Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation ofN-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.

Nrf2: A unifying transcription factor in the pathogenesis of Fuchs’ endothelial corneal dystrophy

“…However, in the U.S approximately 4% of the population over the age of 40 years are diagnosed with FECD. Interestingly, females are more affected than males [ 23 ]. Typically, Asian populations show fewer cases of FECD [ 24 , 25 ].…”

“…Loss of Nrf2 and thus the Nrf2 regulated oxidative stress response in FECD suggests that over an individual's lifetime the constant UV exposure accentuates CEC death to a pathological level. Evidence for which has been obtained from both in vitro studies [ 65 ], as well as an in vivo animal model of UV induced cornea damage [ 23 ]. Cultures of human CECs exposed to UVA have been demonstrated to upregulate both Nrf2 mRNA and result in the translocation of Nrf2 to the nucleus resulting in induction of the Nrf2 regulated genes NQO1 and HO-1 [ 65 ].…”

“…Importantly, UVA exposure on the mouse cornea induces guttae-like deposits within the CE, together with morphological changes similar to FECD. Notably, the corneas from female mice are more susceptible to UVA, compared to male mice, thus recapitulating the sex differences apparent in FECD [ 23 ]. Interestingly, the estrogen metabolizing enzyme CYP1B1 is upregulated by UVA more prominently in CE derived from female mice compared to CE derived from male mice.…”

“…Interestingly, the estrogen metabolizing enzyme CYP1B1 is upregulated by UVA more prominently in CE derived from female mice compared to CE derived from male mice. Furthermore, CYP1B1 has demonstrated to be upregulated in human FECD tissue samples [ 23 ]. However, CYP1B1 can be regulated by NRF2 [ 51 ].…”

Quercetin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes

“…Under normal circumstances, ROS production is maintained at a homeostatic level due to the endogenous antioxidant defense systems, such as superoxide dismutase (SOD), thioredoxin peroxidase (TPX), catalase (CAT), and glutathione peroxidase (GSH-Px) [ 11 , 12 ]. However, excessive production of ROS or a reduced antioxidant capacity leads to an accumulation of ROS in intestinal mucosa or enterocytes, thus causing oxidative stress and damage to macromolecules, including DNA damage [ 13 , 14 ], protein adduction [ 15 ], and lipid peroxidation [ 16 , 17 ]. In vivo and in vitro studies have shown that ROS can trigger apoptosis of intestinal epithelial cells and impair the intestinal mucosal barrier in animals [ 18 , 19 ].…”