Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)

南非锰诱发的神经毒性效应研究 (MINERS)

• 批准号: 9768467
• 负责人: Brad A Racette
• 金额: $ 56.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768467
• 关键词: Accounting; Affect; Astrocytes; Autopsy; Basal Ganglia; Brain; Cell Count; Chronic; Cognitive; Collaborations; Corpus striatum structure; Data; Dose; Dynamin; Environmental and Occupational Exposure; Etiology; Exposure to; Functional disorder; Globus Pallidus; Health; Human; Immunofluorescence Microscopy; Impaired cognition; Inductively Coupled Plasma Mass Spectrometry; Inflammation Mediators; Inflammatory; Injury; Magnetic Resonance Imaging; Manganese; Mediating; Metals; Methods; Microglia; Mining; Mitochondrial Proteins; Motor; NADPH Oxidase; NOS2A gene; Neurons; Neurotoxins; Occupational; Outcome; Pathologic; Policies; Population; Proteins; Research; Research Design; Signal Transduction; South Africa; South African; Stains; Substantia nigra structure; Tissues; Universities; Work; brain pathway; brain tissue; density; follow-up; in vivo; innovation; mortalin; motor disorder; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; novel; olfactory bulb; pars compacta; programs; putamen; response

Abstract Manganese (Mn) is an established neurotoxicant that affects motor and cognitive brain pathways. This proposal builds on a growing body of Mn neurotoxicity research generated by our investigative team and others. Despite these important contributions to studying the health effects of Mn exposure in vivo, defining the associated neuropathology is essential to understand mechanisms of injury and to characterize dose- response relations that will inform regulatory policy. These types of studies are extremely challenging due to the difficulty in acquiring human brain tissue and quantifying lifetime exposure to Mn in the same subjects. Over the last seven years, we have developed a collaboration with the University of the Witwatersrand in Johannesburg, South Africa using the only population-wide, occupational autopsy program in the world. Through this collaboration we have conducted novel preliminary Mn neuropathology studies that support the aims in this proposal. Our data suggest that chronic, low-level Mn exposure in these mines is associated with lower neuronal density and higher microglial/astrocyte ratios in the caudate and putamen, indicating that Mn exposure may cause astrocytic dysfunction which in turn induces a pro-inflammatory neurotoxic state in the corpus striatum (caudate, putamen, globus pallidus), driven by the activation of microglia. Astrocytic dysfunction is likely attributable, in part, to dysregulation of several key mitochondrial proteins induced by Mn exposure. However, our preliminary studies also suggest that Mn mineworkers, with high MRI signal intensity on T1 MRI, have similar corpus striatal tissue Mn concentrations, but possibly lower Fe concentrations, than non-Mn mineworkers. In this proposal, we will follow-up on these preliminary data by collecting brains from deceased Mn mineworkers with contemporaneous Mn exposures and appropriately matched non-Mn mineworkers. We will use unbiased stereologic methods to quantify neurons, astrocytes, and microglia in the caudate, putamen, globus pallidus, substantia nigra pars compacta (SNpc), and olfactory bulbs in both groups of workers and investigate the overall and dose-response associations between these counts and cumulative Mn exposure. We will also use immunofluorescence microscopy to quantify targeted astrocytic mitochondrial proteins and inductively coupled plasma-mass spectrometry to compare corpus striatal Mn and Fe concentrations between groups. This highly innovative study will provide a rare opportunity to advance the field of Mn neurotoxicity by investigating the neuropathologic effects of chronic Mn exposure.

抽象的 锰（MN）是一种已建立的神经毒性，会影响运动和认知脑途径。这 提案建立在我们调查团队和 其他的。尽管对研究Mn暴露在体内的健康影响方面做出了重要贡献，但定义 相关的神经病理学对于了解损伤机制和表征剂量 - 响应关系将为监管政策提供依据。由于 在同一受试者中获取人脑组织和量化MN的寿命暴露的困难。 在过去的七年中，我们与Witwatersrand大学建立了合作 南非约翰内斯堡使用世界上唯一的人口尸检计划。 通过这种合作，我们进行了新的初步MN神经病理学研究，以支持 目的是在此提案中。我们的数据表明，这些矿山中的慢性低级MN暴露与 尾状和壳质中的神经元密度降低和较高的小胶质细胞/星形胶质细胞比例，表明MN 暴露可能会导致星形细胞功能障碍，从而导致促炎性神经毒性状态 由小胶质细胞激活驱动的纹状体（尾状，pe骨，球形pallipus pallidus）。星形细胞 功能障碍可能部分归因于MN诱导的几种关键线粒体蛋白的失调 接触。但是，我们的初步研究还表明，MN矿工具有较高的MRI信号强度 在T1 MRI上，纹状体组织MN浓度相似，但可能较低的Fe浓度，而不是 非MN矿工。在此提案中，我们将通过从中收集大脑来跟进这些初步数据 已故的MN矿工与同时发生的MN暴露并适当匹配非MN 矿工。我们将使用无偏的立体方法来量化神经元，星形胶质细胞和小胶质细胞 两组的尾状，壳壳，球形pallia pallidus，黑质Nigra pars compacta（SNPC）和嗅球 工人并研究这些计数与累积之间的整体和剂量反应关联 MN暴露。我们还将使用免疫荧光显微镜来量化靶向的星形细胞线粒体 蛋白质和电感耦合等离子体质谱法比较纹状体MN和Fe 组之间的浓度。这项高度创新的研究将为促进 MN神经毒性领域通过研究慢性MN暴露的神经病理学作用。