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

BPA、邻苯二甲酸盐

• 批准号: 8547076
• 负责人: Andrea Baccarelli
• 金额: $ 57.6万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547076
• 关键词: Address; Adrenal Glands; Affect; Age; Animal Model; Animals; Archives; Biological Markers; Birth; Blood Pressure; Body fat; CYP11B1 gene; Chemical Exposure; Chemicals; Child; Childhood; Chronic; Costs and Benefits; DNA; DNA Methylation; Deposition; Desire for food; Development; Endocrine; Endocrine Disruptors; Energy Intake; Environment; Epidemic; Epigenetic Process; Equation; Event; Exposure to; Fasting; Fatty acid glycerol esters; Functional disorder; Future; Genes; Glucocorticoid Receptor; Goals; Growth; Hispanics; Hormones; Human; Hydrocortisone; Hypothalamic structure; IGF2 gene; IL6 gene; Individual; Inflammation Mediators; Insulin Resistance; Intervention; Lead; Life; Life Experience; Life Style; Link; Lipids; Measures; Mediator of activation protein; Medical; Mental Depression; Metabolic; Metabolism; Mexican; Mexico; Modeling; Molecular; Neurocognitive; Obesity; Outcome; Pathway interactions; Perinatal Exposure; Phenotype; Pituitary Gland; Plasma; Play; Population; Predisposition; Pregnancy; Pregnancy Trimesters; Prevalence; Production; Psychosocial Stress; Research; Research Infrastructure; Resistance; Resources; Role; Salivary; Signal Transduction; Skinfold Thickness; Social Environment; Societies; Staging; Stress; System; TNF gene; Testing; Time; Umbilical Cord Blood; Urine; Violence; Work; adipokines; aged; biological adaptation to stress; bisphenol A; cohort; early childhood; epigenetic marker; fetal; glucose metabolism; high risk; human study; hypothalamic-pituitary-adrenal axis; indexing; infancy; lipid metabolism; maternal stress; obesity in children; obesity risk; phthalates; prenatal; prenatal exposure; prenatal stress; programs; prospective; response; social stress; stressor; successful intervention; waist circumference

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.

描述（由申请人提供）：在美国和世界范围内，儿童肥胖是一个日益严重的危机。虽然热量摄入增加起着明显的作用，但这种流行病的根本原因可能并不像热量不平衡那么简单。伴随着肥胖率的上升，我们的社会发生了广泛的变化。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物质（EDCs）的增加以及社会心理压力带来的负担不断增加，可能与肥胖有关。尤其是，早在胎儿时期，edc和压力就会导致肥胖风险。在动物中，胎儿暴露于环境内分泌干扰化学物质（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，重新编程个体代谢设定点，导致肥胖。下丘脑轴是代谢程序的中枢系统，也是通过皮质醇产生应激反应的主要媒介。在动物中，胎儿暴露于增加的母亲压力会导致HPA重编程，皮质醇失调和更高的肥胖风险。应激和EDCs不仅调节皮质醇代谢，应激和EDCs还被证明可以改变DNA甲基化，这是HPA轴编程的一种潜在机制。DNA甲基化调节糖皮质激素受体，对环境敏感，这表明表观遗传学可能是肥胖、压力和EDCs之间联系的基础。据我们所知，社会心理压力与双酚a /邻苯二甲酸酯的相互作用从未在人类中进行过研究，也没有在EDCs和肥胖研究中评估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（环境和社会压力因素规划研究）的基础设施和资源，这是一项着眼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，以规模经济的方式进行肥胖和代谢功能障碍的研究。在本提案中，我们将通过以下方式增加PROGRESS: 1)对肥胖和代谢功能障碍儿童进行表型分析；2)检测存档尿液中EDC化学暴露量；3)检查存档脐带血的DNA甲基化测量。我们将确定产前暴露于双酚a和邻苯二甲酸盐是否能预测从出生到7岁的BMI变化轨迹，以及4岁和7岁时更大的肥胖、估计的胰岛素抵抗、血压、脂肪因子和空腹脂质谱。然后，我们将测试BPA和邻苯二甲酸盐暴露是否会破坏母胎HPA轴，这是由唾液皮质醇节律指示的。我们将研究BPA和邻苯二甲酸盐对肥胖相关表型和HPA轴的影响是否在怀孕期间存在母亲社会心理压力的情况下恶化。最后，我们将探讨DNA甲基化作为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。