BPA, Phthalates & Stress: Mechanisms and Interactions for Childhood Obesity

描述（由申请人提供）：儿童肥胖是美国和世界范围内日益严重的危机。虽然增加热量摄入起着明显的作用，但这种流行病的根本原因可能不仅仅是热量不平衡那么简单。肥胖率的增加伴随着我们社会的广泛变化。动物模型表明，这些变化的两个特征，即，制造和接触内分泌干扰化学品（EDCs）的增加以及心理社会压力造成的日益沉重的负担可能与肥胖有关。特别是，内分泌干扰物和压力都可以从胎儿时期就开始规划肥胖风险。在动物中，胎儿暴露于环境内分泌干扰化学品（EDCs），如双酚A（BPA）和邻苯二甲酸酯，通过改变下丘脑-垂体-肾上腺（HPA）信号转导，将个体代谢设定点重新编程为肥胖。HPA轴是代谢程序的中枢系统，也是通过皮质醇产生的应激反应的主要介质。在动物中，胎儿暴露于增加的母体压力会导致HPA重编程，皮质醇失调和更高的肥胖风险。不仅压力和内分泌干扰物调节皮质醇代谢，压力和内分泌干扰物都被证明可以改变DNA甲基化，这是HPA轴编程的潜在机制。DNA甲基化调节糖皮质激素受体，并对环境敏感，这表明表观遗传学可能是肥胖，压力和内分泌干扰物之间联系的基础。据我们所知，心理社会压力与BPA/邻苯二甲酸酯的相互作用从未在人类中进行过研究，也没有人类研究评估过内分泌干扰物和肥胖研究中的皮质醇代谢或表观遗传生物标志物。我们将利用墨西哥PROGRESS研究（环境和社会压力的PROGramming研究）的基础设施和资源，这是一项专注于儿童早期神经认知表型的前瞻性出生队列研究。PROGRESS提供了一个独特的机会，以规模经济的方式对肥胖和代谢功能障碍进行研究。在本提案中，我们将通过以下方式增加进展：1）对肥胖和代谢功能障碍儿童进行表型分析; 2）测量存档尿液中的EDC化学暴露; 3）检查存档脐带血中的DNA甲基化测量。我们将确定产前暴露于BPA和邻苯二甲酸酯是否预示着从出生到7岁BMI的变化轨迹，以及4岁和7岁时更大的肥胖，估计胰岛素抵抗，血压，脂肪因子和空腹血脂谱。然后，我们将测试BPA和邻苯二甲酸酯暴露是否会破坏母胎HPA轴，唾液皮质醇节律指数。我们将研究双酚A和邻苯二甲酸酯对肥胖相关表型和HPA轴的影响是否在怀孕期间母亲心理社会压力的情况下恶化。最后，我们将探讨DNA甲基化作为一种分子机制的作用，有助于编程HPA反应作为一个因素，有助于儿童肥胖和代谢功能障碍。

DESCRIPTION (provided by applicant): Childhood obesity is a growing crisis in the U.S. and worldwide. While increased caloric intake plays an obvious role, the underlying causes of this epidemic are likely not as simple as just caloric imbalance. The increase in obesity rates has been accompanied by extensive changes in our society. Animal models indicate that two features of these changes, i.e., increased manufacturing and exposure to endocrine disrupting chemicals (EDCs) and the ever increasing burden from psychosocial stress, may be linked to obesity. In particular, both EDCs and stress can program obesity risks starting as early as in fetal life. In animals, fetal exposure to environmental endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA) and phthalates, reprograms the individual metabolic set point toward obesity via altered hypothalamic-pituitary-adrenal (HPA) signaling. The HPA axis is a central system for metabolic programming and a primary mediator of stress responses through cortisol production. In animals, fetal exposure to increased maternal stress causes HPA reprogramming, cortisol dysregulation, and higher risk of obesity. Not only do stress and EDCs regulate cortisol metabolism, both stress and EDCs have been shown to alter DNA methylation, a potential mechanism of HPA axis programming. DNA methylation regulates the glucocorticoid receptor and is sensitive to the environment, suggesting that epigenetics may underlie links between obesity, stress and EDCs. To our knowledge, interactions of psychosocial stress with BPA/phthalates have never been studied in humans, nor have human studies assessed cortisol metabolism or epigenetic biomarkers in research on EDCs and obesity. We will leverage the infrastructure and resources of the PROGRESS study (PROGramming Research in Environment and Social Stressors) in Mexico, a prospective birth cohort focused on early childhood neurocognitive phenotypes. PROGRESS provides a unique opportunity to perform research on obesity and metabolic dysfunction at economy of scale. In this proposal, we will add to PROGRESS by: 1) phenotyping children for obesity and metabolic dysfunction; 2) measuring EDC chemical exposure from archived urine; and 3) examining DNA methylation measures from archived cord blood. We will determine whether prenatal exposure to BPA & phthalates predicts altered trajectories of BMI from birth till 7 years, as well as greater adiposity, estimated insuli resistance, blood pressure, adipokines, and fasting lipid profiles at ages 4 & 7 years. We will then test whether BPA and phthalate exposures disrupt the maternal-fetal HPA axis, as indexed by salivary cortisol rhythms. We will examine whether the effects of BPA and phthalates on the obesity-related phenotypes and HPA axis are worsened in the presence of conditions of maternal psychosocial stress during pregnancy. Finally, we will explore the role of DNA methylation as a molecular mechanisms contributing to programming of HPA responses as a factor contributing to childhood obesity and metabolic dysfunction.