Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy

Taiga Miyajima, Geetha Melangath, Shan Zhu, Neha Deshpande, Shivakumar Vasanth, Bodhisattwa Mondal, Varun Kumar, Yuming Chen, Marianne O. Price, Francis W. Price, Eleanor G. Rogan, Muhammad Zahid, Ula V. Jurkunas

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related genetically complex disease characterized by increased oxidative DNA damage and progressive degeneration of corneal endothelial cells (HCEnCs). FECD has a greater incidence and advanced phenotype in women, suggesting a possible role of hormones in the sex-driven differences seen in the disease pathogenesis. In this study, catechol estrogen (4-OHE2), the byproduct of estrogen metabolism, induced genotoxic estrogen-DNA adducts formation, macromolecular DNA damage, and apoptotic cell death in HCEnCs; these findings were potentiated by menadione (MN)-mediated reactive oxygen species (ROS). Expression of NQO1, a key enzyme that neutralizes reactive estrogen metabolites, was downregulated in FECD, indicating HCEnC susceptibility to reactive estrogen metabolism in FECD. NQO1 deficiency in vitro exacerbated the estrogen-DNA adduct formation and loss of cell viability, which was rescued by the supplementation of N-acetylcysteine, a ROS scavenger. Notably, overexpression of NQO1 in HCEnCs treated with MN and 4-OHE2 quenched the ROS formation, thereby reducing the DNA damage and endothelial cell loss. This study signifies a pivotal role for NQO1 in mitigating the macromolecular oxidative DNA damage arising from the interplay between intracellular ROS and impaired endogenous estrogen metabolism in post-mitotic ocular tissue cells. A dysfunctional Nrf2-NQO1 axis in FECD renders HCEnCs susceptible to catechol estrogens and estrogen-DNA adducts formation. This novel study highlights the potential role of NQO1-mediated estrogen metabolite genotoxicity in explaining the higher incidence of FECD in females.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalFree Radical Biology and Medicine
Volume147
DOIs
StatePublished - Feb 1 2020

Keywords

  • Catechol estrogen
  • Corneal endothelium
  • Estrogen-DNA adducts
  • Fuchs endothelial corneal dystrophy
  • Menadione
  • NQO1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Miyajima, T., Melangath, G., Zhu, S., Deshpande, N., Vasanth, S., Mondal, B., Kumar, V., Chen, Y., Price, M. O., Price, F. W., Rogan, E. G., Zahid, M., & Jurkunas, U. V. (2020). Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy. Free Radical Biology and Medicine, 147, 69-79. https://doi.org/10.1016/j.freeradbiomed.2019.12.014