Arsenic Metabolism in Mice Carrying a Locus Humanized by Syntenic Replacement

Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies.

Objectives: The goal of this study was to determine whether humanization of the gene confers a human-like pattern of iAs metabolism in mice.

Methods: We generated a mouse strain in which the gene along with the adjacent gene was humanized by syntenic replacement. We compared expression of the mouse and the human and the rate and pattern of iAs metabolism in the wild-type and humanized mice.

Results: expression in mouse tissues closely modeled that of human and differed substantially from expression of . Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length that catalyzes iAs methylation and the human-specific splicing variant that has been linked to schizophrenia.

Conclusions: These results suggest that is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of in schizophrenia. https://doi.org/10.1289/EHP6943.