Inter- and transgenerational effects of paternal arsenic exposure

摘要/总结 工业化造成了广泛的污染， 几十年目前还不清楚环境暴露的长期影响是否以及如何持续几代人 并在以后的生活中导致慢性疾病。无机砷（iAs）是ATSDR优先考虑的首要化学品 有害物质清单。在这里，我们使用iAs作为原型环境化学品来剖析表观遗传 动物模型中的遗传机制。我们专注于男性血统的暴露，以避免 子宫内暴露导致的发育混杂效应。我们发现，雄性小鼠暴露于iAs， 饮用水导致F1代雌性小鼠葡萄糖耐受不良，并上调肝脏葡萄糖生成，但F1代雌性小鼠则没有。 F1雄性后代。相反，父亲iAs降低肝脏甘油三酯含量和循环游离脂肪酸 F1雄性中的水平，但非F1雌性。F0精子和F1肝脏显示DNA甲基化和表达改变 在与性腺激素信号和脂质代谢相关的基因中。在雄性系的F2代中， iAs暴露，小鼠表现出减少的肥胖、营养吸收不良和改变的肠道微生物组。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， 微生物组解释了iAs在代谢生理学中的代际和跨代效应。我们将 描述父亲iAs暴露如何改变F1代雌性后代的葡萄糖代谢;说明父亲iAs暴露如何改变F1代雌性后代的葡萄糖代谢。 iAs暴露改变F1雄性后代的脂质代谢，并探讨父亲iAs暴露如何影响营养素 通过改变F2后代的肠道微生物组来促进吸收。这项研究的机械见解将 促进我们对环境暴露对代谢生理学的跨代影响的理解 通过破坏内分泌系统。

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.