Motor and Cognitive Health Outcomes in a Mn-Exposed African Community

摘要 锰（Mn）是人体必需的微量元素，也是一种公认的具有复杂药理作用的神经毒物。 在家长补助金，“运动和认知健康结果在锰暴露的非洲社区，”我们 正在进行一项以人群为基础的流行病学研究，研究对象是居住在一个大型锰冶炼厂附近的锰暴露成年人。 梅耶顿，南非，调查环境锰暴露之间的关联，在环境水平 低于目前环境保护局的监管水平，以及运动，认知控制和情绪 功能障碍ViCTER提案扩大了人类流行病学研究的范围，包括 探索性生物标志物开发，并开始对负面影响进行更深入的机理理解 锰暴露对神经认知功能的影响，使用体外人神经元细胞培养模型和体内 果蝇锰暴露模型。这些新的目标将调查锰暴露可能导致 通过由小的非编码基因的合成和分泌驱动的表观遗传过程， RNA，又称微小RNA（miRNAs）。越来越多的证据表明，锰直接参与了 miRNAs在许多慢性疾病发病机制中起重要作用， 抑制其靶mRNA的翻译并调节其降解。在这个提案中，我们采取了独特的 利用锰毒性的细胞和果蝇模型鉴定与锰相关的特异性miRNAs的方法 在人体内暴露，这将用于识别特定的人miRNA从整个 基因组可以作为锰暴露和相关健康结果的生物标志物。我们还将探索和 确认所鉴定的miRNA生物标志物的基因靶标。最终，这个ViCTER将产生新的数据， 将环境锰暴露与可用于监测暴露社区的生物标志物联系起来， 可能有助于更好地了解锰诱导的人类神经毒性的机制。扩大 该提案的范围将提供前所未有的来自人类和模型系统的双向数据， 研究这一重要而常见的神经毒物。

Abstract Manganese (Mn) is an essential trace element and an established neurotoxicant with complex pharmacology. In the parent grant, “Motor and Cognitive Health Outcomes in a Manganese-Exposed African Community,” we are conducting a population-based epidemiology study of Mn-exposed adults living near a large Mn smelter in Meyerton, South Africa, to investigate the association between environmental Mn exposure, at ambient levels below current Environmental Protection Agency regulatory levels, and motor, cognitive control, and mood dysfunction. This ViCTER proposal expands the scope of the parent human epidemiology study by including exploratory biomarker development, and initiating a deeper mechanistic understanding of the negative impact of Mn exposure on neurocognitive functions using in vitro human neuronal cell culture models and in vivo Drosophila Mn exposure models. These new aims will investigate the hypothesis that Mn exposure can lead to poor phenotypic outcomes via epigenetic processes driven by the synthesis and secretion of small, non-coding RNAs, known as micro RNAs (miRNAs). Growing evidence suggests that Mn is directly involved in the synthesis of miRNAs, and that miRNAs play a significant role in the pathogenesis of many chronic diseases, by repressing translation and regulating degradation of their target mRNAs. In this proposal, we take the unique approach of using cellular and Drosophila models of Mn toxicity to identify specific miRNAs associated with Mn exposure in vivo in humans, which will be used to identify specific human miRNAs from across the entire genome that may serve as biomarkers of Mn exposure and related health outcomes. We will also explore and confirm gene targets of the identified miRNA biomarkers. Ultimately, this ViCTER will generate novel data that will link environmental Mn exposure to biomarkers that could be used to monitor exposed communities and may contribute to a better understanding of mechanisms of Mn-induced human neurotoxicity. The expanded scope of this proposal will provide unprecedented bidirectional data from humans and model systems to investigate this important and common neurotoxicant.