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）：在过去的几十年中，肥胖的发生率显着增加。除了高热量食品摄入量和久坐的生活方式外，环境因素的作用还获得了信誉。 Bisphenol A（BPA）是许多消费产品中使用的聚碳酸酯塑料的单体。 BPA发挥多种雌激素样作用，可在全球大多数经过测试的个体的血清中检测到H 1-20 nm。我们发现，低NM剂量的BPA抑制了人类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的抑制作用表现出最高的敏感性。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。较低的血清脂联素水平与代谢综合征的表现有关。因此，抑制脂联素的任何因素都应使暴露的个体患糖尿病或心血管疾病的风险增加。为了支持内分泌破坏者增加与肥胖相关疾病的风险的前提，至关重要的是对人脂肪组织的研究。我们的第一个目标是确定BPA在与环境相关的剂量下抑制脂联素的产生并从人脂肪组织中释放。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迅速抑制脂联素释放并抑制脂联素的表达。具体目标1将比较BPA和雌二醇对脂联素基因表达的抑制作用，并比较肥胖和非肥胖患者的内脏和皮下脂肪外植体中释放的抑制作用。具体目标2将检查BPA的急性和慢性作用的基础机制，重点是雌激素受体（ER1和/或ER2），G蛋白偶联受体30（GPR30）和过氧化物酶体增殖剂 - 活性体受体3（PPAR3）的作用。第二个目标将使用原代人脂肪细胞或LS14（我们的新型人脂肪细胞细胞系）实现。我们的长期目标是建立BPA在人脂肪细胞中的代谢作用，并产生可靠的证据，该证据可以由监管机构可以使用，以确定环境中的BPA是否对人类健康有害。公共卫生相关性：本研究研究了在环境中常见的内分泌干扰物，对人类脂肪组织和脂肪细胞脂联素的生产和释放的双苯酚A的影响。脂联素是一种脂肪特异性细胞因子，在代谢稳态中起着至关重要的作用，其抑制与与代谢综合征相关的糖尿病和心血管疾病的风险增加有关。