Endocrine disruptors, epigenetic programming and neonatal outcomes

内分泌干​​扰物、表观遗传编程和新生儿结局

• 批准号: 8694371
• 负责人: JOHN L. ADGATE
• 金额: $ 58.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694371
• 关键词: 2 year old; Age; Age-Months; Age-Years; Air; Animals; Birth; Birth Weight; Birth length; Blood; Body Composition; Body mass index; Breast Feeding; Cardiovascular Diseases; Chemical Exposure; Chemicals; Choline; Complex; DNA; Data; Development; Diabetes Mellitus; Diet; Dietary Practices; Endocrine Disruptors; Energy Intake; Environment; Environmental Exposure; Epidemic; Epigenetic Process; Ethnic Origin; Expenditure; Exposure to; Fatty acid glycerol esters; Fetus; Folate; Food; Genes; Genome; Genomics; Gestational Age; Goals; Growth; Human; Individual; Infant; Inflammation; Inflammatory; Insulin Resistance; Intake; Lead; Life; Lipids; Literature; Maternal Age; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic Marker; Metabolic syndrome; Methylation; Modification; Neonatal; Newborn Infant; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Organism; Outcome; Pattern; Perinatal Exposure; Plethysmography; Pregnancy; Pregnant Women; Preventive; Public Health; Race; Research; Research Infrastructure; Riboflavin; Risk Factors; Role; Sampling; Smoking; Socioeconomic Status; Structure; Testing; Tissues; Umbilical Cord Blood; Vitamin B 12; Weight; base; bisphenol A; cohort; critical period; environmental chemical; fetal; follow-up; in utero; innovation; interest; neonate; obesogen; offspring; phthalates; pregnant; programs; prospective; public health relevance; response; sex; soy

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.

描述（由申请人提供）：肥胖、代谢综合征（METS）和2型糖尿病（T2 D）在美国正在增加，现在出现在年轻人中，表明肥胖的风险因素在生命早期起作用。虽然肥胖最终是由热量摄入和支出之间的不平衡引起的，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侮辱的反应，从而导致肥胖、炎症、METS的发展，并最终导致T2 D。该提案的目标是研究两类内分泌干扰物的作用：1）邻苯二甲酸酯;和2）多氟烷基化合物（PFC）），以检验胎儿在子宫内暴露于内分泌干扰物与后代肥胖相关结果的发展相关的总体假设。利用前瞻性出生队列健康起步研究（R 01 DK 076648）的独特基础设施，我们建议增加妊娠期间收集的储存母体样本中的内分泌干扰物暴露量。我们将把这些暴露与新生儿肥胖和METS结果以及已经收集的2岁的生长轨迹联系起来，并探索脐带血DNA中的表观遗传基因组修饰，这可能是由于这些暴露于胎儿。这将是第一项使用出生时和4- 6个月时的空气置换体积描记法评价EDC暴露对婴儿脂肪和瘦体重（与简单的出生体重相比）的影响的研究。该提案通过将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、T2 D和METS的中间前体，并探索EDC暴露的后代脂质和炎症特征以及婴儿中详细的表观遗传结局，对PAR 12 -185做出了非常积极的响应。详细的饮食数据还允许探索母亲和早期婴儿饮食（包括大豆配方奶粉）的潜在相关性修改。待测试的具体目标是：目标1。确定一个当代多种族孕妇队列中子宫内暴露于特定内分泌干扰物的水平和相关性。目标2.探讨宫内内分泌干扰物暴露与婴儿肥胖和胰岛素抵抗相关代谢标志物的关系。目标3。探讨子宫内暴露于内分泌干扰物诱导的表观遗传变化，以及特定母体营养素和食物作为可能的效应调节剂的作用。我们探讨了一个重要的公共卫生影响的主题，即常见的内分泌干扰物是否影响肥胖和代谢综合征的发育起源，这两种疾病都是糖尿病和心血管疾病的前兆。它包括几个创新特征：关注敏感发育期，研究婴儿脂肪量和模式而不是出生体重，使用前瞻性出生队列，以及专门测试早期肥胖症发育起源的机制探索。如果成功，他的建议将导致更好地了解作为致肥胖剂的常见环境暴露，并可能导致监管行动，以及强调需要显着减少我们环境中的这些内分泌干扰物。