Inter- and transgenerational effects of paternal arsenic exposure

点击翻译按钮获取中文摘要

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.