Prenatal Toxicant Exposure and Risk of Attention-Deficit Hyperactivity Disorder

描述（由申请人提供）：越来越多的证据表明，在子宫内接触有毒物质会对儿童神经发育产生长期影响。最近的许多研究已将母亲产前尿液中的邻苯二甲酸盐、BPA 和有机磷生物标志物与儿童的认知和行为异常联系起来。尽管这些研究为确立这些关系的合理性奠定了基础，但没有一项研究能够评估临床证实的行为表型，因为注意力缺陷多动障碍 （ADHD）相对罕见，之前的研究使用的出生队列相对较小。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）（一个由超过 100,000 名怀孕者组成的纵向出生队列）中进行一项嵌套病例队列研究，以调查接触邻苯二甲酸盐、BPA 和有机磷农药生物标志物与学龄前 ADHD 之间的关系。将选择所有临床确诊的 ADHD 病例（n = 265），并随机抽取队列样本（n = 530）作为对照组。通过使用嵌套病例队列设计，我们既可以有效地估计 ADHD 的相对风险，也可以持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 BPA 暴露与神经行为结果联系起来的一个可能途径是母体甲状腺激素破坏。因此，我们还将研究这些暴露生物标志物与母体甲状腺激素功能之间的关系。此外，还将检查关键代谢酶 PON1 中的功能基因变异对有机磷酸酯与 ADHD 关系的修改。最后，我们将结合复杂的贝叶斯模型，使用最先进的方法来处理多个相关风险。 公共卫生相关性：孕妇通过使用的产品和食用的食物被动地接触到无数的环境化学物质。其中一些暴露被发现可以穿过胎盘；然而，即使胎儿没有直接接触，后代神经发育障碍也可能是由怀孕期间母体甲状腺激素系统相对较小的破坏所介导的。有一篇新兴文献将某些有毒物质暴露与行为症状梯度联系起来。然而，到目前为止，只有微弱的证据将这些暴露与临床证实的行为表型联系起来。这项研究将通过阐明特定有毒物质暴露与明确的行为终点（ADHD）之间的关系来解决文献中的这一关键空白。

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.