranging from 2-9 mg Mn. Combustion of gasoline containing
methylcyclopentadienyl manganese tricarbonyl releases submicron particles of Mn304 that are
potentially respirable. Biomagnification of manganese in the food chain probably does not occur.
The lungs and gastrointestinal tract absorb some manganese, but the relative amounts absorbed
from each site are not known. Homeostatic mechanisms limit the absorption of manganese from
the gastrointestinal tract. Elimination of manganese occurs primarily by excretion into the bile.
Animal studies indicate that manganese is an essential co-factor for enzymes, such as
hexokinase, superoxide dismutase, and xanthine oxidase. However, no case of manganese
deficiency in humans has been identified, Manganism is a central nervous system disease first
described in the 1800s following exposure to high concentrations of manganese oxides.
Manganese madness was the term used to describe the initial psychiatric syndrome (compulsive
behavior, emotional lability, hallucinations). More commonly, these workers developed a
Parkinson's-like syndrome. Currently, the risks of exposure to low concentrations of manganese
in the industrial and in the environmental settings (e.g., methylcyclopentadienyl manganese
tricarbonyl in gasoline) are being evaluated with regards to the development of subclinical
neuropsychological changes. The American Conference of Governmental and Industrial
Hygienists recently lowered the TLV-TWA for manganese compounds and inorganic manganese
compounds to 0.2 mg Mn/m(3).
9. Bizarro P, Sanchez I, Lopez I, Pasos F, Delgado V, Gonzalez-Villalva A, Colin-Barenque L,
Acevedo S, Nino-Cabrera G, Mussali-Galante P and others. (2004) Morphological Changes In
Testes. After Manganese Inhalation. Study In Mice. Toxicologist 78(1-S): 157.
Manganese (Mn) has been used as an antiknocking agent in gasoline. Its increase in the
atmosphere enhances the risk of its inhalation and the induction of systemic damage. Some
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reports mention that oral administration of MnC12 induces reproductive delay in male mice.
Prostatic cancer has been identified among exposed workers. The objective of this study was to
identify in a murine inhalation model in CD-I male mice. Animals inhaled MnC12 0.02M, lh,
twice a week, for 4 weeks, sacrificed once a week and processed for light and electron
microscopy. Light changes evidenced necrosis of stem cells, binucleated spermatocytes and
dense nuclear structures. Ultrastructural changes in Leydig cells consisted in hyperplastic
endoplasmic reticulum forming whorl-like structures. As a consequence of these modifications
the function of the testes might be altered, as well as its endocrine function.
10. Bourre JM. (2004) The role of nutritional factors on the structure and function of the brain:
an update on dietary requirements. Revue Neurologique 160(8-9):767-792.
The brain is an organ elaborated and functioning from substances present in the diet. Dietary
regulation of blood glucose level (via ingestion of food with a low glycemic index ensuring a
low insulin level) improves the quality and duration of intellectual performance, if only because
at rest the adult brain consumes 50 p. 100 of dietary carbohydrates, 80 p. 100 of them for energy
purposes. The nature of the amino acid composition of dietary proteins contributes to good
cerebral function; tryptophan plays a special role. Many indispensable amino acids present in
dietary proteins help to elaborate neurotransmitters and neuromodulators. Omega-3 fatty acids
provided the first coherent experimental demonstration of the effect of dietary nutrients on the
structure and function of the brain. First it was shown that the differentiation and functioning of
cultured brain cells requires omega-3 fatty acids. It was then demonstrated that alpha-linolenic
acid (ALA) deficiency alters the course of brain development, perturbs the composition and
physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes
(ALA). This leads to physicochemical modifications, induces biochemical and physiological
perturbations, and results in neurosensory and behavioral upset. Consequently, the nature of
polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants
(premature and term) conditions the visual and cerebral abilities, including intellectual abilities.
Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects
of cardiovascular disease (including at the level of cerebral vascularization), and in some
neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's
disease. Their deficiency can prevent the satisfactory renewal of membranes and thus accelerate
cerebral aging. Iron is necessary to ensure oxygenation, to produce energy in the cerebral
parenchyma, and for the synthesis of neurotransmiters. The iodine provided by the thyroid
hormone ensures the energy metabolism of the cerebral cells. The absence of iodine during
pregnancy induces severe cerebral dysfunction, leading to cretinism. Manganese, copper, and
zinc participate in enzymatic mechanisms that protect against free radicals, toxic derivatives of
oxygen. The use of glucose by nervous tissue implies the presence of vitamin Bl. Vitamin B9
preserves memory during aging, and with vitamin B12 delays the onset of signs of dementia,
provided it is administered in a precise clinical window, at the onset of the first symptoms.
Vitamins B6 and B12, among others, are directly involved in the synthesis of neurotransmitters.
Nerve endings contain the highest concentrations of vitamin C in the human body. Among
various vitamin E components, only alpha-tocopherol is involved in nervous membranes. The
objective of this update is to give an overview of the effects of dietary nutrients on the structure
and certain functions of the brain.
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11. Bourre JM. (2006) Effects of nutrients (in food) on the structure and function of the nervous
system: Update on dietary requirements for brain. Part 1: Micronutrients. Journal of Nutrition
Health & Aging 10(5):377-385.
The objective of this update is to give an overview of the effects of dietary nutrients on the
structure and certain functions of the brain. As any other organ, the brain is elaborated from
substances present in the diet (sometimes exclusively, for vitamins, minerals, essential amino-
acids and essential fatty acids, including omega-3 polyunsaturated fatty acids). However, for
long it was not fully accepted that food can have an influence on brain structure, and thus on its
function, including cognitive and intellectuals. In fact, most micronutrients (vitamins and trace-
elements) have been directly evaluated in the setting of cerebral functioning. For instance, to
produce energy, the use of glucose by nervous tissue implies the presence of vitamin B I; this
vitamin modulates cognitive performance, especially in the elderly. Vitamin B9 preserves brain
during its development and memory during ageing. Vitamin B6 is likely to benefit in treating
premenstrual depression. Vitamins B6 and B 12, among others, are directly involved in the
synthesis of some neurotransmitters. Vitamin B 12 delays the onset of signs of dementia (and
blood abnormalities), provided it is administered in a precise clinical timing window, before the
onset of the first symptoms. Supplementation with cobalamin improves cerebral and cognitive
functions in the elderly, it frequently improves the functioning of factors related to the frontal
lobe, as well as the language function of those with cognitive disorders. Adolescents who have a
borderline level of vitamin B 12 develop signs of cognitive changes. In the brain, the nerve
endings contain the highest concentrations of vitamin C in the human body (after the suprarenal
glands). Vitamin D (or certain of its analogues) could be of interest in the prevention of various
aspects of neurodegenerative or neuroimmune diseases. Among the various vitamin E
components (tocopherols and tocotrienols), only alpha-tocopherol is actively uptaken by the
brain and is directly involved in nervous membranes protection. Even vitamin K has been
involved in nervous tissue biochemistry. Iron is necessary to ensure oxygenation and to produce
energy in the cerebral parenchyma (via cytochrome oxidase), and for the synthesis of
neurotransmitters and myelin; iron deficiency is found in children with attention-
deficit/hyperactivity disorder. Iron concentrations in the umbilical artery are critical during the
development of the foetus, and in relation with the IQ in the child; infantile anaemia with its
associated iron deficiency is linked to perturbation of the development of cognitive functions.
Iron deficiency anaemia is common, particularly in women, and is associated, for instance, with
apathy, depression and rapid fatigue when exercising. Lithium importance, at least in psychiatry,
is known for a long time. Magnesium plays important roles in all the major metabolisms: in
oxidation-reduction and in ionic regulation, among others. Zinc participates among others in the
perception of taste. An unbalanced copper metabolism homeostasis (due to dietary deficiency)
could be linked to Alzheimer disease. The iodine provided by the thyroid hormone ensures the
energy metabolism of the cerebral cells; the dietary reduction of iodine during pregnancy
induces severe cerebral dysfunction, actually leading to cretinism. Among many mechanisms,
manganese, copper, and zinc participate in enzymatic mechanisms that protect against free
radicals, toxic derivatives of oxygen. More specifically, the full genetic potential of the child for
physical growth ad mental deveopment may be compromised due to deficiency (even
subclinical) of micronutrients. Children and adolescents with poor nutritional status are exposed
to alterations of mental and behavioural functions that can be corrected by dietary measures, but
only to certain extend. Indeed, nutrient composition and meal pattern can exert either immediate
or long-term effects, beneficial or adverse. Brain diseases during aging can also be due to failure
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for protective mechanism, due to dietary deficiencies, for instance in anti-oxidants and nutrients
(trace elements, vitamins, non essential micronutrients such as polyphenols) related with
protection against free radicals. Macronutrients are presented in the accompanying paper.
12. Bowler RM, Mergler D, Sassine MP, Larribe F, Hudnell K. (1999) Neuropsychiatry effects
of manganese on mood. Neurotoxicology 20(2-3):367-378.
Adverse mood effects of overexposure to Manganese (Mn) have been described in 15 studies
which frequently report an association of Mn exposure with adverse effects in six dimensions of
mood: 1) anxiety, nervousness, irritability; 2) psychotic experiences; 3) emotional disturbance;
4) fatigue lack of vigor, sleep disturbance; 5) impulsive/compulsive behavior; 6) aggression
hostility. Only 1.15 studies used a standardized psychological measure of mood, while the
current study of environmental Mn exposure used two standardized mood scales in evaluating
low levels of Mn exposure and mood sequelae. The Profile of Moods State (POMS) and Brief
Symptom Inventory (BSI) were used, and results indicate that men who are older and have
higher Mn levels show significant disturbances on four of the six mood dimensions. Increased
scores were seen in the anxiety, nervousness, irritability; emotional disturbance; and aggression,
hostility dimensions relative to those who had lower levels of Mn. The BSI and POMS are useful
adjuncts in the assessment of mood/Mn effects. (C) 1999 Inter Press, Inc.
13. Breault JL, Campbell H. (1997) Manganese toxicity. Journal of Family Practice 45(1): 15-16.
14. Chu NS, Hochberg FH, Calne DB, Olanow CW. (1995) Neurotoxicology of manganese.
Chang, L. W. and R. S. Dyer (Ed.). Neurological Disease and Therapy, Vol. 36. Handbook of
Neurotoxicology. Xxi+1103p. Marcel Dekker, Inc.: New York, New York, USA; Basel,
Switzerland. Isbn 0-8247-8873-7.; 0 (0). 1995. 91-103. Biosis copyright: biol abs. rrm book
chapter human absorption parkinson's disease
15. Crossgrove J, Zheng W. (2004) Manganese toxicity upon overexposure. Nmr in
Biomedicine 17(8):544-553.
Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent
mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by
the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging.
The administration of intravenous Mn impacts its homeostatic balance in the human body and
can lead to toxicity. Human Mn deficiency has been reported in patients oil parenteral nutrition
and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder)
and dietary overexposure and is evidenced primarily in the central nervous system, although
lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results
from all accumulation of the metal in brain tissue and results in a progressive disorder of the
extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from
blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-
cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain
Mn accumulation and neurotoxicity. The mechanism for the neuro-degenerative damage specific
to select brain regions is not clearly understood. Disturbances in iron homeostasis and the
valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation
therapy with EDTA and supplementation with levodopa are the current treatment options, which
are mildly and transiently efficacious. In conclusion, repeated administration of Mn Or
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compounds that readily release Mn. may increase the risk of Mn-induced toxicity. Copyright (C)
2004 John Wiley Soils. Ltd.
16. Davis JM. (1998) Methylcyclopentadienyl manganese tricarbonyl: Health risk uncertainties
and research directions. Environmental Health Perspectives 106:191-201.
With the way cleared for increased use of the fuel additive methylcyclopentadienyl manganese
tricarbonyl (MMT) in the United States, the issue of possible public health impacts associated
with this additive has gained greater attention. In assessing potential health risks of particulate
Mn emitted from the combustion of MMT in gasoline, the U.S. Environmental Protection
Agency not only considered the qualitative types of toxic effects associated with inhaled Mn, but
conducted extensive exposure-response analyses using various statistical approaches and also
estimated population exposure distributions of particulate Mn based on data from an exposure
study conducted in California when MMT was used in leaded gasoline. Because of limitations in
available data and the need to make several assumptions and extrapolations, the resulting risk
characterization had inherent uncertainties that made it impossible to estimate health risks in a
definitive or quantitative manner. To support an improved health risk characterization, further
investigation is needed in the areas of health effects, emission characterization, and exposure
analysis.
17. Davis JM. (1999) Inhalation health risks of manganese: An EPA perspective.
Neurotoxicology 20(2-3):511-518.
In 1994, the U.S. Environmental Protection Agency (EPA) denied a petition by Ethyl
Corporation to allow the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in
unleaded gasoline, because of health concerns related to the inhalation of manganese (Mn)
particulate emissions from combusted MMT: Although Ethyl successfully challenged EPA's
denial of the petition on legal grounds, issues raised in EPA's health risk assessment have not
been resolved to date. This paper summarizes features of the EPA health risk characterization,
which included the use of various statistical techniques to derive several estimates of inhalation
reference concentration (RfC) values for Mn as alternatives to the established value of 0.05 mu g
Mn/m(3). An exposure assessment projected distributions of personal exposure levels to
particulate Mn if MMT were used in all unleaded gasoline. If was estimated that exposure levels
of 5-10% of the modeled population might exceed a possible alternative RfC value of 0.1 mu g
Mn/m(3). However, due to data limitations, the risk characterization for Mn/MMT could raise
only qualitative concerns about potential public health impacts and was unable to provide a
quantitative estimate of risk. To improve the risk characterization, better information on
Mn/MMT population exposures and health effects is needed. Much of this information is
expected to be obtained under provisions of Section 211 of the Clean Air Act. Among the
specific issues that remain to be resolved are the form or forms of Mn emitted from the
combustion of MMT in gasoline and the potentially different toxic properties of Mn in different
forms. (C) 1999 Inter Press, Inc.
18. Davis JM, Dorman D. (1998) Health risk assessments of manganese - Differing
perspectives: Session VIII summary and research needs. Neurotoxicology 19(3):488-489.
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19. De Miguel E, Iribarren I, Chacon E, Ordonez A, Charlesworth S. (2007) Risk-based
evaluation of the exposure of children to trace elements in playgrounds in Madrid (Spain).
Chemosphere 66(3):505-513.
Eighty samples of sandy substrate were collected in November 2002 and 2003, from 20
municipal playgrounds in Madrid (Spain) to assess the potential adverse health effects of the
exposure of children to trace elements in this material during their games. In each playground,
two 500 g samples were collected, dried at 45 degrees C for 48 h, sieved below 100 mu m, acid
digested and analyzed by ICP-MS. Doses contacted through ingestion and inhalation and the
dose absorbed through the skin were calculated using USEPAs hourly exposure parameters for
children and the results of an in situ survey. The toxicity values considered in this study were
mostly taken from the US DoEs RAIS compilation. The results of the risk assessment indicate
that the highest risk is associated with ingestion of soil particles and that the trace element of
most concern is arsenic, the exposure to which results in a cancer risk value of 4.19 x 10(-6),
close to the 1 x 10(-5) probability level deemed unacceptable by most regulatory agencies.
Regarding non-cancer effects, exposure to playground substrate yields an aggregate Hazard
Index of 0.28, below the threshold value of I (with As, again, as the largest single contributor,
followed by Pb, Cr, A1 and Mn). Although the uncertainties associated with the estimates of
toxicity values and exposure factors should be reduced before any definite conclusions regarding
potential health effects are drawn, risk assessment has proven to be a very useful tool to identify
the contaminants and exposure pathways of most concern in urban environments, (c) 2006
Elsevier Ltd. All rights reserved.
20. Desoize B. (2003) Metals and metal compounds in carcinogenesis. In Vivo 17(6):529-539.
Several metals and metal containing compounds are potent mutagens and carcinogens. The most
often blamed are chromium, arsenic, nickel, vanadium, iron, copper and manganese. Although
each of them has its own mechanism of action, it is believed that most of their mechanisms of
action involve reactive oxygen species (ROS). Furthermore, nickel modulates gene expression
by induction of DNA methylation and/or suppression of histone acetylation. Arsenic activity on
cell metabolism is multiple; it seems that cell transformation is induced by long-term exposure to
a low level of arsenic. The paradox of arsenic is that it has also a valuable therapeutic efficacy in
cancer treatment. Manganese is known to cause DNA damage, although it does not represent a
significant carcinogenic risk. Magnesium deficiency and iron excess,are not exactly
carcinogenetic, but certain concentrations of these metal ions are needed to prevent cancer.
21. Dobson AW, Erikson KM, Aschner M. (2004) Manganese neurotoxicity. Redox-Active
Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp 115-128.
Manganese is an essential trace element and it is required for many ubiquitous enzymatic
reactions. While manganese deficiency rarely occurs in humans, manganese toxicity is known to
occur in certain occupational settings through inhalation of manganese-containing dust. The
brain is particularly susceptible to this excess manganese, and accumulation there can cause a
neurodegenerative disorder known as manganism. Characteristics of this disease are described as
Parkinson-like symptoms. The similarities between the two disorders can be partially explained
by the fact that the basal ganglia accumulate most of the excess manganese compared with other
brain regions in manganism, and dysfunction in the basal ganglia is also the etiology of
Parkinson's disease. It has been proposed that populations already at heightened risk for
neurodegeneration may also be more susceptible to manganese neurotoxicity, which highlights
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the importance of investigating the human health effects of using the controversial compound,
methylcyclopentadienyl manganese tricarbonyl (MMT), in gasoline to increase octane. The
mechanisms by which increased manganese levels can cause neuronal dysfunction and death are
yet to be elucidated. However, oxidative stress generated through mitochondrial perturbation
may be a key event in the demise of the affected central nervous system cells. Our studies with
primary astrocyte cultures have revealed that they are a critical component in the battery of
defenses against manganese-induced neurotoxicity. Additionally, evidence for the role of
oxidative stress in the progression of manganism is reviewed here.
22. Egyed M, Wood GC. (1996) Risk assessment for combustion products of the gasoline
additive MMT in Canada. Science of the Total Environment 190:11-20.
Methylcyclopentadienyl manganese tricarbonyl (MMT) has been used as an octane enhancer in
Canadian gasoline since 1976. The main potential health concern is from manganese oxides
produced on combustion (mainly Mn304), given the known neurotoxicity of chronic inhalation
of manganese (Mn) dust from mining and industrial use. Relevant epidemiological studies of
occupational exposure to respirable Mn are briefly reviewed; an ambient air reference value of
0.1 mu g Mn/m(3), and associated inhalation tolerable daily intake (TDI) and tolerable daily
uptake (TDU) of 0.035 and 0.021 mu g/kg b.w./day are derived. Ambient levels of PM(2.5)
(respirable) Mn in Canadian cities have remained unchanged or have decreased between 1986
and 1992, and do not reflect large changes in MMT usage during that time. Ambient levels of
PM(10) Mn in Canadian cities in 1992 were less than or equal to 0.025 mu g Mn/m(3). Mean,
90th and 98th percentiles of PM(10) Mn inhalation uptake based on ambient monitoring data
from high traffic areas and from estimates of personal exposure are below the inhalation uptake
criterion. An assessment of exposure from air, food, water and soil revealed that <1% of total
daily Mn uptake is derived from inhalation for all age groups. Therefore, based on current
information, Mn derived from the combustion of MMT-containing gasoline is unlikely to
represent a significant health risk to Canadians.
23. EPA. 2004. Drinking Water Health Advisory for Manganese. U.S. Environmental Protection
Agency Office of Water. Report nr EPA-822-R-04-003.
24. Erikson KM, Aschner M. (2003) Manganese neurotoxicity and glutamate-GABA
interaction. Neurochemistry International 43(4-5):475-480.
Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent
metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate
homeostasis is essential for the normal functioning of the central nervous system (CNS).
Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the
primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper
manganese levels is important for normal brain functioning. Several in vivo and in vitro studies
have linked increased manganese concentrations with alterations in the content and metabolism
of neurotransmitters, namely dopamine, gamma-antinobutyric acid, and glutamate. It has been
reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese
displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate.
Furthermore, decreased uptake of glutamate has been associated with decreased gene expression
of glutamate:aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional
studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a
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consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that
excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing
a proximate mechanism for manganese-induced neurotoxicity. (C) 2003 Elsevier Science Ltd.
All rights reserved.
25. Erikson KM, Syversen T, Aschner JL, Aschner M. (2005) Interactions between excessive
manganese exposures and dietary iron-deficiency in neurodegeneration. Environmental
Toxicology and Pharmacology 19(3):415-421.
For nearly a century, manganese has been recognized as an essential nutrient for proper bone
formation, lipid, amino acid and carbohydrate metabolism. While manganese deficiency is
characterized by symptoms ranging from stunted growth and poor bone remodeling to ataxia, it
is manganese toxicity that is far more devastating from a public health standpoint. Most cases of
manganese toxicity are the result of occupational exposure to high levels of the metal, and are
characterized by specific neurological symptoms referred to as manganism. While manganism
shares many common features with Parkinson's disease, there are distinct differences between
the two disorders suggesting that manganism might indirectly affect nigrostriatal dopaminergic
function. Recent studies from our laboratory show that dietary iron deficiency is a risk factor for
brain manganese accumulation and that the striatum is particularly vulnerable. This review
briefly discusses manganese from nutritional and toxicological aspects. © 2005 Elsevier
B.V. All rights reserved.
26. Erikson KM, Syversen T, Soldin OP, Wu Q, Aschner M. (2003) Iron deficiency-induced
manganese accumulation in the developing rat brain is associated with increased DMT-1 protein
levels. Drug Metabolism Reviews 35:96-96.
27. Erikson KM, Thompson K, Aschner J, Aschner M. (2007) Manganese neurotoxicity: A
focus on the neonate. Pharmacology & Therapeutics 113(2):369-377.
Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal
amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare
in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be
especially vulnerable. Mn neurotoxicity is most commonly associated with occupational
exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m(3)) of Mn,
consumption of contaminated well water, or parenteral nutrition therapy in patients with liver
disease or immature hepatic functioning such as the neonate. This review will focus primarily on
the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the
neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing
on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral
nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of
exposure becomes salient in this population. We will briefly review some of the mechanisms of
Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported
area of neurotoxicity, (c) 2006 Elsevier Inc. All rights reserved.
28. Finley JW. (2004) Does environmental exposure to manganese pose a health risk to healthy
adults? Nutrition Reviews 62(4): 148-153.
Manganese is an essential nutrient that also may be toxic at high concentrations. Subjects
chronically exposed to manganese-laden dust in industrial settings develop neuropsychological
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changes that resemble Parkinson's disease. Manganese has been proposed as an additive to
gasoline (as a replacement for the catalytic properties of lead), which has generated increased
research interest in the possible deleterious effects of environmental exposure to manganese.
Low-level exposure to manganese has been implicated in neurologic changes, decreased learning
ability in school-aged children, and increased propensity for violence in adults. However, a
thorough review of the literature shows very weak cause-and-effect relationships that do not
justify concern about environmental exposure to manganese for most of the North American
population.
29. Finley JW, Davis CD. (1999) Manganese deficiency and toxicity: Are high or low dietary
amounts of manganese cause for concern? Biofactors 10(1): 15-24.
Manganese is an essential trace element that is required for the activity of several enzymes.
Manganese is also quite toxic when ingested in large amounts, such as the inhalation of Mn-
laden dust by miners. This review examines Mn intake by way of the food supply and poses the
question: Is there reason to be concerned with Mn toxicity or deficiency in free-living
populations in North America? Although much remains to be learned of the Functions of Mn, at
present there are only a few vaguely described cases of Mn deficiency in the medical literature.
Given the heterogeneity of the North American food supply, it is difficult to see the possibility of
more than greatly isolated and unique instances of Mn deficiency. However, low Mn-dependent
superoxide dismutase activity may be associated with cancer susceptibility, and deserves further
study. There may be reasons, however, to be concerned about Mn toxicity under some very
specialized conditions. Increasing numbers of young people are adopting a vegetarian lifestyle
which may greatly increase Mn intake. Iron deficiency may increase Mn absorption and further
increase the body-burden of Mn, especially in,vegetarians. Mn is eliminated primarily through
the bile, and hepatic dysfunction could depress Mn excretion and further contribute to the body
burden. Would such a combination of events predispose substantial numbers of people to chronic
Mn toxicity? At present, there is no definite proof of this occurring, but given the state of
knowledge at the present time, more studies with longer time-frames and more sensitive methods
of analysis are needed.
30. Fitsanakis VA, Aschner M. (2005) The importance of glutamate, glycine, and gamma-
aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity.
Toxicology and Applied Pharmacology 204(3):343-354.
Historically, amino acids were studied in the context of their importance in protein synthesis. In
the 1950s, the focus of research shifted as amino acids were recognized as putative
neurotransmitters. Today, many amino acids are considered important neurochemicals. Although
many amino acids play a role in neurotransmission, glutamate (Glu), glycine (Gly), and gamma-
aminobutyric acid (GABA) are among the more prevalent and better understood. Glu, the major
excitatory neurotransmitter, and Gly and GAB A, the major inhibitory neurotransmitters, in the
central nervous system, are known to be tightly regulated. Prolonged exposure to environmental
toxicants, such as manganese (Mn), mercury (Hg), or lead (Pb), however, can lead to
dysregulation of these neurochemicals and subsequent neurotoxicity. While the ability of these
metals to disrupt the regulation of Glu, Gly and GABA have been Studied, few articles have
examined the collective role of these amino acids in the respective metal's mechanism of
toxicity. For each of the neurotransmitters above, we will provide a brief synopsis of their
regulatory function, including the importance of transport and re-uptake in maintaining their
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optimal function. Additionally, the review will address the hypothesis that aberrant homeostasis
of any of these amino acids, or a combination of the three, plays a role in the neurotoxicity of
Mn, Hg, or pb. (c) 2004 Elsevier Inc. All rights reserved.
31. Fitsanakis VA, Au C, Erikson KM, Aschner M. (2006) The effects of manganese on
glutamate, dopamine and gamma-aminobutyric acid regulation. Neurochemistry International
48(6-7):426-433.
Exposure to high levels of manganese (Mn) results in a neurological disorder, termed
manganism, which shares a similar phenotype to Parkinson's disease due to the involvement of
the basal ganglia circuitry in both. The initial symptoms of manganism are likely due to the
involvement of the globus pallidus, a region rich gamma-aminobutyric acid (GAB A) projections,
while those of Parkinson's disease are related to the degeneration of the substantia nigra, a
dopaminergic nucleus. Additionally, it is known that glutamate regulation is affected by
increases in brain Mn levels. As Mn predominantly accumulates in the basal ganglia, it
potentially could affect the regulation and interactions of all three neurotransmitters. This review
will focus on the circuitry of these neurotransmitters within the basal ganglia and address
potential sites for, as well as the temporal relationship, between Mn exposure and changes in the
levels of these neurotransmitters. While most research has focused on perturbations in the
dopaminergic system, there is evidence to support that early consequences of manganism, also
include disturbances in GABA regulation as well as glutarnatergic-related excitotoxicity.
Finally, we suggest that current research focus on the interdependence of these basal ganglial
neurochemicals, with a greater emphasis on the GABAergic and glutamatergic systems. (C)
2006 Elsevier Ltd. All rights reserved.
32. Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M. (2006) The use of
magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology
27(5):798-806.
Manganese (Mn), an element found in many foods, is an important and essential nutrient for
proper health and maintenance. It is toxic in high doses, however, and exposure to excessive
levels can result in the onset of a neurological disorder similar to, but distinct from, Parkinson's
disease. Historically, Mn neurotoxicity was most commonly associated with various
occupations, such as Mn mining, welding and steel production. More recently, increases in both
blood and brain Mn levels have been observed in persons with liver disease or those receiving
prolonged parenteral nutrition. Additionally, rodent data suggest that iron deficiency and anemia
may be risk factors for Mn neurotoxicity. Clinically, brain Mn accumulation can be monitored in
vivo using non-invasive magnetic resonance imaging (MRI) due to the paramagnetic nature of
this element. Indeed, MRI has been used in a variety of settings to evaluate the brain Mn
deposition in various populations. This review focuses on the use of MRI technology in studies
related specifically to Mn neurotoxicity. Thus, we will examine reports using MRI to confirm
brain Mn accumulation in human populations, and conclude with data from non-human primate
and rodent models of Mn neurotoxicity. (C) 2006 Elsevier Inc. All rights reserved.
33. Forbes A, Jawhari A. (1996) Manganese toxicity and parenteral nutrition. Lancet
347(9017): 1774-1774.
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34. FreelandGraves JH, Turnlund JR. (1996) Deliberations and evaluations of the approaches,
endpoints and paradigms for manganese and molybdenum dietary recommendations. Journal of
Nutrition 126(9):S2435-S2440.
The background of the current dietary recommendations for manganese and molybdenum are
described. This article reviews how the previous and current estimated safe and adequate daily
dietary intakes (ESADDI) were set, shortcomings in the methods used, concerns about the
current recommendations, and brief summaries of new research reports. New approaches,
endpoints and paradigms to use for the development of useful recommendations are given.
35. Friberg L, Nordberg GF, Vouk VB. (2007) Handbook of the Toxicology of Metals. 3rd ed.,
Elsevier Science Publishing Company; pp. 476.
Handbook of the Toxicology of Metals is the standard reference work for physicians,
toxicologists and engineers in the field of environmental and occupational health. This new
edition is a comprehensive review of the effects on biological systems from metallic elements
and their compounds. An entirely new structure and illustrations represent the vast array of
advancements made since the last edition. Special emphasis has been placed on the toxic effects
in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-
to-date reference provides easy access to a broad range of basic toxicological data and also gives
a general introduction to the toxicology of metallic compounds.
36. Gassmann B. (2001) Dietary reference intakes, report 4: Trace elements. Ernahrungs-
Umschau 48(4): 148-+.
Part 2 deals with a set of reference values established for chromium, copper, iodine, iron,
manganese, molybdenum, and zinc to replace Recommended Dietary Allowances (RDAs),
Estimated Safe and Adequate Daily Dietary Intakes published in 1989. In addition, the evidence
of beneficial and adverse effects of arsenic, boron, nickel, silicon, and vanadium has been
analyzed. AU RDAs, Adequate Intakes (AIs), and Tolerable Upper Intake Levels (ULs] reported
are summarized, commented and compared with the DACH reference values 2000. Many
questions that were raised about requirements for and recommended intakes of trace elements
were not answered fully because of inadequacies in the published database. Thus RDAs have
only been set for copper, iodine, iron, molybdenum, and zinc. Far most of the trace elements,
there is no direct information allowing to estimate the amounts required by children, adolescents,
the elderly, and pregnant and lactating women. Because of the lack of data to estimate average
requirements of adults, AIs have to be set for chromium and manganese based on representative
dietary intake data from healthy individuals in the United States, in the case of arsenic, boron,
nickel, silicon, and vanadium, there is evidence that they have a beneficial role in physiological
processes in some species. In some cases measurable responses of human subjects to changes in
dietary intake have been demonstrated. However, the available data are not sufficient to
determine average requirements. Nor could data available about dietary intake be used to
establish an AI. For boron, copper, iodine, iron, manganese, molybdenum, nickel, vanadium, and
zinc ULs have been established. For arsenic, chromium, and silicon data were sparse for setting
ULs, precluding reliable estimates of how much can be ingested safely. Although there are some
differences in their reference values, the Institute pf Medicine and DACH Societies used similar
models for establishing reference intakes of trace elements.
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37. Grandjean P, Landrigan PJ. (2006) Developmental neurotoxicity of industrial chemicals.
Lancet 368(9553):2167-2178.
Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and
cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly
unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls
[PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and
subclinical brain dysfunction. Exposure to these chemicals during early fetal development can
cause brain injury at doses much lower than those affecting adult brain function. Recognition of
these risks has led to evidence-based programmes of prevention, such as elimination of lead
additives in petrol. Although these prevention campaigns are highly successful, most were
initiated only after substantial delays. Another 200 chemicals are known to cause clinical
neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals
have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in
the developing human brain are not known and they are not regulated to protect children. The
two main impediments to prevention of neurodevelopmental deficits of chemical origin are the
great gaps in testing chemicals for developmental neurotoxicity and the high level of proof
required for regulation. New, precautionary approaches that recognise the unique vulnerability of
the developing brain are needed for testing and control of chemicals.
38. Hazell AS. (2002) Astrocytes and manganese neurotoxicity. Neurochemistry International
41(4):271-277.
Increasing evidence suggests that astrocytes are the site of early dysfunction and damage in
manganese neurotoxicity. Astrocytes accumulate manganese by a high affinity, high capacity,
specific transport system. Chronic exposure to manganese leads to increased pallidal signal
hyperintensities on T1-weighted magnetic resonance images and selective neuronal loss in basal
ganglia structures together with characteristic astrocytic changes known as Alzheimer type II
astrocytosis. Manganese is sequestered in mitochondria where it inhibits oxidative
phosphorylation. Exposure of astrocytes to manganese results in important changes including (i)
decreased uptake of glutamate; (ii) increased densities of binding sites for the "peripheral-type"
benzodiazepine receptor (PTBR), a class of receptor localized to mitochondria of astrocytes and
involved in oxidative metabolism, mitochondrial proliferation, and neurosteroid synthesis; (iii)
increased gene expression and activity of the glycolytic enzyme glyceraldehyde-3-phosphate
dehydrogenase (GAPDH), known to be associated with apoptosis; (iv) increased uptake of L-
arginine, a precursor of nitric oxide, together with increased expression of the inducible form of
nitric oxide synthase (iNOS). Potential consequences of these alterations in astrocytic gene
expression include failure of energy metabolism, production of reactive oxygen species (ROS),
increased extracellular glutamate concentration and excitotoxicity which could play a key role in
manganese-induced neuronal cell death as a direct result of impaired astrocytic-neuronal
interactions. (C) 2002 Elsevier Science Ltd. All rights reserved.
39. Keen CL, Ensunsa JL, Clegg MS. (2000) Manganese metabolism in animals and humans
including the toxicity of manganese. Metal Ions in Biological Systems, Vol 37. NEW YORK:
MARCEL DEKKER. pp 89-121.
Draft Bibliography: Manganese Lit. Search
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40. Keen CL, Ensunsa JL, Watson MH, Baly DL, Donovan SM, Monaco MH, Clegg MS.
(1999) Nutritional aspects of manganese from experimental studies. Neurotoxicology 20(2-
3):213-223.
In experimental animals, dietary manganese deficiency can result in numerous biochemical and
structural abnormalities. Deficient animals can be characterized by impaired insulin production,
alterations in lipoprotein metabolism, an impaired oxidant defense system, and perturbations in
growth factor metabolism, if the deficiency occurs during early development there can be
pronounced skeletal abnormalities and an irreversible ataxia. Several lines of evidence suggest
that manganese deficiency may be a problem in some human populations. Manganese toxicity
can also pose a significant health risk. In experimental animals, acute manganese toxicity can
result in numerous biochemical pathologies. However, the above occurs typically when the
manganese is given via injection; most animals show considerable resistance to dietary
manganese toxicosis. Similarly, confirmed cases of manganese toxicity in humans are currently
restricted to cases of exposure to high levels of airborne manganese, and to cases when
manganese excretory pathways are compromised. (C) 1999 Inter Press, Inc.
41. Kim Y. (2006) Neuroimaging in manganism. Neurotoxicology 27(3):369-372.
Neuroimaging such as magnetic resonance imaging (MRI), positron emission tomography
(PET), and single-photon emission computed tomography (SPECT) have been used in the last
decade for investigating the neurotoxicolgy of manganese (Mn). Increased signal intensities on a
T1-weighted image may reflect increased Mn deposits (e.g., due to exposure to Mn) but not
necessarily manganism. In a biologically based dose-response model, our recent results strongly
suggest that signal intensities in T1-weighted MRI reflect a target site dose. However, the
threshold of signal intensity associated with clinical symptoms of manganism remains lobe
solved. Functional neuroimaging such as PET or SPECT examines the integrity of the
nigrostriatal dopaminergic system, and thus is very important for the differential diagnosis of
manganism. However, neuroimaging research should also aim at developing specific and
sensitive parameters for manganism in Mn-exposed individuals, (c) 2005 Elsevier Inc. All rights
reserved.
42. Lee JW. (2000) Manganese intoxication. Archives of Neurology 57(4): 597-599.
Manganese plays an important role as a cofactor in many enzymatic reactions in humans but in
excess amounts can cause irreversible nervous system damage.(1,2) Although manganism is a
rare condition, it can be the cause of complex nervous system symptoms, especially in the setting
of environmental exposure.(3,4) Specifically, manganese is a well-known cause of dystonic
parkinsonism.(5) This article highlights several historical descriptions of the clinical
manifestations, pathological changes, and attempted therapeutic intervention in manganese
intoxication.
43. Lewis RJS. 2004. Sax's Dangerous Properties of Industrial Materials: Manganese 7439-96-5.
Sax's Dangerous Properties of Industrial Materials John Wiley & Sons, Inc.
44. Liang Yx, Su Z, Wu Wa, Lu Bq, Fu Wz, Yang L, Gu Jy. (2003) New trends in the
development of occupational exposure limits for airborne chemicals in China. Regulatory
Toxicology and Pharmacology 38(2): 112-123.
Draft Bibliography: Manganese Lit. Search
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Occupational exposure limits (OELs) are well established in many countries, which serve
occupational professionals as benchmarks of industrial hygiene practice at workplaces
worldwide. Starting in the mid-1950s, the central government of...
45. McMillan DE. (1999) A brief history of the neurobehavioral toxicity of manganese: Some
unanswered questions. Neurotoxicology 20(2-3):499-507.
It was observed by Couper in 1837 that manganese dust produces a neurological syndrome
characterized by muscle weakness, tremor, bent posture, whispered speech and excess salivation.
The similarity of these symptoms to those of Parkinson's disease were not recognized for many
years. In addition to its Parkinson-like effects, manganese produces behavioral symptoms in
humans including nervousness, hallucinations, memory loss, cognitive problems, bizarre
behaviors and flight of ideas. Despite these signs and symptoms, there have been few systematic
attempts to study the effects of manganese on behavior using animal models. The need to better
understand the effects of manganese on behavior is becoming more important due to the
potential of increased environmental exposure to manganese due to its use, or proposed use as a
gasoline additive in a number of countries. However, there is debate as to which manganese
compounds should receive priority for testing, what route of administration should be used in
this testing, what dosing regimens should be used, what species are appropriate for behavioral
testing, and what behavioral tests should be selected. Research to answer these questions is
needed so that the behavioral effects of manganese can be described comprehensively and the
mechanisms underlying these effects can be understood. (C) 1999 Inter Press, Inc.
46. Mergler D, Baldwin M. (1997) Early manifestations of manganese neurotoxicity in humans:
An update. Environmental Research 73(l-2):92-100.
BIOSIS COPYRIGHT: BIOL ABS. It is possible to detect early signs of neurotoxic dysfunction
associated with occupational and environmental exposure to manganese; neurophysiologic and
neurobehavioral tests can be used in the absence of clinical manifestations. Although outcomes
from individual studies vary, they collectively show a pattern of slowing motor functions,
increased tremor, reduced response speed, enhanced olfactory sense, possible memory and
intellectual deficits, and mood changes. This overall portrait is consistent with the action of
manganese on the central nervous system. In reports to date, there is little consistency in dose-
effect relationships between internal parameters of manganese exposure (blood manganese,
urinary manganese, hair manganese) and external measures and neurologic outcomes. Several
studies suggest the existence of dose-effect relationships, but additional clarification is needed.
47. Misselwitz B, Muhler A, Weinmann HJ. (1995) A Toxicologic Risk for Using Manganese
Complexes - a Literature Survey of Existing Data through Several Medical Specialties.
Investigative Radiology 30(10):611-620.
This article summarizes data from the literature about biologic functions, toxicity, and
biokinetics of manganese to help the reader assess the importance of complex stability of
manganese-based contrast agents. Free manganese may present a greater risk than free
gadolinium, especially because it has a physiologic role and can therefore trigger multiple
functions, Of particular interest are the deleterious effects of manganese on the central nervous
system (it can cross the intact blood-brain barrier) and on developing life (it penetrates the
placental barrier as well and is teratogenic), After intravenous contrast injection, normal (enteral)
regulation mechanisms for manganese homeostasis are bypassed, and there is a danger of
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individual overdosing, Excess manganese, for example in patients with chronic liver disease or
with chronic parenteral nutrition, has already been detected by magnetic resonance imaging in
the basal ganglia and was found to coincide with neurologic symptoms. Decomplexation with
release of free manganese substantially prolongs the elimination of the metal because manganese
can be excreted only slowly via the biliary system, This may be of particular importance in
patients with impaired hepatic function. Although minimal amounts of free manganese ions are
not considered harmful to the human body, significant decomplexation of manganese complexes
will require careful analysis of the diagnostic benefit versus the potential risk posed by the free
metal ions.
48. Montgomery EB. (1995) Heavy-Metals and the Etiology of Parkinsons-Disease and Other
Movement-Disorders. Toxicology 97(l-3):3-9.
Heavy metals, such as iron and manganese, are involved in neurologic disease. Most often these
diseases are associated with abnormal environmental exposures or abnormal accumulations of
heavy metals in the body. There is increasing recognition that heavy metals normally present in
the body also may play a role in disease pathogenesis through free radical formation. When a
part of the brain known as the basal ganglia is affected, movements become disordered.
Parkinson's disease is one of the most common movement disorders and is related to destruction
of neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. The combination of
high concentration of iron and the neurotransmitter, dopamine, may contribute to the selective
vulnerability of the SNpc. Dopamine can auto-oxidize to produce free radicals particularly in the
presence of iron and other heavy metals.
49. Neu E, Gebefuegi I, Graw J, Jaekl G, Magour S, Michailov MC, Seidenbusch W, Weiss DG,
Welscher U. (2001) Complex pathophysiological and genotoxic effects of radiation, heavy
metals (Cd, Hg, Mn, Pb, Pu, U), and other toxicants. Toxicology 164(l-3):72-72.
50. NIOSH. 2007. Pocket Guide to Chemical Hazards: Manganese compounds and fume (as
Mn) In: NIOSH, editor. NIOSH Pocket Guide: NIOSH.
NIOSH REL*: TWA 1 mg/m3 ST 3 mg/m3 [*Note: Also see specific listings for Manganese
cyclopentadienyl tricarbonyl, Methyl cyclopentadienyl manganese tricarbonyl, and Manganese
tetroxide.
51. OEHHA. 2001. Prioritization of Toxic Air Contaminants - Children's Environmental Health
Protection Act for Manganese & Compounds California Environmental Protection Agency
(Cal/EPA). 1-8 p.
52. Ostiguy C, Asselin P, Malo S. (2006) The emergence of manganese-related health problems
in Quebec: An integrated approach to evaluation, diagnosis, management and control.
Neurotoxicology 27(3):350-356.
This paper describes the strategy developed in Quebec to deal with an emerging problem:
manganism in welders. Only two cases of manganism had been reported to the Commission de la
sante et de la securite du travail (CSST, Workers Compensation Board in Quebec) before 2000.
In the fall of 200 1, the CSST was informed of a possible cluster of manganism and received 20
compensation claims from one plant. Action was rapidly taken to understand and tackle this
emerging problem. Under the leadership of the CSST, a coordinating working group
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implemented medical and environmental subcommittees involving representatives of the
different partners of the prevention network. After a literature review to document the health
risks associated with manganese and the lack of some important information, a panel of
international experts was formed to try to reach agreement on the parameters to consider in the
diagnosis and management of manganism. The CSST compensation management policies would
be adjusted accordingly. Simultaneously, all the available industrial hygiene data were analyzed
to estimate where and at what levels workers were exposed to manganese. To complete these
data, the exposure of workers in more than 50 industrial plants was evaluated and existing
control measures were documented. All these data have been presented for a revision of the
Quebec permissible exposure limit (PEL). In this integrated approach, the next step targets the
formation of neurologists and neuropsychologists for a standardized medical evaluation, to
complete workplace evaluation in the high risk sectors, inform workers and employers and
recommend control measures where required, based on a revised PEL. Many strategies will be
used to inform the prevention network (about 1000 people), employers and employees of the
risks of overexposure to manganese and of the measures to control exposure in all the plants
where workers are susceptible to be exposed to manganese, (c) 2005 Elsevier Inc. All rights
reserved.
53. Park RM, Bowler RM, Eggerth DE, Diamond E, Spencer KJ, Smith D, Gwiazda R. (2006)
Issues in neurological risk assessment for occupational exposures: The Bay Bridge welders.
Neurotoxicology 27(3):373-384.
The goal of occupational risk assessment is often to estimate excess lifetime risk for some
disabling or fatal health outcome in relation to a fixed workplace exposure lasting a working
lifetime. For sub-chronic or sub-clinical health effects measured as continuous variables, the
benchmark dose method can be applied, but poses issues in defining impairment and in
specifying acceptable levels of excess risk. Such risks may also exhibit a dose-rate effect and
partial reversibility such that effects depend on how the dose is distributed over time.
Neurological deficits as measured by a variety of increasingly sensitive neurobehavioral tests
represent one such outcome, and the development of a parkinsonian syndrome among welders
exposed to manganese fume presents a specific instance. Welders employed in the construction
of piers for a new San Francisco-Oakland Bay Bridge in San Francisco were previously
evaluated using a broad spectrum of tests. Results for four of those tests (Rey-Osterrieth
Complex Figure Test, Working Memory Index, Stroop Color Word Test and Auditory
Consonant Trigrams Test) were used in the benchmark dose procedure. Across the four
outcomes analyzed, benchmark dose estimates were generally within a factor of 2.0, and
decreased as the percentile of normal performance defining impairment increased. Estimated
excess prevalence of impairment, defined as performance below the 5th percentile of normal,
after 2 years of exposure at the current California standard (0.2 mg/m(3), 8 h TWA), ranged 15-
32% for the outcomes studied. Because these exposures occurred over a 1-2-year period,
generalization to lifetime excess risk requires further consideration of the form of the exposure
response and whether short-term responses can be generalized to equivalent 45-year period.
These results indicate unacceptable risks at the current OSHA PEL for manganese (5.0 mg/m(3)
15 min) and likely at the Cal OSHA PEL as well, (c) 2005 Elsevier Inc. All rights reserved.
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54. Pfeifer GD, Roper JM, Dorman D, Lynam DR. (2004) Health and environmental testing of
manganese exhaust products from use of methylcyclopentadienyl manganese tricarbonyl in
gasoline. Science of the Total Environment 334-35:397-408.
This paper reviews recent research on the environmental effects of methylcyclopentadienyl
manganese tricarbonyl (MMT), personal exposures to airborne Mn as a result of MMT use,
chemical characterization of the manganese particulates emitted from the tailpipe and progress in
developing a Physiologically based Pharmacokinetic (PBPK) model for manganese in rodents.
Recent studies show that manganese is emitted as a mixture of compounds with an average
valence of about 2.2. The major products are sulfate, phosphate, and smaller amounts of oxides.
Because only small amounts of Mn are used in gasoline (<18 mg Mn/gal) and less than 15% of
the combusted Mn is emitted, soil along busy roads is not elevated in Mn, even after long-term
use of MMT. A very large population-based study of manganese exposures in the general
population in Toronto, where MMT has been used continuously for over 20 years, showed that
manganese exposures were quite low, the median annual exposure was 0.008 mug Mn/m(3). A
great amount of toxicological research on Mn has been carried out during the past few years that
provides data for use in developing a PBPK model in rodents. These data add greatly to the
existing body of knowledge regarding the relationship between Mn exposure and tissue
disposition. When complete, the PBPK model will contribute to our better understanding of the
essential neurotoxic dynamics of Mn. (C) 2004 Elsevier B.V. All rights reserved.
55. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT, Swanson PD, Checkoway H.
(2003) Parkinson's disease risks associated with dietary iron, manganese, and other nutrient
intakes. Neurology 60(11): 1761-1766.
Background: Dietary influences on oxidative stress have been thought to play important role in
the etiology of PD. Objective: To examine associations of PD with dietary nutrients, including
minerals, vitamins, and fats. Methods: A population-based case-control study was conducted
among newly diagnosed case (n = 250) and control subjects (n = 388) identified between 1992
and 2002 from enrollees of the Group Health Cooperative health maintenance organization in
western Washington state. Controls were frequency matched to cases on sex and age. In-person
interviews elicited data on food frequency habits during most of adult life. Nutrient intakes were
calculated and analyzed by adjusting each person's nutrient intake by their total energy intake (
the nutrient density technique). Results: Subjects with an iron intake in the highest quartile
compared with those in the lowest quartile had an increased risk of PD ( odds ratio = 1.7, 95%
CI: 1.0, 2.7, trend p = 0.016). There was an apparent joint effect of iron and manganese; dietary
intake above median levels of both together conferred a nearly doubled risk compared with
lower intakes of each nutrient ( odds ratio = 1.9, 95% CI: 1.2, 2.9). No strong associations were
found for either antioxidants or fats. Conclusion: A high intake of iron, especially in combination
with high manganese intake, may be related to risk for PD.
56. Sayre LM, Perry G, Atwood CS, Smith MA. (2000) The role of metals in neurodegenerative
diseases. Cellular and Molecular Biology 46(4):731-741.
There is increasing evidence in a number of neurodegenerative diseases that transition metal-
mediated abnormalities play a crucial role in disease pathogenesis. In this treatise, we review the
role of metal homeostasis as it pertains to alterations in brain function in neurodegenerative
diseases. In fact, while there is documented evidence for alterations in transition metal
homeostasis, redox-activity and localization, it is also important to realize that alterations in
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specific copper- and iron-containing metalloenzymes also appear to play a crucial role in the
neurodegenerative process.
57. Solomons NW, Ruz M. (1998) Trace element requirements in humans: An update. Journal
of Trace Elements in Experimental Medicine 11(2-3): 177-195.
Concepts about nutrient intake requirements and recommendations have emerged from a period
of relative consensus about concepts and goals to one of vertiginous shifts of paradigms and a
proliferation of agendas, often competing, for making nutrient and dietary recommendations in
public policy. The recommendations for intakes of those trace elements considered to be
essential in human nutrition are updated in the context of the ferment and controversy regarding
how to establish a recommended intake. It is our contention that making universal
recommendations for the intake of trace elements to cover all societies among the diverse
geographic and ecological settings of the world is a futile effort. Differences in ethnicity, body
size, traditional diets, genetics, and environmental stressors condition distinct needs at distinct
locations. It is speculated that lower than "usual" body stores of certain trace elements may be
adaptive, i.e., to improve human survival under certain adverse and challenging environmental
conditions. Additionally, gaps in our knowledge regarding the bases for nutrient
recommendations in the very old and the impact of new, engineered foods and dietary guidelines
for intake regimes that prevent chronic diseases need to be filled. As trace elements are inorganic
and can accumulate in tissues, recommendations for usual intakes confront the issue of the upper
limits of tolerance and potential toxic consequences. Iron, copper, and manganese are among the
trace elements for which this consideration is ever latent. The community of scientists involved
in trace element biology must follow closely the chaotic situation regarding changing paradigms
and agendas of oral intake recommendations, participate in the discussions when called upon,
but continue to produce new findings. J. Trace Elem. Exp. Med. 11:177-195, 1998. (C) 1998
Wiley-Liss,Inc.
58. Sunderman FW. (2001) Review: Nasal toxicity, carcinogenicity, and olfactory uptake of
metals. Annals of Clinical and Laboratory Science 31(l):3-24.
Occupational exposures to inhalation of certain metal dusts or aerosols can cause loss of
olfactory acuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or
sinonasal cancer. Anosmia and hyposmia have been observed in workers exposed to Ni- or Cd-
containing dusts in alkaline battery factories, nickel refineries, and cadmium industries. Ulcers of
the nasal mucosa and perforated nasal septum have been reported in workers exposed to Cr(VI)
in chromate production and chrome plating, or to As(III) in arsenic smelters. Atrophy of the
olfactory epithelium has been observed in rodents following inhalation of NiS04 or alpha
Ni3S2. Cancers of the nose and nasal sinuses have been reported in workers exposed to Ni
compounds in nickel refining, cutlery factories, and alkaline battery manufacture, or to Cr(VI) in
chromate production and chrome plating. Ill animals, several metals (eg, Al, Cd, Co, Hg, Mn,
Ni, Zn) have been shown to pass via olfactory receptor neurons from the nasal lumen through the
cribriform plate to the olfactory bulb. Some metals (eg. Mn, Ni, Zn) can cross synapses in the
olfactory bulb and migrate via secondary olfactory neurons to distant nuclei of the brain. After
nasal instillation of a metal-containing solution, transport of the metal via olfactory axons can
occur rapidly within hours or a few days (eg, Mn), or slowly other days or weeks (eg, Ni). The
olfactory bulb tends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greater avidity
than other regions of the brain. The molecular mechanisms responsible for metal translocation in
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olfactory neurons and deposition in the olfactory bulb are unclear, but complexation by metal-
binding molecules such as carnosine (beta -alanyl-L-histidine) may be involved.
59. Takeda A. (2004) Essential trace metals and brain function. Yakugaku Zasshi-Journal of the
Pharmaceutical Society of Japan 124(9):577-585.
Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the
brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system,
i.e., the blood-brain and blood-cerebrospinal fluid barriers. Trace metals usually serve the
function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the
presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and
manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via
the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an
inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by
manganese might mean functional and toxic aspects in the synapse. Dietary zinc deficiency
affects zinc homeostasis in the brain, followed by an enhanced susceptibility to the excitotoxicity
of glutamate in the hippocampus. Transferrin may be involved in the physiological transport of
iron and manganese into the brain and their utilization there. It is reported that the brain
transferrin concentration is decreased in neurodegenerative diseases such as Alzheimer's disease
and Parkinson's disease and that brain iron metabolism is also altered. The homeostasis of trace
metals in the brain is important for brain function and also for the prevention of brain diseases.
60. Taylor A. (1996) Detection and monitoring of disorders of essential trace elements. Annals
of Clinical Biochemistry 33:486-510.
61. Tenorio FA, Ensunsa JL, Keen CL, Symons JD. (2002) Does manganese deficiency reduce
arginase activity to an extent whereby vascular function is altered? Arteriosclerosis Thrombosis
and Vascular Biology 22(5):A45-A45.
62. Tilson HA. (1996) Evolution and current status of neurotoxicity risk assessment. Drug
Metabolism Reviews 28(1-2): 121-139.
63. Verity MA. (1999) Manganese neurotoxicity: A mechanistic hypothesis. Neurotoxicology
20(2-3):489-497.
This review provides a summary of the presentations and abstracts presented at the 15(th)
International Neurotoxicology Conference which may contribute to an understanding of the
mechanism and pathogenesis of manganese (Mn2+) neurotoxicity. We propose that an
understanding of the pathogenesis of Mn2+ neurotoxicity must incorporate data on (I) the factors
controlling Mn2+ uptake and distribution within the CNS, (2) account for the apparent
selectivity of dopaminergic neurons, (3) analyze the role of mitochondrial dysfunction and (4)
provide da ta to support or refute the role of oxidative injury in the genesis of toxicity. We
propose a multifactor hypothesis coupling Mn2+ uptake with coincident transport of aluminum
and iron. Selectivity of dopaminergic neurons is dependent upon interactions of Mn2+ with
dopamine transport and the role of Mn2+ as a pro-oxidative toxicant in conjunction with changes
in iron concentration. Within the synaptic milieu, Mn2+-mitochondrial interaction will influence
mitochondrial - Ca2+ transport kinetics leading to defective mitochondrial function, decreased
oxidative phosphorylation, decreased ATP and accumulation of reactive oxygen species. Under
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the influence of excessive depolarization, energy failure will occur leading to secondary
activation of an excitotoxic state. These conceptual ideas provide for mechanistic based
hypotheses and testing and are likely to lead to rational therapeutic avenues directed against
Mn2+ neurotoxicity. (C) 1999 Inter Press, Inc.
64. Weiss B. (1999) Manganese in the context of an integrated risk and decision process.
Neurotoxicology 20(2-3):519-525.
Current approaches to risk assessment regard it as a process that should embody both health and
ecological risks, soc-ietal values, and cost-benefit analysis, that should seek the views of affected
parties, and that should examine available options more holistically than in the past. Even with a
single agent, manganese, the process requires a greath breadth of information and keen attention
to how all of its different components fit together. An evaluation of exposure variables alone
needs to consider contributions from multiple media, their physical forms and path ways such as
inhaled fumes and particles, and ingestion of water, food soil, and dust (especially by children).
Endpoints need also to be broadened, especially to include susceptibility across the life cycle and
the impact of low-level neurotoxicity on rate of aging. Finally, the pursuit of risk reduction
options for manganese should be embedded in a process that clarifies all the consequences of a
particular option, including the raising or lowering of other risks and the full economic
consequences. (C) 1999 Inter Press, Inc.
65. WHO. 2000. Air Quality Guidelines for Europe. Report nr 91. 288 p.
The second edition of the guidelines that aim to provide a basis for protecting public health from
adverse effects of air pollutants and to eliminate or reduce exposure to those pollutants that are
known or likely to be hazardous to human health or wellbeing. New data and research are
included.
66. Yokel RA. (2005) Selective Blood-Brain Barrier Transport Of Aluminum, Manganese, And
Other Metals In Metal-Induced Neurodegeneration. Toxicol Sci 84(l-S):338-339.
Excessive concentrations of aluminum (Al), copper (Cu), iron (Fe), mercury (Hg), manganese
(Mn), tin (Sn) and zinc (Zn) have been shown or hypothesized to contribute to one or more
neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD),
Wilson's disease (WD) and Friedreich's ataxia. The uptake of metals into the brain is often
mediated by selective carriers or transporters localized at the blood-brain barrier (BBB). Thus,
the regulation of metal transport by the BBB is fundamental to subsequent metal-induced
neurotoxicities. This presentation will first review the evidence supporting and refuting roles of
Mn in PD and Al in AD, including disparities between Mn-induced Parkinsonism and idiopathic
PD, epidemiological evidence of Al neurotoxicity, clinical studies of brain Al in AD patients,
and biochemical effects produced by Al that mimic AD. It will then focus on the selective metal
transporters at the BBB as a key factor in the potential for metals to produce neurotoxicity. The
specific interaction of a unique chemical species (form) of a neurotoxic metal with a particular
membrane transporter at the BBB serves as a good example of selective transport of metals by
the BBB. The ability of the methyl-Hg-cysteine complex to mimic methionine and to serve as a
substrate for an amino acid transporter illustrates this mechanism of brain metal entry. Another
mechanism that may mediate brain entry of several metals is transferrin - receptor mediated
endocytosis. This presentation will further discuss the role of similar mechanisms in Al and Mn
brain influx and efflux. The evidence for carriermediated influx and efflux of Al across the BBB
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will be presented, as will the evidence for carrier-mediated influx, but only diffusion-mediated
efflux, of Mn. Our incomplete knowledge of the mechanisms mediating A1 and Mn flux across
the BBB will be contrasted to the understanding of the Cu transporter that plays a central role in
WD and the paucity of data on BBB flux of Sn and Zn.
67. Yokel RA. (2006) Blood-brain barrier flux of aluminum, manganese, iron and other metals
suspected to contribute to metal-induced neurodegeneration. Journal of Alzheimers Disease
10(2-3):223-253.
The etiology of many neurodegenerative diseases has been only partly attributed to acquired
traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has
been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier
(the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal
uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-
brain barrier are listed to illustrate the extensive possibilities for moving substances into and out
of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting
brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by
system Xc(-) and an organic anion transporter, and results suggesting transporter-mediated
aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like
syndrome, evidence suggesting manganese uptake by transferrin-and non-transferrin-dependent
mechanisms which may include store-operated calcium channels, and the lack of transporter-
mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and
independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and
ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is
facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain
lead uptake may involve a non-energy-dependent process, store-operated calcium channels,
and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine
that mimics methionine, enabling its transport by the L system. The putative roles of zinc
transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake
mechanisms for some metals have been identified, metal efflux from the brain has received little
attention, preventing integration of all processes that contribute to brain metal concentrations.
68. Zatta P, Lucchini R, van Rensburg SJ, Taylor A. (2003) The role of metals in
neurodegenerative processes: aluminum, manganese, and zinc. Brain Research Bulletin
62(1): 15-28.
Until the last decade, little attention was given by the neuroscience community to the
neurometabolism of metals. However, the neurobiology of heavy metals is now receiving
growing interest, since it has been linked to major neurodegenerative diseases. In the present
review some metals that could possibly be involved in neurodegeneration are discussed. Two of
them, manganese and zinc, are essential metals while aluminum is non-essential. Aluminum has
long been known as a neurotoxic agent. It is an etiopathogenic factor in diseases related to long-
term dialysis treatment, and it has been controversially invoked as an aggravating factor or
cofactor in Alzheimer's disease as well as in other neurodegenerative diseases. Manganese
exposure can play an important role in causing Parkinsonian disturbances, possibly enhancing
physiological aging of the brain in conjunction with genetic predisposition. An increased
environmental burden of manganese may have deleterious effects on more sensitive subgroups
of the population, with sub-threshold neurodegeneration in the basal ganglia, generating a pre-
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Parkinsonian condition. In the case of zinc, there has as yet been no evidence that it is involved
in the etiology of neurodegenerative diseases in humans. Zinc is redox-inactive and, as a result
of efficient homeostatic control, does not accumulate in excess. However, adverse symptoms in
humans are observed on inhalation of zinc fumes, or accidental ingestion of unusually large
amounts of zinc. Also, high concentrations of zinc have been found to kill bacteria, viruses, and
cultured cells. Some of the possible mechanisms for cell death are reviewed. (C) 2003 Elsevier
Inc. All rights reserved.
69. Zayed J. (2001) Use of MMT in Canadian gasoline: Health and environment issues.
American Journal of Industrial Medicine 39(4):426-433.
Background Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic derivative of
manganese (Mn) used in Canadian gasoline since 1976 as an antiknock agent and to improve
octane rating. Combustion products of MMT are mainly a mixture of Mn phosphate and Mn
sulfate. In 1997 the Canadian federal government adopted a law (C-29) which banned both the
interprovincial trade and the importation for commercial purposes of manganese-based
substances, including MMT: However the government reworded this law in July 1998 so that
manganese-based fuel additives were not included in the restrictions, MMT is now approved for
use in Argentina, Australia, Bulgaria, the United States, France, Russia, and conditionally in
New Zealand. Nevertheless, these countries are nor using MMT intensively and they are waiting
for strong evidence of the absence of effects on human health. Even after several years of use of
MMT in Canada, many uncertainties remain. Methods Different methods were used in order to
assess (1) environmental contamination and human exposure to the parental form of MMT (2)
nitrogen oxides (NOx) and carbon monoxide (CO) emissions associated with the use of MMT
and (3) qualitative and quantitative assessments of Mn emissions to the environment. Results
The results provide timely information with regard to the impact of MMT on
environmental/ecosystem Mn contamination in abiotic and biotic systems as well as on human
exposure. Moreover results raise major concerns with regard to public health effects related to
exposure to Mn. Conclusions Obviously, there is still an important lack of adequate toxicological
information and further studies are needed to provide successful implementation of evidence-
based risk assessment approaches. (C) 2001 Wiley-Liss, Inc.
70. Zheng W. (2001) Neurotoxicology of the brain barrier system: New implications. Journal of
Toxicology-Clinical Toxicology 39(7):711-719.
The concept of a barrier system in the brain has existed for nearly a century. The barrier that
separates the blood from the cerebral interstitial fluid is defined as the blood-brain barrier, while
the one that discontinues the circulation between the blood and cerebrospinal fluid is named the
blood-cerebrospinal fluid barrier. Evidence in the past decades suggests that brain barriers are
subject to toxic insults from neurotoxic chemicals circulating in blood. The aging process and
some disease states render barriers more vulnerable to insults arising inside and outside the
barriers. The implication of brain barriers in certain neurodegenerative diseases is compelling,
although the contribution of chemical-induced barrier dysfunction in the etiology, of any of these
disorders remains poorly understood. This review examines what is currently, understood about
brain barrier systems in central nervous system disorders by focusing on chemical-induced
neurotoxicities including those associated with nitrobenzenes, N-methyl-D-aspartate,
cyclosporin A, pyridostigmine bromide, aluminum, lead, manganese, l-methyl-4-phenyl-l,2,3,6-
tetrahydropyridine, and 3-nitropropionic acid. Contemporary research questions arising from this
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growing understanding show enormous promises for brain researchers, toxicologists, and
clinicians.
71. Zheng W. (2001) Toxicology of choroid plexus: Special reference to metal-induced
neurotoxicities. Microscopy Research and Technique 52(1):89-103.
The chemical stability in the brain underlies normal human thinking, learning, and behavior.
Compelling evidence demonstrates a definite capacity of the choroid plexus in sequestering toxic
heavy metal and metalloid ions. As the integrity of blood-brain and blood-CSF barriers, both
structurally and functionally, is essential to brain chemical stability, the role of the choroid
plexus in metal-induced neurotoxicities has become an important, yet under-investigated
research area in neurotoxicology. Metals acting on the choroid plexus can be categorized into
three major groups. A general choroid plexus toxicant can directly damage the choroid plexus
structure such as mercury and cadmium. A selective choroid plexus toxicant may impair specific
plexus regulatory pathways that are critical to brain development and function, rather than
induce massive pathological alteration. The typical examples in this category include lead-
induced alteration in transthyretin production and secretion as well as manganese interaction
with iron in the choroid plexus. Furthermore, a sequestered choroid plexus toxicant, such as iron,
silver, or gold, may be sequestered by the choroid plexus as an essential CNS defense
mechanism. Our current knowledge on the toxicological aspect of choroid plexus research is still
incomplete. Thus, the future research needs have been suggested to focus on the role of choroid
plexus in early CNS development as affected by metal sequestration in this tissue, to explore
how metal accumulation alters the capacity of the choroid plexus in regulation of certain
essential elements involved in the etiology of neurodegenerative diseases, and to better
understand the blood-CSF barrier as a defense mechanism in overall CNS function. (C) 2001
Wiley-Liss, Inc.
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APPENDIX E:
KEY REFERENCES NOT OBTAINED IN PDF
Draft Bibliography: Manganese Lit. Search January 31, 2008
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KEY REFERENCES NOT OBTAINED IN PDF (83)
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3. Anonymous. (1997) Manganese. RAIS Toxicity Profiles (1997).
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threshold limit values and biological exposure indices Vol:7th Ed (2001) 6 p.
5. Anonymous. (2001) Manganese Cyclopentadienyl Tricarbonyl. ACGIH. Documentation of
the threshold limit values and biological exposure indices Vol:7th Ed (2001) 2 p.
6. Anonymous. (2003) Methylcyclopentadienyl Manganese Tricarbonyl (MMT). NICNAS:
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7. Arnich N, Cunat L, Lanhers MC, Burnel D. (2004) Comparative in situ study of the
intestinal absorption of aluminum, manganese, nickel, and lead in rats. Biological Trace
Element Research 99(1-3): 157-171.
8. Aschner M, Erikson KM, Dorman DC. (2005) Manganese dosimetry: Species differences
and implications for neurotoxicity. Critical Reviews in Toxicology 35(1): 1-32.
9. Aschner M, Fitsanakis VA, Milatovic D, Erikson KM. (2006) Dietary iron modulates
manganese neurotoxicity. Journal of Neurochemistry 96:89-89.
10. Aschner M. (2005) Manganese transport, toxicity and speciation in the CNS. Journal of
Neurochemistry 94:8-8.
11. Boojar MMA, Goodarzi F. (2002) A longitudinal follow-up of pulmonary function and
respiratory symptoms in workers exposed to manganese. Journal of Occupational and
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12. Bowler RM, Roels HA, Nakagawa S, Drezgic M, Diamond E, Park R, Koller W, Bowler
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confined space bridge welders. Occupational and Environmental Medicine 64(3): 167-177.
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Neurotoxicology 20(2-3):477-487.
14. Chen MT, Cheng GW, Lin CC, Chen BH, Huang YL. (2006) Effects of acute manganese
chloride exposure on lipid peroxidation and alteration of trace metals in rat brain. Biological
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uptake and deposition in the brain and other organs of the rat. Biological Trace Element
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influence of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat.
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exposure guideline for manganese using the benchmark method. Risk Analysis 23(5): 1031-
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19. Deschamps FJ, Guillaumot A, Raux S. (2001) Neurological effects in workers exposed to
manganese. Journal of Occupational and Environmental Medicine 43(2): 127-132.
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manganese, iron, and other essential nutrients. Toxicological Sciences 72:117-117.
21. Eder K, Kralik A, Kirchgessner M. (1996) The effect of manganese supply on thyroid
hormone metabolism in the offspring of manganese-depleted dams. Biological Trace
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22. Erikson KA, Shihabi ZK, Aschner JL, Aschner M. (2002) Manganese accumulates in iron-
deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical
alterations. Biological Trace Element Research 87(1-3): 143-156.
23. Erikson KM, Jones SR, Aschner M. (2005) Brain manganese accumulation due to toxic
exposure is mediated by the dopamine transporter. Faseb Journal 19(5):A1033-A1034.
24. Fechter LD. (1999) Distribution of manganese in development. Neurotoxicology 20(2-
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25. Fored CM, Fryzek JP, Brandt L, Nise G, Sjogren B, McLaughlin JK, Blot WJ, Ekbom A.
(2006) Parkinson's disease and other basal ganglia or movement disorders in a large
nationwide cohort of Swedish welders. Occupational and Environmental Medicine
63(2):135-140.
26. Fryzek JP, Hansen J, Cohen S, Bonde JP, Llambias MT, Kolstad HA, Skytthe A, Lipworth
L, Blot W, Olsen JH. (2005) A cohort study of Parkinson's disease and other
neurodegenerative disorders in Danish welders. Journal of Occupational and Environmental
Medicine 47(5):466-472.
27. Garcia SJ, Syversen T, Gellein K, Aschner M. (2005) Iron Deficient And Manganese
Enhanced Diets Alter Metals And Transporters In The Developing Rat Brain. Toxicol Sci
84(1-S):122.
28. Gianutsos G, Morrow GR, Morris JB. (1997) Accumulation of manganese in rat brain
following intranasal administration. Fundamental and Applied Toxicology 37(2): 102-105.
29. Gibbs JP, Crump KS, Houck DP, Warren PA, Mosley WS. (1999) Focused medical
surveillance: A search for subclinical movement disorders in a cohort of U.S. workers
exposed to low levels of manganese dust. Neurotoxicology (Little Rock) 20(2-3):299-314.
30. Greger JL. (1998) Dietary standards for manganese: Overlap between nutritional and
toxicological studies. Journal of Nutrition 128(2):368S-371S.
31. Greger JL. (1999) Nutrition versus toxicology of manganese in humans: Evaluation of
potential biomarkers. Neurotoxicology 20(2-3):205-212.
32. Gwiazda R, Kern C, Smith D. (2005) Progression Of Neurochemical Effects In Different
Brain Regions As A Function Of The Magnitude And Duration Of Manganese Exposure.
Toxicol Sci 84(1-S): 122-123.
33. HaMai D, Bondy SC. (2004) Oxidative basis of manganese neurotoxicity. Redox-Active
Metals in Neurological Disorders. NEW YORK: NEW YORK ACAD SCIENCES, pp 129-
141.
34. Hochberg F, Miller G, Valenzuela R, McNelis S, Crump KS, Covington T, Valdivia G,
Hochberg B, Trustman JW. (1996) Late motor deficits of Chilean manganese miners: A
blinded control study. Neurology 47(3):788-795.
35. Hudnell HK. (1999) Effects from environmental Mn exposures: A review of the evidence
from non-occupational exposure studies. Neurotoxicology 20(2-3):379-397.
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36. Hussain S, Lipe GW, Slikker W, Ali SF. (1997) The effects of chronic exposure of
manganese on antioxidant enzymes in different regions of rat brain. Neuroscience Research
Communications 21(2): 135-144.
37. Ingersoll RT, Montgomery EB, Aposhian HV. (1995) Central-Nervous-System Toxicity of
Manganese . 1. Inhibition of Spontaneous Motor-Activity in Rats after Intrathecal
Administration of Manganese Chloride. Fundamental and Applied Toxicology 27(1): 106-
113.
38. Iregren A. (1999) Manganese neurotoxicity in industrial exposures: Proof of effects, critical
exposure level, and sensitive tests. Neurotoxicology 20(2-3):315-323.
39. Jadhav SH, Sarkar SN, Tripathit HC. (2006) Cytogenetic effects of a mixture of selected
metals following subchronic exposure through drinking water in male rats. Indian J Exp Biol
44(12):997-1005.
40. Jankovic J. (2005) Searching for a relationship between manganese and welding and
Parkinson's disease. Neurology 64(12):2021-2028.
41. Jiang YM, Zheng W. (2005) Cardiovascular toxicities upon manganese exposure.
Cardiovascular Toxicology 5(4):345-354.
42. Kim Y, Kim KS, Yang JS, Park IJ, Kim E, Jin YW, Kwon KR, Chang KH, Kim JW, Park
SH and others. (1999) Increase in signal intensities on T1-weighted magnetic resonance
images in asymptomatic manganese-exposed workers. Neurotoxicology 20(6):901-907.
43. Kimura M, Ujihara M, Yokoi K. (1996) Tissue manganese levels and liver pyruvate
carboxylase activity in magnesium-deficient rats. Biological Trace Element Research
52(2): 171-179.
44. Klos KJ, Chandler M, Kumar N, Ahlskog JE, Josephs KA. (2006) Neuropsychological
profiles of manganese neurotoxicity. European Journal of Neurology 13(10): 1139-1141.
45. Kobayashi H, Uchida M, Sato I, Suzuki T, Hossain MM, Suzuki K. (2004) Neurotoxicity
and brain regional distribution of manganese in mice, (vol 22, pg 679, 2003). Journal of
Toxicology-Toxin Reviews 23(4):556-557.
46. Komiskey H. (2005) Influence Of Subacute Manganese Sulfate On Dopamine And N-
Methyl-D-Aspartate Receptors. Toxicol Sci 84(1-S):122.
47. Lees-Haley PR, Greiffenstein MF, Larrabee GJ, Manning EL. (2004) Methodological
problems in the neuropsychological assessment of effects of exposure to welding fumes and
manganese. Clinical Neuropsychologist 18(3):449-464.
48. Levy BS, Nassetta WJ. (2003) Neurologic effects of manganese in humans: A review.
International Journal of Occupational and Environmental Health 9(2): 153-163.
49. Li G, Liu J, Waalkes MP, Zheng W. (2005) Manganese Exposure Alters Iron Regulatory
Mechanisms At Blood-Cerebrospinal Fluid Barrier (BCB) And Selected Regions Of
Bloodbrain Barrier (BBB) In Rats. Toxicol Sci 84(1-S): 121-122.
50. Lipe GW, Duhart H, Newport GD, Slikker W, Ali SF. (1999) Effect of manganese on the
concentration of amino acids in different regions of the rat brain. Journal of Environmental
Science and Health Part B-Pesticides Food Contaminants and Agricultural Wastes
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51. Lucchini R, Selis L, Folli D, Apostoli P, Mutti A, Vanoni O, Iregren A, Alessio L. (1995)
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52. Malecki EA, Devenyi AG, Beard JL, Connor JR. (1999) Existing and emerging mechanisms
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53. Newland MC. (1999) Animal models of manganese's neurotoxicity. Neurotoxicology 20(2-
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54. Ohtake T, Negishi K, Okamoto K, Oka M, Maesato K, Moriya H, Kobayashi S. (2005)
Manganese-induced parkinsonism in a patient undergoing maintenance hemodialysis.
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55. Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, Beal MF, Calne
DB, Perl DP. (1996) Manganese intoxication in the rhesus monkey: A clinical, imaging,
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57. Pal PK, Samii A, Calne DB. (1999) Manganese neurotoxicity: A review of clinical features,
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58. Penland JG, Davis CD, Finley JW, Pettit RE. (2000) Moderately high dietary intakes of
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59. Ponnapakkam TP, Henry-Sam GA, Iszard MB. (2001) A comparative study of the
reproductive toxicity of manganese in rats and mice. Faseb Journal 15(4):A585-A585.
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