Diet and arsenic interactions in the development of diabetes

饮食和砷在糖尿病发展中的相互作用

基本信息

批准号：
8997082
负责人：
EMILY HO
金额：
$ 18.35万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997082
关键词：
Address Affect Anatomy Animals Anti-Inflammatory Agents Antioxidants Arsenic Biological Models Cell physiology Cells Chemical Exposure Chemicals Chronic Disease DNA Defect Development Developmental Process Diabetes Mellitus Diet Dietary Zinc Dose Embryo Embryonic Development Experimental Models Exposure to Food Supply Functional disorder Genetic Goals Growth and Development function Guidelines Health Human Human Biology In Vitro Individual Inflammation Inflammatory Inflammatory Response Insulin Intake Islet Cell Islets of Langerhans Life Long-Term Effects Longevity Metabolic syndrome Metals Micronutrients Modeling Molecular Monitor Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Nutritional Nutritional status Organ Organism Outcome Oxidative Stress Perinatal Exposure Physiology Play Population Predisposition Pregnant Women Prevalence Production Public Health Reactive Oxygen Species Risk Role Signal Transduction Structure of beta Cell of islet Study models System Time Toxic effect Work Zebrafish Zinc Zinc deficiency base contaminated drinking water cytokine early life exposure glucose metabolism ground water improved in utero in vivo in vivo Model innovation insight knock-down novel nutrition offspring organ growth pancreatic islet function response skills stressor tool toxicant transcription factor zebrafish development

项目摘要

DESCRIPTION (provided by applicant): Globally, over one hundred million people are exposed to elevated levels of inorganic arsenic from consuming contaminated drinking water. Although nutritional status may be a major determinant of individual susceptibility to arsenic and other toxicants, the impact of relevant nutrient levels in determining toxicological risks is rarel considered. Interestingly, arsenic contamination in the food supply and ground water also co-exists in many of the regions of the world that are prone to zinc deficiency. Zinc is an essential micronutrient important in growth and development, yet it has been estimated up to 82% of pregnant women worldwide have inadequate intakes of zinc. Zinc deficiency and arsenic exposures target similar mechanisms and both impact key developmental processes. In utero exposures to zinc deficiency and arsenic have both been associated with poor health outcomes including increased risk for metabolic syndrome and type 2 diabetes. However, the interactions between parental zinc deficiency and arsenic, and increased risk of developmental defects and associated mechanisms remain unclear. Our long-term goal is to identify diet-based susceptibility factors, such as zinc deficiency, that influence susceptibility to arsenic toxicity. Major barriers in identifying the mechanistic role of zinc during toxicological exposures is a lack of in vivo experimental models that allow us to directly study the effects of parental zinc on embryonic development. To overcome these barriers, we have chosen to use the premier vertebrate model for studying development, the zebrafish, because both early developmental processes and long term effects can be easily studied. Our central hypothesis is that in utero zinc deficiency sensitizes the developing embryo to low-dose arsenic toxicity leading to increased oxidative stress, inflammation and propensity to metabolic syndrome & diabetes development. Specifically, in aim 1, we will define developmental and mechanistic consequences of developmental zinc deficiency, arsenic exposures and their interaction related to development, pancreatic islet cell function, diabetes and metabolic syndrome. We will also identify targets such as oxidative stress and inflammation, as mechanisms by which zinc status alters sensitivity to arsenic-induced toxicities. In aim 2, we will identify contributing mechanism with a focus on Nrf2, a key regulator of the adaptive response to oxidative stress. The unique attributes of zebrafish provide a novel and innovative in vivo model to directly examine the effects of parental zinc status and developmental arsenic exposure on embryonic function and development of type 2 diabetes in vivo. Collectively these studies will aid in the identification o mechanisms by which parental nutrient deficits and early life exposure to toxicants affect the developing embryo and alters susceptibility to chronic disease later in life. This will ultimately help define nutritional strategies to improve health outcomes arsenic susceptible populations.

描述（由申请人提供）：全球有超过一亿人因饮用受污染的饮用水而接触到高浓度的无机砷。尽管营养状况可能是个体对砷和其他毒物易感性的主要决定因素，但很少考虑相关营养水平在确定毒理学风险方面的影响。有趣的是，在世界上许多容易缺锌的地区，食品供应和地下水中的砷污染也同时存在。锌是一种对生长和发育至关重要的必需微量营养素，但据估计，全球高达 82% 的孕妇锌摄入量不足。缺锌和砷暴露具有相似的机制，并且都会影响关键的发育过程。子宫内暴露于缺锌和砷均与不良健康结果相关，包括增加代谢综合征和 2 型糖尿病的风险。然而，父母缺锌和砷之间的相互作用以及发育缺陷风险增加和相关机制仍不清楚。我们的长期目标是确定基于饮食的易感因素，例如缺锌，这些因素会影响砷中毒的易感性。缺乏确定锌在毒理学暴露过程中的机制作用的主要障碍体内实验模型使我们能够直接研究亲代锌对胚胎发育的影响。为了克服这些障碍，我们选择使用研究发育的首要脊椎动物模型——斑马鱼，因为可以轻松研究早期发育过程和长期影响。我们的中心假设是，子宫内缺锌会使发育中的胚胎对低剂量砷毒性敏感，导致氧化应激、炎症以及代谢综合征和糖尿病发展的倾向增加。具体来说，在目标 1 中，我们将定义发育性锌缺乏、砷暴露及其与发育、胰岛细胞功能、糖尿病和代谢综合征相关的相互作用的发育和机制后果。我们还将确定氧化应激和炎症等目标，作为锌状态改变对砷引起的毒性敏感性的机制。在目标 2 中，我们将重点确定 Nrf2 的贡献机制，Nrf2 是氧化应激适应性反应的关键调节因子。斑马鱼的独特属性提供了一种新颖且创新的体内模型，可以直接检查亲代锌状态和发育砷暴露对胚胎功能和体内2型糖尿病发展的影响。总的来说，这些研究将有助于确定父母营养缺乏和生命早期接触有毒物质影响发育中的胚胎并改变以后对慢性疾病的易感性的机制。这最终将有助于制定营养策略，以改善砷易感人群的健康状况。