Does perinatal exposure to Bisphenol A contribute to adult obesity

描述(申请人提供)：肥胖是美国最常见的健康问题之一。美国肥胖率的迅速上升表明，主要原因可能是环境因素。虽然饮食和体力活动的改变长期以来一直被认为是这方面的主要罪魁祸首，但有新的信息表明，环境内分泌干扰物是潜在的致病因素。 在进行旨在了解围产期暴露于环境相关水平的雌激素双酚A(BPA)的影响的实验时，我们观察到这些动物在成年后体重大幅增加，并持续到成年。进一步检查发现肥胖、吞噬功能亢进和葡萄糖尿。这种肥胖背后的代谢异常的性质尚不清楚，但其在停止暴露很长时间后的持久性表明，双酚A对代谢编程产生了早期的、不可逆转的影响。我们的工作假设是，胎儿和新生儿生命中暴露于BPA会扰乱关键代谢调节网络的发展(在系统器官和/或在中枢神经系统)，导致参与调节食物摄入、甘油三酯合成代谢和分解代谢、和/或葡萄糖利用的基因表达持续变化。 具体目标1将评估从妊娠第9天到哺乳期暴露于双酚A的怀孕小鼠后代体重增加的性质。以下参数将在出生后和两个以后的年龄测量：身体大小；质量和线性增长率及其组成、食物消耗量、组织质量和脂肪细胞数量、单个脂肪库的大小；与代谢相关的血浆代谢物和激素的空腹水平。 具体目标2将探索编码代谢相关基因的基因的表达模式，作为参与控制能量平衡的组织中主要合成代谢和分解代谢途径的相对活动水平和调节状态的指示器。它们包括白色脂肪组织中的C/EBP-α、PPAR-γ、Fas、GLUT-4、HSL和瘦素，棕色脂肪组织中的UCP1，以及下丘脑中的POMC和NPY。这些参数将使用实时RT-PCR进行研究；在双酚A暴露期间，以及在目标1中检查的相同年龄和剂量的两个稍后时间点，将测量mRNA水平。 这些研究将表明肥胖的程度，以及围产期双酚A治疗后是否存在特定脂肪储备的不同参与或脂肪细胞数量的增加。它们还将提供所涉及的主要候选通路的指标，并将指导关于这一现象背后的机制的假说的发展，包括中枢神经系统和外周通路的失调和相互作用。预计这些结果反过来可能会更好地了解肥胖症问题，并提供有助于制定解决这一严重公共卫生问题的健全政策的要素。

DESCRIPTION (provided by applicant): Obesity is one of the most common health problems in the US. The rapid increase in the prevalence of obesity in the U.S. suggests that primary causes may be environmental. Although changes in diet and physical activity have long been considered the major culprit in this regard, there is novel information that points to environmental endocrine disrupters as potential causative agents. While performing experiments aimed at understanding the effects of perinatal exposure to environmentally relevant levels of the estrogen bisphenol-A (BPA) we observed a substantial increase in body weight that persisted throughout the adult life of these animals. Further exploration revealed adiposity, hyperphagia and glucosuria. The nature of the metabolic aberrations underlying this type of obesity is unknown, but its persistence long after cessation of exposure suggests that BPA exerts early, irreversible effects on metabolic programming. Our working hypothesis is that exposure to BPA during fetal and neonatal life disrupts the development of key metabolic regulatory networks (in systemic organs and/or in the CNS), leading to sustained alterations in expression of genes involved in regulation of food intake, triglyceride anabolism and catabolism, and/or glucose utilization. Specific Aim 1 will assess the nature of the weight gain in the offspring of pregnant mice exposed to BPA from gestational day 9 through lactation. The following parameters will be measured postnatally and at two later ages: body size; mass and linear growth rates and composition, food consumption, tissue mass and adipose cell number, size of individual adipose depots; fasting levels of metabolically relevant plasma metabolites and hormones. Specific Aim 2 will explore the expression pattern of genes encoding metabolically relevant genes as indicators of the relative activity levels and state of regulation of major anabolic and catabolic pathways in tissues involved in the control of energy balance. They include C/EBP-alpha, PPAR-gamma, FAS, Glut-4, HSL, and leptin in white adipose tissue, UCP1 in brown adipose tissue, and POMC and NPY in the hypothalamus. These parameters will be investigated using real-time RT-PCR; mRNA levels will be measured during the period of BPA exposure, and at two later points at the same ages and doses examined in Aim 1. These studies will indicate the extent of obesity and whether there is differential involvement of specific adipose depots or increases in adipocyte numbers following perinatal BPA treatment. They also will provide indicators of the major candidate pathways involved, and will guide the development of hypotheses about the mechanisms underlying this phenomenon, including dysregulation and interactions of CNS and peripheral pathways. It is expected that these results, in turn, may generate a better understanding of the obesity problem, and provide elements to help devise a sound policy addressing this serious public health problem.