Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance

本申请的目的是确定早期接触的剂量和机制(S)。 普遍存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)。先前的研究和我们的初步数据表明，早期(围产期)暴露于双酚A 通过增加肥胖、改变胰腺胰岛素分泌来促进IR和T2 DM，而在女性中， 促进一种类似于人类多囊卵巢综合征(POOS)的表型，通常包括 肥胖和胰岛素抵抗。建议进行研究的理由是，有关预防霍乱的公共卫生政策 通过对双酚A在胰岛素抵抗和2型糖尿病中作用的明确的、机械性的研究，胰岛素抵抗和2型糖尿病将显著增强。 促进肥胖和/或血糖和胰岛素稳态失调。因此，该项目将 探讨早期接触双酚A(孕期至出生后第21天)对胰岛素抵抗的影响。 雄性和雌性大鼠的T2 DM和肥胖以及雌性大鼠潜在的卵巢功能障碍。葡萄糖 动态平衡、肥胖症和肥胖症相关的生物体液和组织读数将在4、8、12 雄性和雌性大鼠分别暴露于车辆和4种不同剂量的双酚A后18个月。血液和组织 (白色和棕色脂肪库、胰腺、肝脏、骨骼肌和卵巢)将被收集用于各种 生物体液、组织学、生化、基因表达和表观遗传学分析。具体目标1将 围产期双酚A致成年大鼠糖/胰岛素稳态失调剂量(S)的测定 并将决定这一失调的时间顺序和进展。《特定目标2》将测试 假设双酚A诱导的胰岛素抵抗反映了肥胖和/或炎症的代谢和炎症影响 女性荷尔蒙失调。特定目标3将识别双酚A诱导的转录和表观遗传 白色和棕色脂肪组织的变化(DNA和组蛋白甲基化)与 胰岛素抵抗和/或肥胖的发展。目标1-3的完成及其成果的整合将提供一个深入的 早期接触双酚A对血糖受损影响的评估 成人的动态平衡、胰岛素抵抗和2型糖尿病及其相关的双酚A诱导的脂肪、胰腺和卵巢 可能促进这种代谢失调的变化。拟议研究的意义在于它们 识别双酚A暴露对基因表达、新陈代谢、身体成分的多重影响的能力 以及可能导致肥胖、胰岛素抵抗和2型糖尿病的社会增加的激素。

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.