Humanized mouse models for arsenic toxicology

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PROJECT SUMMARY Contamination of drinking water and foods with inorganic arsenic (iAs) represents a major public health risk in the U.S. and worldwide. Exposure to iAs has been linked to cancer, diabetes, cardiovascular, respiratory and neurological diseases. Humans and most other mammalian species have developed mechanism for detoxification of iAs, which involves a two-step conversion of iAs to methyl-As (MAs) and dimethyl-As (DMAs) and excretion of the methylated metabolites in urine. In mammals, iAs methylation is catalyzed by orthologs of a single enzyme, arsenic methyltransferase (AS3MT). An impaired capacity to methylate iAs, e.g., due to AS3MT polymorphism, has been linked to increased risk of diseases associated with iAs exposure. Mechanisms underlying the adverse effects of iAs exposure have been extensively studied using laboratory models. However, laboratory research has been hindered by substantial differences between laboratory animals and humans in their capacity to metabolize iAs. In particular, laboratory mice have been shown to methylate and detoxify iAs much more efficiently than humans, making it difficult to reproduce in mice some of the adverse phenotypes reported in population studies, specifically cancer and diabetes. The ultimate goal of the proposed research is to develop novel mouse models, in which iAs metabolism resembles that in humans and in which iAs-associated diseases can be studied at environmentally relevant iAs exposure levels. We have recently generated a new mouse strain in which the Borcs7/As3mt locus was humanized by syntenic replacement. AS3MT expression in tissues of the humanized (Hs/Hs) mice resembles that in human tissues and differs from expression of mouse As3mt: AS3MT expression is lower in livers and much higher in adrenals. Notably, the different pattern of AS3MT expression in tissues of Hs/Hs mice is associated with low efficiency of iAs detoxification and with the profiles for iAs and its methylated metabolites in tissues and excreta that are consistent with those reported in humans. The goals of this project are: (1) To characterize susceptibility of Hs/Hs mice to adverse effects of iAs exposure, focusing on the diabetogenic effects, (2) to generate a new mouse strain expressing AS3MT haplotype that has been linked to impaired iAs methylation and risk of iAs-induced diseases in human cohorts, and (3) to explore association between AS3MT expression in adrenals and adrenal function. The proposed research will generate and validate unique mouse models for iAs toxicology. These models will make it possible to study adverse effects of iAs at environmentally relevant exposure levels and in context with human-like metabolism of iAs and AS3MT polymorphism. Using these models will markedly improve translatability and impact of laboratory studies focusing on iAs induced diseases.