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

 描述(由申请人提供)：这个K99/R00将为丽塔·斯特拉科夫斯基博士的独立研究生涯做准备。斯特拉科夫斯基博士接受过广泛的动物模型培训，以解决与产妇健康相关的问题，但她强烈希望将培训扩展到流行病学领域。已经组建了一支由流行病学、生物统计学、环境健康和生殖/内分泌毒理学专业知识组成的杰出导师团队。两位导师在整合动物和人类研究方面拥有丰富的经验。主要的培训目标是发展环境流行病学方面的专业知识，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。职业发展计划包括流行病学/生物统计学方面的严格课程工作以及环境流行病学方面的指导性研究。育龄妇女每天接触双酚A(BPA)和邻苯二甲酸盐。这些化学物质可以扰乱动物模型中雌激素的合成，但还没有人类研究评估双酚A或邻苯二甲酸盐与怀孕期间雌激素的关系。此外，还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，斯特拉科夫斯基博士将利用正在进行的怀孕队列来调查这些化学物质与母亲雌激素水平之间的关系，以及母亲体脂百分比或腰臀比是否可以改变这种关系(目标1)。双酚A和邻苯二甲酸酯将在怀孕期间收集的5个样本的混合尿中进行评估。将在妊娠雌激素的低、中、峰值浓度下采集3个尿样进行雌激素检测。假设怀孕期间尿BPA或邻苯二甲酸盐代谢物较高的女性在整个怀孕期间尿雌激素代谢物较低，母亲的体脂百分比和腰臀比和/或婴儿的性别将改变这种关系。影响母亲体内雌激素水平的因素可能会改变母亲脂肪组织储存的积累和释放，从而改变胎儿LC-PUFA的供应，这对神经发育至关重要。在啮齿动物身上的研究表明，双酚A和邻苯二甲酸盐可以改变胎盘LC-PUFA的含量(这与胎儿LC-PUFA的供应直接相关)，但尚不清楚这种情况是否也发生在人类身上。在独立阶段，斯特拉科夫斯基博士将研究母亲双酚A和邻苯二甲酸盐暴露与胎儿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。推测妊娠期间尿BPA或邻苯二甲酸盐代谢产物增多与n-6/n-3比值升高、脐血LC-PUFAs降低有关。进一步假设，双酚A或邻苯二甲酸盐与母体雌激素的关系将调节这种关系，并且这种关系将是 被婴儿的性别改变了。这些发现将为两种广泛存在的环境毒物对孕产妇和胎儿健康的影响提供新的信息。

 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.