Inter- and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic.
Inter- and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic.
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父亲接触无机砷的代际和跨代影响
DOI：
10.1002/advs.202002715
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Sun Z
中科院分区：
文献类型：
--
作者：
Gong Y;Xue Y;Li X;Zhang Z;Zhou W;Marcolongo P;Benedetti A;Mao S;Han L;Ding G;Sun Z
现代代谢紊乱的兴起主要归因于环境。然而，环境化学物质对哺乳动物后代代谢健康的遗传影响尚不清楚。无机砷（iAs）是有毒物质和疾病登记局危险物质优先列表上的首要化学品。在这里，我们评估了iAs在纯男性血统传播范式中的跨代影响。雄性小鼠暴露于250 ppb iAs会导致F1代雌性小鼠（而非雄性小鼠）葡萄糖耐受不良和肝脏胰岛素抵抗，且不影响体重。在F1代雌性中，葡萄糖代谢基因、葡萄糖输出和胰岛素信号传导的肝脏表达被破坏。葡萄糖6-磷酸酶复合物的抑制掩盖了iAs的代际效应，证明了肝脏葡萄糖产生的致病作用。来自祖父iAs暴露的F2后代在早期表现出暂时的生长迟缓，这在成年后减少。然而，减少肥胖持续到中年，并与肠道微生物组的改变和棕色脂肪产热增加有关。相比之下，雄性谱系iAs暴露的F3后代显示肥胖增加，尤其是在高热量饮食中。这些发现揭示了iAs对代谢生理学的性别和世代特异性遗传效应，这对理解基因-环境相互作用具有广泛的意义。无机砷（iAs）通过雄性生殖系对哺乳动物的代谢生理具有性别和世代特异性遗传效应。父亲暴露于iAs会导致F1代雌性动物葡萄糖耐受不良和肝脏胰岛素抵抗，但不会导致雄性动物。来自祖父iAs暴露的F2后代显示出减少的肥胖。雄性谱系iAs暴露的F3后代显示肥胖增加。
The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross‐generational effects of iAs in an exclusive male‐lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6‐phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male‐lineage iAs exposure show increased adiposity, especially on a high‐calorie diet. These findings have unveiled sex‐ and generation‐specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene‐environment interactions. Inorganic arsenic (iAs) has sex‐ and generation‐specific heritable effects on metabolic physiology in mammals through the male germline lineage. Paternal exposure to iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males. F2 offspring from grand paternal iAs exposure show reduced adiposity. F3 offspring of the male‐lineage iAs exposure show increased adiposity.
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影响因子：
64.5
作者：
Carone BR;Fauquier L;Habib N;Shea JM;Hart CE;Li R;Bock C;Li C;Gu H;Zamore PD;Meissner A;Weng Z;Hofmann HA;Friedman N;Rando OJ
通讯作者：
Rando OJ
影响因子：
10.4
作者：
Ditzel EJ;Nguyen T;Parker P;Camenisch TD
通讯作者：
Camenisch TD
影响因子：
2.2
作者：
Camacho J;Allard P
通讯作者：
Allard P
影响因子：
4.8
作者：
Grun, Felix;Blumberg, Bruce
通讯作者：
Blumberg, Bruce
影响因子：
3.7
作者：
Hu HJ;Park SG;Jang HB;Choi MK;Park KH;Kang JH;Park SI;Lee HJ;Cho SH
通讯作者：
Cho SH