Methylmercury (MeHg) is an environmental neurotoxicant that causes developmental and adult toxicity. Exposure results from eating MeHg-contaminated seafood and fresh water fish. Effects of lifetime exposure to low levels of MeHg as might occur by regular seafood consumption, especially interactions between MeHg and aging, are unexplored. Previously, we demonstrated that disruption by MeHg of intracellular Ca2+i homeostasisiscrucialtoearlyonsetofMeHg-inducedcytotoxicity.Neuronal[Ca2+]i homeostasisandsynaptic function are also altered significantly during aging. The present proposal focuses on in vivo chronic lifetime exposure of animals to MeHg during beginning adulthood. The proposed studies will specifically examine whether chronic adult-onset (lifetime) exposure to MeHg accelerates cerebellar synaptic dysfunction associated with aging, ant its'sensitivity to protection by Ca2+ channel blocker treatment. The role of radial Type II astrocytes--the Bergmann cells in MeHg--induced cerebellar dysfunction will also be examinine, as these cells regulate the ionic environment at cerebellar glutamatergic synapses and their dysfunction could contribute to MeHg neurotoxicity. We hypothesize that adult exposure to MeHg enhances the severity of, or speeds up the onset of Ca2+-mediated neuronal dysfunction which has been well described in aging. An integratedsetofstudiesusingsophisticatedcellimaging,singlecellelectrophysiological,neurobehavioraland pathological methods will test: 1) whether chronic adult-onset MeHg exposure disrupts cerebellar synaptic transmission, and to what extent these effects are brain region, or neuron-type specific;2) to what extent the effects on Ca2+i homeostasis seen in vitro translate into established behavioral effects of adult-onset MeHg exposure in the adult or aging organism, and whether MeHg accelerates behavioral consequences of aging; and 3) whether adult-onset exposure of rats to low levels of MeHg accelerates the onset of, or severity of aging-related increased [Ca2+]I with potential effects on L-type Ca2+ channels and/or glutamate transport (or do you want this to read: ?involves disruption of Bergmann cell function??). The ability of an L-type Ca2+ channel blocker to prevent, reduce or delay effects of MeHg exposure will be tested. Morphological studies will determine whether cellular and behavioral effects of MeHg during aging are accompanied by structural alterations. The proposed studies will be the first to integrate cellular mechanistic, behavioral, and morphometric effects of MeHg in a whole animal and chronic exposure model. They would also be the first to combine behavioral endpoints with cellular electrophysiology and imaging to study how a known neurotoxicant disrupts brain function. These studies are important for public health, particularly for a society with increasing life-span, because they examine a potential interaction between a well-known environmental contaminant and the aging process. Methylmercury (MeHg) is an environmental neurotoxicant that causes developmental and adult toxicity. One brain area affected by MeHg is the cerebellum - a region involved in motor learning and memory, as well as movement. The present proposal is designed to test if this area would be susceptible to effects of MeHg during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003299-23
Application #
8291303
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
1984-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
23
Fiscal Year
2012
Total Cost
$706,275
Indirect Cost
$136,264
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Rudgalvyte, Martina; VanDuyn, Natalia; Aarnio, Vuokko et al. (2013) Methylmercury exposure increases lipocalin related (lpr) and decreases activated in blocked unfolded protein response (abu) genes and specific miRNAs in Caenorhabditis elegans. Toxicol Lett 222:189-96
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