HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2 was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans.

This is a pre-copyedited, author-produced version of an article accepted for publication in Toxicological Sciences following peer review. The version of record Ernest W Wang, Max L Trojano, Mechelle M Lewis, Guangwei Du, Hairong Chen, Gregory L Brown, Leslie C Jellen, Insung Song, Elizabeth Neely, Lan Kong, James R Connor, Xuemei Huang, HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers, Toxicological Sciences, Volume 181, Issue 1, May 2021, Pages 47–57 is available online at: https://doi.org/10.1093/toxsci/kfab020.

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Work Title HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers
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Open Access
Creators
  1. Ernest W. Wang
  2. Max L. Trojano
  3. Mechelle M. Lewis
  4. Guangwei Du
  5. Hairong Chen
  6. Gregory L. Brown
  7. Leslie C. Jellen
  8. Insung Song
  9. Elizabeth Neely
  10. Lan Kong
  11. James R. Connor
  12. Xuemei Huang
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Toxicological Sciences
Publication Date March 18, 2021
Publisher Identifier (DOI)
  1. https://doi.org/10.1093/toxsci/kfab020
Deposited November 19, 2021

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  • Created
  • Added Wang-H63D_Paraquat-Authors_Manuscript.pdf
  • Added Creator Ernest W. Wang
  • Added Creator Max L. Trojano
  • Added Creator Mechelle M. Lewis
  • Added Creator Guangwei Du
  • Added Creator Hairong Chen
  • Added Creator Gregory L. Brown
  • Added Creator Leslie C. Jellen
  • Added Creator Insung Song
  • Added Creator Elizabeth Neely
  • Added Creator Lan Kong
  • Added Creator James R. Connor
  • Added Creator Xuemei Huang
  • Published
  • Updated
  • Updated
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