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

摘要 锰是人体必需的微量元素，也是一种公认的神经毒物，具有复杂的药理作用。 在“接触锰的非洲社区的运动和认知健康结果”的父母资助中，我们 正在对居住在中国一家大型锰冶炼厂附近的接触锰的成年人进行一项基于人群的流行病学研究 研究环境中锰暴露与环境水平之间的关系 低于环境保护局当前的监管水平，以及运动、认知控制和情绪 功能障碍。维克特的这项建议扩大了亲代人类流行病学研究的范围，包括 探索性生物标记物的开发，并启动对负面影响的更深层次的机制理解 用体外和体内神经细胞培养模型研究锰暴露对神经认知功能的影响 果蝇锰暴露模型。这些新的目标将调查接触锰可能导致 由小的、非编码的合成和分泌驱动的表观遗传过程导致的较差的表型结果 RNAs，称为微RNAs(MiRNAs)。越来越多的证据表明，锰直接参与了 MiRNAs的合成，miRNAs在许多慢性疾病的发病机制中发挥重要作用，通过 抑制其靶基因的翻译并调节其降解。在这项提案中，我们采用了独特的 利用细胞和果蝇锰中毒模型鉴定与锰相关的特异性miRNAs的方法 在人体内的暴露，这将被用来从整个 可作为锰暴露和相关健康后果的生物标志物的基因组。我们还将探索和 确认已鉴定的miRNA生物标记物的基因靶点。最终，这个胜利者将产生新的数据， 将环境锰暴露与生物标志物联系起来，这些生物标志物可用于监测暴露的社区和 可能有助于更好地了解锰致人类神经毒性的机制。扩展后的 该提案的范围将提供前所未有的从人类和模型系统到 调查这种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.