Diet and arsenic interactions in the development of diabetes

描述（由申请人提供）：在全球范围内，超过1亿人因饮用受污染的饮用水而暴露于高浓度的无机砷。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，但有关营养水平在确定毒理学风险方面的影响很少得到考虑。有趣的是，在世界上许多容易缺锌的地区，食物供应和地下水中的砷污染也同时存在。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。锌缺乏和砷暴露针对类似的机制，两者都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，包括代谢综合征和2型糖尿病的风险增加。然而，父母锌缺乏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尚不清楚。我们的长期目标是确定以饮食为基础的易感性因素，如锌缺乏，影响对砷毒性的易感性。

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.