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Inter- and transgenerational effects of paternal arsenic exposure

父亲砷暴露的代际和跨代影响

基本信息

批准号：
10565361
负责人：
Zheng Sun
金额：
$ 47.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-08 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565361
关键词：
Address Adipose tissue Affect Age Air Pollution Animal Model Arsenic Blood Brain C57BL/6 Mouse Chemicals Chronic Disease DNA Methylation Developed Countries Development Diabetes Mellitus Dyslipidemias Eating Elderly Endocrine disruption Endocrine system Energy Metabolism Environmental Exposure Enzymes Epidemic Epigenetic Process Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Etiology Exposure to Fatty acid glycerol esters Female Food Energy Gene Expression Generations Genes Germ-Free Glucose Glucose Intolerance Gonadal Hormones Growth Hazardous Substances Hepatic Hepatocyte Hypothalamic structure Industrialization Knockout Mice Lead Length Lipids Liver Malabsorption Syndromes Mammals Masks Metabolic Metabolic syndrome Metabolism Methylation Molecular Mus Muscle Nonesterified Fatty Acids Nutrient Obesity Ovariectomy Phenotype Physiology Pituitary Gland Poison Pollution Predisposition Role Signal Transduction Solid Triglycerides Untranslated RNA Urbanization Water Pollution bisulfite sequencing comparison control disease registry drinking water environmental chemical fatty acid oxidation fecal transplantation glucose metabolism glucose production gut microbiome hormonal signals insight intergenerational lipid biosynthesis lipid metabolism male metabolic phenotype microbiome microbiome alteration mouse model nutrient absorption offspring pharmacologic pituitary gonadal axis prenatal exposure prototype sex sperm cell transcriptomics wasting whole genome zygote

项目摘要

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.

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。