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.

项目摘要/摘要无机砷（IAS）是ATSDR优先级危险物质的最高化学物质。它的作用癌变已经进行了广泛的研究，而其在代谢障碍中的作用却没有。最近的人流行病学研究已经确定了2型糖尿病（T2D）和砷暴露之间的相关性。我们发现IAS对新陈代谢的影响显示小鼠的性二态性，雄性小鼠更容易受到影响葡萄糖不耐症和雌性小鼠更容易受到肝脂质积累的变化。我们假设IAS的代谢和转录组作用是通过雌激素调节的受体（ER）及其含有组蛋白脱乙酰基酶3（HDAC3）的共抑制剂复合物 IAS在糖尿病中的性别特异性作用。我们将确定雌激素受体（ER）的丧失是否增加对IAS诱导的糖尿病的敏感性；是否通过HDAC3的基因操纵来获得功能的功能预防IAS诱导的糖尿病； ER如何调节IAS诱导的转录组变化，以及是否是否 HDAC抑制剂（HDI）可以模仿这种调节。我们的研究解决了知识差距性别特定对疾病或环境毒素的敏感性，并且具有明显的翻译价值鉴于选择性的可用性雌激素受体调节剂（SERM）和表观基因组修饰HDI。