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Principal Investigator: Ulrike Dydak
Organization: PURDUE UNIVERSITY
Fiscal Year: 2024
Award: $561,236
Funding agency: National Institute of Environmental Health Sciences
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.
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