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.

Public Health Relevance

BPA and phthalates are introduced in the environment in massive amounts every year. Understanding the role of chemicals that program obesity requires understanding their interactions with the social environment, as interactions among prenatal obesogenic chemicals and high social stress could explain the observation that obesity tracks along lower SES gradients. A study that addresses all these issues prospectively, rather than cross-sectionally, in a population at high risk such as the Mexican population, is best suited towards identifying successful interventions to mitigate the obesity epidemic. Our results will be directly transferable to similar high-risk U.S. populations, such as Hispanics living in the U.S., and could be generalized to the U.S. population at large.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-D (55))
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Heindel, Jerrold
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Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
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