Diabetogenic effects of arsenic exposure in C57BL/6 N mice carrying the human AS3MT gene: the role of sex and exposure window.

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes in both humans and laboratory mice. Prior studies highlight that the mechanism underlying the diabetogenic effects of iAs and the manifestation of iAs-associated diabetes depend, in part, on the exposure window. We have shown that exposure to iAs prior to conception or in utero consistently produced diabetic phenotypes in wild-type (WT) C57BL/6J mice and that this phenotype was characterized primarily by insulin resistance. The effects of postnatal iAs exposures have been less consistent. However, significance of these findings for human exposure remains unclear because WT mice metabolize and detoxify iAs more efficiently than humans. The present study describes the diabetogenic effects of iAs in humanized C57BL/6 N mice that express the human arsenic methyltransferase and exhibit human-like patterns of iAs metabolism. We examined diabetes indicators in male and female offspring of parents exposed to 0 (controls) or 200 ppb iAs (arsenite) prior to conception (PC), and offsprings exposed to iAs in utero (IU), or during the whole life, including the PC and IU windows. We found that only PC exposure produced diabetic phenotype in male offspring. This phenotype was characterized by elevated fasting blood glucose (FBG) and decreased HOMA-B, the indicator of beta cell function. However, fasting plasma insulin and HOMA-IR, the indicator of insulin resistance, were not affected. FBG was also higher in male mice after IU exposure as compared to control male mice, but this difference was not statistically significant. LL exposure had no significant effects in male offspring. No differences in diabetes markers were found between iAs-exposed and control female mice regardless of exposure window. These results suggest that PC exposure produced fasting hyperglycemia in the humanized male mice by impairing the function of insulin secreting beta cells. However, postnatal iAs exposure appeared to attenuate these effects, suggesting that activation of compensatory mechanisms may take place after birth. These findings may inform designs of population studies that examine iAs-associated diabetes, as well as the interpretation of data collected in these studies.