Arsenic Exposure in C57BL/6 Mice Carrying Human AS3MT Elevates Fasting Glycemia and Impairs Beta Cell Function According to Sex and Developmental Window of Exposure
Creators: name: Singh, Navkaran
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2024
Subjects: Arsenic Induced Diabetes

description: Inorganic arsenic (iAs) is a common drinking water contaminant. Chronic exposure to iAs has been linked to various adverse outcomes, including diabetes, in both epidemiological and laboratory studies (Maull et al, 2012). Methylation of iAs by arsenic (+3 oxidation state) methyltransferase (AS3MT), which converts iAs to monomethyl-arsenic (MAs) and dimethylarsenic (DMAs), has been shown to play an important role in susceptibility to arsenic- associated diabetes in population studies (Drobná et al, 2013). Mice have been used to study the diabetogenic effects of iAs exposure in laboratory settings. However, mice methylate and detoxify iAs more efficiently than humans, making it difficult to translate results of laboratory studies to human populations. We have recently established a humanized C57BL/6 mouse strain, which expresses the human BORCS7/AS3MT locus. The metabolism of iAs in the humanized mice resembles that of humans and is characterized by an inefficient iAs methylation and high retention of iAs and MAs in tissues, including tissues associated with diabetes. The goal of this study was to examine diabetic indicators in humanized C57BL/6 mice, which were exposed to iAs in drinking water (200 ppb, arsenite) during three different developmental windows: prior to conception, in utero, and whole life. I have examined the metabolic phenotype of these mice, comparing differences in diabetic indicators between exposed and control mice within each exposure window, as well as between the three exposure windows themselves. When examining end point indicators, preconception exposure to iAs resulted in a significant increase in fasting blood glucose (FBG) in adult males but had only a marginal effect on FBG in adult female mice. A significant increase in FBG was also found in male mice exposed to iAs in utero. This exposure had no effect on FBG in female mice. Only a marginal increase in FBG in both male and female mice was associated with whole life exposure to iAs. Males exposed to iAs in utero had a significantly lower HOMA-β measure compared to controls; males exposed to iAs during whole life had a marginally lower HOMA-β measure compared to controls. None of the exposures significantly altered HOMA-IR, fasting plasma insulin (FPI), or body composition (%lean and %fat mass). There were no significant differences in FBG, FPI, HOMA-IR, HOMA- β, or body composition either in male or female mice exposed to iAs between different exposure windows. These results suggest that the preconception and in utero exposures play key roles in development of the diabetic phenotype in the humanized mice. However, the effects of these exposures are sex-dependent, affecting mainly or exclusively males. The lack of effects on FPI and HOMA-IR in the presence of elevated FBG and differences in HOMA-β suggests a potential impairment of pancreatic beta-cell function, characterized by an inability to compensate for the increase in FBG through increased insulin secretion.