Estrogen genotoxicity causes preferential development of Fuchs endothelial corneal dystrophy in females

Varun Kumar, Neha Deshpande, Mohit Parekh, Raymond Wong, Shazia Ashraf, Muhammad Zahid, Hanna Hui, Annie Miall, Sylvie Kimpton, Marianne O. Price, Francis W. Price, Frank J. Gonzalez, Eleanor Rogan, Ula V. Jurkunas

Research output: Contribution to journalArticlepeer-review

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, age-related, female-predominant disorder characterized by loss of post-mitotic corneal endothelial cells (CEnCs). Ultraviolet-A (UVA) light has been shown to recapitulate the morphological and molecular changes seen in FECD to a greater extent in females than males, by triggering CYP1B1 upregulation in females. Herein, we investigated the mechanism of greater CEnC susceptibility to UVA in females by studying estrogen metabolism in response to UVA in the cornea. Loss of NAD(P)H quinone oxidoreductase 1 (NQO1) resulted in increased production of estrogen metabolites and mitochondrial-DNA adducts, with a higher CEnC loss in Nqo1−/− female compared to wild-type male and female mice. The CYP1B1 inhibitors, trans-2,3′,4,5′-tetramethoxystilbene (TMS) and berberine, rescued CEnC loss. Injection of wild-type male mice with estrogen (E2; 17β-estradiol) increased CEnC loss, followed by increased production of estrogen metabolites and mitochondrial DNA (mtDNA) damage, not seen in E2-treated Cyp1b1−/−male mice. This study demonstrates that the endo-degenerative phenotype is driven by estrogen metabolite-dependent CEnC loss that is exacerbated in the absence of NQO1; thus, explaining the mechanism accounting for the higher incidence of FECD in females. The mitigation of estrogen-adduct production by CYP1B1 inhibitors could serve as a novel therapeutic strategy for FECD.

Original languageEnglish (US)
Article number102986
JournalRedox Biology
Volume69
DOIs
StatePublished - Feb 2024

Keywords

  • Berberine
  • CYP1B1
  • Catechol estrogen
  • Estrogen metabolism
  • Estrogen-DNA adducts
  • Fuchs endothelial corneal dystrophy
  • Mitochondrial DNA damage
  • NQO1
  • Oxidized estrogen
  • TMS
  • Ultraviolet-A

ASJC Scopus subject areas

  • Organic Chemistry

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