Phthalates, BPA, Trajectories of In and Ex Utero Growth and Cardiometabolic Risks

描述（由申请人提供）：纽约大学医学院、伊拉斯谟大学医学中心和纽约州卫生部对PA-12-185做出回应，建议研究产前和儿童期邻苯二甲酸酯和双酚A（BPA）暴露与胎儿生长、体重、胰岛素抵抗、脂肪量和儿童期血压的关系。邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种常见于加工食品中的高分子量邻苯二甲酸酯，邻苯二甲酸单（2-乙基己基）酯增加了三种过氧化物酶体增殖物--DEHP代谢产物--激活受体的表达，这些受体在脂质和碳水化合物代谢中起关键作用，为儿童肥胖和胰岛素抵抗中的DEHP代谢产物提供了生物相容性。双酚A，这是用来制造聚碳酸酯树脂用于涂层食品和饮料容器，已被发现产生肥胖和胰岛素抵抗的分子标志。过去对这些化学品暴露和肥胖的研究是针对年龄较大的儿童和青少年的横断面研究，而DEHP代谢物和BPA更有可能破坏生命早期的发育内分泌过程，并产生导致肥胖的慢性热量失衡。我们建议分析来自R世代1431对母婴的三个时间点和两个儿童时间点的样本，这是一项前瞻性、纵向多种族出生队列研究，纵向跟踪了2002-2006年期间出生日期的9,778例妊娠。研究人群中的BPA（调整后的中位数为1.6 μ g/g Cr）和总DEHP代谢物（调整后的中位数为88.4 μ g/g Cr）与NHANES样本一致，增加了研究结果对美国环境的适用性。PI，L。Trasande是全国知名的儿童环境健康专家，也是第一项研究的第一作者，该研究在全国代表性样本中确定了环境化学物质与儿童肥胖的关联。拟议的研究还受益于R世代的大力支持，包括主任（V. Jaddoe），一位经验丰富的儿科和围产期流行病学家，在研究心血管疾病和A的早期决定因素方面有着良好的记录。Burdorf博士为研究人群制定了标准化的胎儿生长曲线。该提案的一个主要优点是分析怀孕三个时间点的尿液样本，这将允许检查邻苯二甲酸酯代谢物和BPA与体重、胰岛素抵抗和心血管风险的特定时期相关性。分析将由K进行。他在精确测量尿液中的邻苯二甲酸酯和BPA生物标志物方面有着丰富的经验。拟议的工作努力挑战现有的临床实践范式，即肥胖预防应仅关注改善能量平衡，以认识到环境中化学因素的作用，这些因素可能独立地带来风险。

DESCRIPTION (provided by applicant): NYU School of Medicine, Erasmus University Medical Center and New York State Department of Health respond to PA-12-185, proposing to study prenatal and childhood phthalate and bisphenol A (BPA) exposures in relationship to fetal growth, body mass, insulin resistance, fat mass and blood pressure in childhood. Di-2- ethylhexylphthalate (DEHP) is a high-molecular weight phthalate ester commonly found in processed foods, and mono-(2-ethylhexyl) phthalate increases expression of three peroxisome proliferator- , a DEHP metabolite, activated receptors which play key roles in lipid and carbohydrate metabolism, providing biological plausibility for DEHP metabolites in childhood obesity and insulin resistance. BPA, which is used to manufacture polycarbonate resin used to coat food and beverage containers, has been found to produce molecular hallmarks of obesity, and insulin resistance. Past studies of these chemical exposures and obesity have been cross-sectional and of older children and adolescents, whereas DEHP metabolites and BPA are more likely to disrupt developmental endocrine processes earlier in life and produce the chronic caloric imbalance that leads to obesity. We propose to analyze samples from three timepoints in pregnancy and two in childhood from 1431 mother-infant pairs in Generation R, a prospective, longitudinal multi-ethnic birth cohort study which has longitudinally followed 9,778 pregnancies with birth dates between 2002-2006. BPA (adjusted median 1.6 �g/g Cr) and total DEHP metabolites (adjusted median 88.4 �g/g Cr) in the study population are consistent with NHANES samples, increasing applicability of study findings to the US context. The PI, L. Trasande, is a nationally renowned expert in children's environmental health and first author on the first study to identify an association of an environmental chemical with childhood obesity in a nationally representative sample. The proposed study also benefits from strong support from Generation R, including the Director (V. Jaddoe), an experienced pediatric and perinatal epidemiologist with a strong record in studying early determinants of cardiovascular disease and A. Burdorf, who has developed standardized fetal growth curves for the study population. A major strength of this proposal is analysis of urine samples from three timepoints in pregnancy, which will permit examination of period-specific associations of phthalate metabolites and BPA with body mass, insulin resistance and cardiovascular risks. Analyses will be performed by K. Kannan at Wadsworth Laboratories of the New York State Department of Health, who has deep experience with precise measurement of phthalate and BPA biomarkers in urine. The proposed work endeavors to challenge existing clinical practice paradigms that obesity prevention should focus only on improved energy balance to an approach that also recognizes the role of chemical factors in the environment that may impart risk independently.