The approved use of manganese (Mn) as an additive to gasoline is likely to result in increased accumulation of this metal in the environment. Chronic exposure to low-levels of Mn may pose a health risk to humans, but it is not known to what extent this may occur. A small number of studies describe acute neurological symptoms in humans after occupational exposure to Mn which resemble those observed in Parkinson?s disease. However, neither the mechanism of action nor the neurological consequences of chronic, low-level exposure to Mn is known. The objective of this proposal is to describe behavioral, in vivo neurochemical, and neuropathological changes that occur as a result of chronic exposure to low levels of Mn. The findings from the proposed studies will be fundamental in understanding the mechanism(s) of chronic, low-level Mn neurotoxicity. Moreover, these data will identify sensitive markers for the early detection of Mn neurotoxicity that can be used in vivo in humans. We propose that Mn neurotoxicity be studied in the non-human primate, Macaca mulatta (rhesus monkey), by assessing behavioral and in vivo brain chemistry using a prospective study design. Serial brain imaging will be performed by positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, throughout Mn exposure. The type of PET/SPECT scan performed will depend on the molecular endpoint to be examined. The MRI scans will show the regional brain distribution of Mn, as well as provide an anatomical template of the PET/SPECT scan images from each monkey brain. The MRS studies will provide brain metabolic changes resulting from Mn exposure. Following the conclusion of the behavioral and brain imaging studies, neuropathological techniques will be performed on the post-mortem tissue to fully characterize and define the changes found by the brain imaging studies and to assess other neuronal systems which may also be affected. This proposal merges the disciplines of behavioral toxicology, brain imaging, neuroscience and neurotoxicology in an innovative research proposal directly relevant to assessing human health risk to Mn exposure. Our long-term objective is to describe the neurotoxicity associated with exposure to chronic, low level Mn exposure and establish the basis for its mechanism of action. The proposed research using state-of the-art techniques will provide the best possible data with which to make human risk assessment and regulatory decisions about Mn in gasoline. The proposed studies will help us understand potential interactions between exposure to environmental agents and neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010975-02
Application #
6621341
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Kirshner, Annette G
Project Start
2002-02-18
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$1,114,624
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Austin, Rachel Narehood; Freeman, Jennifer L; Guilarte, Tomás R (2016) Neurochemistry of lead and manganese. Metallomics 8:561-2
Guilarte, Tomás R; Gonzales, Kalynda K (2015) Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson's Disease: Environmental and Genetic Evidence. Toxicol Sci 146:204-12
Schneider, J S; Williams, C; Ault, M et al. (2015) Effects of chronic manganese exposure on attention and working memory in non-human primates. Neurotoxicology 48:217-22
Stansfield, Kirstie H; Bichell, Terry Jo; Bowman, Aaron B et al. (2014) BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity. J Neurochem 131:655-66
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
Neal, April P; Guilarte, Tomas R (2013) Mechanisms of lead and manganese neurotoxicity. Toxicol Res (Camb) 2:99-114
Schneider, J S; Williams, C; Ault, M et al. (2013) Chronic manganese exposure impairs visuospatial associative learning in non-human primates. Toxicol Lett 221:146-51
Calderón-Garcidueñas, Lilian; Serrano-Sierra, Alejandro; Torres-Jardón, Ricardo et al. (2013) The impact of environmental metals in young urbanites' brains. Exp Toxicol Pathol 65:503-11
Racette, Brad A; Aschner, Michael; Guilarte, Tomas R et al. (2012) Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology 33:881-6
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

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