Effects of Arsenite Exposure during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Disease in Male Mice.
Effects of Arsenite Exposure during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Disease in Male Mice.
复制标题
DOI：
10.1289/ehp.1409501
复制
发表时间：
2016-02
影响因子：
10.4
通讯作者：
Camenisch TD
中科院分区：
文献类型：
--
作者：
Ditzel EJ;Nguyen T;Parker P;Camenisch TD
在不同的生命阶段和一系列暴露中长期暴露于砷剂与心脏代谢和肝脏疾病有关，但发育暴露的疾病易感性仍不清楚。在子宫内和断奶后暴露于三价砷（AsIII）的西式饮食的背景下进行了检查，以确定是否AsIII暴露影响代谢性疾病。雄性Swiss韦伯斯特小鼠在子宫内、断奶后或同时暴露于100 ppb AsIII。断奶后，自由进食西式饮食，并分析血浆代谢组学、肝组织病理学、肝酶活性和基因表达。肝脏脂质成分和组织病理学显示，发育AsIII暴露加剧了西式饮食诱导的脂肪肝疾病。持续AsIII暴露增加心脏代谢危险因素，包括体重增加、胰岛素抵抗、高血糖和血浆甘油三酯。AsIII暴露减少了糖酵解和TCA循环的中间体，同时增加了酮。肝脏异柠檬酸脱氢酶活性也降低，这证实了TCA循环的破坏。发育AsIII暴露增加参与脂肪酸合成，脂肪生成，炎症和包装甘油三酯的基因的表达，这表明增加乙酰辅酶A（乙酰辅酶A）负荷。在子宫内和生命早期连续暴露于AsIII破坏了正常代谢，并增加了维持高脂肪饮食的小鼠患脂肪肝的风险。我们的研究结果表明，在关键发育期暴露于AsIII的个体，以及在西式饮食背景下仍然暴露于AsIII的个体，在以后的生活中患代谢性疾病的风险可能会增加。Ditzel EJ，Nguyen T，帕克P，Camenisch TD. 2016.胚胎发育期砷暴露对雄性小鼠能量代谢和饮食诱导脂肪肝易感性的影响。环境健康展望124：201-209; http：dx.doi.org/10.1289/ehp.1409501
Chronic exposure to arsenicals at various life stages and across a range of exposures has been implicated in cardiometabolic and liver disease, but disease predisposition from developmental exposures remains unclear. In utero and post-weaning exposure to trivalent arsenic (AsIII) was examined on the background of a Western-style diet to determine whether AsIII exposure affects metabolic disease. Male Swiss Webster mice were exposed to 100 ppb AsIII in utero, after weaning, or both. Ad libitum access to a Western-style diet was provided after weaning, and the plasma metabolome, liver histopathology, liver enzyme activity, and gene expression were analyzed. Hepatic lipid composition and histopathology revealed that developmental AsIII exposure exacerbated Western-style diet–induced fatty liver disease. Continuous AsIII exposure increased cardiometabolic risk factors including increased body weight, insulin resistance, hyperglycemia, and plasma triglycerides. AsIII exposure produced a decrease in the intermediates of glycolysis and the TCA cycle while increasing ketones. Hepatic isocitrate dehydrogenase activity was also decreased, which confirmed disruption of the TCA cycle. Developmental AsIII exposure increased the expression of genes involved in fatty acid synthesis, lipogenesis, inflammation, and packaging of triglycerides, suggesting an increased acetyl coenzyme A (acetyl-CoA) load. In utero and continuous early-life exposure to AsIII disrupted normal metabolism and elevated the risk for fatty liver disease in mice maintained on a high-fat diet. Our findings suggest that individuals exposed to AsIII during key developmental periods and who remain exposed to AsIII on the background of a Western-style diet may be at increased risk for metabolic disease later in life. Ditzel EJ, Nguyen T, Parker P, Camenisch TD. 2016. Effects of arsenite exposure during fetal development on energy metabolism and susceptibility to diet-induced fatty liver disease in male mice. Environ Health Perspect 124:201–209; http://dx.doi.org/10.1289/ehp.1409501