Pre- and Postnatal PBDE Exposure, Thyroid Hormones, and Neurodevelopment

描述(申请人提供)：实验证据表明，发育过程中暴露于多溴二苯醚(PBDEs)会扰乱甲状腺激素功能，并具有神经毒性，导致学习和行为障碍。少数流行病学研究，每一项都有显著的局限性，类似地建议但没有证实这些关系。这些关系尚未在人类研究中得到测试，该研究可以1)检查多溴二苯醚暴露对整个大脑发育窗口(从妊娠到青春期)认知和行为结果的纵向影响；以及2)确定多溴二苯醚暴露对甲状腺激素的影响作为多溴二苯醚诱导的整个儿童神经毒性的独立影响或中介。在此应用程序中要检验的中心假设是 出生前和出生后接触多溴二苯醚都会改变儿童时期循环中的甲状腺激素，从而影响认知和行为发育指数。我们将在哥伦比亚儿童环境健康中心的纵向出生队列研究的现有基础设施内对这一假设进行评估。这项研究对居住在纽约市市中心社区的350名儿童从出生到12岁的化学和社会环境进行了表征，并对儿童整个童年的认知、行为和甲状腺激素状况进行了详细的纵向评估。通过测量三个发育时间点(出生、2-3岁和5-7岁)采集的外周血液中的多溴二苯醚，我们将追求以下特定目标：1)确定多溴二苯醚暴露是否会影响儿童的认知发育(包括学习、工作记忆和空间记忆)；2)评估多溴二苯醚暴露是否会影响儿童行为(包括多动、注意力和社交问题)；以及3)评估多溴二苯醚暴露是否影响甲状腺功能，以及甲状腺激素干扰是否调节多溴二苯醚暴露与儿童认知发育和行为之间的关联。这项拟议的研究具有创新性，因为它填补了现有流行病学文献中的几个重要空白 阻碍了我们确定儿童时期多溴二苯醚暴露对神经发育的纵向影响的能力。通过在一项大型的美国纵向队列研究中评估出生前和出生后暴露于多溴二苯醚的神经毒性影响，这项研究将提供多溴二苯醚对人类造成的神经毒性的“指纹”，提供牵连或反驳甲状腺激素干扰作用的证据。虽然美国计划从2013年起逐步停止生产所有含多溴二苯醚的产品，但我们预计，由于其持久性，多溴二苯醚的暴露将在此后通过住宅和膳食水库持续多年。了解多溴二苯醚指纹将使我们能够很容易地将其影响与其他潜在的神经毒性环境暴露区分开来。这些信息将为关于如何最好地管制这些和其他无处不在的环境污染物的紧急和正在进行的政策辩论提供信息。

DESCRIPTION (provided by applicant): Experimental evidence indicates that developmental exposure to polybrominated diphenyl ethers (PBDEs) disrupts thyroid hormone function and is neurotoxic, leading to deficits in learning and behavior. A small number of epidemiologic studies, each with significant limitations, similarly suggest but do not confirm these associations These relationships have yet to be tested in a human study that can 1) examine the longitudinal impact of PBDE exposure on cognitive and behavioral outcomes throughout the window of brain development (from gestation through adolescence); and 2) determine the impact of PBDE exposure on thyroid hormones as an independent effect or mediator of PBDE-induced neurotoxicity throughout childhood. The central hypothesis to be tested in this application is that both prenatal and postnatal exposure to PBDEs alters circulating thyroid hormones during childhood, thereby influencing cognitive and behavioral developmental indices. We will evaluate this hypothesis within the existing infrastructure of the Columbia Center for Children's Environmental Health's longitudinal birth cohort study. This study has characterized the chemical and social environments of 350 children, residing in inner-city communities of New York City, from birth through age 12 and has conducted detailed assessments of child cognition, behavior, and thyroid hormone status longitudinally throughout childhood. By measuring PBDEs in peripheral blood collected at three developmental time points (birth, ages 2-3, and 5-7 years), we will pursue the following specific aims in children at ages 3-5, 7- 9, and 10-11: 1) determine whether PBDE exposure affects child cognitive development (including learning, working memory and spatial memory); 2) evaluate whether PBDE exposure affects child behavior (including hyperactivity, attention and social problems); and 3) assess whether PBDE exposure affects thyroid function and if thyroid hormone disruption mediates associations between PBDE exposure and child cognitive development and behavior. The proposed research is innovative because it fills several important gaps in the existing epidemiologic literature that have thus far impeded our ability to characterize the longitudinal impact of PBDE exposure occurring throughout childhood on neurodevelopment over time. By evaluating the neurotoxic effects of both pre- and postnatal PBDE exposure in a large, U.S.-based longitudinal cohort study, this study will provide a "fingerprint" of PBDE-induced neurotoxicity in humans, supplying evidence that will implicate or refute the role of thyroid hormone disruption. While the production of all PBDE-containing products is slated to be phased out in the U.S. as of 2013, we anticipate that due to its persistence, PBDE exposure will continue for many years thereafter through residential and dietary reservoirs. Understanding the PBDE fingerprint will allow us to readily distinguish its effects from other potentially neurotoxic environmental exposures. This information will inform the urgent and ongoing policy debate about how best to regulate these and other ubiquitous environmental pollutants.