Defining the role of BPA in promoting obesity and associated metabolic complicati

描述(申请人提供)：肥胖及其并发症在美国和其他工业化国家是一个主要的健康问题。根据近几十年来工业化学品产量的同步增长和体重的迅速上升，工业化国家中化学品暴露的增加和肥胖症的流行之间存在机械联系。双酚A(BPA)是一种普遍存在的雌激素内分泌干扰化学物质，用于聚碳酸酯塑料和环氧树脂，通常存在于食品和饮料容器中，它还存在于我们日常接触的无数其他物品中。在接受检查的美国人中，93%的人的尿液中检测到了双酚A，其中6至12岁的儿童的尿液中检测到的双酚A水平最高。我们实验室的数据显示，围产期双酚A暴露对CD-1小鼠体重和肥胖的影响具有剂量依赖性。然而，BPA相关体重增加的原因或这种体重增加的病理代谢后遗症目前都不清楚。这项提案寻求资金来检验这一假设，即早期接触BPA会通过改变关键代谢组织中的能量代谢来促进CD-1小鼠成年后出现肥胖和代谢综合征的特征。拟议研究的目标是：1)确定与双酚A暴露水平有关的内部剂量，这些水平会促进成人发作性肥胖及其并发症；2)确定围产期双酚A暴露与围产期和青春期联合暴露对成人发育性肥胖风险的相对影响；3)检验早期双酚A暴露会加剧食用西式饮食(即高饱和脂肪)对肥胖和代谢影响的假设；4)验证双酚A通过改变脂肪组织和骨骼肌中相关代谢途径而促进肥胖的假设。以及5)确定BPA相关的转录和表观遗传变化，这些变化是BPA暴露小鼠代谢率改变和/或促进肥胖相关病理的基础。拟议的研究是高度协作的，涉及五名研究人员的综合努力，他们在双酚A、肥胖和新陈代谢、糖尿病、基因图谱和表观遗传学方面具有不同但互补的专业知识。成功完成这项拨款申请的研究将提供第一个全面和综合的研究，研究早期接触双酚A如何促进成人肥胖及其相关并发症。这些研究将确定BPA对体重的作用所涉及的分子、细胞生物学和生理机制，这样做，这些研究可能有助于有关BPA的公共卫生决策。 与公众健康相关：双酚A(BPA)是塑料中普遍存在的一种化学物质，通常存在于食品和饮料容器中。我们实验室的初步研究显示，在生命早期暴露于双酚A的啮齿动物体重呈剂量依赖性增加。这项提案将进一步调查双酚A在成年后促进肥胖的可能性。

DESCRIPTION (provided by applicant): Obesity and its complications are a major health concern in the US and other industrialized nations. Based on the coincident increase in industrial chemical production and the meteoric rise in body weight in recent decades, a mechanistic connection between increased chemical exposure and the obesity 'epidemic' in industrialized nations has been postulated. Bisphenol A (BPA) is a ubiquitous estrogenic endocrine-disrupting chemical used in polycarbonate plastics and epoxy resins commonly found in food and beverage containers, and it is also present in countless other items that we come into contact with daily. BPA has been detected in the urine of 93% of the US population examined with the highest levels detected in the youngest cohort studied, children between 6 and 12 years of age. Data from our laboratory reveal a dose-dependent effect of perinatal BPA exposure on body weight and adiposity in CD-1 mice. However, neither the cause of BPA- associated weight gain nor the pathologic metabolic sequelae of this weight gain are currently elucidated. This proposal seeks funds to test the hypothesis that early life exposure to BPA promotes adult-onset obesity and hallmarks of the Metabolic Syndrome in CD-1 mice by altering energy metabolism in key metabolic tissues. Goals of the proposed research are to 1) determine the internal dose associated with BPA exposure levels that promote adult onset obesity and its complications, 2) determine the relative impact of perinatal vs. combined perinatal and prepubertal BPA exposure on risk for adult-onset obesity, 3) test the hypothesis that early BPA exposure exacerbates the obesitogenic and metabolic impacts of eating a 'western" diet (i.e., high in saturated fats), 4) test the hypothesis that BPA promotes obesity by altering relevant metabolic pathways in adipose tissue and skeletal muscle, and 5) identify BPA-associated transcriptional and epigenetic changes that underlie altered metabolic rate and/ or promote obesity-associated pathology in BPA-exposed mice. The proposed studies are highly collaborative, involving the integrated efforts of five investigators with distinct but complementary expertise in BPA, obesity and metabolism, diabetes, gene profiling, and epigenetics. Successful completion of the studies in this grant application will provide the first comprehensive and integrated study of how early life BPA exposure promotes adult obesity and its associated complications. These studies will identify the molecular, cell biological, and physiological mechanisms involved in the action of BPA on body weight and in so doing, these studies are likely to contribute to public health policy decisions concerning BPA. PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA), is a ubiquitous chemical used in plastics and commonly found in food and beverage containers. Preliminary studies in our lab have revealed a dose- dependent increase in body weight in rodents exposed to BPA early in life. This proposal will further investigate the potential for BPA to promote obesity in adulthood.