Diverse genetic backgrounds play a prominent role in the metabolic phenotype of CC021/Unc and CC027/GeniUNC mice exposed to inorganic arsenic.

Abstract Arsenic methyltransferase (AS3MT) is the key enzyme in the pathway for the methylation of inorganic arsenic (iAs), a potent human carcinogen and diabetogen. AS3MT converts iAs to mono- and dimethylated arsenic species (MAs, DMAs) that are excreted mainly in urine. Polymorphisms in AS3MT is a key genetic factor affecting iAs metabolism and toxicity. The present study examined the role of As3mt polymorphisms in the susceptibility to the diabetogenic effects of iAs exposure using two Collaborative Cross mouse strains, CC021/Unc and CC027/GeniUnc, carrying different As3mt haplotypes. Male mice from the two strains were exposed to iAs in drinking water (0, 0.1 or 50 ppm) for 11 weeks. Blood glucose and plasma insulin levels were measured after 6 -h fasting and 15 min after i.p. injection of glucose. Body composition was determined using magnetic resonance imaging. To asses iAs metabolism, the concentrations of iAs, MAs and DMAs were measured in urine. The results show that CC021 mice, both iAs-exposed and controls, had higher body fat percentage, lower fasting blood glucose, higher fasting plasma insulin, and were more insulin resistant than their CC027 counterparts. iAs exposure had a minor effect on diabetes indicators and only in CC027 mice. Blood glucose levels 15 min after glucose injection were significantly higher in CC027 mice exposed to 0.1 ppm iAs than in control mice. No significant differences were found in the concentrations or proportions of arsenic species in urine of CC021 and CC027 mice at the same exposure level. These results suggest that the differences in As3mt haplotypes did not affect the profiles of iAs or its metabolites in mouse urine. The major differences in diabetes indicators were associated with the genetic backgrounds of CC021 and CC027 mice. The effects of iAs exposure, while minor, were genotype- and dose-dependent.