Does perinatal exposure to Bisphenol A contribute to ad*

描述（由申请人提供）：肥胖是美国最常见的健康问题之一。美国肥胖症患病率的迅速增加表明，主要原因可能是环境因素。虽然饮食和体育活动的变化长期以来一直被认为是这方面的主要罪魁祸首，但有新的信息指出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的体重在整个成年期持续大幅增加。进一步检查发现肥胖、摄食过多和糖尿。这种类型的肥胖症背后的代谢畸变的性质尚不清楚，但其在停止暴露后的长期持续性表明BPA对代谢程序产生早期不可逆的影响。我们的工作假设是，在胎儿和新生儿的生活中暴露于双酚A破坏了关键的代谢调控网络（在全身器官和/或中枢神经系统）的发展，导致持续的基因表达的变化，参与调节食物摄入量，甘油三酸酯的增加和减少，和/或葡萄糖的利用。 具体目标1将评估从妊娠第9天到哺乳期暴露于BPA的妊娠小鼠的后代体重增加的性质。将在出生后和随后两个年龄测量以下参数：体型;质量和线性生长率和组成、摄食量、组织质量和脂肪细胞数量、个体脂肪库的大小;代谢相关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，作为参与能量平衡控制的组织中主要合成代谢和分解代谢途径的相对活性水平和调节状态的指标。它们包括白色脂肪组织中的C/EBP-α、PPAR-gamma、FAS、Glut-4、HSL和瘦素，棕色脂肪组织中的UCP 1，以及下丘脑中的POMC和NPY。将使用实时RT-PCR研究这些参数;将在BPA暴露期间以及目标1中检查的相同年龄和剂量的两个稍后时间点测量mRNA水平。 这些研究将表明肥胖的程度，以及围产期BPA治疗后是否存在特定脂肪库的差异参与或脂肪细胞数量的增加。他们还将提供所涉及的主要候选途径的指标，并将指导关于这种现象的机制的假说的发展，包括CNS和外周途径的失调和相互作用。预计这些结果，反过来，可能会产生更好的了解肥胖问题，并提供元素，以帮助制定一个健全的政策，解决这一严重的公共卫生问题。

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.