Diet and arsenic interactions in the development of diabetes

描述(申请人提供)：全球有超过1亿人因饮用受污染的饮用水而暴露在无机砷水平升高的环境中。虽然营养状况可能是个人对砷和其他毒物易感性的主要决定因素，但相关营养水平在确定毒理学风险方面的影响很少被考虑。有趣的是，在世界上许多容易缺锌的地区，食物供应中的砷污染和地下水中的砷污染也共存。锌是一种对生长发育至关重要的必需微量营养素，但据估计，全世界高达82%的孕妇锌摄入量不足。缺锌和砷暴露的目标是类似的机制，都会影响关键的发育过程。在子宫内暴露于缺锌和砷都与不良的健康结果有关，包括增加患代谢综合征和2型糖尿病的风险。然而，亲代缺锌和砷之间的相互作用以及发育缺陷风险的增加及其相关机制仍不清楚。我们的长期目标是确定基于饮食的易感因素，如缺锌，这些因素会影响砷中毒的易感性。 在毒物学暴露中确定锌的机制作用的主要障碍是缺乏 体内实验模型，使我们能够直接研究父母锌对胚胎发育的影响。为了克服这些障碍，我们选择使用主要的脊椎动物模型斑马鱼来研究发育，因为早期发育过程和长期影响都可以很容易地研究。我们的中心假设是，在子宫内，锌缺乏会使发育中的胚胎对低剂量的砷毒性敏感，从而增加氧化应激、炎症和代谢综合征和糖尿病的发病倾向。具体地说，在目标1中，我们将定义发育缺锌、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靶标，作为锌状态改变对砷诱导的毒性敏感性的机制。在目标2中，我们将确定作用机制，重点是Nrf2，一个对氧化应激的适应性反应的关键调节因子。斑马鱼的独特特性提供了一种新颖和创新的体内模型，可以直接检测亲代锌状态和发育中砷暴露对胚胎功能和体内2型糖尿病发生的影响。总而言之，这些研究将有助于确定父母营养缺乏和早期接触毒物影响发育中的胚胎并改变晚年慢性病易感性的机制。这最终将有助于确定营养战略，以改善砷敏感人群的健康结果。

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.