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

描述(申请人提供)：儿童肥胖在美国和世界范围内是一个日益严重的危机。虽然卡路里摄入量的增加起到了明显的作用，但这一流行病的根本原因可能不只是卡路里失衡那么简单。肥胖率的上升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，即制造业的增加和内分泌干扰物(EDCs)的暴露，以及来自心理社会压力的不断增加的负担，可能与肥胖有关。特别是，内分泌细胞和压力都可以编程肥胖风险，早在胎儿时期就开始了。在动物中，胎儿暴露于环境内分泌干扰物(EDCs)，如双酚A(BPA)和邻苯二甲酸盐，通过改变下丘脑-垂体-肾上腺(HPA)信号，重新编程个体代谢起点走向肥胖。HPA轴是新陈代谢编程的中枢系统，也是通过皮质醇产生应激反应的主要中介。在动物中，胎儿暴露在母亲增加的压力下会导致HPA重新编程，皮质醇失调，以及更高的肥胖风险。不仅压力和内分泌细胞调节皮质醇代谢，压力和内分泌细胞都被证明改变DNA甲基化，这是HPA轴编程的一个潜在机制。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、压力和内分泌细胞之间联系的基础。据我们所知，心理社会压力与BPA/邻苯二甲酸酯的相互作用在人类中从未被研究过，也没有人的研究在内分泌细胞和肥胖的研究中评估皮质醇代谢或表观遗传生物标记物。我们将利用墨西哥的进展研究(环境和社会压力源的编程研究)的基础设施和资源，这是一个关注儿童早期神经认知表型的前瞻性出生队列。进展提供了一个独特的机会，在规模经济中开展肥胖和代谢障碍的研究。在这项提案中，我们将通过以下方式增加进展：1)对肥胖和代谢功能障碍的儿童进行表型鉴定；2)测量存档尿液中的EDC化学暴露；以及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双酚A和邻苯二甲酸酯是否预示着从出生到7岁体重指数的变化轨迹，以及更大的肥胖症、估计的胰岛素抵抗、血压、脂肪因子和4-7岁时的空腹血脂谱。然后，我们将测试双酚A和邻苯二甲酸盐暴露是否扰乱了以唾液皮质醇节律为指标的母婴HPA轴。我们将检查双酚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甲基化作为促进HPA反应编程的分子机制作为儿童肥胖和代谢功能障碍的一个因素。

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.