Developmental windows for arsenic-associated diabetes

项目总结 IAS暴露与2型糖尿病(T2D)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接触IAS会产生糖尿病的影响 (例如，出生前或出生后)和潜在的机制知之甚少。IAS代谢的作用 作为一个关键因素，在这些暴露窗口改变IAS的效果也不清楚。此项目将使用 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，出生前和出生后暴露于IAS都会导致糖尿病，但 表型和潜在机制将是不同的，部分取决于 IAS新陈代谢。我们预计，仅产前暴露就会导致基因的表观遗传重新编程。 调节β细胞和胰岛素功能的基因，这些基因在成人和 我们在墨西哥的同龄人中的新生儿。我们预计，出生后的暴露将主要与胰岛素的抑制有关 分泌或胰岛素信号，这些影响将与IAS或其代谢物在体内的浓度相关 胰腺中的葡萄糖代谢组织。膳食补充叶酸或维生素B12，捐赠者 或IAS甲基化的甲基，以及催化IAS甲基化的AS3MT的敲除有望 修改出生前和出生后暴露于IAS的糖尿病致糖尿病效应。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 野生型(WT)男女空腹血糖、糖耐量、胰岛素抵抗和β细胞功能 C57BL/6小鼠出生前和出生后饮水中暴露IAS。我们将确定代谢功能障碍 与每个曝光窗口相关联。 2.确定出生前或出生后暴露于IAS的糖尿病效应的潜在机制。我们 将评估WT小鼠胰岛的完整性和功能以及组织中的胰岛素信号 我们还将检测CpG甲基化和12个T2D-1的表达。 在我们的人群研究中，相关基因因暴露于IAS而发生差异甲基化。 3.确定IAS代谢对出生前和出生后糖尿病的影响的调节作用 IAS暴露。我们将研究糖尿病小鼠的表型和潜在机制。 叶酸/B12的补充或AS3MT基因敲除将改变IAS的代谢能力。 该项目将首次比较出生前和出生后IAS暴露对糖尿病的影响，并将 确定IAS新陈代谢作为这些影响的调节剂的作用。结果将为设计和目标提供信息 由PI(Styblo博士和Fry博士)进行的当前和未来的人口研究，也将有助于优化 IAS相关性T2D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.