Gender-Specific Effects of Arsenic in Diabetes

砷对糖尿病的性别特异性影响

• 批准号: 9231112
• 负责人: Zheng Sun
• 金额: $ 59.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231112
• 关键词: Address; Animal Genetics; Animal Model; Arsenic; Binding; Blood; Chemicals; Complex; DNA Methylation; Deacetylase; Development; Diabetes Mellitus; Disease; Environmental Hazards; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Euglycemic Clamping; Exposure to; Female; Gender; Gene Expression; Glucose Intolerance; HDAC3 gene; Hazardous Substances; Hepatic; Hepatocyte; Histone Deacetylase Inhibitor; Hormones; Human; Knock-in; Knock-in Mouse; Knock-out; Knowledge; Light; Lipids; Liver; Measurement; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Receptors; Ovariectomy; Postmenopause; Predisposition; Prevention; Process; Public Health; Pyruvate; Reporting; Resistance; Role; Running; Selective Estrogen Receptor Modulators; Techniques; Testing; Toxic Environmental Substances; Toxic effect; Transcriptional Activation; Work; blood glucose regulation; carcinogenesis; enzyme activity; epidemiology study; epigenome; gain of function; gender difference; genetic manipulation; glucose metabolism; glucose tolerance; hepatic gluconeogenesis; human disease; insulin signaling; insulin tolerance; knock-down; male; novel; nuclear receptor co-repressor; pandemic disease; protective effect; sexual dimorphism; small molecule; transcriptome sequencing; transcriptomics

Project Summary/Abstract Inorganic arsenic (iAs) is the top chemical on the ATSDR priority list of hazardous substances. Its role in carcinogenesis has been studied extensively, whereas its role in metabolic disorders has not. Recent human epidemiology studies have identified correlation between type 2 diabetes (T2D) and arsenic exposure. We found that the effect of iAs on metabolism shows sexual dimorphism in mice, with male mice more susceptible to glucose intolerance and female mice more susceptible to changes in hepatic lipid accumulation. We hypothesize that the metabolic and transcriptomic effect of iAs is modulated by estrogen through estrogen receptor (ER) and its co-repressor complex containing histone deacetylase 3 (HDAC3), which accounts for gender-specific effects of iAs in diabetes. We will determine whether loss of estrogen receptor (ER) increases susceptibility to iAs-induced diabetes; whether gain-of-function of ER through genetic manipulation of HDAC3 protects against iAs-induced diabetes; how ER modulates iAs-induced transcriptomic changes, and whether such modulation can be mimicked by HDAC inhibitors (HDIs). Our study addresses the knowledge gap in gender-specific susceptibility to diseases or environmental toxins, and has obvious translational value in prevention and treatment against environmental hazards in both genders, given the availability of selective estrogen receptor modulators (SERMs) and epigenome-modifying HDIs.

项目总结/摘要 无机砷（iAs）是ATSDR危险物质优先列表上的首要化学品。的作用 致癌作用已被广泛研究，而其在代谢紊乱中的作用还没有。最近人类 流行病学研究已经确定了2型糖尿病（T2 D）和砷暴露之间的相关性。我们 发现iAs对代谢的影响在小鼠中表现出两性异形，雄性小鼠更容易受到影响 对葡萄糖耐受不良和雌性小鼠更容易发生肝脏脂质蓄积的变化。我们 假设iAs的代谢和转录组学效应是通过雌激素调节的 受体（ER）及其含有组蛋白脱乙酰酶3（HDAC 3）的共阻遏物复合物，其占 iAs在糖尿病中的性别特异性影响。我们将确定雌激素受体（ER）的丢失是否会增加 对iAs诱导的糖尿病的易感性;是否通过HDAC 3的遗传操作获得ER的功能 预防iAs诱导的糖尿病; ER如何调节iAs诱导的转录组学变化，以及是否 这种调节可以通过HDAC抑制剂（HDIs）模拟。我们的研究解决了知识差距， 对疾病或环境毒素的性别特异性易感性，并在以下方面具有明显的转化价值： 考虑到有选择的环境保护措施的可用性， 雌激素受体调节剂（SERMs）和表观基因组修饰HDIs。