Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance

本申请的目的是确定生命早期暴露于 无处不在的工业化学品双酚A（BPA）会促进胰岛素抵抗（IR）和2型糖尿病 （T2 DM）成人。先前的研究和我们的初步数据表明，生命早期（围产期）暴露于BPA 通过增加肥胖、改变胰腺胰岛素分泌促进IR和T2 DM，在女性中， 促进与人类多囊卵巢综合征（POOS）相似的表型，其通常包括 肥胖和IR。拟议研究的理由是，关于预防肥胖的公共卫生政策， 通过对BPA作用的确定性机制研究，胰岛素抵抗和T2 DM将显着增强 促进肥胖和/或葡萄糖和胰岛素稳态失调。因此，该项目将 研究早期BPA暴露（妊娠期至出生后第21天）对IR发展的影响， 雄性和雌性大鼠中的T2 DM和肥胖以及雌性大鼠中的潜在卵巢功能障碍。葡萄糖 将在4、8、12监测稳态、肥胖和肥胖相关生物体液和组织读数 在暴露于溶剂和4种不同剂量BPA的雄性和雌性大鼠中，持续18个月。血液和组织 将收集各种不同的（白色和棕色脂肪库、胰腺、肝脏、骨骼肌和卵巢） 生物体液、组织学、生物化学、基因表达和表观遗传学分析。具体目标1将 确定围产期BPA暴露的剂量，其使成年大鼠的葡萄糖/胰岛素稳态失调 并将决定这种失调的时间顺序和进展。具体目标2将测试 假设BPA诱导的IR反映了肥胖和/或 女性荷尔蒙失调。具体目标3将确定BPA诱导的转录和表观遗传 在白色和棕色脂肪组织中的变化（DNA和组蛋白甲基化），这些变化与 IR和/或肥胖的发展。目标1-3的完成及其结果的整合将提供一个深入的 评估早期BPA暴露对血糖受损发展的影响 稳态、IR和T2 DM以及相关BPA诱导的脂肪、胰腺和卵巢 这些变化可能会促进这种代谢失调。所提出的研究的意义在于， 识别BPA暴露对基因表达、代谢、身体成分的多重影响的能力 以及可能导致肥胖、IR和T2 DM社会性增加的激素。

The objective of this application is to determine the doses and mechanism(s) by which early-life exposure to the ubiquitous industrial chemical, bisphenol A (BPA), promotes insulin resistance (IR) and type 2 diabetes (T2DM) in adults. Prior studies and our preliminary data suggest that early-life (perinatal) exposure to BPA promotes IR and T2DM by increasing adiposity, altering pancreatic insulin secretion, and in females, promoting a phenotype similar to human polycystic ovarian syndrome (POOS), which typically includes obesity and IR. The rationale for the proposed studies is that public health policy regarding the prevention of insulin resistance and T2DM will be significantly enhanced by definitive, mechanistic studies of BPA's role in promoting obesity and / or dysregulating glucose and insulin homeostasis. Accordingly this project will investigate the effects of early BPA exposure (gestation through postnatal day 21) on the development of IR, T2DM and obesity in male and female rats and potential ovarian dysfunction in female rats. Glucose homeostasis, adiposity and adiposity-related biohumoral and tissue read-outs will be monitored at 4, 8,12 and 18 months in male and female rats exposed to vehicle and 4 different doses of BPA. Blood and tissues (white and brown adipose depots, pancreas, liver, skeletal muscle and ovaries) will be collected for various biohumoral, histological, biochemical, gene expression and epigenetic analyses. Specific Aim 1 will determine the dose(s) of perinatal BPA exposure that dysregulate glucose / insulin homeostasis in adult rats and will determine the chronology and progression of this dysregulation. Specific Aim 2 will test the hypothesis that BPA-induced IR reflects the metabolic and inflammatory impacts of obesity and / or hormonal dysregulation in females. Specific Aim 3 will identify BPA-induced transcriptional and epigenetic changes (DNA and histone methylation) in both white and brown adipose tissue that are associated with the development of IR and / or obesity. Completion of Aims 1-3 and integration of their results will provide an indepth assessment of the effects of early-life BPA exposure on the development of impaired glucose homeostasis, IR and T2DM in the adult and the associated BPA-induced adipose, pancreatic and ovarian changes that may promote this metabolic dysregulation. Ttie significance of the proposed studies lies in their ability to identify the multiple effects of BPA exposure on gene expression, metabolism, body composition and hormones that may be contributing to societal increases in obesity, IR and T2DM.