Prenatal Toxicant Exposure and Risk of Attention-Deficit Hyperactivity Disorder

描述(申请人提供)：有越来越多的证据表明，在子宫内暴露于毒物会对儿童神经发育产生长期影响。最近的一些研究将孕妇产前尿液中的邻苯二甲酸盐、双酚A和有机磷生物标记物与儿童的认知和行为异常联系起来。尽管这些研究为建立这些关系的合理性奠定了基础，但自从注意缺陷多动障碍以来，还没有一项研究被用来评估临床证实的行为表型。 (ADHD)相对罕见，之前的研究利用了相对较小的出生队列。至 为了解决文献中的这一空白，我们建议在挪威母婴队列(MOBA)内进行嵌套病例队列研究，该队列是一个由100,000多名孕妇组成的纵向出生队列，以调查邻苯二甲酸酯、双酚A和有机磷农药生物标志物暴露与学龄前儿童ADHD的关系。将选择所有临床确诊的ADHD病例(n=265)，并从队列中随机抽取样本(n=530)作为对照组。通过嵌套病例队列设计，我们既可以有效地估计ADHD的相对风险，又可以连续检查暴露与症状严重程度之间的关系。将邻苯二甲酸盐和双酚A暴露于神经行为结果之间的一个看似合理的途径是母体甲状腺激素紊乱。因此，我们还将调查暴露的这些生物标志物与母亲甲状腺激素功能之间的关系。此外，还将研究关键代谢酶PON1中的功能基因变体对有机磷-ADHD关系的修改。最后，我们将结合复杂的贝叶斯模型，使用最先进的方法处理多个相关的暴露。 与公共健康相关：孕妇被动地接触到她们使用的产品和食物中的无数环境化学物质。其中一些暴露已被发现通过胎盘；然而，即使没有直接的胎儿暴露，怀孕期间母亲甲状腺激素系统相对较小的破坏也可能导致后代神经发育障碍。有一个新兴的文献将某些毒物暴露与行为症状的梯度联系起来；然而，到目前为止，只有微弱的证据将这些暴露与临床确认的行为表型联系起来。这项研究将通过阐明特定毒物暴露与明确定义的行为终点ADHD之间的关系来解决文献中的这一关键差距。

DESCRIPTION (provided by applicant): There is accumulating evidence that exposure to toxicants in utero can have long-lasting consequences on child neurodevelopment. A number of recent studies have linked maternal prenatal urinary phthalate, BPA and organophosphate biomarkers to cognitive and behavioral abnormalities in children. Although these studies have been foundational in establishing the plausibility of these relations, none have been powered to evaluate clinically-confirmed behavioral phenotypes, since attention-deficit hyperactivity disorder (ADHD) is relatively rare and the previous studies have utilized relatively small birth cohorts. To address this gap in the literature, we propose a nested case-cohort study within the Norwegian Mother and Child Cohort (MoBa), a longitudinal birth cohort consisting of over 100,000 pregnancies, in order to investigate the relation between exposure to phthalate, BPA and organophosphate pesticide biomarkers and preschool ADHD. All clinically-confirmed cases of ADHD will be selected (n = 265), and a random sample of the cohort (n = 530) will be assembled to serve as the comparison group. By using the nested case-cohort design, we can both validly estimate the relative risk of ADHD and also examine the relationship between exposure and symptom severity continuously. A plausible pathway linking phthalate and BPA exposure to neurobehavioral outcomes is maternal thyroid hormone disruption. Thus we will also be investigating the relations between these biomarkers of exposure and maternal thyroid hormone function. Additionally, modification of the organophosphate-ADHD relation by functional gene variants in a key metabolism enzyme, PON1, will be examined. Finally, we will be incorporating sophisticated Bayesian models to handle multiple correlated exposures using state-of-the-art methodology. PUBLIC HEALTH RELEVANCE: Pregnant women are passively exposed to countless environmental chemicals from the products they use and the food they eat. Some of these exposures have been found to cross the placenta; however, even without direct fetal exposure, offspring neurodevelopmental impairment could potentially be mediated by relatively minor disruptions in the maternal thyroid hormone system during pregnancy. There is an emerging literature linking certain toxicant exposures to gradients in behavioral symptoms; however, as of yet there is only weak evidence linking these exposures to a clinically-confirmed behavioral phenotype. This study will address this critical gap in the literature by elucidating the relationsip between select toxicant exposures and a well-defined behavioral endpoint, ADHD.