Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors

描述(申请人提供)：合成化学的进步导致了数以万计的新化合物的工业使用，在所有的进化史上，生物体都没有接触过这些化合物。有趣的是，这些合成化学品产量的指数增长与人类肥胖率和糖尿病发病率的协调上升是相映成趣的。此外，越来越多的流行病学研究将环境内分泌干扰物(EDCs)与能量平衡紊乱联系在一起，但EDCs发挥细胞效应的分子机制仍不清楚。拟议的研究将检验这样一种假设，即以不同方式调节脂肪细胞功能的内分泌细胞相互作用 具有共同的代谢应激源，以改变血糖稳态和减肥能力。此外，实验计划将询问这样的假设，即内分泌细胞的新陈代谢效应可以在子宫内编程，并在以后的生活中被揭开。将研究两种机制上不同的内分泌细胞：新型糖皮质激素受体(GR)激动剂甲苯氟烷(Tf)和过氧化体增殖物激活受体？(PPAR？？)激动剂三丁基锡(TBT)。由于这两种受体都促进脂肪生成，但可以不同地影响胰岛素的作用，这些研究将确定具有不同机制的内分泌细胞是否会产生相反的代谢表型。在第一个具体目标中，将全面分析这些内分泌细胞在标准饲养条件下以及在高脂饮食的协调代谢应激期间对全球能量代谢的影响。这些内分泌细胞对抗体重减轻的能力也将在暴露的成年小鼠中进行分析。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，将使用成年后随后的增重/减重方案来评估宫内暴露于胰岛素调节的内分泌细胞的不同代谢后果。这些方法将分析发育可塑性期间EDC暴露对代谢设定点建立的影响，以确定EDC暴露是否在对抗体重减轻的同时增强高脂饮食诱导的胰岛素抵抗。重要的是，这些研究将把EDC介导的全球能量稳态的改变与细胞胰岛素作用的特定干扰联系起来。这项研究不仅将描述暴露于一类全新的内分泌细胞(Tf)的全球代谢后果，而且还将增加关于环境肥胖来源TBT的重要新信息，据我们所知，尚未有报告研究TBT对妊娠期间血糖稳态的影响，它与肥胖饮食的相互作用，以及它损害减肥的能力。我们还将研究脂肪细胞细胞水平上的分子和代谢变化，以了解这些结构不同的内分泌细胞改变全球能量平衡的机制。了解这些内分泌细胞如何在不同的代谢压力下以不同的方式调节能量平衡，将大大有助于我们理解环境污染物对肥胖和糖尿病等代谢性疾病风险的影响。

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.