Developmental windows for arsenic-associated diabetes

项目摘要 iAs暴露与2型糖尿病（T2 D）之间的联系得到了来自流行病学和 实验室研究然而，在特定的发育窗口期，iAs暴露的致糖尿病效应 (e.g.,产前或产后），并且对潜在的机制知之甚少。iAs代谢的作用 作为一个关键因素，修改的影响，iAs在这些曝光窗口也不清楚。该项目将使用一个 独特的动物模型和跨学科的设计，以解决这些关键的知识差距。 我们的假设是，产前和产后暴露于iAs将导致糖尿病，但 表型和潜在的机制将是不同的，并将取决于，部分，在效率上， iAs代谢。我们预计，产前暴露本身将导致表观遗传基因重编程 调节β细胞和胰岛素功能，并且在成人中通过iAs暴露而差异甲基化， 新生儿的数量。我们预计，出生后暴露将主要与胰岛素抑制有关 这些作用将与iAs或其代谢产物的浓度相关， 胰腺中的葡萄糖代谢组织。饮食中补充叶酸或维生素B12， 或甲基基团，并敲除催化iAs甲基化的As 3 mt， 修改产前和产后暴露于iAs的致糖尿病效应。具体目标是： 1.比较出生前或出生后暴露于iAs的糖尿病表型。我们将研究 雄性和雌性野生型（WT）的空腹血糖、葡萄糖耐量、胰岛素抵抗和β细胞功能 C57 BL/6小鼠在出生前或出生后暴露于饮用水中的iAs。我们将鉴别代谢功能障碍 与每个曝光窗口相关联。 2.确定出生前或出生后暴露于iAs的致糖尿病效应的潜在机制。我们 将评估暴露前或暴露后WT小鼠组织中胰岛完整性和功能以及胰岛素信号传导。 出生后至目标1中的iAs。我们还将检测12个T2 D-1基因的CpG甲基化和表达。 在我们的人群研究中，iAs暴露差异甲基化的相关基因。 3.确定iAs代谢作为产前和产后糖尿病发生效应调节剂的作用 iAs暴露。我们将研究小鼠的糖尿病表型和潜在机制， 代谢iAs的能力将通过叶酸/B12补充或通过As 3 mt敲除来改变。 该项目将是第一个比较产前和产后iAs暴露的致糖尿病效应的项目， 确定iAs代谢作为这些效应的修饰剂的作用。研究结果将为项目的设计和目标提供信息， 目前和未来的人口研究进行PI的（博士Styblo和弗莱），也将有助于优化 iAs相关T2 D的治疗和预防策略。

PROJECT SUMMARY The link between iAs exposure and type-2 diabetes (T2D) is supported by strong data from epidemiologic and laboratory studies. However, the diabetogenic effects of iAs exposure during specific developmental windows (e.g., prenatal or postnatal) and the underlying mechanisms are poorly understood. The role of iAs metabolism as a key factor modifying the effects of iAs at these exposure windows is also unclear. This project will use a unique animal model and a transdisciplinary design to address these critical knowledge gaps. Our hypothesis is that both prenatal and postnatal exposures to iAs will result in diabetes, but the phenotypes and underlying mechanisms will be different and will depend, in part, on the efficiency of iAs metabolism. We anticipate that prenatal exposure alone will result in epigenetic reprograming of genes that regulate β-cell and insulin function, and that were differentially methylated by iAs exposure in adults and newborns in our cohorts in Mexico. We expect that postnatal exposure will be tied primarily to inhibition of insulin secretion or insulin signaling, and that these effects will correlate with concentrations of iAs or its metabolites in the pancreas in the glucose metabolizing tissues. Dietary supplementation with folate or vitamin B12, the donors or methyl groups for iAs methylation, and knockout of As3mt that catalyzes iAs methylation are expected to modify the diabetogenic effects of both prenatal and postnatal exposure to iAs. The specific aims are: 1. Compare the diabetic phenotypes associated with pre- or postnatal exposure to iAs. We will examine fasting glycemia, glucose tolerance, insulin resistance and β-cell function in male and female wild-type (WT) C57BL/6 mice exposed to iAs in drinking water prenatally or after birth. We will identify metabolic dysfunction associated with each exposure window. 2. Identify mechanisms underlying the diabetogenic effects of pre- or postnatal exposure to iAs. We will assess pancreatic islet integrity and function and insulin signaling in tissues of WT mice exposed pre- or postnatally to iAs in Aim 1. We will also examine the CpG methylation and expression of twelve T2D- associated genes that were differentially methylated by iAs exposure in our population studies. 3. Determine the role of iAs metabolism as a modulator of the diabetogenic effects of pre- and postnatal iAs exposure. We will examine diabetic phenotypes and underlying mechanisms in mice in which the capacity to metabolize iAs will be modified by folate/B12 supplementation or by As3mt knockout. This project will be the first to compare the diabetogenic effects of pre- and postnatal iAs exposures and to determine the role of iAs metabolism as a modifier of these effects. Results will inform design and aims of the current and future population studies carried out by both PI's (Drs. Styblo and Fry), and will also help to optimize the treatment and prevention strategies for iAs-associated T2D.