Gender-Specific Effects of Arsenic in Diabetes

砷对糖尿病的性别特异性影响

• 批准号: 10132317
• 负责人: Zheng Sun
• 金额: $ 39.37万
• 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/10132317
• 关键词: Address; Animal Genetics; Animal Model; Arsenic; Binding; Blood; Chemicals; DNA Methylation; Deacetylase; Development; Diabetes Mellitus; Disease; Environmental Hazards; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exposure to; Female; Gender; Gene Expression; Glucose Clamp; 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; NCOR1 gene; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Receptors; Ovariectomy; Postmenopause; Predisposition; Prevention; Process; Public Health; Pyruvate; Reporting; Repressor Proteins; 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 corepressor; genetic manipulation; glucose metabolism; glucose tolerance; hepatic gluconeogenesis; human disease; insulin signaling; insulin tolerance; knock-down; male; novel; 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。

项目成果

RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis.

RNA结合蛋白RBM46调节精子发生中有丝分裂到减数分裂的转变

• DOI: 10.1126/sciadv.abq2945
• 发表时间: 2022-08-26
• 期刊: Science advances
• 影响因子: 13.6

Central Circadian Clock Regulates Energy Metabolism.

• DOI: 10.1007/978-981-13-1286-1_5
• 发表时间: 2018
• 期刊: Advances in experimental medicine and biology
• 作者: Ding G;Gong Y;Eckel-Mahan KL;Sun Z
• 通讯作者: Sun Z

HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.

HDAC3 通过在精子发生减数分裂出口处的酶独立转录调节来控制男性生育力。

• DOI: 10.1093/nar/gkab313
• 发表时间: 2021-05-21
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Yin H;Kang Z;Zhang Y;Gong Y;Liu M;Xue Y;He W;Wang Y;Zhang S;Xu Q;Fu K;Zheng B;Xie J;Zhang J;Wang Y;Lin M;Zhang Y;Feng H;Xin C;Guan Y;Huang C;Guo X;Wang PJ;Baur JA;Zheng K;Sun Z;Ye L
• 通讯作者: Ye L