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

项目摘要 健康与疾病的发展起源(DOHAD)理论认为，早期的生活环境预示着 对健康的不利影响可能在几十年内都不会显现。青春期是一个未被充分研究的人生阶段。 以深刻的脑部重塑和行为发育为特征，这可能受到早期 生活环境。我们假设接触神经活性(即神经毒性和神经保护性)金属 出生后早期(0-2岁)对大脑轨迹和执行功能的影响 发展，特别是在注意力和工作记忆方面。对轨迹的研究需要评估 表型发育随时间的变化，而不是像环境中最常见的那样在单个时间点 健康研究。我们建议研究纵向脑结构/功能和执行功能(EF) 使用多模式磁共振成像(MRI)和计算机化EF任务的轨迹 加速纵向设计(ALD)。ALD是一种常用的流行病学工具，可以缩短发病时间 与传统的纵向队列设计相比，需要评估神经发育轨迹。我们有 因此，通过利用PHIME(金属暴露对公共健康的影响)研究， 意大利北部。PHIME社区三分之一的人住在一家钢铁厂附近，这家工厂排放的废气 神经活性金属，支持我们研究混合金属暴露对健康的作用。先前 我们已经展示了更常见的植物之一--锰(Mn)之间的横截面联系 排放，以及不利的神经发育后果。最近，我们用了一颗新奇的、经过验证的牙齿 在自然脱落的乳牙中重建产前和儿童早期锰暴露的生物标记物，允许我们 显示早期生活锰暴露对青少年神经发育的预期影响 时间点。在这次更新中，我们扩展了我们的牙齿生物标记物，以重建过去接触过的混合 常见金属(锰、铅、锌、铜和铬)与特定暴露生命阶段[即胎儿寿命[(14周)]有关 从怀孕到出生)、出生后早期生活(0-2岁)和童年(2-6岁)]到 整个青春期的结构/功能脑发育和神经行为。补充牙齿 我们将招募新的队列成员来评估7-25岁的表型轨迹(即 在青春期结束时发病)。这一更新建立了先前的横断面和前瞻性研究结果 通过创建青少年大脑结构/功能和EF的发展轨迹的生命历程研究。全 Tell，我们的生命历程研究在一个赠款周期中涵盖了25年，并将成为未来研究早期 生活环境与青春期健康，这是一个未被充分研究的生命阶段，代表着向成年期的过渡。在……里面 总而言之，PHIME内的这次更新将确定早期生命金属暴露的关键暴露窗口 青少年发展轨迹，这是一项关键的研究需要，以便干预措施可以在 适当年龄，以促进最佳发展和改善健康。

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.