Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Endocrine disruptors, epigenetic programming and neonatal outcomes

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Obesity, the metabolic syndrome (METS), and type 2 diabetes (T2D) are increasing in the US and are now present at younger ages, indicating that risk factors for obesity operate early in life. While obesity ultimately results from an imbalance between caloric intake and expenditure, emerging evidence suggests that endocrine disrupting chemicals (EDCs) may, at critical periods in the lifecourse, alter an organism's response to environmental insults, contributing to the development of obesity, inflammation, METS, and ultimately T2D. The goal of this proposal is to study the role of two classes of EDCs: 1) Phthalates; and 2) Polyfluoroalkyl compounds (PFCs)) to test the overarching hypothesis that fetal exposure to EDCs in utero is associated with development of adiposity-related outcomes in the offspring. Using the unique infrastructure of the prospective birth cohort Healthy Start study (R01DK076648), we propose to add measures of exposure to EDCs from stored maternal samples collected during pregnancy. We will relate these exposures to neonatal adiposity and METS outcomes and growth trajectories to 2 years age already collected, and explore the epigenetic genome modification in cord blood DNA that may result from these exposures to the fetus. This will be the first study to evaluate EDC exposures on infant fat and lean mass (in contrast to simply birthweight) using air displacement plethysmography at birth and at 4- 6 months. This proposal is very responsive to PAR12-185 by adding EDC measurements to an existing study to explore vulnerable windows of development, studying intermediate precursors of obesity, T2D and METS, and exploring offspring lipid and inflammatory profiles with EDC exposure, together with detailed epigenetic outcomes in the infant. Detailed dietary data also allows the exploration of potential modifications of associations of interest by both maternal and early infant diet, including soy-based formulas. The specific aims to be tested are: Aim 1. To determine the levels and correlates of in utero exposure to specific EDCs in a contemporary, multi-ethnic cohort of pregnant women. Aim 2. To explore the associations of in utero exposure to EDCs with infant adiposity and insulin resistance-related metabolic markers. Aim 3. To explore the epigenetic changes induced by in utero exposure to EDCs, and the role of specific maternal nutrients and foods as possible effect modifiers. We explore a topic of significant of public health impact, that of whether common EDCs impact the developmental origins of obesity and metabolic syndrome, both precursors of later diabetes and cardiovascular disease. It includes several innovative features: focus on sensitive developmental period, study of infant fat mass and patterning rather than birth weight, use of a prospective birth cohort, and mechanistic exploration to specifically test the developmental origins of early life adiposity. If successful, his proposal will lead to better understanding of common environmental exposures that act as obesogens, and could lead to regulatory action, as well as highlighting the need for significant reductions of these EDCs in our environment.
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