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

• 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
• 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

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）：在全球范围内，超过一亿人因饮用受污染的饮用水而暴露于无机砷水平升高的环境中。虽然营养状况可能是个体对砷和其他毒物敏感性的主要决定因素，但在确定毒理学风险时，相关营养水平的影响很少被考虑。有趣的是，在世界上许多容易缺锌的地区，食物供应和地下水中的砷污染也同时存在。锌是一种重要的生长和发育的必需微量营养素，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，都影响关键的发育过程。在子宫内暴露于锌缺乏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，以及发育缺陷的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性因素，如锌缺乏，影响砷中毒的易感性。 在确定锌在毒理学暴露过程中的机制作用方面缺乏主要障碍 体内实验模型，使我们能够直接研究母体锌对胚胎发育的影响。为了克服这些障碍，我们选择使用首要的脊椎动物模型来研究发育，斑马鱼，因为早期发育过程和长期影响都很容易研究。我们的中心假设是，在子宫内缺锌使发育中的胚胎对低剂量砷毒性敏感，导致氧化应激增加，炎症和代谢综合征和糖尿病发展的倾向。具体而言，在目标1中，我们将定义发育性缺锌、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。我们还将确定目标，如氧化应激和炎症，作为锌状态改变砷诱导的毒性敏感性的机制。在目标2中，我们将确定促进机制，重点是Nrf2，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的和创新的体内模型，以直接检查母体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早期生活中暴露于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。这将最终帮助确定营养策略，以改善砷敏感人群的健康状况。