Neuroimaging of Manganese Toxicity

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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.