Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, CB# 7461, Chapel Hill, NC, USA.
Arch Toxicol. 2018 Jun;92(6):1925-1937. doi: 10.1007/s00204-018-2206-z. Epub 2018 May 2.
Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied. The role of factors that modulate iAs metabolism and toxicity in adults and their potential to influence diabetogenic effects of prenatal iAs exposure are also unclear. The goal of this study was to determine if prenatal exposure to iAs impairs glucose metabolism in mice and if maternal supplementation with folate and methylcobalamin (B12) can modify this outcome. C57BL/6J dams were exposed to iAs in drinking water (0, 100, and 1000 µg As/L) and fed a folate/B12 adequate or supplemented diet from before mating to birth of offspring. After birth, dams and offspring drank deionized water and were fed the folate/B12 adequate diet. The metabolic phenotype of offspring was assessed over the course of 14 weeks. Male offspring from iAs-exposed dams fed the folate/B12-adequate diet developed fasting hyperglycemia and insulin resistance. Maternal folate/B12 supplementation rescued this phenotype but had only marginal effects on iAs metabolism in dams. The diabetogenic effects of prenatal iAs exposure in male offspring were not associated with changes in global DNA methylation in the liver. Only minimal effects of prenatal iAs exposure or maternal supplementation were observed in female offspring. These results suggest that prenatal iAs exposure impairs glucose metabolism in a sex-specific manner and that maternal folate/B12 supplementation may improve the metabolic phenotype in offspring. Further studies are needed to identify the mechanisms underlying these effects.
无机砷（iAs）是一种已被确认的环境致糖尿病物。来自成人人群队列和成年实验动物的证据支持 iAs 暴露与糖尿病之间的关联。产前 iAs 暴露对糖尿病的发展及其潜在机制的研究还很有限。调节成人 iAs 代谢和毒性的因素的作用及其对产前 iAs 暴露致糖尿病作用的潜在影响也不清楚。本研究的目的是确定产前 iAs 暴露是否会损害小鼠的葡萄糖代谢，以及母体补充叶酸和甲基钴胺素（B12）是否可以改变这种结果。C57BL/6J 孕鼠在饮用水中暴露于 iAs（0、100 和 1000μg As/L），并在交配前到后代出生期间喂食叶酸/B12 充足或补充饮食。出生后，孕鼠和幼鼠饮用去离子水，并喂食叶酸/B12 充足饮食。在 14 周的时间内评估后代的代谢表型。喂食叶酸/B12 充足饮食的 iAs 暴露孕鼠的雄性后代出现空腹高血糖和胰岛素抵抗。母体叶酸/B12 补充挽救了这种表型，但对孕鼠的 iAs 代谢只有轻微影响。产前 iAs 暴露对雄性后代的致糖尿病作用与肝脏中全基因组 DNA 甲基化的变化无关。在雌性后代中仅观察到产前 iAs 暴露或母体补充的最小影响。这些结果表明，产前 iAs 暴露以性别特异性方式损害葡萄糖代谢，而母体叶酸/B12 补充可能改善后代的代谢表型。需要进一步的研究来确定这些影响的机制。
