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

描述(由申请人提供) 这项拟议研究的首要目标是阐明产前暴露于复杂的内分泌干扰物(EDCs)混合物与儿童不利的神经发育后遗症的机制。已知有几类内分泌细胞会干扰甲状腺功能。妊娠期间充足的甲状腺功能是胎儿大脑发育成功的已知决定因素，而在实验动物和人类中，母亲甲状腺激素不足与不利的发育结果有关。尽管有几项研究评估了与接触单一类别的内分泌细胞相关的风险，但这些研究对人类暴露组内复杂混合物的评估有限，也没有探索导致不良后果的大脑发育的结构性缺陷。这项拟议的研究试图通过开发对内分泌细胞的身体负担的综合指数，并通过应用脑成像方法来阐明暴露后大脑结构和功能的变化，来解决这些局限性。具体地说，研究人员建议评估产前暴露于复杂的EDCs混合物是否与a)母亲甲状腺功能受损，b)5岁儿童大脑结构和功能的变化，以及c)5岁儿童神经行为和心理功能不良有关。 培训和研究将在正在进行的大都会化学品与妊娠健康研究(家长研究)(R21ES016610-01，首席研究员-瓦普纳)范围内进行。这是一项对316名怀孕期间登记的母亲进行的前瞻性研究。家长研究提供了当前提议的关键信息，包括产前暴露于多溴联苯醚(PBDEs)和高氯酸盐的水平，对怀孕第二个月期间母亲甲状腺功能的评估，以及同意联系母亲对其子女进行预期随访。此外，储存的生物样本可用于额外的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。结合多溴二苯醚和高氯酸盐的数据，她将开发和应用复杂的统计方法来检查复杂的EDCs混合物对产妇甲状腺功能的影响。同样在K99阶段，霍顿博士将在纽约州精神病学研究所接受在流行病学研究中使用大脑成像的强化培训。在该奖项的R00阶段向独立过渡期间，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(解剖和功能磁共振成像)和神经发育测试。最后，霍顿博士将利用这些数据，通过冥想模型研究产前EDC暴露、母亲甲状腺功能、儿童大脑结构和功能以及发育结果之间的复杂关系。 这份K99/R00提案是候选人之前在儿童环境健康方面工作的直接延伸，也是作为一名专注于环境暴露的终身流行病学家的职业生涯的合乎逻辑的进步。在该奖项结束时，候选人将在化学混合物分析和脑成像等新兴领域获得专业知识。这些技能的获得将几个学科的能力结合在一起，使候选人超越了其他研究人员。 公共卫生相关性：这项建议旨在了解产前暴露于甲状腺干扰化合物、母亲甲状腺功能和子代神经功能之间的关系。通过这项研究工作产生的信息对于填补研究空白和为人类风险评估提供信息至关重要。

DESCRIPTION (provided by applicant) 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, the investigators 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, principal investigators-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 second 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. Public Health Relevance: This proposal aims to understand the relationship between prenatal exposure to thyroid disrupting compounds, maternal thyroid function, and neurologic function in offspring. Information generated through this research effort is essential to fill research gaps and inform human risk assessment.