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

锰在正常生长和发育中起着至关重要的作用；然而， 过量暴露于锰可导致神经毒性。锰作为必需矿物质的双重作用和 神经毒物对神经发育健康呈双相剂量-反应曲线 对儿童的影响。儿童可能特别容易受到神经毒性作用的影响 环境中的锰暴露，因为他们的大脑正在经历一个动态的生长过程， 分化、通路方向和细胞凋亡，所有这些都可以受到 环境因素。磁共振成像(MRI)和核磁共振成像的最新进展 光谱学(MRS)可以提供有关锰对大脑影响的新的、定量的信息。 解剖学和生理学；然而这些成像方法从未被应用于青少年 慢性环境锰暴露人群。鉴于锰既是营养物质，又是营养物质 神经毒物，我们预计接触锰的生物标记物将呈现双相剂量- 反应与青少年神经行为、神经运动功能、脑功能的关系 解剖学和生理学，并假设低(第一个四分位数)和高(第四个四分位数) 四分位数)暴露水平将与这些方面的缺陷显著相关 域名。这一最重要的假设将通过两个具体目标来阐述。 具体目标1：用锰的历史和当前生物标记物评估神经发育 对农村青少年进行队列调查，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、行为和 神经运动状态。具体目标2：在以前的基础上对青少年进行一项分研究 应用定量核磁共振/S法测定锰生物标志物以评价锰的作用 从必需到过量暴露对神经解剖、代谢、组织、功能和 连通性。神经成像结果(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 目前锰的生物标志物。这项针对青少年的纵向队列研究具有很好的特点 加深我们对锰对神经发育、脑解剖和 使用创新的核磁共振成像方法的生理学。这些模式在定义 锰的基本益处和神经毒性危害。这项研究的发现将 对神经科学的发展具有区域、国家和全球影响，并将 用于通知汽油和环境空气标准中与锰相关的政策。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.