Endocrine disruptors, epigenetic programming and neonatal outcomes

描述(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，现在出现在更年轻的年龄，这表明肥胖的风险因素在生命早期起作用。虽然肥胖最终是由卡路里摄入和消耗之间的失衡造成的，但新出现的证据表明，内分泌干扰物(EDCs)可能在生命过程的关键时期改变有机体对环境侮辱的反应，导致肥胖、炎症、Met，并最终导致T2D。这项建议的目的是研究两类内分泌细胞的作用：1)邻苯二甲酸盐；2)多氟烷基化合物(PFC)，以检验胎儿在宫内接触内分泌细胞与后代肥胖相关结局发展相关的最重要的假设。使用预期出生队列健康启动研究(R01DK076648)的独特基础设施，我们建议增加从怀孕期间收集的储存母亲样本中暴露于EDCs的措施。我们将把这些暴露于新生儿肥胖、蛋氨酸转归和生长轨迹与已经收集的2岁儿童联系起来，并探索这些暴露于胎儿可能导致的脐带血DNA的表观遗传学改变。这将是第一项使用出生时和4-6个月的空气置换体积描记仪评估EDC暴露于婴儿脂肪和瘦体重(与简单的出生体重相反)的研究。这项建议对PAR12-185非常有响应，通过将EDC测量添加到现有的研究中，以探索脆弱的发育窗口，研究肥胖、T2D和METS的中间前体，并探索暴露EDC的后代的血脂和炎症情况，以及婴儿的详细表观遗传结果。详细的饮食数据还允许探索母亲和早期婴儿饮食，包括以大豆为基础的配方，对感兴趣的关联的潜在修改。要测试的具体目标是：目标1。确定当代多民族孕妇队列中宫内暴露于特定内分泌细胞的水平和相关性。目的2.探讨宫内EDCs暴露与婴儿肥胖和胰岛素抵抗相关代谢标志物的关系。目的3.探讨宫内暴露内皮细胞引起的表观遗传学改变，以及特定的母体营养和食物作为可能的效应调节剂的作用。我们探讨了一个对公共健康有重大影响的话题，即常见的内分泌细胞是否影响肥胖和代谢综合征的发育起源，这两种疾病都是后来糖尿病和心血管疾病的先兆。它包括几个创新特征：关注敏感的发育期，研究婴儿脂肪质量和模式而不是出生体重，使用预期出生队列，以及专门测试早期肥胖的发育起源的机械性探索。如果成功，他的提议将使人们更好地了解作为肥胖来源的常见环境暴露，并可能导致监管行动，以及强调在我们的环境中大幅减少这些EDC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.