Developmentally Programmed Hyperphagia and Obesity via BPA enhanced Neurogenesis

通过 BPA 增强神经发生来控制发育性贪食和肥胖

• 批准号: 8571418
• 负责人: Mina Desai
• 金额: $ 19.55万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571418
• 关键词: Acetylation; Adipocytes; Adipose tissue; Adult; Amniotic Fluid; Animal Model; Animals; Astrocytes; Autistic Disorder; Behavioral; Birth; Brain; Canned Foods; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cells; Chemical Exposure; Chemicals; Childhood; Clinical; Cognitive; Consensus; Data; Desire for food; Development; Diet; Disease; Dose; Eating; Endocrine Disruptors; Environment; Epidemiologic Studies; Epigenetic Process; Estrogens; Etiology; Exposure to; Fatty acid glycerol esters; Fetal Development; Fetus; Glial Fibrillary Acidic Protein; Growth and Development function; Health; Histones; Hormonal; Human; Hyperphagia; Hypothalamic structure; In Vitro; Incidence; Industry; Learning; Mediating; Methylation; Modeling; Mothers; Mus; Neurons; Neuropeptides; Nutrient; Nutritional; Obesity; Organ; Overweight; Paper; Physical activity; Plasma; Plastics; Population; Pregnant Women; Prevalence; Public Health; Regulation; Risk; Risk Factors; Rodent; Satiation; Secondary to; Signal Transduction; Stem cells; Structure of nucleus infundibularis hypothalami; United States; Up-Regulation; Water; adult neurogenesis; bisphenol A; cell growth; early onset; endocrine disruptor exposure; environmental chemical; feeding; fetal; histone modification; in utero; in vivo; increased appetite; nerve stem cell; neurogenesis; nutrition; obesity in children; offspring; precursor cell; programs; public health relevance; transcription factor

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.

描述（由申请人提供）：儿童和成人疾病（如自闭症、行为/学习异常、肥胖）的多样性增加，部分归因于发育营养和化学暴露造成的编程效应。双酚A（BPA）是一种普遍存在的化学品，广泛用于塑料（例如，水瓶、食品罐内衬）和造纸业中，在孕妇、胎儿血浆和羊水中始终观察到大量的六溴二苯醚。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/功能的最终组成。与这一前提一致，研究表明，内分泌干扰物改变成体神经祖细胞（NPC）的神经发生。尽管EDC诱导的认知和行为效应的阵列，但EDC对胎儿NPC增殖和分化的影响的数据很少，这些功能对大脑发育至关重要。我们已经证实，肥胖，营养过剩的母鼠和BPA暴露的对照母鼠的后代早发性肥胖。利用NPC模型，我们已经证明了NPC增殖的剂量依赖性增加，Hes 1（神经增殖因子）的表达增加，而在分化培养基中，BPA增加了Mash 1（原神经发生因子），Tuj 1和GFAP（神经元和星形胶质细胞标志物），以及LSD 1（组蛋白去甲基化酶）。我们认为，母体BPA暴露与母体肥胖具有相加或协同作用，从而改变下丘脑发育，导致食欲与饱腹感神经元的增加。使用NPC神经球培养和体内/离体啮齿动物研究，该提案提供了一个独特的机会，以确定BPA暴露的后代中导致后代肥胖的程序性摄食过多的机制。