Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance

双酚 A 在肥胖和胰岛素抵抗中的年龄依赖性作用

• 批准号: 8232645
• 负责人: ANDREW S GREENBERG
• 金额: $ 3.95万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232645
• 关键词: Adipocytes; Adipose tissue; Adult; Age; Area; Biochemical; Blood; Blood Glucose; Body Composition; Body Weight; Brown Fat; Cells; Chemicals; Chronology; CpG Islands; Cyst; DNA; Data; Development; Diabetes Mellitus; Dose; Endocrine Disruptors; Energy Metabolism; Environment; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Exposure to; Fasting; Fatty Acids; Fatty acid glycerol esters; Female; Figs - dietary; Functional disorder; Funding; Gastrocnemius Muscle; Gene Expression; Genes; Glucose; Goals; Health; Health Care Costs; Health Policy; Hepatic; Histologic; Histones; Histopathology; Homeostasis; Hormonal; Hormones; Human; Hyperglycemia; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Instruction; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Life; Life Style; Liver; Measures; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methylation; Mission; Molecular Weight; Monitor; Muscle; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian; Ovary; Overnutrition; Pancreas; Pathology; Perinatal; Perinatal Exposure; Phenotype; Play; Polycystic Ovary Syndrome; Pregnancy; Prevalence; Prevention; Public Health; Rattus; Reading; Regulation; Reporting; Research; Research Design; Research Personnel; Role; Serum; Skeletal Muscle; Societies; Sprague-Dawley Rats; Syndrome; Testing; Testosterone; Time; Tissues; Triglycerides; Uterus; Weight; adiponectin; age related; base; bisphenol A; blood glucose regulation; cohort; early life exposure; in vivo; inflammatory marker; insulin secretion; insulin tolerance; intraperitoneal; lipid biosynthesis; lipid metabolism; male; postnatal; programs; promoter; response; sedentary

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.

描述（由申请人提供）：本申请的目的是确定生命早期接触普遍存在的工业化学品双酚 A (BPA) 会促进成人胰岛素抵抗 (IR) 和 2 型糖尿病 (T2DM) 的剂量和机制。该调查小组的先前研究和初步数据表明，生命早期（围产期）接触 BPA 可通过增加肥胖、改变胰腺胰岛素分泌来促进 IR 和 T2DM，并且在女性中，促进类似于人类多囊卵巢综合征 (PCOS) 的表型，PCOS 通常包括肥胖和 IR。拟议研究的基本原理是，通过对 BPA 在促进肥胖和/或血糖和胰岛素稳态失调方面的作用进行明确的机制研究，将显着加强有关预防胰岛素抵抗和 T2DM 的公共卫生政策。因此，该项目将研究早期 BPA 暴露（妊娠至出生后第 21 天）对雄性和雌性大鼠 IR、T2DM 和肥胖的发展以及雌性大鼠潜在卵巢功能障碍的影响。将在第 4、8、12 和 18 个月时监测暴露于媒介物和 4 种不同剂量 BPA 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。将收集血液和组织（白色和棕色脂肪库、胰腺、肝脏、骨骼肌和卵巢）用于各种生物体液、组织学、生物化学、基因表达和表观遗传分析。具体目标 1 将确定导致成年大鼠葡萄糖/胰岛素稳态失调的围产期 BPA 暴露剂量，并将确定这种失调的时间顺序和进展。具体目标 2 将检验以下假设：BPA 诱导的 IR 反映了女性肥胖和/或激素失调对代谢和炎症的影响。具体目标 3 将鉴定白色和棕色脂肪组织中 BPA 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/或肥胖的发生相关。目标 1-3 的完成及其结果的整合将深入评估生命早期 BPA 暴露对成人葡萄糖稳态受损、IR 和 T2DM 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它们能够确定 BPA 暴露对基因表达、新陈代谢、身体成分和激素的多重影响，这些影响可能导致社会上肥胖、IR 和 T2DM 的增加。