Developmental Effects of Manganese Exposure in Rural Adolescents: The CARES Cohort Comes of Age

锰（Mn）在正常生长和发育中起着至关重要的作用;然而， 过度暴露于Mn可导致神经毒性。锰作为必需矿物质的双重作用， 神经毒物对神经发育健康呈双相剂量反应曲线 儿童的成果。儿童可能特别容易受到 环境锰暴露，因为他们的大脑正在经历一个动态的生长过程， 分化、途径方向和凋亡，所有这些都可以受到 环境因素磁共振成像（MRI）的最新进展， 磁共振波谱（MRS）可以提供有关锰对脑影响的新的定量信息 解剖学和生理学;然而，这些成像方法从未应用于青少年 暴露于慢性环境锰的人群。考虑到锰作为营养物质和 神经毒物，我们预计锰暴露的生物标志物将表现出双相剂量- 反应与青少年神经行为，神经运动功能，脑 解剖学和生理学，并假设低（第一四分位数）和高（第四 四分位数）的暴露水平将显着相关的赤字，这些 域.这一总体假设将通过两个具体目标加以解决。 具体目标1：在神经发育中使用Mn的历史和当前生物标志物评价神经发育。 农村青少年队列，以评估锰从必需到过量对 执行功能，注意力和反应时间，认知，成就，行为， 神经运动状态具体目标2：根据先前的研究，对青少年进行子研究 使用定量MRI/S测定Mn生物标志物，以评价Mn的影响 暴露从必要到过度的神经解剖，代谢，组织，功能和 连通性。神经影像学结局（体积、代谢物浓度、扩散指标 张量，功能激活和网络连接）将与历史和 Mn的当前生物标志物。这项特征鲜明的青少年纵向队列研究将 促进我们对锰对神经发育和大脑解剖学的影响的理解， 使用创新的MRI方法学。这些模式可能有助于定义 锰的基本益处和神经毒理学危害。这项研究的结果将 对神经科学的发展具有区域、国家和全球影响， 用于为汽油中锰含量和环境空气标准相关政策提供信息。这项建议 利用美国唯一可以直接实现这些目标的队列。

Manganese (Mn) plays an essential role in normal growth and development; however, overexposure to Mn can result in neurotoxicity. This dual role of Mn as essential mineral and neurotoxicant appears as a biphasic dose-response curve for neurodevelopmental health outcomes in children. Children may be particularly susceptible to the neurotoxic effects of ambient Mn exposure, as their brains are undergoing a dynamic process of growth, differentiation, pathway direction, and apoptosis, all of which can be influenced by environmental factors. Recent developments in magnetic resonance imaging (MRI) and spectroscopy (MRS) can provide novel, quantitative information about the effects of Mn on brain anatomy and physiology; yet these imaging methods have never been applied to an adolescent population exposed to chronic ambient Mn. Given the role of Mn as both nutrient and neurotoxicant, we anticipate that biomarkers of Mn exposure will exhibit a biphasic dose- response association with adolescent neurobehavior, neuromotor function, brain anatomy and physiology, and hypothesize that both low (1st quartile) and high (4th quartile) levels of exposure will be significantly associated with deficits in these domains. This overarching hypothesis will be addressed through two specific aims. Specific Aim 1: Evaluate neurodevelopment with historic and current biomarkers of Mn in a cohort of rural adolescents in order to evaluate the impact of Mn from essential to excess on executive function, attention and reaction time, cognition, achievement, behavior, and neuromotor status. Specific Aim 2: Conduct a sub-study of adolescents based on previously determined Mn biomarkers using quantitative MRI/S in order to evaluate the effects of Mn exposure from essential to excess on neuroanatomy, metabolism, organization, function and connectivity. Neuroimaging outcomes (volume, metabolite concentrations, metrics for diffusion tensor, functional activation, and network connectivity) will be compared with historic and current biomarkers of Mn. This well-characterized longitudinal cohort study of adolescents will advance our understanding of the impact of Mn on neurodevelopment, and brain anatomy and physiology using innovative MRI methodologies. These patterns may be useful in defining the lines of essential benefit and neurotoxicological harm from Mn. The findings from this study will have regional, national and global implications for advancement of neuroscience and will be used to inform policy related to Mn in gasoline and ambient air standards. This proposal leverages the only cohort available in the United States that can directly address these aims.