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Principal Investigator: Ernest W Wang
Organization: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
Fiscal Year: 2024
Award: $30,431
Funding agency: National Institute of Environmental Health Sciences
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
Terms: <0-11 years old><Address><Affect><Age><Aspartate><Brain><Brain Mapping><Brain Nervous System><Brain region><Bronze Diabetes><CD71><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Chemicals><Child><Child Youth><Children (0-21)><Chronic><Cohort Studies><Complex><Concurrent Studies><Data><Data Analyses><Data Analysis><Development><Dose><Encephalon><Exposure to><Fe element><Fellowship><Gene variant><Guidelines><Hemochromatosis><Histidine><Human><Image><Individual><Iron><L-Aspartate><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Manganese><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mn element><Modeling><Modern Man><Motor><NMR Imaging><NMR Tomography><Nuclear Magnetic Resonance Imaging><Nucleus Caudatus><Occupational Exposure><Outcome><Physicians><Population><Population Study><Position><Positioning Attribute><Proteins><Regulatory Protein><Relaxation><Role><Safety><Scientist><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Structure><Subcellular Process><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Testing><Time><Training><Transferrin Receptor><Transferrin Receptor 1><Welding><Zeugmatography><ages><allele variant><allelic variant><caudate nucleus><cofactor><cohort><data interpretation><developmental><extracellular><ferroportin><ferroportin1 protein><genetic regulatory protein><genetic variant><genomic variant><high dimensional data><image processing><imaging><interest><iron storage disorder><kids><loss of function><metal transporting protein 1><multidimensional data><multidimensional datasets><neurobehavior><neurobehavioral><neuron toxicity><neuronal toxicity><neurotoxic><neurotoxicity><neurotoxicology><population-based study><population-level study><public health relevance><receptor mediated endocytosis><recruit><regulatory gene product><response><social role><solute carrier family 40 (iron-regulated transporter), member 1><statistical analysis><studies of populations><study of the population><workplace exposure><youngster>