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

产前环境暴露和儿童神经发育的调节因素和调节因素：DNA 甲基化、产前饮食和认知刺激 (MEND)

• 批准号: 10744833
• 负责人: Brent Russell Collett
• 金额: $ 150.93万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744833
• 关键词: Address; Affect; Attenuated; Brain; Chemicals; Child; Child Health; Childhood; Clinical; Cognitive; Communities; Consent; DNA Methylation; Data; Development; Diet; Disease; Early identification; Environment; Environmental Exposure; Epigenetic Process; Equilibrium; Exposure to; Family; Flame Retardants; Future; Geography; Goals; Government Agencies; Harm Reduction; Hispanic; Home environment; Individual; Informal Social Control; Intervention; Life; Machine Learning; Mediating; Mediator; Mentorship; Methods; Methylation; Mission; Molecular Target; Mothers; Neurologic; Neurotoxins; Organophosphates; Outcome; Oxidative Stress; Parents; Participant; Pathway interactions; Patient Recruitments; Phenotype; Policies; Pregnancy; Pregnant Women; Prenatal Nutrition; Protocols documentation; Publishing; Qualifying; Research; Research Personnel; Risk; Rural; Rural Community; Sampling; Science; Scientist; Site; Socioeconomic Status; Toxic effect; Umbilical Cord Blood; Underrepresented Minority; United States National Institutes of Health; Urban Community; Visit; Washington; clinically significant; cognitive ability; cohort; community partnership; dietary; dietary guidelines; early childhood; environmental chemical; ethnic diversity; fetal; fetal programming; improved; improved outcome; innovation; low socioeconomic status; machine learning model; mother nutrition; multidisciplinary; neural network; neurobehavior; neurobehavioral; neurodevelopment; neurotoxic; neurotoxicity; novel; novel strategies; phthalates; prenatal; prenatal environmental exposure; prenatal exposure; prospective; protective factors; racial diversity; recruit

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

项目总结/摘要 产前暴露于神经毒性化学物质可能对儿童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预后相关性，忽视了潜在的 多次暴露对广泛的神经行为结果的协同效应， 行动机制和干预目标。拟议的研究，产前检查的中介和修饰 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收集的现有和前瞻性数据， 环境对儿童结果的影响项目，研究邻苯二甲酸酯和有机磷酸盐的影响 阻燃剂（OPFRs）对儿童神经行为的影响。这些化合物特别重要， 因为它们在环境中无处不在，并且因为它们被认为通过 共享机制（例如，氧化应激、DNA甲基化）。我们的研究将继续路径差距 (PWG)队列，从农村和城市社区招募的650多名参与者的多样化样本， 华盛顿州拥有丰富的产前和纵向数据。我们的长期目标是确定 神经毒性暴露和可采取行动的干预目标，可以减轻这些暴露的影响。 我们提出以下建议：目标1。检查产前接触邻苯二甲酸酯与 OPFR、脐带血DNA甲基化和儿童神经行为，并评估产前饮食氧化平衡 作为一种潜在的调节剂。目标2（a）使用机器学习开发儿童的多结果表型特征 （B）采用这些特征来检查产前邻苯二甲酸酯与 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会改变产前邻苯二甲酸酯和OPFR之间的关系， 儿童神经行为结果，包括建立的结构和新的表型概况。目标3。（一） 使用量身定制的策略（如在ECHO范围内和个人分享）保留多样化的参与者样本 以及（B）以高保真度实现ECHO协议。我们的团队拥有互补的专业知识， 实现这些宏伟目标。与NIH/ECHO增强多样化观点的使命一致，我们 该小组包括四个代表性不足的少数民族和初级调查员和高级调查员， 优秀的研究指导记录。的