Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance

描述(申请人提供)：本申请的目的是确定早期接触普遍存在的工业化学品双酚A(BPA)促进成人胰岛素抵抗(IR)和2型糖尿病(T2 DM)的剂量和机制(S)。先前的研究和来自该研究小组的初步数据表明，早期(围产期)暴露于BPA通过增加肥胖、改变胰腺胰岛素分泌而促进IR和T2 DM，在女性中，促进类似于人类多囊卵巢综合征(PCOS)的表型，通常包括肥胖和IR。拟议研究的基本原理是，通过对双酚A在促进肥胖和/或葡萄糖和胰岛素稳态失调方面的作用进行明确的、机械性的研究，将大大加强关于预防胰岛素抵抗和T2 DM的公共卫生政策。因此，本项目将研究早期BPA暴露(妊娠至出生后第21天)对雄性和雌性大鼠IR、T2 DM和肥胖的发展以及雌性大鼠潜在的卵巢功能障碍的影响。在4、8、12和18个月时，将监测暴露于载体和4种不同剂量双酚A的雄性和雌性大鼠的血糖稳态、肥胖和肥胖相关的生物体液和组织读数。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将确定围产期双酚A暴露的剂量(S)，该剂量将扰乱成年大鼠的血糖/胰岛素稳态，并将确定这种失调的时间顺序和进展。特定目标2将测试假设，即双酚A诱导的IR反映了肥胖和/或激素失调对女性代谢和炎症的影响。具体目标3将确定BPA在白色和棕色脂肪组织中诱导的转录和表观遗传变化(DNA和组蛋白甲基化)，这些变化与IR和/或肥胖的发展有关。AIMS 1-3的完成及其结果的整合将深入评估早期BPA暴露对成人血糖稳态受损、IR和T2 DM的发展的影响，以及可能促进这种代谢失调的相关BPA诱导的脂肪、胰腺和卵巢变化。拟议研究的意义在于，他们能够确定双酚A暴露对基因表达、新陈代谢、身体成分和激素的多重影响，这些影响可能导致肥胖、胰岛素抵抗和2型糖尿病的社会增加。

DESCRIPTION (provided by applicant): 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 type2 diabetes (T2DM) in adults. Prior studies and preliminary data from this investigative team 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 (PCOS), 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. The 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.