Developmentally Programmed Hyperphagia and Obesity via BPA enhanced Neurogenesis

描述(由申请人提供)：儿童和成人各种疾病(如自闭症、行为/学习异常、肥胖)的增加部分归因于发育营养和化学物质暴露造成的编程影响。双酚A(BPA)是一种普遍存在的化学物质，广泛用于塑料(如水瓶、食品罐头衬里)和造纸业，在孕妇和胎儿血浆和羊水中持续观察到显著水平。BPA扮演内分泌干扰物(EDC)的角色，流行病学研究证实，发育期间EDC的暴露可能会影响干细胞的生长和发育，从而影响器官、细胞种群和细胞信号/功能的最终组成。与这一前提一致的是，研究表明，内源性DC改变了成人神经前体细胞(NPC)的神经发生。尽管EDC诱导了一系列的认知和行为影响，但关于EDC对胎儿鼻咽癌增殖和分化的影响的数据一直很少，这两个功能对大脑发育至关重要。我们已经证实，肥胖、过度饲养的水坝和暴露于BPA的对照水坝的后代都会出现早发性肥胖。利用鼻咽癌模型，我们证明了随着Hes1(神经增殖因子)表达的增加，鼻咽癌增殖呈剂量依赖性增加，而在分化介质中，BPA增加了Mash1(神经源性因子)、Tuj1和GFAP(神经元和星形胶质细胞标记物)以及LSD1(组蛋白去甲基酶)。我们认为，母体BPA暴露与母体肥胖相加或协同作用，改变下丘脑发育，导致食欲增加而不是饱腹感神经元。利用鼻咽癌神经球培养和体内/体外啮齿动物研究，这一建议提供了一个独特的机会来确定暴露于BPA的子代程序性吞噬过度导致子代肥胖的机制。

DESCRIPTION (provided by applicant): Increases in a diversity of childhood and adult diseases (eg, autism, behavioral/learning abnormalities, obesity) have been attributed, in part, to programming effects resulting from developmental nutrient and chemical exposures. Bisphenol A (BPA) is a ubiquitous chemical widely used in plastics (e.g., water bottles, food can liners) and paper industries, and significant levels are consistently observed in pregnant women and fetal plasma and amniotic fluid. BPA acts an endocrine disrupter (EDC), and epidemiological studies confirm that EDC exposure during developmental periods may impact stem cell growth and development, and hence the ultimate make-up of organs, cell populations, and cell signaling/function. Consistent with this premise, studies have shown that EDCs alter neurogenesis of adult neural progenitor cells (NPC). Despite the array of EDC-induced cognitive and behavioral effects, there has been scant data of the effects of EDCs on fetal NPC proliferation and differentiation, functions which are critical for brain development. We have confirmed that offspring of both obese, overnourished dams and BPA-exposed control dams develop early onset obesity. Utilizing a model of NPC, we have demonstrated a dose dependent increase in NPC proliferation with increased expression of Hes1 (neuroproliferative factor), whereas in differentiation media, BPA increased Mash1 (proneurogenic factor), Tuj1 and GFAP (neuronal and astrocyte markers), and LSD1 (histone demethylase). We propose that maternal BPA exposure acts additively or synergistically with maternal obesity to alter hypothalamic development, resulting in an increase in appetite versus satiety neurons. Using both NPC neurosphere culture and in vivo/ex vivo rodent studies, this proposal provides a unique opportunity to determine mechanisms of programmed hyperphagia in BPA-exposed offspring which contribute to offspring obesity.