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: 10242754
• 负责人: Brad A Racette
• 金额: --
• 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 2023-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242754
• 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) 是一种已知的神经毒物，会影响大脑运动和认知通路。这 该提案建立在我们的研究团队进行的越来越多的锰神经毒性研究的基础上 其他的。尽管对研究体内锰暴露的健康影响做出了这些重要贡献，但定义 相关的神经病理学对于理解损伤机制和描述剂量特征至关重要 响应关系将为监管政策提供信息。这些类型的研究极具挑战性，因为 获取人类脑组织并量化同一受试者终生接触锰的难度。 在过去的七年里，我们与威特沃特斯兰德大学在以下领域开展了合作： 南非约翰内斯堡使用世界上唯一的全人口职业尸检计划。 通过这次合作，我们进行了新颖的初步锰神经病理学研究，支持 本提案的目的。我们的数据表明，这些矿山中长期、低水平的锰暴露与 尾状核和壳核中神经元密度较低，小胶质细胞/星形胶质细胞比率较高，表明 Mn 接触可能会导致星形胶质细胞功能障碍，进而诱发促炎性神经毒性状态 纹状体（尾状核、壳核、苍白球），由小胶质细胞的激活驱动。星形胶质细胞 功能障碍可能部分归因于锰诱导的几种关键线粒体蛋白的失调 接触。然而，我们的初步研究也表明，锰矿工人具有高 MRI 信号强度 在 T1 MRI 上，具有相似的语料体纹状体组织 Mn 浓度，但可能较低的 Fe 浓度， 非锰矿工人。在本提案中，我们将通过收集来自以下组织的大脑来跟踪这些初步数据： 已故的锰矿工，具有同期的锰暴露和适当匹配的非锰 矿工。我们将使用无偏的体视学方法来量化神经元、星形胶质细胞和小胶质细胞 两组的尾状核、壳核、苍白球、黑质致密部 (SNpc) 和嗅球 的工人，并调查这些计数和累积值之间的总体和剂量反应关联 锰暴露。我们还将使用免疫荧光显微镜来量化靶向星形细胞线粒体 蛋白质和电感耦合等离子体质谱法比较纹状体锰和铁 组间浓度。这项高度创新的研究将为推进 通过研究慢性锰暴露的神经病理学影响，研究锰神经毒性领域。