Gender-Specific Effects of Arsenic in Diabetes

砷对糖尿病的性别特异性影响

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要无机砷 (iAs) 是 ATSDR 危险物质优先清单中排名第一的化学品。其作用在于致癌作用已被广泛研究，但其在代谢紊乱中的作用尚未得到广泛研究。最近的人类流行病学研究已确定 2 型糖尿病 (T2D) 与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性别二态性，雄性小鼠更容易受影响葡萄糖不耐症和雌性小鼠更容易受到肝脏脂质积累变化的影响。我们假设 iAs 的代谢和转录组效应受到雌激素通过雌激素的调节受体 (ER) 及其含有组蛋白脱乙酰酶 3 (HDAC3) 的共阻遏物复合物，该复合物负责 iAs 对糖尿病的性别特异性影响。我们将确定雌激素受体 (ER) 的损失是否增加对 iAs 诱发的糖尿病的易感性；是否通过 HDAC3 基因操作获得 ER 功能预防 iAs 诱发的糖尿病； ER 如何调节 iAs 诱导的转录组变化，以及是否 HDAC 抑制剂 (HDI) 可以模仿这种调节。我们的研究解决了以下方面的知识差距性别特异性对疾病或环境毒素的易感性，并且在以下方面具有明显的转化价值：预防和治疗男女环境危害，考虑到有选择的可利用性雌激素受体调节剂 (SERM) 和表观基因组修饰 HDIs。