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Inter‐ and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic
Advanced Science ( IF 15.1 ) Pub Date : 2021-02-18 , DOI: 10.1002/advs.202002715 Yingyun Gong 1, 2 , Yanfeng Xue 2, 3 , Xin Li 2 , Zhao Zhang 4 , Wenjun Zhou 2 , Paola Marcolongo 5 , Angiolo Benedetti 5 , Shengyong Mao 3 , Leng Han 4 , Guolian Ding 2, 6 , Zheng Sun 2, 7
Advanced Science ( IF 15.1 ) Pub Date : 2021-02-18 , DOI: 10.1002/advs.202002715 Yingyun Gong 1, 2 , Yanfeng Xue 2, 3 , Xin Li 2 , Zhao Zhang 4 , Wenjun Zhou 2 , Paola Marcolongo 5 , Angiolo Benedetti 5 , Shengyong Mao 3 , Leng Han 4 , Guolian Ding 2, 6 , Zheng Sun 2, 7
Affiliation
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.
中文翻译:
父亲接触无机砷的代际和跨代影响
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清单中的首要化学品。在这里,我们评估了 iAs 在独特的男性谱系传播范式中的跨代效应。雄性小鼠暴露于 250 ppb iAs 会导致 F1 雌性小鼠出现葡萄糖不耐受和肝脏胰岛素抵抗,但雄性小鼠不会,且不会影响体重。F1 雌性中葡萄糖代谢基因、葡萄糖输出和胰岛素信号的肝脏表达被破坏。葡萄糖 6-磷酸酶复合物的抑制掩盖了 iAs 的代际效应,证明了肝葡萄糖生成的致病作用。祖辈 iAs 暴露的 F2 后代在幼年时表现出暂时的生长迟缓,这种情况在成年后会减少。然而,肥胖的减少持续到中年,并且与肠道微生物组的改变和棕色脂肪生热作用的增加有关。相比之下,暴露于 iAs 的雄性谱系的 F3 后代表现出肥胖增加,尤其是在高热量饮食下。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,这对于理解基因与环境的相互作用具有广泛的意义。
更新日期:2021-04-08
中文翻译:
父亲接触无机砷的代际和跨代影响
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清单中的首要化学品。在这里,我们评估了 iAs 在独特的男性谱系传播范式中的跨代效应。雄性小鼠暴露于 250 ppb iAs 会导致 F1 雌性小鼠出现葡萄糖不耐受和肝脏胰岛素抵抗,但雄性小鼠不会,且不会影响体重。F1 雌性中葡萄糖代谢基因、葡萄糖输出和胰岛素信号的肝脏表达被破坏。葡萄糖 6-磷酸酶复合物的抑制掩盖了 iAs 的代际效应,证明了肝葡萄糖生成的致病作用。祖辈 iAs 暴露的 F2 后代在幼年时表现出暂时的生长迟缓,这种情况在成年后会减少。然而,肥胖的减少持续到中年,并且与肠道微生物组的改变和棕色脂肪生热作用的增加有关。相比之下,暴露于 iAs 的雄性谱系的 F3 后代表现出肥胖增加,尤其是在高热量饮食下。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,这对于理解基因与环境的相互作用具有广泛的意义。