Manganese-Induced Neurotoxic Effects Research in South Africa

摘要 锰（Mn）是一种公认的神经毒物，影响运动和认知脑通路。这 该提案建立在我们的调查团队产生的越来越多的锰神经毒性研究的基础上， 他人尽管这些重要的贡献，研究健康的影响锰暴露在体内，定义 相关的神经病理学对于理解损伤机制和表征剂量是必不可少的， 反应关系，将告知监管政策。这些类型的研究极具挑战性，因为 获取人脑组织和量化同一受试者终生暴露于锰的难度。 在过去的七年里，我们与威特沃特斯兰德大学合作， 南非约翰内斯堡使用世界上唯一的全民职业尸检项目。 通过这种合作，我们进行了新的初步锰神经病理学研究，支持 在这个提案中。我们的数据表明，在这些矿山慢性低水平锰暴露与 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 暴露可能导致星形胶质细胞功能障碍，这反过来又诱导了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， exposure.然而，我们的初步研究也表明，锰矿工，具有高MRI信号强度， 在T1 MRI上，具有相似的纹状体组织Mn浓度，但可能低于Fe浓度， 无锰矿工在这项提案中，我们将通过收集大脑来跟踪这些初步数据， 死亡锰矿工与同期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定量神经元，星形胶质细胞和小胶质细胞在 尾状核、壳核、苍白球、黑质和嗅球 并调查这些计数和累积剂量之间的总体和剂量反应关系 锰暴露。我们还将使用免疫荧光显微镜定量靶向星形胶质细胞线粒体 蛋白质和电感耦合等离子体质谱比较纹状体锰和铁 组间浓度。这项极具创新性的研究将提供一个难得的机会， 通过研究慢性锰暴露的神经病理学效应，探讨锰的神经毒性。

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.