Estrogen genotoxicity causes preferential development of Fuchs endothelial corneal dystrophy in females
REDOX BIOLOGY(2024)
摘要
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 sus-ceptibility 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; 17 beta-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.
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关键词
Fuchs endothelial corneal dystrophy,Estrogen metabolism,TMS,NQO1,Mitochondrial DNA damage,Berberine,Estrogen -DNA adducts,Catechol estrogen,Oxidized estrogen,Ultraviolet-A
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