The long term objective of our laboratory is to identify those factors that underlie human susceptibility to methylmercury (MeHg) poisoning. MeHg is a highly toxic environmental pollutant: clinical and experimental studies demonstrate that exposure to MeHg results primarily in neurological damage characterized by ataxia, sensory disturbances and changes in the mental state. The brain is the principal target tissue for MeHg in both adult and prenatal life. The only way to prevent or ameliorate toxicity once MeHg has been ingested is to accelerate its removal from the body. The principal pathway for eliminating MeHg is the gastrointestinal tract: fecal excretion accounts for approximately 90% of the total excretion in humans or animals exposed to MeHg, and therefore effectively determines the biological half-time. Gastrointestinal excretion is in turn determined primarily by biliary secretion. Neither the mechanism by which MeHg crosses the blood-brain barrier to reach its target tissue, nor the fundamental mechanism of MeHg transport across the liver cell canalicular plasma membrane into bile have yet been identified. The overall objective of the proposed studies is to characterize these transport mechanisms at the cellular and subcellular level, under the general hypothesis that factors influencing the rate and extent of transport will affect the disposition and therefore the toxicity of MeHg. We propose to test a common working model, that MeHg forms complexes with endogenous thiol compounds that structurally mimic other endogenous substrates carried across the cell membrane by specific transport proteins. Knowing the mechanisms of membrane transport across these two key barriers, we plan to examine new approaches to controlling the body burden of methylmercury.
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