Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors

胎儿或成人暴露于环境内分泌干扰物的代谢影响

• 批准号: 8723826
• 负责人: Robert M Sargis
• 金额: $ 23.46万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723826
• 关键词: Accounting; Adipocytes; Adipose tissue; Adult; Affect; Agonist; Attention; Body Composition; Body Weight decreased; Body fat; Cell Differentiation process; Chemical Exposure; Chemicals; Child; Data; Deterioration; Development; Diabetes Mellitus; Diet; Disease; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Elderly; Endocrine; Endocrine Disruptors; Energy Metabolism; Environmental Pollutants; Environmental Pollution; Epidemic; Epidemiologic Studies; Explosion; Exposure to; Fatty acid glycerol esters; Fetus; Functional disorder; Future; Gestational Diabetes; Glucocorticoid Receptor; Gonadal Steroid Hormones; Health; Homeostasis; Human; Individual; Insulin; Insulin Resistance; Link; Lipids; Longevity; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Overweight; Pathogenesis; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Phenotype; Population; Pregnancy; Prevalence; Production; Protocols documentation; Recording of previous events; Reporting; Risk; Scanning; Signal Transduction; Synthesis Chemistry; Techniques; Testing; Thyroid Hormones; Time; United States; Weight Gain; base; blood glucose regulation; comparative; developmental plasticity; environmental chemical; feeding; fetal; glucose tolerance; in utero; in vivo; innovation; insight; insulin sensitivity; insulin signaling; insulin tolerance; lipid biosynthesis; mortality; novel; nutrition; obesogen; programs; public health relevance; receptor; research study; response; stressor; transcription factor; tributyltin

DESCRIPTION (provided by applicant): Advances in synthetic chemistry have led to the industrial use of tens of thousands of novel compounds to which organisms have not been exposed in all of evolutionary history. Interestingly, the exponential increase in production of these synthetic chemicals is mirrored by a coordinate rise in obesity and diabetes rates in humans. Furthermore, an expanding body of epidemiological studies has linked environmental endocrine disruptors (EDCs) with disturbances in energy homeostasis, but the molecular mechanisms by which EDCs exert their cellular effects remain poorly understood. The proposed studies will test the hypothesis that EDCs that differentially modulate adipocyte function interact with common metabolic stressors to alter glucose homeostasis and the capacity for weight loss. Furthermore, the experimental plan will interrogate the supposition that the metabolic effects of EDCs can be programmed in utero and unmasked in later life. Two mechanistically distinct EDCs will be studied: the novel glucocorticoid receptor (GR) agonist tolylfluanid (TF) and the peroxisome proliferator activated receptor-? (PPAR??) agonist tributyltin (TBT). Since both receptors promote adipogenesis yet can differentially affect insulin action, these studies will ascertain whether EDCs with distinct mechanisms generate opposing metabolic phenotypes. In the first Specific Aim, the effects of these EDCs on global energy metabolism will be comprehensively analyzed under standard feeding conditions as well as during the coordinate metabolic stress of a high fat diet. The ability of these EDCs to antagonize weight loss will also be analyzed in exposed adult mice. In the second Specific Aim, the capacity of each EDC to promote gestational diabetes will be assessed. In conjunction with these experiments, the differential metabolic consequences of in utero exposure to insulin-modulating EDCs will be evaluated using a subsequent weight gain/loss protocol during adulthood. These approaches will analyze the impact of EDC exposure during periods of developmental plasticity on the establishment of metabolic set points to determine whether EDC exposure augments high fat diet-induced insulin resistance while antagonizing weight loss. Importantly, these studies will lin EDC-mediated alterations in global energy homeostasis with specific disruptions in cellular insulin action. The present study will not only characterize the global metabolic consequences of exposure to an entirely novel class of EDCs (TF), but it will also add significant new information about the environmental obesogen TBT, as to our knowledge no reports have investigated its effects on glucose homeostasis during pregnancy, its interaction with obesogenic diets, and its ability to impair weight loss. We will also investigate molecular and metabolic changes at the cellular level of the adipocyte to understand the mechanisms by which these structurally distinct EDCs alter global energy homeostasis. Understanding how these EDCs differentially modulate energy homeostasis under various metabolic stresses will add significantly to our understanding of the impact of environmental pollutants on the risk of metabolic diseases such as obesity and diabetes.

描述（由申请人提供）：合成化学的进步已经导致数万种新化合物的工业应用，生物体在所有进化史中都没有暴露于这些化合物。有趣的是，这些合成化学物质的产量呈指数级增长，这反映在人类肥胖和糖尿病发病率的协调上升上。此外，越来越多的流行病学研究将环境内分泌干扰物（EDCs）与能量稳态紊乱联系起来，但EDCs发挥其细胞效应的分子机制仍然知之甚少。拟议的研究将检验这一假设，即差异调节脂肪细胞功能的内分泌干扰物相互作用， 与常见的代谢应激源一起改变葡萄糖稳态和减肥能力。此外，实验计划将询问假设，即内分泌干扰物的代谢作用可以在子宫内编程，并在以后的生活中暴露。两种机制不同的内分泌干扰物将进行研究：新的糖皮质激素受体（GR）激动剂甲苯氟胺（TF）和过氧化物酶体增殖物激活受体-？(PPAR??)激动剂三丁基锡（TBT）。由于这两种受体促进脂肪生成，但可以差异影响胰岛素的作用，这些研究将确定是否有不同的机制产生相反的代谢表型的内分泌干扰物。在第一个具体目标中，这些内分泌干扰物对整体能量代谢的影响将在标准饲养条件下以及在高脂肪饮食的协调代谢应激期间进行全面分析。还将在暴露的成年小鼠中分析这些EDC拮抗体重减轻的能力。在第二个具体目标中，将评估每个EDC促进妊娠期糖尿病的能力。结合这些实验，将使用随后的成年期体重增加/减轻方案评估子宫内暴露于胰岛素调节性EDCs的不同代谢后果。这些方法将分析发育可塑性期间EDC暴露对建立代谢设定点的影响，以确定EDC暴露是否增强高脂饮食诱导的胰岛素抵抗，同时拮抗体重减轻。重要的是，这些研究将把EDC介导的整体能量稳态的改变与细胞胰岛素作用的特定破坏联系起来。本研究不仅将表征暴露于一种全新的内分泌干扰物（TF）的全球代谢后果，而且还将增加有关环境致胖剂TBT的重要新信息，据我们所知，没有报告调查其对妊娠期间葡萄糖稳态的影响，其与致胖饮食的相互作用，以及其损害减肥的能力。我们还将研究脂肪细胞水平的分子和代谢变化，以了解这些结构不同的内分泌干扰物改变整体能量稳态的机制。了解这些内分泌干扰物如何在各种代谢应激下差异调节能量稳态，将大大增加我们对环境污染物对肥胖和糖尿病等代谢疾病风险影响的理解。