Bisphenol A mediated effects on offspring glucocorticoid homeostasis and obesity

双酚 A 介导的对后代糖皮质激素稳态和肥胖的影响

基本信息

批准号：
8892575
负责人：
Juanita K. Jellyman
金额：
$ 6.57万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892575
关键词：
Address Adipocytes Adipose tissue Adrenal Glands Adult Amniotic Fluid Animals Birth Blood Body Weight Canned Foods Cell Culture Techniques Cell Proliferation Chemicals Child Childhood Consensus Corticosterone Corticotropin Corticotropin-Releasing Hormone Development Diet Elderly Endocrine Disruptors Environment Enzymes Epidemic Etiology Exhibits Exposure to Fatty acid glycerol esters Fetus Gene Expression Glucocorticoid Receptor Glucocorticoids Goals Homeostasis Human Hydrocortisone Hydroxysteroid Dehydrogenases In Vitro Knowledge Lactation Lead Lipids Mediating Metabolic Diseases Metabolism Modeling Molecular Obesity Oxidoreductase Pathway interactions Perinatal Perinatal Exposure Phenotype Pituitary-Adrenal System Plasma Plastics Pregnancy Pregnant Women Prevention strategy Public Health Rattus Serum Stem cells Time Tissues Visceral Water Weaning bisphenol A clinically relevant enzyme activity fetal hypothalamic-pituitary-adrenal axis in utero in vivo innovation lipid biosynthesis novel offspring programs protein expression public health relevance receptor expression steroid hormone steroidogenic acute regulatory protein subcutaneous transcription factor

项目摘要

DESCRIPTION (provided by applicant): The past 40 years has witnessed an epidemic of childhood and adult obesity, attributed in part to programming effects of the in utero environment. During this time period, the use of plastics (e.g., water bottles, food can liners) containing bisphenol A (BPA) has accelerated in parallel to obesity rates. BPA, an endocrine disruptor (EDC) chemical, is ubiquitous with significant levels in pregnant women, fetal plasma and amniotic fluid. Using a clinically relevant rat model of maternal BPA-exposure during pregnancy and lactation we have demonstrated that BPA increases offspring body weights, adiposity and adipocyte progenitor cell proliferation and lipid storage. However, the mechanisms by which BPA exerts its effects on adiposity are unknown. The underlying cause of BPA-programmed obesity may be attributed to BPA effects on glucocorticoid pathways, specifically through activation of the hypothamalic-pituitary-adrenal (HPA) axis and/or increased adipose tissue-specific glucocorticoid exposure. The proposed studies will determine basal and stimulated functioning of the HPA axis in control and BPA-treated offspring. Since BPA-programmed increases in adipocyte proliferation and lipid storage may also be due to the effects of local adipose tissue glucocorticoid exposure, we will further address the gene and protein expression of the enzyme 11ßhydroxysteroid dehydrogenase, which converts inactive ketoglucocorticoids to active 11ß-hydroxyglucocorticoids, thereby regulating activation of the glucocorticoid receptor at the adipose tissue level. The studies will utilize BPA-offspring at birt (P1), at weaning (P21) and in adulthood (6 months) to first determine the effects of BPA-exposure during pregnancy and lactation on offspring glucocorticoid homeostasis, and second to determine whether BPA-increased glucocorticoid exposure persists into adulthood. In view of the dramatic increase in obesity, especially in children, understanding the mechanisms underlying how perinatal BPA exposure contributes to the etiology of obesity is essential to the development of effective strategies for the prevention and treatment of the global obesity epidemic.

描述（由申请人提供）：过去 40 年见证了儿童和成人肥胖症的流行，部分原因是子宫内环境的编程效应。在此期间，塑料（例如水瓶、食品罐头）的使用。含有双酚 A (BPA) 的内衬）与肥胖率同步加速，BPA 是一种内分泌干扰物 (EDC) 化学物质，在孕妇、胎儿血浆和体内普遍存在。使用妊娠和哺乳期间母体 BPA 暴露的临床相关大鼠模型，我们证明 BPA 会增加后代体重、肥胖和脂肪祖细胞增殖和脂质储存，但 BPA 对肥胖产生影响的机制。 BPA 程序性肥胖的根本原因可能是由于 BPA 对糖皮质激素途径的影响，特别是通过激活下丘脑-垂体-肾上腺。 (HPA) 轴和/或脂肪组织特异性糖皮质激素暴露的增加，拟议的研究将确定对照和 BPA 治疗的后代中 HPA 轴的基础功能和刺激功能，因为 BPA 程序性的脂肪细胞增殖和脂质储存的增加也可能受到影响。由于局部脂肪组织糖皮质激素暴露的影响，我们将进一步解决11β羟基类固醇脱氢酶的基因和蛋白质表达问题，该酶将无活性的酮糖皮质激素转化为活性 11β-羟基糖皮质激素，从而调节脂肪组织水平上糖皮质激素受体的激活。这些研究将利用 BPA 后代在出生时 (P1)、断奶时 (P21) 和成年期 (6 个月) 首先确定其效果。怀孕和哺乳期间接触 BPA 对后代糖皮质激素稳态的影响，其次确定是否BPA 增加的糖皮质激素暴露持续到成年期，鉴于肥胖症的急剧增加，尤其是儿童，了解围产期 BPA 暴露如何导致肥胖病因的机制对于制定预防和治疗肥胖的有效策略至关重要。全球肥胖流行病。