Developmental windows for arsenic-associated diabetes

砷相关糖尿病的发育窗口

• 批准号: 9769729
• 负责人: Rebecca Fry
• 金额: $ 44.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769729
• 关键词: Address; Adult; Affect; Animal Model; Arsenic; Beta Cell; Birth; Blood; C57BL/6 Mouse; Cell physiology; Child; DNA; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet; Dietary Intervention; Dietary Supplementation; Dose; Epigenetic Process; Experimental Designs; Exposure to; Fasting; Fatty acid glycerol esters; Female; Folic Acid; Future; Genes; Glucose; Insulin; Insulin Resistance; Islets of Langerhans; Knock-out; Knockout Mice; Knowledge; Laboratories; Laboratory Study; Link; Liver; Measures; Metabolic dysfunction; Metabolism; Methylation; Methyltransferase; Mexico; Mus; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Phenotype; Play; Population; Population Study; Pregnant Women; Prevention strategy; Production; Public Health Practice; Publishing; RNA; Research; Role; S-Adenosylmethionine; Skeletal Muscle; Supplementation; Testing; Tissues; Urine; Vitamin B 12; Wild Type Mouse; blood glucose regulation; burden of illness; clinical practice; cohort; design; diabetes risk; diabetic; diabetogen; diabetogenic; disease phenotype; drinking water; epidemiologic data; epidemiology study; folic acid supplementation; glucose tolerance; improved; in utero; insulin secretion; insulin signaling; male; methyl group; mitochondrial metabolism; mouse model; offspring; postnatal; pregnant; prenatal; prenatal exposure; public health relevance; treatment optimization; treatment strategy

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.

项目摘要 IAS暴露与2型糖尿病（T2D）之间的联系得到了流行病学和 实验室研究。但是，在特定发育窗口中，IAS暴露的糖尿病生成作用 （例如，产前或产后）和潜在的机制知之甚少。 IAS代谢的作用 作为修改IAS在这些曝光窗口中影响的关键因素也不清楚。这个项目将使用 独特的动物模型和跨学科设计，以解决这些关键的知识差距。 我们的假设是，产前和产后对IAS的暴露都会导致糖尿病，但是 表型和潜在机制将有所不同，并部分取决于 IAS代谢。我们预计单独的产前暴露将导致基因的表观遗传重编程 调节β细胞和胰岛素功能，并且通过成人和 我们在墨西哥的同伙中的新生儿。我们预计产后暴露将主要与胰岛素抑制有关 分泌或胰岛素信号传导，并且这些作用将与IAS浓度或其代谢物浓度相关 葡萄糖代谢组织中的胰腺。用叶酸或维生素B12补充饮食 或用于IAS甲基化的甲基，以及预期催化IAS甲基化的AS3MT敲除将于 修改产前和产后暴露于IAS的糖尿病生成作用。具体目的是： 1。比较与IAS发生前或产后暴露有关的糖尿病表型。我们将检查 雄性和女性野生型（WT）的空腹血糖，葡萄糖耐量，胰岛素抵抗和β细胞功能 C57BL/6小鼠在产前或出生后暴露于饮用水中的IAS。我们将确定代谢功能障碍 与每个曝光窗口相关联。 2。确定产前或产后暴露于IAS的糖尿病生成作用的机制。我们 将评估WT小鼠组织中胰岛完整性和功能和胰岛素信号传导暴露于前或 在AIM 1中的产后IAS。我们还将检查十二t2d-的CpG甲基化和表达 在我们的人群研究中，通过IAS暴露对甲基甲基甲基化的相关基因。 3。确定IAS代谢作为产后和产后糖尿病作用的调节剂的作用 IAS暴露。我们将检查小鼠的糖尿病表型和潜在机制 代谢IAS的能力将通过补充叶酸/B12或AS3MT敲除来改变。 该项目将是第一个比较出生前和产后IAS暴露的糖尿病性影响以及 确定IAS代谢作为这些影响的修饰符的作用。结果将为设计和目标提供信息 PI的当前和未来人口研究（Styblo和Fry博士）都将有助于优化 IAS相关T2D的治疗和预防策略。