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

描述（由申请人提供）：肥胖及其并发症是美国和其他工业化国家的主要健康问题。基于近几十年来工业化学品生产的同步增长和体重的急剧上升，人们假设在工业化国家中化学品接触增加与肥胖“流行”之间存在着一种机制联系。双酚A （BPA）是一种普遍存在的雌激素内分泌干扰化学物质，用于食品和饮料容器中常见的聚碳酸酯塑料和环氧树脂中，也存在于我们日常接触的无数其他物品中。在93%的美国人的尿液中检测到双酚a，其中在年龄最小的研究人群中检测到的水平最高，他们是6至12岁的儿童。我们实验室的数据揭示了围产期BPA暴露对CD-1小鼠体重和肥胖的剂量依赖性影响。然而，BPA相关的体重增加的原因和这种体重增加的病理代谢后遗症目前都没有阐明。该提案寻求资金来验证这样的假设，即早期暴露于BPA会通过改变关键代谢组织的能量代谢来促进CD-1小鼠成年后的肥胖和代谢综合征的特征。该研究的目标是：1)确定与BPA暴露水平相关的促进成人发病肥胖及其并发症的内剂量；2)确定围产期与围产期和青春期前双酚a暴露对成人发病肥胖风险的相对影响；3)验证早期BPA暴露会加剧“西方”饮食（即高饱和脂肪）的致肥性和代谢影响的假设。4)验证BPA通过改变脂肪组织和骨骼肌的相关代谢途径促进肥胖的假设；5)在BPA暴露的小鼠中，确定BPA相关的转录和表观遗传变化，这些变化是代谢率改变和/或促进肥胖相关病理的基础。拟议的研究是高度合作的，涉及五位研究人员的综合努力，他们在双酚a、肥胖和代谢、糖尿病、基因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中的研究将提供第一个关于早期BPA暴露如何促进成人肥胖及其相关并发症的全面综合研究。这些研究将确定双酚a对体重作用的分子、细胞生物学和生理学机制，因此，这些研究可能有助于制定有关双酚a的公共卫生政策。

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.