Epha2 genotype influences ultraviolet radiation induced cataract in mice

Age-related cataract is the major cause of blindness worldwide. Both genetic and environmental factors contribute to the disease. Genetic variation in the <i>Ephrin type-A receptor 2</i> (<i>EPHA2</i>) gene is associated with the risk of age-related cataract in multiple populations, and exposure to ultraviolet-B (UV-B) radiation is a well-established risk factor for the disease. <i>Epha2</i> knockout and UV-B radiation independently lead to cataract in mice, and UV-B radiation reportedly alters <i>EPHA2</i> expression in cultured cells. We hypothesised that an interaction between UV-B radiation exposure and <i>Epha2</i> signalling may influence cataract development. To test this hypothesis, 5-week-old <i>Epha2</i>+/+ and <i>Epha2</i>+/- mice (n = 8 per group) were exposed to repeated below-threshold doses of UV-B radiation (0.0125-0.05 J/cm²), before development of <i>Epha2</i>-mediated cataract. Cataract development was monitored after termination of exposure and at least one month later. Histological analysis of exposed and unexposed lenses was performed to assess pathological changes, and gene expression analysis to investigate the mechanism underlying cataract. Both <i>Epha2</i>+/+ and <i>Epha2</i>+/- mice developed UV-B dose-dependent anterior polar cataract; cataract severity in both genotypes of mice exposed to either 0.025 or 0.05 J/cm² UV-B was significantly higher than that in matched unexposed mice (<i>p</i> < 0.05). Histological analysis of lenses of both genotypes of mice exposed to 0.025 or 0.05 J/cm² UV-B radiation consistently revealed disruption of the lens architecture. A month after the exposure, cataract severity increased in <i>Epha2</i>+/+ mice treated with the highest dose of UV-B radiation (<i>p</i> = 0.03) but remained unchanged in <i>Epha2</i>+/- mice. Gene expression analysis of lenses of both genotypes of mice showed significant upregulation of the cell proliferation marker <i>Mki67</i> in <i>Epha2</i>+/+ (<i>p</i> = 0.036) but not in <i>Epha2</i>+/- mice exposed to the highest dose of UV-B radiation compared to matched unexposed mice. In conclusion, this study suggests that repeated exposure to doses of UV-B radiation lower than the single minimum dose required for inducing cataract leads to cataract in wild-type and <i>Epha2</i> heterozygous knockout mice. Furthermore, this study indicates, for the first time, a potentially favourable effect of partial <i>Epha2</i> deficiency against UV radiation-induced damage in the lens.