Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
Toxicology. 2021 Mar 30;452:152696. doi: 10.1016/j.tox.2021.152696. Epub 2021 Jan 29.
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.
砷甲基转移酶（AS3MT）是无机砷（iAs）甲基化途径中的关键酶，iAs 是一种强有力的人类致癌剂和致糖尿病物。AS3MT 将 iAs 转化为单甲基砷（MAs）和二甲基砷（DMAs），这些物质主要通过尿液排泄。AS3MT 多态性是影响 iAs 代谢和毒性的关键遗传因素。本研究使用两种携带不同 AS3MT 单倍型的协作交叉小鼠品系（CC021/Unc 和 CC027/GeniUnc），研究了 As3mt 多态性在 iAs 暴露致糖尿病易感性中的作用。两种品系的雄性小鼠均通过饮用水暴露于 iAs（0、0.1 或 50 ppm）11 周。禁食 6 小时后和腹腔注射葡萄糖后 15 分钟测量血糖和血浆胰岛素水平。使用磁共振成像测定身体成分。为评估 iAs 代谢，测量尿液中的 iAs、MAs 和 DMAs 浓度。结果表明，暴露于 iAs 的 CC021 小鼠和对照组小鼠的体脂百分比均较高，空腹血糖较低，空腹血浆胰岛素较高，胰岛素抵抗程度高于 CC027 小鼠。iAs 暴露对糖尿病指标的影响较小，仅在 CC027 小鼠中。与对照组小鼠相比，暴露于 0.1 ppm iAs 的 CC027 小鼠腹腔注射葡萄糖后 15 分钟的血糖水平显著升高。在相同暴露水平下，CC021 和 CC027 小鼠尿液中的砷形态浓度或比例无显著差异。这些结果表明，AS3MT 单倍型的差异不影响小鼠尿液中 iAs 或其代谢物的特征。糖尿病指标的主要差异与 CC021 和 CC027 小鼠的遗传背景有关。iAs 暴露的影响虽小，但具有基因型和剂量依赖性。
