Developmentally Programmed Hyperphagia and Obesity via BPA enhanced Neurogenesis

描述（由申请人提供）：儿童和成人疾病多样性的增加（例如，自闭症，行为/学习异常，肥胖）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、食品罐头衬垫）和造纸工业，在孕妇和胎儿血浆和羊水中一直观察到显著水平。BPA是一种内分泌干扰物（EDC），流行病学研究证实，发育期间暴露于EDC可能会影响干细胞的生长和发育，从而影响器官、细胞群和细胞信号/功能的最终构成。与这一前提相一致，研究表明，EDCs改变成体神经祖细胞（NPC）的神经发生。尽管edc诱导了一系列认知和行为影响，但edc对胎儿鼻咽癌增殖和分化的影响却缺乏数据，而这些功能对大脑发育至关重要。我们已经证实，肥胖、营养过剩的水坝和bpa暴露的对照水坝的后代都会出现早发性肥胖。利用鼻咽癌模型，我们证明了鼻咽癌增殖的剂量依赖性增加与Hes1（神经增殖因子）的表达增加，而在分化培养基中，BPA增加了Mash1（前神经原因子），Tuj1和GFAP（神经元和星形胶质细胞标记物），以及LSD1（组蛋白去甲基化酶）。我们提出母体BPA暴露与母体肥胖共同或协同作用改变下丘脑发育，导致食欲和饱腹感神经元增加。通过NPC神经球培养和体内/离体啮齿动物研究，本研究提供了一个独特的机会来确定bpa暴露的后代程序性贪食的机制，从而导致后代肥胖。

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.