Molecular Mechanisms of Obesity in Children Exposed to Phthalates in Utero

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): In the last 30 years, the prevalence of obesity has risen sharply among children, and minority populations are particularly vulnerable. In the CHAMACOS birth cohort, a Mexican-American population from the agricultural Salinas Valley, CA, children have a particularly high prevalence of obesity (>39% at age 9) compared to both Mexican-American children (25%) and children of all races (20%) in the United States. Changes in diet and physical activity patterns do not completely explain the current obesity epidemic. Recent research suggests that exposure to environmental obesogens, particularly during the prenatal period, may also contribute to increases in obesity. Evidence from animals and epidemiologic studies suggests that phthalates, components of plastics and cosmetics ubiquitously found in humans, may be obesogenic. For instance, as shown in animals, they can change levels of biomarkers of obesity such as adipokines, protein hormones that regulate adipogenesis. There is also growing evidence that environmental exposures can influence DNA methylation (one of the main types of epigenetic markers) and result in adverse health outcomes. However, to date, no data are available on the effects of prenatal phthalate exposure on the molecular mechanisms of obesity in children or the potential role of epigenetic dysregulation. The overall goal of this proposal is to determine whether prenatal phthalate exposure contributes to the development of childhood obesity and metabolic syndrome (MetS) and to examine whether epigenetic changes mediate this relationship. We hypothesize that in utero phthalate exposure alters DNA methylation and leads to changes in adipokines (adiponectin and leptin), oxidative stress (isoprostanes), and higher risk of obesity and metabolic MetS in children. First, we will assess whether early and/or late pregnancy exposures are associated with a) biomarkers (adiponectin, leptin and isoprostane) and b) parameters of obesity and MetS in children at 5, 9 and 14 years of age. Second, we will characterize DNA methylation patterns in children at birth and 9 years of age, and examine whether site-specific changes in the methylome (by 450K array) are associated with a) prenatal phthalate exposure and b) biomarkers and parameters of obesity and MetS. Finally, we will validate 450K array data using next generation bisulfite sequencing and the most advanced expression and bioinformatic methodologies. The proposed research utilizes the rich collection of biological samples and data on exposures, diet, activities, and health outcomes in CHAMACOS participants. By extending assessment of children to age 14, this study will include critical periods of obesity development spanning pregnancy through adolescence. Our results will help elucidate the longitudinal effects of phthalates on obesity, explore the role of epigenetics and adipokines in the development of obesity and MetS, and address important gaps in our understanding of obesity. They will also inform policies aimed at improving children's health and preventing child obesity.