Metal mixtures, exposure windows, and neurodevelopmental trajectories from adolescence to adulthood

金属混合物、暴露窗口和从青春期到成年的神经发育轨迹

• 批准号: 10392069
• 负责人: Megan K Horton
• 金额: $ 74.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392069
• 关键词: 16 year old; 21 year old; Address; Adolescence; Adolescent; Adolescent Development; Adult; Age; Attention; Behavioral; Biological Markers; Birth; Brain; Brain region; Childhood; Chromium; Communities; Complement; Complex Mixtures; Copper; Data; Development; Disease; Enrollment; Environment; Environmental Health; Environmental Risk Factor; Epidemiology; Exposure to; Future; Geographic Locations; Grant; Health; Individual; Intervention; Italy; Lead; Life; Life Cycle Stages; Link; Literature; Longitudinal Studies; Longitudinal cohort; Magnetic Resonance Imaging; Manganese; Measures; Mediating; Metal exposure; Metals; Methods; Modality; Modeling; Neuropsychology; Newborn Infant; Outcome; Phenotype; Plants; Predisposition; Pregnancy; Public Health; Research; Role; Short-Term Memory; Steel; Structure; Sum; Testing; Time; TimeLine; Tooth structure; Zinc; adolescent brain development; adolescent health; behavioral phenotyping; brain remodeling; cohort; computerized; design; early childhood; early life exposure; executive function; fetal; improved; in utero; infancy; innovation; longitudinal design; member; multimodality; neural circuit; neurobehavior; neurobehavioral; neurodevelopment; neuroimaging; neurotoxic; novel; postnatal; postnatal period; preadolescence; prenatal; prevent; programs; prospective; public health intervention; theories; tool

Project Summary The Developmental Origins of Health and Disease (DOHaD) theory posits that early life environment predicts adverse health effects that may not manifest for decades. Adolescence is an understudied life stage characterized by profound brain remodeling and behavioral development, which may be influenced by the early life environment. We hypothesize that exposure to neuroactive (i.e., neurotoxic and neuroprotective) metals during the early postnatal period (0-2 years) impacts the trajectory of brain and executive function development, particularly in attention and working memory. The study of trajectories necessitates assessment of phenotypic development over time, rather than at a single time point as is most common in environmental health research. We propose studying longitudinal brain structure/function and executive function (EF) trajectories using multi-modal magnetic resonance imaging (MRI) and computerized EF tasks in an accelerated longitudinal design (ALD). An ALD is a commonly used epidemiologic tool that shortens the time needed to assess neurodevelopmental trajectories compared to a traditional longitudinal cohort design. We do so by leveraging the PHIME (Public Health Impact of Metals Exposure) study, a cohort of adolescents in Northern Italy. One third of the PHIME community lives proximal to a steel producing plant that emits neuroactive metals, supporting our ability to study the role of mixed metal exposures on health. Previously we have shown cross-sectional associations between manganese (Mn), one of the more common plant emissions, and adverse neurodevelopmental outcomes. More recently, we employed a novel, validated tooth biomarker to reconstruct prenatal and early childhood Mn exposures in naturally shed baby teeth, allowing us to show the prospective effects of early life Mn exposure on adolescent neurodevelopment measured at one time point. In this renewal, we extend our tooth biomarker to reconstruct past exposure to a mixture of common metals (Mn, Pb, Zn, Cu and Cr) and link specific exposure life stages [i.e., fetal life [(14 weeks gestation through birth), early postnatal life (0-2 years) and childhood (2-6 years)] to trajectories of structural/functional brain development and neurobehavior throughout adolescence. To complement the tooth biomarker, we will enroll new cohort members to assess phenotype trajectories from age 7-25 years (i.e. the onset through conclusion of adolescence). This renewal builds prior cross-sectional and prospective findings by creating a life course study of adolescent developmental trajectories of brain structure/function and EF. All told, our life course study covers 25 years in a single grant cycle and will be a model for future studies of early life environment and adolescent health, an understudied life stage representing the transition into adulthood. In sum, this renewal within PHIME will determine the critical exposure windows for early life metal exposure on adolescent developmental trajectories, a key research need so that interventions may be applied at the appropriate age to promote optimal development and improved health.

项目概要 健康与疾病的发育起源（DOHaD）理论认为，早期生活环境可以预测 对健康的不利影响可能几十年后才会显现出来。青春期是一个未被充分研究的生命阶段 其特点是深刻的大脑重塑和行为发展，这可能受到早期的影响 生活环境。我们假设接触神经活性（即神经毒性和神经保护）金属 产后早期（0-2岁）影响大脑轨迹和执行功能 发展，特别是注意力和工作记忆。轨迹研究需要评估 随着时间的推移，而不是在环境中最常见的单一时间点，表型的发展 健康研究。我们建议研究纵向大脑结构/功能和执行功能（EF） 使用多模态磁共振成像 (MRI) 和计算机化 EF 任务来确定轨迹 加速纵向设计（ALD）。 ALD 是一种常用的流行病学工具，可以缩短时间 与传统的纵向队列设计相比，需要评估神经发育轨迹。我们做 因此，通过利用 PHIME（金属暴露对公共健康的影响）研究，一组青少年 意大利北部。三分之一的 PHIME 社区居住在一家钢铁生产厂附近，该工厂排放废气 神经活性金属，支持我们研究混合金属暴露对健康的作用的能力。之前 我们展示了锰 (Mn) 之间的横截面关联，锰是最常见的植物之一 排放和不良的神经发育结果。最近，我们采用了一种新颖的、经过验证的牙齿 生物标记物可重建自然脱落乳牙中产前和儿童早期的锰暴露情况，使我们能够 显示生命早期接触锰对青少年神经发育的预期影响 时间点。在这次更新中，我们扩展了牙齿生物标志物，以重建过去暴露于混合物质的情况 常见金属（Mn、Pb、Zn、Cu 和 Cr）并链接特定暴露生命阶段 [即胎儿生命 [（14 周） 妊娠到出生）、产后早期（0-2岁）和童年（2-6岁）]的轨迹 整个青春期的结构/功能性大脑发育和神经行为。来补充牙齿 生物标志物，我们将招募新的队列成员来评估 7-25 岁的表型轨迹（即 从青春期开始一直到青春期结束）。此次更新建立了先前的横截面和前瞻性发现 通过创建青少年大脑结构/功能和 EF 发育轨迹的生命历程研究。全部 据说，我们的生命历程研究在一个资助周期内涵盖了 25 年，并将成为未来早期研究的典范。 生活环境和青少年健康，这是代表向成年过渡的一个未被研究的生命阶段。在 总而言之，PHIME 内的更新将确定生命早期金属暴露的关键暴露窗口 青少年发展轨迹，一项关键的研究需求，以便可以在青少年中应用干预措施 适当的年龄可促进最佳发育和改善健康。