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响应PA-12-185，提议研究产前和儿童时期邻苯二甲酸盐和双酚A （BPA）暴露与胎儿生长、体重、胰岛素抵抗、脂肪量和儿童血压的关系。邻苯二甲酸二-2-乙基己基酯（DEHP）是一种高分子量的邻苯二甲酸酯，常见于加工食品中，邻苯二甲酸单-（2-乙基己基）酯增加了DEHP代谢物3过氧化物酶体增殖体-的表达，激活了在脂质和碳水化合物代谢中起关键作用的受体，为DEHP代谢物在儿童肥胖和胰岛素抵抗中的作用提供了生物学上的可能性。BPA用于制造用于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破坏发育内分泌过程，产生导致肥胖的慢性热量失衡。我们拟对1431对“R世代”（Generation R）的母亲和婴儿进行孕期三个时间点和儿童期两个时间点的样本分析。“R世代”是一项前瞻性、纵向多民族出生队列研究，在2002-2006年期间对9778名出生日期为出生日期的孕妇进行了纵向跟踪调查。研究人群中的双酚a（调整中值1.6 μ g/g Cr）和DEHP总代谢物（调整中值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，也是第一个在全国代表性样本中确定环境化学物质与儿童肥胖之间关系的研究的第一作者。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，在研究心血管疾病的早期决定因素方面有着良好的记录，以及a . Burdorf，他为研究人群制定了标准化的胎儿生长曲线。该建议的一个主要优势是对孕期三个时间点的尿液样本进行分析，这将允许检查邻苯二甲酸代谢物和BPA与体重、胰岛素抵抗和心血管风险的特定时期的关联。分析将由纽约州卫生部Wadsworth实验室的K. Kannan进行，他在精确测量尿液中的邻苯二甲酸酯和双酚a生物标志物方面有着丰富的经验。提出的工作努力挑战现有的临床实践范式，即肥胖预防应该只关注改善能量平衡，同时也认识到环境中可能独立赋予风险的化学因素的作用。

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.