Manganese (Mn) is an essential metal for human health, but exposure to excess levels can cause neurological disease. Emerging evidence suggests that long-term exposures to low levels of anthropogenic or environmental sources of Mn may have detrimental effects on human neurological health. Automobile combustion of gasoline containing methylcyclopentadienyl manganese tricarbonyl (MMT) has the potential to significantly increase Mn exposures to human populations where this fuel additive is used. However, there is a paucity of knowledge on the neurological health effects of chronic exposures to low-levels of Mn. While moderate to high levels of Mn exposure are associated with motor abnormalities and cognitive dysfunction as well as basal ganglia dopaminergic dysfunction in humans and non-human primates. The extent to which lower levels of Mn exposure may target specific cognitive domains and alter brain chemistry is not known. The studies described in this application are the result of a unique and productive on-going collaboration of scientists with expertise in behavioral neuroscience, molecular imaging, molecular and cellular neuroscience, neurotoxicology, neurochemistry and neuropathology applying the latest state-of-the-art behavioral and neuroimaging modalities to understand the behavioral dysfunction and underlying molecular and cellular mechanisms of Mn-induced neurological disease in the living non-human primate brain. Our most recent evidence suggests that chronic low level Mn exposure in non-human primates produces in vivo neurochemical changes resembling those in schizophrenia patients. Further, exposure to Mn produces a cellular stress response and diffuse amyloid-2 plaques in the frontal cortex resembling those in the aging brain and in Alzheimer's disease. These preliminary findings provide a putative link of exposure to an environmental toxicant (Mn) and neurochemical and neuropathological changes associated with mental and neurological diseases. The proposed studies will expand on these findings and provide the most comprehensive assessment to date on the neurological consequences of chronic Mn exposure on the non-human primate brain. The knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population. Relevance: The work that we describe in this proposal will define the behavioral, in vivo neurochemistry and neuropathological effects at increasingly lower levels of chronic Mn exposure in non-human primates. They represent the most comprehensive assessment to date on the neurological consequences of chronic exposure to levels of Mn that segments of the population are likely to encounter in their environment. These studies have already provided novel findings and the knowledge gained will help set future public health policies and guidelines to limit Mn exposures in occupational settings and to the general population.

Public Health Relevance

The long-term goal of the proposed studies is to determine the behavioral, neuroimaging and neuropathological effects of chronic exposure to increasingly lower concentrations of manganese (Mn) in order to identify the level of cumulative exposure that produces the earliest changes in behavior and brain chemistry. The ultimate goal is to determine the extent to which chronic exposure to environmentally- or occupationally- relevant levels of Mn contributes to human neurological disease. A major advantage of our unique collaboration is that behavioral and in vivo brain chemistry changes are monitored prospectively and in parallel with Mn exposure in non-human primates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010975-09
Application #
8274461
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2001-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$765,985
Indirect Cost
$131,518
Name
Columbia University (N.Y.)
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Verina, Tatyana; Schneider, Jay S; Guilarte, Tomas R (2013) Manganese exposure induces ýý-synuclein aggregation in the frontal cortex of non-human primates. Toxicol Lett 217:177-83
Schneider, J S; Williams, C; Ault, M et al. (2013) Chronic manganese exposure impairs visuospatial associative learning in non-human primates. Toxicol Lett 221:146-151
Verina, Tatyana; Kiihl, Samara F; Schneider, Jay S et al. (2011) Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates. Neurotoxicology 32:215-26
Guilarte, Tomas R; Chen, Ming-Kai (2007) Manganese inhibits NMDA receptor channel function: implications to psychiatric and cognitive effects. Neurotoxicology 28:1147-52
Aschner, Michael; Guilarte, Tomas R; Schneider, Jay S et al. (2007) Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol 221:131-47
Schneider, Jay S; Decamp, Emmanuel; Koser, Amy Jo et al. (2006) Effects of chronic manganese exposure on cognitive and motor functioning in non-human primates. Brain Res 1118:222-31
Zhou, Yun; Chen, Ming-Kai; Endres, Christopher J et al. (2006) An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge. Neuroimage 33:550-63
Chen, Ming-Kai; Lee, Jae-Sung; McGlothan, Jennifer L et al. (2006) Acute manganese administration alters dopamine transporter levels in the non-human primate striatum. Neurotoxicology 27:229-36
Guilarte, Tomas R; McGlothan, Jennifer L; Degaonkar, Mahaveer et al. (2006) Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: a 1H-MRS and MRI study. Toxicol Sci 94:351-8

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