Endocrine disruptors, epigenetic programming and neonatal outcomes

描述（由申请人提供）：肥胖、代谢综合征（METS）和2型糖尿病（T2D）在美国正在增加，并且现在出现在更年轻的年龄，这表明肥胖的危险因素在生命早期就开始起作用。虽然肥胖的最终原因是热量摄入和消耗之间的不平衡，但新出现的证据表明，内分泌干扰化学物质（EDCs）可能在生命过程的关键时期改变生物体对环境损害的反应，从而导致肥胖、炎症、METS和最终的T2D的发展。本提案的目的是研究两类EDCs的作用：1)邻苯二甲酸酯；2)多氟烷基化合物（pfc）)，以验证胎儿在子宫内接触EDCs与后代肥胖相关结局的发展相关的总体假设。利用前瞻性出生队列健康开始研究（R01DK076648）的独特基础设施，我们建议增加妊娠期间收集的储存的母体样本中EDCs暴露的测量。我们将把这些暴露与新生儿肥胖、METS结果和2岁前的生长轨迹联系起来，并探索这些暴露可能导致胎儿脐带血DNA的表观遗传基因组修饰。这将是第一个在婴儿出生时和4- 6个月时使用空气置换容积描图来评估EDC暴露对婴儿脂肪和瘦肉质量（与简单的出生体重相比）的影响的研究。该提案非常响应PAR12-185，将EDC测量添加到现有研究中，以探索发育的脆弱窗口，研究肥胖，T2D和METS的中间前体，并探索EDC暴露的后代脂质和炎症谱，以及婴儿的详细表观遗传结果。详细的饮食数据也允许探索潜在的变化，通过母亲和早期婴儿的饮食，包括大豆为基础的配方。需要测试的具体目标是：目标1。确定当代多民族孕妇在子宫内暴露于特定EDCs的水平及其相关性。目标2。探讨子宫内暴露于EDCs与婴儿肥胖和胰岛素抵抗相关代谢标志物的关系。目标3。探讨子宫内暴露于EDCs引起的表观遗传变化，以及特定母体营养素和食物作为可能的影响调节剂的作用。我们探讨了一个具有重大公共卫生影响的主题，即常见的EDCs是否影响肥胖和代谢综合征的发育起源，两者都是后来糖尿病和心血管疾病的前兆。它包括几个创新特点：关注敏感发育时期，研究婴儿脂肪质量和模式而不是出生体重，使用前瞻性出生队列，以及专门测试早期生活肥胖的发育起源的机制探索。如果成功，他的建议将有助于更好地了解作为致肥源的常见环境暴露，并可能导致监管行动，同时强调我们环境中显著减少这些EDCs的必要性。

DESCRIPTION (provided by applicant): 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.