Mediators and Modifiers of Prenatal Environmental Exposures and Child Neurodevelopment: DNA methylation, Prenatal Diet, and Cognitive Stimulation (MEND)

项目摘要/摘要 产前暴露于神经毒性化学物质可能会对儿童的神经行为结果产生长期影响。 大多数已发表的研究集中在孤立的暴露-结果关联上，而忽略了 多次暴露对广泛的神经行为结果和未能识别的协同效应 行动机制和干预目标。建议的研究、产前调节因子和调节因子 环境暴露与儿童神经发育：DNA甲基化、产前饮食和认知 刺激研究(MEND)，利用NIH收集的现有和预期数据，解决了这些差距 环境对儿童结局的影响邻苯二甲酸盐和有机磷的影响研究项目 阻燃剂(OPFR)对儿童神经行为的影响。这些化合物具有特别重要的意义 因为它们在环境中无处不在，而且据信它们通过 共同的机制(例如，氧化应激、DNA甲基化)。我们的研究将继续-GAPPS (PWG)队列，从农村和城市社区招募的650多名不同样本的参与者 华盛顿州有丰富的产前和纵向数据。我们的长期目标是确定 神经毒性暴露和可操作的干预目标，可减轻这些暴露的影响。 我们提出如下建议：目标1.研究产前邻苯二甲酸盐暴露与 OPFR、脐血DNA甲基化和儿童神经行为及产前饮食氧化平衡评估 作为潜在的修饰语。目标2(A)使用机器学习来开发儿童的多结果表型特征 神经行为；(B)使用这些特征来检查产前邻苯二甲酸酯和 OPFR、脐带血DNA甲基化、产前饮食氧化平衡和儿童神经行为；(C)探索 父母的认知刺激是否改变了产前邻苯二甲酸盐和OPFR之间的关系 儿童神经行为结果，包括已建立的结构和新的表型特征。目标3.(A) 使用量身定制的策略留住不同的参与者样本，例如共享回声范围和个人 结果和(B)实现高保真的回声协议。我们的团队拥有互补的专业知识 实现这些雄心勃勃的目标。与NIH/ECHO的使命一致，以增强不同的视角，我们的 团队包括四名代表不足的少数族裔，以及初级调查人员和高级调查人员的组合，这些调查人员 在研究指导方面有很好的记录。这个

PROJECT SUMMARY/ABSTRACT Prenatal exposure to neurotoxic chemicals can have long-lasting effects on child neurobehavioral outcomes. The majority of published studies focus on isolated exposure-outcome associations, ignoring the potential for synergistic effects of multiple exposures on a broad range of neurobehavioral outcomes and failing to identify mechanisms of action and targets for intervention. The proposed study, Mediators and Modifiers of Prenatal Environmental Exposures and Child Neurodevelopment: DNA methylation, Prenatal Diet, and Cognitive Stimulation study (MEND), addresses these gaps, leveraging extant and prospective data collected in the NIH Environmental Influences on Child Outcomes project to study the effects of phthalates and organophosphate flame retardants (OPFRs) on child neurobehavior. These compounds are of particular importance both because they are ubiquitous in the environment and because they are believed to exert neurotoxicity through shared mechanisms (e.g., oxidative stress, DNA methylation). Our study will continue the PATHWAYS-GAPPS (PWG) cohort, a diverse sample of over 650 participants recruited from rural and urban communities in Washington state with rich prenatal and longitudinal data. Our long-term goals are to identify mechanisms of neurotoxic exposure and actionable targets for intervention that could attenuate the effects of those exposures. We propose the following: Aim 1. Examine the relationship between prenatal exposure to phthalates and OPFRs, cord blood DNA methylation, and child neurobehavior and assess prenatal dietary oxidative balance as a potential modifier. Aim 2 (a) Use machine learning to develop multi-outcome phenotypic profiles of child neurobehavior; (b) Employ these profiles to examine the relationships between prenatal phthalates and OPFRs, cord blood DNA methylation, prenatal dietary oxidative balance, and child neurobehavior; (c) Explore whether parental cognitive stimulation modifies the relationship between prenatal phthalates and OPFRs and child neurobehavioral outcomes, including established constructs and novel phenotypic profiles. Aim 3. (a) Retain a diverse sample of participants using tailored strategies such as sharing ECHO-wide and individual results and (b) implement the ECHO protocol with high fidelity. Our team has the complementary expertise to carry out these ambitious aims. Consistent with the NIH/ECHO mission to enhance diverse perspectives, our team includes four under-represented minorities and a mix of junior investigators and senior investigators with a strong track record of research mentorship. The