The overall objective of this 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 in neurologic damage characterized by ataxia, sensory disturbances and changes in mental state. The only way to prevent or ameliorate toxicity once MeHg has been ingested is to accelerate its removal from the body. Our goal is to identify and characterize the mechanisms by which MeHg crosses cell membranes to reach its target sites, or conversely, to be eliminated from the cell. This information is critical both for defining mechanisms of toxicity, and for developing effective biomarkers of exposure and therapeutic strategies. Our previous work provided the first direct demonstration of the mechanism by which MeHg crosses the blood-brain barrier to reach its target tissue, and of the mechanism by which MeHg is transported across the liver cell canalicular membrane into bile, a major route for its excretion. Recent studies have also identified a novel antidote for MeHg, namely N-acetylcysteine (NAC). Our working hypothesis is that NAC enhances urinary MeHg excretion because it leads to the formation of the anionic MeHg-NAC complex, which is a substrate for the renal organic anion transporters. The proposed studies aim to characterize these MeHg transport mechanisms at the molecular and cellular level.
Our Specific Aims are: I. Examine the mechanism by which the MeHg-L-cysteine complex is transported on the L-type amino acid transporters LAT1 and LAT2. II. Test whether the MeHg-glutathione complex (MeHg-SG) is a substrate for some members of the MRP family of transporters. III. Evaluate the molecular mechanism by which NAC stimulates renal excretion of MeHg. IV. Test the hypothesis that urinary excretion of MeHg following an NAC oral challenge may be used as a new biomarker of MeHg exposure.
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