Project 2: Arsenic- Obesity- Diabetes Interactions

摘要：项目2 无机砷（iAs）是一种普遍存在的自然环境毒物，影响超过2亿人 世界各地的人们。长期暴露于iAs与许多人类疾病有关，包括2型 糖尿病（T2 D）。流行病学研究的结果表明，iAs代谢的效率，这取决于 iAs-甲基转移酶（AS 3 MT）和其他遗传因素的多态性部分影响T2 D的风险 iAs暴露人群的风险。肥胖是T2 D的头号危险因素，也被证明会改变iAs 最近的一项研究发现，肥胖个体在暴露于T2 D时患T2 D的风险较高。 到iAs。此外，我们的初步研究表明，肥胖加重了iAs暴露小鼠的T2 D表型， 一种性别依赖的方式，和糖尿病的影响，iAs暴露的反应不同之间 基因多样的小鼠品系。项目2解决了在理解相互作用方面的一个根本性差距 iAs暴露，iAs代谢，遗传学，肥胖和性别之间的T2 D型病因的背景下。我们的目标 是确定这五个关键因素对T2 D风险的相对贡献，使用遗传多样性男性， 以及代谢iAs能力不同的雌性小鼠。我们假设有一种相互作用 iAs暴露，iAs代谢和肥胖之间的关系，增加了T2 D的风险， 取决于基因背景和性别我们计划使用一种独特的老鼠种群，协作交叉， 来验证我们的假设四个关键的发现支持我们的假设：（1）AS 3 MT的多态性与两个 iAs代谢（甲基化）iAs的能力和暴露于iAs的人群中T2 D风险的差异;（2） iAs的甲基化代谢物作为β细胞功能和胰岛素信号传导的抑制剂比iAs更有效， 实验室模型;（3）肥胖影响iAs代谢，增加人类T2 D风险，并加剧 暴露于iAs的小鼠中的糖尿病表型;最后（4）遗传学，已知遗传学会影响小鼠的代谢健康， 肥胖的个体，也被证明会影响对iAs暴露的致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维莱纳，Styblo，Fry和Zou博士）领导， 在遗传学、分子生物学、iAs毒理学和代谢、iAs诱导的T2 D和 统计我们使用独特的协作交叉人口，最先进的技术和精心控制的状态 实验设计，以表征iAs暴露、iAs代谢和肥胖之间的相互作用， 增加了T2 D的风险，并将建立遗传背景和性别的影响。该项目是一致的 UNC-SRP的主题是“确定减少iAs暴露的新方法并阐明机制”， 潜在的iAs诱导的代谢功能障碍与疾病预防的愿景。新机械论 了解肥胖，遗传，性别和剂量在疾病中的作用，沿着将这些转化为 这些发现将使新的切实解决方案能够减轻iAs诱导的T2 D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.