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 homeostasisi s crucial to earlyonset of MeHg-induced cytotoxicity. Neuronal[Ca2+]i homeostasis and synaptic 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 integrated set of studies using sophisticated cell imaging, single cell electrophysiological, neurobehavioral and 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.

Public Health Relevance

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 #
5R01ES003299-22
Application #
8079022
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
1984-01-01
Project End
2013-05-31
Budget Start
2011-06-28
Budget End
2012-05-31
Support Year
22
Fiscal Year
2011
Total Cost
$997,070
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Tsai, Tidao; Yuan, Yukun; Hajela, Ravindra K et al. (2017) Methylmercury induces an initial increase in GABA-evoked currents in Xenopus oocytes expressing ?1and ?6subunit-containing GABAAreceptors. Neurotoxicology 60:161-170
Colón-Rodríguez, Alexandra; Hannon, Heidi E; Atchison, William D (2017) Effects of methylmercury on spinal cord afferents and efferents-A review. Neurotoxicology 60:308-320
Bradford, Aaron B; Mancini, Jayme D; Atchison, William D (2016) Methylmercury-Dependent Increases in Fluo4 Fluorescence in Neonatal Rat Cerebellar Slices Depend on Granule Cell Migrational Stage and GABAA Receptor Modulation. J Pharmacol Exp Ther 356:2-12
Hoffman, Daniel J; Newland, M Christopher (2016) A microstructural analysis distinguishes motor and motivational influences over voluntary running in animals chronically exposed to methylmercury and nimodipine. Neurotoxicology 54:127-139
Shen, Andrew Nathanael; Cummings, Craig; Pope, Derek et al. (2016) A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection. Behav Brain Res 311:147-159
Yuan, Yukun; Atchison, William D (2016) Multiple Sources of Ca2+ Contribute to Methylmercury-Induced Increased Frequency of Spontaneous Inhibitory Synaptic Responses in Cerebellar Slices of Rat. Toxicol Sci 150:117-30
Shen, Andrew Nathanael; Pope, Derek A; Hutsell, Blake A et al. (2015) Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice. Behav Processes 118:59-70
Tiernan, Chelsea T; Edwin, Ethan A; Hawong, Hae-Young et al. (2015) Methylmercury impairs canonical dopamine metabolism in rat undifferentiated pheochromocytoma (PC12) cells by indirect inhibition of aldehyde dehydrogenase. Toxicol Sci 144:347-56
Newland, M Christopher; Reed, Miranda N; Rasmussen, Erin (2015) A hypothesis about how early developmental methylmercury exposure disrupts behavior in adulthood. Behav Processes 114:41-51
VanDuyn, Natalia; Nass, Richard (2014) The putative multidrug resistance protein MRP-7 inhibits methylmercury-associated animal toxicity and dopaminergic neurodegeneration in Caenorhabditis elegans. J Neurochem 128:962-74

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