Neuroimaging of Manganese Toxicity

摘要 通过吸入焊接烟雾暴露于锰(Mn)仍然是一个健康风险因素， 导致电焊工大脑中锰的积累和神经化学变化，从而进一步导致变化 在情绪、认知和运动功能方面。然而，人们对其剂量-反应关系知之甚少。 人脑特定脑区对锰的吸收和排出。此外，虽然动物和 细胞研究强烈表明氧化应激是锰中毒的主要机制之一，标记物 氧化应激及其与症状的关系尚未在人脑中得到研究。我们的小说 磁共振成像(MRI)和波谱(MRS)技术可以生成全脑地图 以及谷胱甘肽(GSH)的测定，谷胱甘肽(GSH)是氧化应激的标志，G- 氨基丁酸(GABA)，人脑中主要的抑制性神经递质。使用这些技术， 拟议工作的主要目标是阐明时空吸收和消除 电焊工脑组织中锰的含量及其与氧化应激标志物的关系 情绪、认知和运动功能的特定大脑区域的神经递质失衡。我们的预赛 数据表明，沿白质束扩散可能有助于大脑皮层区域的锰沉积，并且 大脑中锰的消除时间在不同的大脑中是不同的。此外，暴露导致的增加 减少锰暴露后，丘脑GABA似乎是可逆的。利用纵向研究 设计，我们独一无二地接触到一批职业焊工，以进行个人空气采样和准确曝光 评估，以及我们最先进的神经成像技术，这项提议将检验中心假设 人类大脑中锰沉积和消除的剂量-反应关系不同 不同的大脑区域和导联，通过氧化应激和神经递质失衡，到达大脑区域 特定症状。为了测试大脑对锰的吸收积累是否按顺序发生 大脑，导致氧化应激和GABA失衡，目标1将通过以下方式研究大脑动态锰沉积 对20名新的焊接学徒在他们的焊接生涯中进行了两年的跟踪调查，采用个人空气采样， 全脑定量核磁共振和新颖的MRS编辑技术，Hermes。在目标2中，我们将招募40人 活跃的有经验的焊工和40名对照工人检测丘脑中的GSH和GABA， 小脑和额叶皮质。一个测试情绪、认知和运动功能变化的电池将是 用于研究与神经化学变化的关系。在目标3中，将使用相同的方法来研究 通过跟踪20名停止接触锰(退休、换工作)的焊工两次来消除脑锰 好几年了。了解人脑锰沉积的时空特征，神经化学 反应及其与症状的关系将对我们理解 研究了焊接过程中锰的剂量-反应关系，并将告知职业性锰暴露的安全水平。

ABSTRACT Exposure to manganese (Mn) through inhalation of welding fumes continues to be a health risk factor, resulting in accumulation of brain Mn and neurochemical changes in welders, which further lead to changes in mood, cognitive and motor function. Yet, not much is known about the dose-response relationships of uptake and elimination of Mn in specific brain regions of the human brain. Furthermore, while animal and cell studies strongly suggest oxidative stress as one of the primary mechanisms of Mn toxicity, markers of oxidative stress and their relation to symptoms have not yet been explored in the human brain. Our novel magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques allow generating whole-brain maps of Mn deposition, as well as the measurement of glutathione (GSH), a marker of oxidative stress, and g- aminobutyric acid (GABA), the main inhibitory neurotransmitter in the human brain. Using these techniques, the primary objective of the proposed work is to elucidate the spatial-temporal uptake and elimination of manganese in the human brain of welders, and the relationship of oxidative stress markers and neurotransmitter imbalances in specific brain regions to mood, cognition and motor function. Our preliminary data suggest that diffusion along white matter tracts may contribute to Mn deposition in cortical areas, and that the time of elimination of brain Mn varies across the brain. Furthermore, exposure-induced increase of thalamic GABA seems to be reversible upon reduction of Mn exposure. Making use of a longitudinal study design, our unique access to a cohort of career welders for personal air sampling and accurate exposure assessment, and our state-of-the-art neuroimaging technology, this proposal will test the central hypothesis that the dose-response relationship of Mn deposition and elimination in the human brain varies across different brain regions and leads, via oxidative stress and neurotransmitter imbalance, to brain region specific symptoms. To test whether the uptake of brain Mn accumulation occurs sequentially across the brain, leading to oxidative stress and GABA imbalance, Aim 1 will study dynamic Mn brain deposition by following 20 new welding apprentices for two years into their welding career, using personal air sampling, whole-brain quantitative MRI and the novel MRS editing technique, HERMES. In Aim 2 we will recruit 40 active experienced welders and 40 control workers to probe GSH and GABA in the thalamus, the cerebellum and the frontal cortex. A test battery for changes in mood, cognition and motor function will be used to study associations with neurochemical changes. In Aim 3 the same methods will be used to study elimination of brain Mn by following 20 welders who cease to be exposed to Mn (retire, change job) for two years. Understanding the spatio-temporal characteristics of human brain Mn deposition, neurochemical responses and their relation to symptoms will have significant translational impact on our understanding of the Mn dose-response relationship in welding and will inform safe levels of occupational Mn exposure.