High
myopia is recognized as a risk factor for earlier onset of nuclear
cataracts. One possible explanation for this is that
lenses in highly myopic eyes are exposed to higher levels of
oxygen than normal eyes owing to earlier vitreous liquefaction and, hence, are subjected to oxidative insults. Here, we first compared the methylation levels of six essential
antioxidant genes (GSTP1, NRF2, OGG1, TXN, TXNRD1 and TXNRD2) between highly myopic
cataract (HMC) and age-related
cataract (
ARC) lens epithelial samples via Sequenom MassARRAY. We found that specific CpG units in the promoters of GSTP1 and TXNRD2 were hypermethylated and that the expression levels of these two genes were lower in the HMC group than in the
ARC group. A
luciferase reporter assay confirmed the significance of differentially methylated fragments in the activation of transcription. The importance of GSTP1 and TXNRD2 in
antioxidant capacity was confirmed by overexpression or knockdown experiments on cultured lens epithelial cells (LECs). In addition, the expression of
DNA methyl
transferase 1 (DNMT1) was higher in the lens epithelium of HMC patients than that of
ARC patients, and the expression of GSTP1 and TXNRD2 was upregulated by use of a DNMT inhibitor in cultured LECs. Finally, we mimicked the intraocular environment of highly myopic eyes by treating LECs with
hydrogen peroxide (H2O2) and observed both alterations in the methylation status of the GSTP1 and TXNRD2 promoters and time-dependent altered expression levels. Therefore, we propose that in an environment with high
oxygen, in which
lenses in highly myopic eyes are immersed, there exists a vicious cycle composed of increased oxidative stress and decreased enzymatic
antioxidants via the hypermethylation of
antioxidant genes.