Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

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PROJECT SUMMARY/ABSTRACT Manganese (Mn) is an essential cofactor for many cellular processes, but at elevated concentrations is known to exert neurotoxic effects on the brain. To date, population-based studies of Mn-exposed children and welders have consistently shown that chronic Mn exposure (X) is associated with deficits in motor and neurobehavioral outcomes (Y). Additionally, magnetic resonance imaging (MRI) has shown that both Mn exposure and outcomes are associated with brain Mn accumulation (M). While these associations have raised interest in the development of imaging-based safety guidelines, it is presently unknown as to how brain Mn accumulation may mediate the relationship between Mn exposure and motor and neurobehavior outcomes (X→M→Y). This lack of understanding has led some to attempt complex, high-dimensional data analyses to deconvolve the underlying relationships governing neurotoxicity in Mn-exposed individuals. However, few so far have accounted for common genetic variants that are likely to have significant moderating effects. Importantly, Mn levels are known to be influenced by iron (Fe) levels and the expression of Fe-regulatory proteins. Chemically similar, Mn and Fe move between intra- and extracellular compartments through shared transport mechanisms. The human hemochromatosis protein (HFE) is an Fe-regulatory protein that negatively regulates mechanisms facilitating Mn entry into the brain. The HFE histidine-to-aspartate substitution at position 63 (H63D) is a commonly carried gene variant that results in HFE partial loss-of-function. Thus, the central hypothesis of this fellowship application is that HFE H63D moderates the relationships between welding, brain Mn accumulation, and neurobehavioral and motor outcomes. In doing so, H63D may moderate the neurotoxic effects of prolonged Mn exposure. Uncovering these effects is of particular