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

Cailing Liu, Taiga Miyajima, Geetha Melangath, Takashi Miyai, Shivakumar Vasanth, Neha Deshpande, Varun Kumar, Stephan Ong Tone, Reena Gupta, Shan Zhu, Dijana Vojnovic, Yuming Chen, Eleanor G. Rogan, Bodhiswatta Mondal, Muhammad Zahid, Ula V. Jurkunas

Research output: Contribution to journalArticle

4 Scopus citations

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 of N-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.

Original languageEnglish (US)
Pages (from-to)573-583
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number1
DOIs
StatePublished - Jan 7 2020

Keywords

  • CYP1B1
  • Estrogen metabolism
  • Fuchs endothelial corneal dystrophy
  • Mitochondrial DNA damage
  • Ultraviolet light

ASJC Scopus subject areas

  • General

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    Liu, C., Miyajima, T., Melangath, G., Miyai, T., Vasanth, S., Deshpande, N., Kumar, V., Tone, S. O., Gupta, R., Zhu, S., Vojnovic, D., Chen, Y., Rogan, E. G., Mondal, B., Zahid, M., & Jurkunas, U. V. (2020). Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected. Proceedings of the National Academy of Sciences of the United States of America, 117(1), 573-583. https://doi.org/10.1073/pnas.1912546116