Project 2: Arsenic- Obesity- Diabetes Interactions

摘要：项目2 无机砷是一种普遍存在的自然产生的环境毒物，影响着2亿多人。 世界各地的人们。长期接触IAS与许多人类疾病有关，包括II型 糖尿病(T2D)。流行病学研究结果表明，IAS新陈代谢的效率取决于 IAS-甲基转移酶(AS3MT)和其他遗传因素的部分多态影响T2D的风险 暴露于IAS的人群中的风险。肥胖是T2D的头号风险因素，也被证明会影响IAS 新陈代谢和最近的一项研究发现，肥胖个体在暴露于环境中时患T2D的风险更高 致国际会计准则。此外，我们的初步研究表明，肥胖加剧了IAS暴露小鼠的T2D表型。 一种性别依赖的方式，并且对IAS暴露的糖尿病致病效应的反应在 遗传多样性的小鼠品系。项目2解决了在理解交互方面的一个根本差距 在T2D型病因学背景下，IAS暴露、IAS代谢、遗传学、肥胖和性别之间的关系。我们的目标 是确定这五个关键因素对T2D风险的相对贡献，使用遗传多样性的男性 以及具有不同代谢IAS能力的雌性小鼠。我们假设有一种相互作用 IAS暴露、IAS代谢和增加T2D风险的肥胖之间的关系，以及结果 取决于遗传背景和性别。我们计划使用一种独特的老鼠种群，协作十字， 来检验我们的假设。我们的假设有四个关键发现：(1)AS3MT基因的多态与这两个基因相关 暴露于IAS的人群代谢(甲基化)IAS的能力和T2D风险的差异；(2) IAS的甲基化代谢产物作为β细胞功能和胰岛素信号转导的抑制物比IAS更有效 实验室模型；(3)肥胖影响IAS代谢，增加人类T2D风险，并加剧 暴露于IAS的小鼠的糖尿病表型；最后(4)已知影响代谢健康的遗传学 肥胖的个体，也已被证明影响对IAS暴露的糖尿病效应的易感性 老鼠和人类。该项目由一个强大的团队(Pardo-Manuel de Villena博士、Styblo博士、Fry博士和邹某博士)领导， 免费提供遗传学、分子生物学、IAS毒理学和新陈代谢、IAS诱导的T2D和 统计数据。我们使用独特的协作交叉种群，最先进的技术和精心控制 研究IAS暴露、IAS代谢和肥胖之间相互作用的实验设计 增加了T2D的风险，并将确立遗传背景和性别的影响。该项目是一致的 以《联合国气候变化框架公约》--《战略行动纲领》为主题，确定减少国际会计准则暴露的新方法和阐明机制 潜在的IAS引起的代谢功能障碍，并着眼于疾病预防。新机制 了解肥胖、遗传、性别和剂量在疾病中的作用，以及将这些因素转化为 对人类群体的研究结果，将使新的切实的解决方案能够减轻IAS诱导的T2D的影响。

ABSTRACT: PROJECT 2 Inorganic arsenic (iAs) is a ubiquitous, naturally-occurring environmental toxicant that affects over 200 million people worldwide. Chronic exposure to iAs is associated with numerous human diseases, including type 2 diabetes (T2D). Results of epidemiological studies suggest that efficiency of iAs metabolism, which depends in part on polymorphisms in iAs-methyltransferase (AS3MT) and on other genetic factors, affects the risk of T2D risk in iAs-exposed populations. Obesity, the number 1 risk factor for T2D, has also been shown to modify iAs metabolism and a recent study found that obese individuals are at higher risk of developing T2D when exposed to iAs. In addition, our preliminary studies show that obesity exacerbates T2D phenotype in iAs-exposed mice in a sex-dependent manner, and that the responses to the diabetogenic effects iAs exposure differ between genetically diverse mouse strains. Project 2 addresses a fundamental gap in understanding the interaction between iAs exposure, iAs metabolism, genetics, obesity and sex in the context of type T2D etiology. Our goal is to determine the relative contributions of these five critical factors to T2D risk, using genetically diverse male and female mice with different capacities to metabolize iAs. We hypothesize that there is an interaction between iAs exposure, iAs metabolism and obesity that increases the risk of T2D, and that the outcome depends on genetic background and sex. We plan to use a unique mouse population, the Collaborative Cross, to test our hypothesis. Four key findings underlie our hypothesis: (1) Polymorphisms in AS3MT are linked to both the differences in the capacity to metabolize (methylate) iAs and to T2D risk in populations exposed to iAs; (2) methylated metabolites of iAs are more potent than iAs as inhibitors of beta cell function and insulin signaling in laboratory models; (3) obesity affects iAs metabolism and increases T2D risk in humans, and exacerbates diabetic phenotype in mice exposed to iAs; finally (4) genetics, which is known to influence metabolic health in obese individuals, has also been shown to affect susceptibility to the diabetogenic effects of iAs exposure in both mice and humans. This project is led by a strong team (Drs. Pardo-Manuel de Villena, Styblo, Fry and Zou) with complimentary expertise in genetics, molecular biology, iAs toxicology and metabolism, iAs-induced T2D and statistics. We use the unique Collaborative Cross population, state of the art techniques and carefully controlled experimental design to characterize the interaction between iAs exposure, iAs metabolism and obesity that increases the risk of T2D, and will establish the influence of genetic background and sex. The project is aligned with the theme of the UNC-SRP “Identifying novel methods to reduce iAs exposure and elucidating mechanisms underlying iAs-induced metabolic dysfunction with a vision for disease prevention.” New mechanistic understanding of the role of obesity, genetics, sex and dose in disease, along with the vision of translating these findings to human populations, will enable novel tangible solutions to mitigate the effects of iAs-induced T2D.