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接触邻苯二甲酸盐和双酚A(BPA)与胎儿生长、体重、胰岛素抵抗、脂肪质量和童年血压的关系。邻苯二甲酸二乙基己酯(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)酯可增加DEHP代谢产物三种过氧化物酶体增殖物的表达，激活的受体在脂肪和碳水化合物的代谢中发挥关键作用，为DEHP代谢产物在儿童肥胖和胰岛素抵抗中提供了生物学上的可能性。BPA用于制造食品和饮料容器涂层的聚碳酸酯树脂，已被发现会产生肥胖和胰岛素抵抗的分子特征。过去对这些化学物质暴露和肥胖的研究是横断面的，研究对象是年龄较大的儿童和青少年，而DEHP代谢物和BPA更有可能在生命早期扰乱发育的内分泌过程，并产生导致肥胖的慢性热量失衡。我们建议分析R世代1431对母婴中三个孕期和两个儿童期的样本，这是一项前瞻性的、纵向的多种族出生队列研究，纵向跟踪了2002-2006年间出生日期为9,778例的孕妇。研究人群中的双酚A(调整中位数1.6�g/g铬)和总DEHP代谢物(调整中值88.4�g/g铬)与NHANES样本一致，增加了研究结果对美国背景的适用性。这位名叫L.Trasande的人是全国知名的儿童环境健康专家，也是第一个在具有全国代表性的样本中确定环境化学物质与儿童肥胖症之间关系的研究的作者。这项拟议的研究还得益于R世代的大力支持，其中包括儿科和围产期流行病学主任(V.Jaddoe)，他在研究心血管疾病的早期决定因素方面有着丰富的记录，以及A.Burdorf，他为研究人群开发了标准化的胎儿生长曲线。这项建议的一个主要优势是对怀孕三个时间点的尿样进行分析，这将允许检查特定时期的邻苯二甲酸酯代谢物和双酚A与体重、胰岛素抵抗和心血管风险的关系。分析将由纽约州卫生部沃兹沃斯实验室的K.Kannan进行，他在精确测量尿液中的邻苯二甲酸盐和BPA生物标志物方面拥有丰富的经验。这项拟议的工作试图挑战现有的临床实践范式，即肥胖预防只应侧重于改善能量平衡，以实现一种也认识到环境中可能独立传递风险的化学因素的作用的方法。

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.