Brain Influences of Phthalates and Bisphenols in Adolescents

项目摘要 这项提案将利用荷兰出生队列的前所未有的数据来研究邻苯二甲酸酯的影响 在多个潜在易感期暴露于双酚对执行功能和行为的影响， 青少年。大量文献研究了产前暴露于邻苯二甲酸酯的负面影响 和双酚对认知和行为的发展规划。然而很少有研究 儿童早期之后的接触。此外，早期研究的严谨性是有限的，因为缺乏对 机制和未能采用生命过程方法。我们建议测量尿液中邻苯二甲酸盐的含量 和双酚在9-10岁和13-14岁的1000名参与者的R一代，最大的 一项在一般儿科人群中进行的神经影像学研究，产前入组，随访至青春期。 我们将评估16-18岁儿童的执行功能和行为，并测量性激素。 关于产前和5-6岁时化学品测量的现有数据， 母亲和儿童，9-10岁和13-14岁时的脑磁共振成像，以及随访的可行性 在青春期提供了一个特殊的机会，解析出神经毒性的影响，产前和产后 暴露和识别机制。大样本量将允许评估性别作为生物学 变量具体目标是：1）确定产前、儿童和青少年早期邻苯二甲酸酯的影响 和双酚暴露对青少年执行功能和行为的影响; 2）检查潜在的 邻苯二甲酸酯和双酚不良影响的潜在机制，包括甲状腺和性激素 破坏以及脑结构异常和白色物质完整性。我们假设化学物质 儿童和青少年时期的暴露与执行功能和行为受损有关。 问题，独立于产前暴露。甲状腺和性激素的紊乱被假设为 部分解释了这种关联。我们希望观察儿童和青少年早期暴露的影响， 顶叶、注意力网络、前额叶和边缘束，独立于 产前化学品暴露。这一建议是基于证据表明，显着的增长和 青春期大脑的成熟是对荷尔蒙变化的反应。我们的初步数据显示， 邻苯二甲酸二-2-乙基己酯对青少年的雄激素作用和产前邻苯二甲酸酯对甲状腺的破坏， 双酚暴露。由于荷兰队列和美国样本的暴露水平相似， 这项研究的结果将适用于美国的情况。了解邻苯二甲酸盐的神经毒性， 双酚在青春期有很高的影响，因为青少年大脑的可塑性， 这是一个相当大的干预机会的时期。如果发现青少年的大脑受到 因此，可以提供指导，对产前期以后的化学品接触进行管制。

Project Summary This proposal will leverage unprecedented data from a Dutch birth cohort to examine the influence of phthalate and bisphenol exposures in multiple potentially susceptible periods on executive function and behavior in adolescents. Substantial literature has investigated the negative impact of prenatal exposures to phthalates and bisphenols on developmental programming of cognition and behavior. Yet few studies have examined exposures beyond early childhood. Further, the rigor of earlier studies is limited due to the lack of focus on mechanisms and failure to apply a life course approach. We propose to measure urinary levels of phthalates and bisphenols at ages 9–10 and 13–14 years in ≈ 1000 participants of Generation R, the largest neuroimaging study in the general pediatric population enrolled prenatally with follow-up through adolescence. We will evaluate executive function and behavior in children at age 16–18 years and measure sex hormones. Available data on measures of chemicals during the prenatal period and at 5–6 years, thyroid function in both mother and child, brain magnetic resonance imaging at ages 9–10 and 13–14 years, and feasibility of follow-up during adolescence provide an exceptional opportunity to parse out neurotoxic effects of pre- and postnatal exposures and identify the mechanisms. The large sample size will allow assessing sex as a biological variable. Specific aims are 1) to determine the impact of prenatal, childhood, and early adolescent phthalate and bisphenol exposures on executive function and behavior in adolescents and 2) to examine potential mechanisms underlying adverse influences of phthalates and bisphenols including thyroid and sex hormone disruption as well as brain structural abnormalities and white matter integrity. We hypothesize that chemical exposures during childhood and adolescence are associated with impaired executive function and behavioral problems, independent of prenatal exposure. Perturbations of thyroid and sex hormones are hypothesized to partly explain this association. We expect to observe the impact of childhood and early adolescence exposures on parietal lobe, attention networks, and prefrontal and limbic tracts, independent of the global effect of prenatal chemical exposures. This proposal is grounded on evidence showing that significant growth and maturation of the adolescent brain occurs in response to hormonal changes. Our preliminary data show anti- androgenic effects of di-2-ethylhexylphthalate in adolescents and thyroid disruption by prenatal phthalate and bisphenol exposures. Because of similarities in exposure levels in this Dutch cohort and the US samples, findings of this study will be applicable to the US context. Understanding the neurotoxicity of phthalates and bisphenols during adolescence has high implications because the plasticity of the adolescent brain makes this period a time of considerable opportunity for intervention. If the adolescent brain is found to be affected by chemicals then guidance in regulations of chemical exposures beyond the prenatal period might be indicated.