Exposure to Bisphenol A: Inhibition of Adiponectin Release by Human Adipocytes

接触双酚 A：抑制人脂肪细胞释放脂联素

• 批准号: 7510030
• 负责人: Nira Ben-Jonathan
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510030
• 关键词: Abdomen; Acute; Address; Adipocytes; Adipose tissue; Affect; Animals; Attention; Biological; Breast; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Chronic; Clinical; Cultured Cells; Data; Diabetes Mellitus; Dose; Eating; Endocrine; Endocrine Disruptors; Endoplasmic Reticulum; Environment; Environmental Risk Factor; Estradiol; Estrogen Receptors; Europe; Exogenous Factors; Exposure to; G-Protein-Coupled Receptors; Gene Expression; Glucose; Goals; Health; Homeostasis; Hormones; Human; Incidence; Individual; Japan; Laboratory Animals; Laboratory Study; Life Style; Mediating; Metabolic; Metabolic syndrome; Mus; Non obese; Obesity; Obesity associated disease; Patients; Peroxisome Proliferator-Activated Receptors; Plant Roots; Play; Production; Protein Isoforms; Public Health; Publishing; Risk; Rodent; Role; Serum; Solid; Testing; Tissue Sample; Tissues; Visceral; Xenobiotics; adiponectin; bisphenol A; consumer product; cytokine; in utero; lipid biosynthesis; lipid metabolism; monomer; novel; polycarbonate plastic; prevent; programs; sedentary; subcutaneous

DESCRIPTION (provided by applicant): The incidence of obesity has risen dramatically over the last few decades. In addition to high caloric food intake and sedentary life style, the role of environmental factors is gaining credence. Bisphenol A (BPA) is a monomer of polycarbonate plastics used in many consumer products. BPA exerts multiple estrogenic-like actions and is detectable at H 1-20 nM in serum from the majority of tested individuals worldwide. We found that BPA at low nM doses suppresses adiponectin release from human adipose explants, with visceral explants from morbidly obese patients showing the highest sensitivity to the suppressive effect of BPA. Adiponectin is an adipocyte-specific hormone which plays a key role in metabolic homeostasis. Lower serum adiponectin levels are associated with the manifestation of the metabolic syndrome. Thus, any factor which suppresses adiponectin should subject the exposed individuals to increased risks of developing diabetes or cardiovascular disease. To support the premise that endocrine disruptors increase the risk of obesity-associated diseases, studies with human adipose tissue are critically needed. Our first objective is to establish that BPA, at environmentally relevant doses, inhibits adiponectin production and release from human Adipose tissue. Our second objective is to explore whether BPA rapidly inhibits adiponectin release and suppresses adiponectin expression by interacting with classical and non-classical estrogen receptors. Specific aim 1 will compare the suppressive effects of BPA and estradiol on adiponectin gene expression and release from visceral and subcutaneous adipose explants from obese and non-obese patients. Specific aim 2 will examine the mechanisms underlying acute and chronic effects of BPA, focusing on the roles of estrogen receptors (ER1 and/or ER2), G-protein-coupled receptor 30 (GPR30) and peroxisome proliferator- activated receptor 3 (PPAR3). The second aim will be accomplished using primary human adipocytes or LS14, our novel human adipocyte cell line. Our long term goal is to establish the metabolic effects of BPA in human adipocytes and generate solid evidence that can be used by regulatory agencies to determine whether BPA in the environment is hazardous to human health. PUBLIC HEALTH RELEVANCE: This study examines the effects of bisphenol A, an endocrine disruptor that is common in the environment, on the production and release of adiponectin from human adipose tissue and adipocytes. Adiponectin is an adipose-specific cytokine that plays a critical role in metabolic homeostasis and its suppression is associated with increased risk of developing diabetes and cardiovascular diseases that are associated with the metabolic syndrome.

描述（由申请人提供）：在过去的几十年里，肥胖的发病率急剧上升。除了高热量食物摄入和久坐不动的生活方式外，环境因素的作用也越来越得到认可。双酚A （BPA）是许多消费品中使用的聚碳酸酯塑料的单体。BPA具有多种雌激素样作用，在世界上大多数受测者的血清中在h1 -20 nM可检测到。我们发现，低nM剂量的BPA可抑制人体脂肪外植体的脂联素释放，病态肥胖患者的内脏外植体对BPA的抑制作用最敏感。脂联素是一种脂肪细胞特异性激素，在代谢稳态中起关键作用。血清脂联素水平降低与代谢综合征的表现有关。因此，任何抑制脂联素的因素都应该使暴露的个体增加患糖尿病或心血管疾病的风险。为了支持内分泌干扰物增加肥胖相关疾病风险的前提，迫切需要对人类脂肪组织进行研究。我们的第一个目标是确定BPA在环境相关剂量下抑制人体脂肪组织中脂联素的产生和释放。我们的第二个目标是探索BPA是否通过与经典和非经典雌激素受体相互作用来快速抑制脂联素的释放和抑制脂联素的表达。具体目的1将比较BPA和雌二醇对肥胖和非肥胖患者内脏和皮下脂肪外植体中脂联素基因表达和释放的抑制作用。特异性目标2将研究BPA的急性和慢性作用机制，重点关注雌激素受体（ER1和/或ER2）、g蛋白偶联受体30 （GPR30）和过氧化物酶体增殖物激活受体3 （PPAR3）的作用。第二个目标将使用原代人脂肪细胞或我们的新型人脂肪细胞系LS14来完成。我们的长期目标是确定BPA在人体脂肪细胞中的代谢作用，并产生可靠的证据，供监管机构用来确定环境中的BPA是否对人体健康有害。公共卫生相关性：本研究探讨了环境中常见的内分泌干扰物双酚A对人体脂肪组织和脂肪细胞中脂联素的产生和释放的影响。脂联素是一种脂肪特异性细胞因子，在代谢稳态中起关键作用，其抑制与糖尿病和与代谢综合征相关的心血管疾病的风险增加有关。