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

摘要 锰是一种公认的神经毒物，会影响运动和认知大脑通路。这 该提案建立在我们调查团队产生的越来越多的锰神经毒性研究的基础上，并 其他。尽管在研究体内暴露的锰对健康的影响方面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表征剂量- 将为监管政策提供信息的回应关系。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接触锰的困难。 在过去的七年里，我们与威特沃特斯兰德大学建立了合作关系 南非约翰内斯堡，使用世界上唯一的全人口职业尸检程序。 通过这次合作，我们进行了新的初步MN神经病理学研究，支持 在这项提案中的目标。我们的数据表明，这些矿场长期、低水平的锰暴露与 尾状核和壳核的神经元密度较低，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，而星形胶质细胞功能障碍又会导致大鼠的促炎神经毒性状态 纹状体(尾状核、壳核、苍白球)，由小胶质细胞激活驱动。星形细胞 功能障碍可能部分归因于锰诱导的几个关键线粒体蛋白的失调。 曝光。然而，我们的初步研究也表明，具有高MRI信号强度的锰矿工 在T1磁共振上，纹状体组织中的锰浓度与纹状体组织相似，但铁浓度可能低于 非锰矿工人。在这项提案中，我们将通过从以下地点收集大脑来跟进这些初步数据 死亡的锰矿工人同时接触锰和适当匹配的非锰矿工 矿工。我们将使用无偏见的体视学方法对脑内神经元、星形胶质细胞和小胶质细胞进行量化。 两组的尾状核、壳核、苍白球、黑质致密部(SNPC)和嗅球 并调查这些计数和累积之间的总体和剂量-反应关系 锰暴露。我们还将使用免疫荧光显微镜对目标星形细胞线粒体进行量化。 蛋白质和电感耦合等离子体质谱比较纹状体锰和铁 组之间的浓度。这项极具创新性的研究将提供一个难得的机会来推动 通过研究慢性锰暴露的神经病理效应，研究锰的神经毒性领域。

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.