# Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

> **NIH NIH F30** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $32,781

## Abstract

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

## Key facts

- **NIH application ID:** 9926083
- **Project number:** 5F30ES030607-02
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Ernest W Wang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $32,781
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926083

## Citation

> US National Institutes of Health, RePORTER application 9926083, Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity (5F30ES030607-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926083. Licensed CC0.

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