Inter- and transgenerational effects of paternal arsenic exposure

摘要/摘要 工业化造成了广泛的污染，发达国家的污染在近几年来一直在稳步下降 几十年。目前尚不清楚环境暴露的长期影响是否以及如何在几代人之间持续下去 并在晚年导致慢性病。无机砷(IAS)是ATSDR优先考虑的首要化学品 危险物质清单。在这里，我们使用IAS作为一个原型环境化学物质来剖析表观遗传学 动物模型中的遗传机制。我们只关注男性血统的暴露，以避免 宫内暴露造成的发育混杂效应。我们发现，雄性小鼠对IAS的暴露在 饮用饮用水导致F1代女性葡萄糖耐量增加和肝脏葡萄糖生成增加，但在 F1雄性后代。相反，父亲的IAS降低了肝脏甘油三酯的含量和循环中的游离脂肪酸 在F1男性中的水平，但在F1女性中不是。F0精子和F1肝脏的DNA甲基化和表达发生变化 在与性腺激素信号和脂质代谢相关的基因中。在来自男性世系的F2代中 在暴露的情况下，小鼠的肥胖度降低，营养吸收不良，肠道微生物群发生变化。我们 假设雌激素受体、DNA甲基化、非编码RNA和肠道之间的相互作用 微生物组在代谢生理学中解释了IAS的代际和跨代效应。我们会 描述父亲的IAS暴露如何改变F1雌性后代的葡萄糖代谢；解决父亲如何 IAS暴露改变F1雄性子代的脂代谢，并探讨父亲暴露IAS如何影响营养 通过改变F2代的肠道微生物群来吸收。这项研究的机械论见解将 促进我们对环境暴露对代谢生理的跨代影响的理解 通过扰乱内分泌系统。

ABSTRACT/SUMMARY Industrialization had created widespread pollution, which has been steadily declining in developed countries for decades. It is unclear whether and how long-lasting effects of environmental exposure persist across generations and contribute to chronic diseases in later life. Inorganic arsenic (iAs) is the top chemical on the ATSDR priority list of hazardous substances. Here we use iAs as a prototype environmental chemical to dissect the epigenetic inheritance mechanisms in animal models. We focus exclusively on male-lineage exposure to avoid developmental confounding effects due to in utero exposure. We found that the exposure of male mice to iAs in drinking water caused glucose intolerance and upregulated hepatic glucose production in F1 females but not in F1 male offspring. In contrast, paternal iAs decreased liver triglyceride content and circulating free fatty acids levels in F1 males, but not F1 females. F0 sperm and F1 livers display altered DNA methylation and expression in genes related to gonadal hormone signaling and lipid metabolism. In the F2 generation from the male-lineage iAs exposure, mice display reduced adiposity, nutrient malabsorption, and the altered gut microbiome. We hypothesize that the interplay between estrogen receptor, DNA methylation, non-coding RNAs, and gut microbiome accounts for the inter- and transgenerational effects of iAs in metabolic physiology. We will characterize how paternal iAs exposure alters glucose metabolism in F1 female offspring; address how paternal iAs exposure alters lipid metabolism in F1 male offspring, and explore how paternal iAs exposure affects nutrient absorption through altering the gut microbiome in F2 offspring. The mechanistic insights from this study will advance our understanding of the cross-generational effects of environmental exposure on metabolic physiology through the disruption of the endocrine system.