Prenatal exposure to a mixture of EDCs, maternal thyroid function and child neuro

拟议研究的首要目标是阐明与产前有关的机制。 暴露于内分泌干扰物(EDCs)的复杂混合物中 儿童神经发育后遗症。已知有几类EDC会干扰 甲状腺功能。孕期甲状腺功能正常是成功的已知决定因素 胎儿大脑发育和母亲甲状腺激素不足与不良反应相关 实验动物和人类的发育结果。尽管有几项研究已经 评估与暴露于单一类别的EDC有关的风险，这些研究仅限于 他们对人体暴露组内的复杂混合物进行了评估，尚未探索 大脑发育中的结构性缺陷会导致不良后果。拟议的研究试图 为了解决这些限制，开发了一个对内分泌中心的身体负担的综合指数，并通过 应用脑成像方法阐明脑结构和功能的变化 曝光。具体地说，我们建议评估产前接触一种复杂的 胚胎发育障碍与a)母亲甲状腺功能紊乱，b)大脑结构改变和 5岁儿童的功能和c)不良的神经行为和心理功能 5岁的儿童。 培训和研究将在正在进行的大都会化学品研究和 妊娠健康(家长研究)(R21ES016610-01 PI.瓦普纳)。这是一项前瞻性研究。 在怀孕期间登记的316名母亲中。家长研究提供了当前 建议包括产前暴露于多溴联苯醚(PBDEs)和 高氯酸盐，怀孕中期孕妇甲状腺功能的评估，以及 同意与母亲联系，以便对其后代进行预期的后续跟踪。此外，储存的生物 样品可用于额外的EDC分析。在最初的K99阶段，霍顿博士 建议测量储存的母体尿样中的双酚A和邻苯二甲酸盐。结合使用 多溴二苯醚和高氯酸盐数据，她将开发和应用复杂的统计方法 研究一种复杂的EDCs混合物对孕妇甲状腺功能的影响。也是在 K99阶段，霍顿博士将接受在流行病学中使用脑成像的强化培训 在纽约州精神病研究所学习。在R00向独立过渡期间 在颁奖阶段，她建议将这些培训应用于家长研究的背景下。 具体地说，她将跟踪75名儿童，根据暴露状态选择，进行大脑成像(解剖学 和功能磁共振成像)和神经发育测试。最后，霍顿博士 将应用这些数据来研究产前EDC暴露之间的复杂关系， 母体甲状腺功能、儿童脑结构和功能及发育结局 一个冥想的模特。 这份K99/R00提案是候选人先前在儿童领域工作的直接延伸 环境健康和作为一名专注于终身流行病学家的职业生涯的合理进展 在环境暴露方面。在这个奖项结束时，候选人将获得 在化学混合物分析和脑成像等新兴领域的专业知识。收购 这些技能通过将几个领域的能力结合在一起，使应聘者超越了其他研究人员 纪律。

The overarching goal of the proposed research is to elucidate mechanisms relating prenatal exposure to complex mixtures of endocrine disrupting compounds (EDCs) to adverse neurodevelopment sequelae in children. Several classes of EDCs are known to interfere with thyroid function. Adequate thyroid function during pregnancy is a known determinant of successful fetal brain development and maternal thyroid hormone insufficiency is associated with adverse developmental outcomes in experimental animals and humans. Although several studies have evaluated risks associated with exposure to single classes of EDCs, these studies are limited in their evaluation of the complex mixtures within the human exposome and have not explored structural deficits in brain development leading to adverse outcomes. The proposed study attempts to address these limitations by developing a composite index of body burden to EDCs and by applying brain imaging methods to elucidate changes in brain structure and function following exposure. Specifically, we propose to evaluate whether prenatal exposure to a complex mixture of EDCs is associated with a) disrupted maternal thyroid function, b) changes in brain structure and function in children at 5 years of age and c) adverse neurobehavioral and psychological function in children at 5 years of age. The training and research will take place within the ongoing Metropolitan Study of Chemicals and Pregnancy Health (The Parent Study) (R21ES016610-01 PI. Wapner). This is a prospective study of 316 mothers enrolled during pregnancy. The parent study provides information key to the current proposal including prenatal exposure levels to polybrominated diphenyl ethers (PBDEs) and perchlorate, an assessment of maternal thyroid function during the 2nd trimester of pregnancy, and consent to contact mothers for prospective follow-up of their offspring. Additionally, stored biological samples are available for additional EDC analysis. During the initial K99 phase, Dr. Horton proposes to measure BPA and phthalates in stored maternal urine samples. In combination with the PBDE and perchlorate data, she will develop and apply sophisticated statistical methodologies to examine the impact of a complex mixture of EDCs on maternal thyroid function. Also during the K99 phase, Dr. Horton will receive intensive training in the use of brain imaging in epidemiological studies at the New York State Psychiatric Institute. During the transition to independence in the R00 phase of the award, she proposes to apply these trainings within the context of the parent study. Specifically she will follow 75 children, selected on exposure status, with brain imaging (anatomical and functional magnetic resonance imaging) and neurodevelopmental testing. Finally, Dr. Horton will apply these data to examine the complex relationships between prenatal EDC exposure, maternal thyroid function, children's brain structure and function and developmental outcomes using a meditational model. This K99/R00 proposal is a direct extension of the candidate's previous work in children's environmental health and a logical progression into a career as a life-course epidemiologist focused on environmental exposures. At the conclusion of this award, the candidate will have gained expertise in the emerging fields of chemical mixture analysis and brain imaging. The acquisition of these skills sets the candidate above other researchers by combining competence across several disciplines.