Endocrine Disruptors: Maternal Estrogen, Metabolism and Fetal Fatty Acid Supply

 描述（由申请人提供）：这K99/R 00将准备丽塔Strakovsky博士的独立研究生涯。Strakovsky博士接受过使用动物模型解决与孕产妇健康相关问题的广泛培训，但她强烈希望将培训扩展到流行病学。组建了一支杰出的导师团队，他们具有流行病学、生物统计学、环境卫生和生殖/内分泌毒理学方面的专业知识。两位导师在整合动物和人类研究方面拥有丰富的经验。主要培训目标是发展环境流行病学的专业知识，最终目标是在制定流行病学研究问题时应用机械实验室动物研究的知识。职业发展计划包括严格的流行病学/生物统计学课程以及环境流行病学的指导研究。育龄妇女每天都接触双酚A（BPA）和邻苯二甲酸盐。这些化学物质可以破坏动物模型中的雌激素合成，但没有人类研究评估BPA或邻苯二甲酸酯与怀孕期间雌激素之间的关系。此外，没有研究评估母亲肥胖是否可以改变这种关系。在指导阶段，Strakovsky博士将利用正在进行的妊娠队列研究这些化学物质与母体雌激素水平之间的关系，以及母体体脂百分比或腰/臀比是否可以改变这种关系（目标1）。将在整个妊娠期间采集的5份样本的合并尿液中评估BPA和邻苯二甲酸盐。将在妊娠雌激素的低、中和峰值浓度下采集3份尿样，测量雌激素。据推测，在整个怀孕期间尿BPA或邻苯二甲酸酯代谢产物较高的女性在整个怀孕期间尿雌激素代谢产物较低，母体%体脂和腰/臀比和/或婴儿的性别将改变这种关系。影响母亲雌激素水平的因素可能会改变母体脂肪组织储存的增加和释放，从而改变胎儿LC-PUFA的供应，这对神经发育至关重要。啮齿类动物的研究表明，BPA和邻苯二甲酸酯可以改变胎盘LC-PUFA含量（与胎儿LC-PUFA供应直接相关），但尚不清楚这是否也发生在人类中。在独立阶段，Strakovsky博士将研究母体BPA和邻苯二甲酸酯暴露与胎儿LC-PUFA供应之间的关系（目标2）。出生时采集的脐带血将用于测量花生四烯酸、亚油酸、α-亚麻酸、二十二碳六烯酸和n-6/n-3脂肪酸比率。据推测，整个妊娠期间较高的尿BPA或邻苯二甲酸酯代谢物将与n-6/n-3比值增加和脐带血LC-PUFA减少相关。进一步假设BPA或邻苯二甲酸酯与母体雌激素的关联将介导这种关系，并且这种关系将是 被婴儿的性别所改变。这些发现将提供新的信息，关于两种广泛的环境毒物对孕产妇和胎儿健康的影响。

 DESCRIPTION (provided by applicant): This K99/R00 will prepare Dr. Rita Strakovsky for an independent research career. Dr. Strakovsky has extensive training using animal models to address questions related to maternal health, but has a strong desire to expand her training to epidemiology. An exceptional team of mentors has been assembled with expertise in epidemiology, biostatistics, environmental health, and reproductive/endocrine toxicology. Two mentors have extensive experience integrating animal and human research. The primary training goal is to develop expertise in environmental epidemiology, with the eventual goal of applying knowledge from mechanistic lab animal research when formulating epidemiologic research questions. The career development plan includes rigorous course work in epidemiology/biostatistics as well as mentored research in environmental epidemiology. Women of reproductive age are exposed to bisphenol A (BPA) and phthalates on a daily basis. These chemicals can disrupt estrogen synthesis in animal models, but no human studies have assessed the relationship between BPA or phthalates and estrogen during pregnancy. Furthermore, no studies have assessed whether maternal adiposity can modify this relationship. In the mentored phase, Dr. Strakovsky will leverage an ongoing pregnancy cohort to investigate the association between these chemicals and maternal estrogen levels, and whether maternal % body fat or waist/hip ratio can modify this relationship (Aim 1). BPA and phthalates will be assessed in pooled urine from 5 samples collected across pregnancy. Estrogens will be measured in 3 urine samples collected at the low, middle, and peak concentrations of gestational estrogen. It is hypothesized that women with higher urinary BPA or phthalate metabolites across pregnancy will have lower urinary estrogen metabolites throughout pregnancy, and maternal % body fat and waist/hip ratio and/or the infant's sex will modify this relationship. Factors that affect estrogen levels in the mother could alter the accretion and release of maternal adipose tissue stores, and thus fetal LC-PUFA supply, which is critical for neurodevelopment. Studies in rodents show that BPA and phthalates can alter placental LC-PUFA content (which is directly related to fetal LC-PUFA supply), but it is not known whether this also occurs in humans. In the independent phase, Dr. Strakovsky will investigate the relationship between maternal BPA and phthalate exposures and fetal LC-PUFA supply (Aim 2). Cord blood collected at birth will be used to measure arachidonic, linoleic, α-linolenic, docosahexaenoic, and the n-6/n-3 fatty acid ratio. It is hypothesized that higher urinary BPA or phthalate metabolites across pregnancy will be associated with increased n-6/n-3 ratio, and decreased cord blood LC-PUFAs. It is further hypothesized that the association of BPA or phthalates with maternal estrogen will mediate this relationship, and that the relationship will be modified by the infant's sex. These findings will provide novel information regarding the impact of two widespread environmental toxicants on maternal and fetal health.