Cataractogenesis in neonatal Sprague-Dawley rats by N-methyl-N-nitrosourea

Cataract was induced by a single intraperitoneal injection of 100 mg/kg N-m ethyl-N-nitrosourea (MNU) to 0-, 5-, 10-, 15-, or 20-day-old male and femal e Sprague-Dawley rats. In day 0, 5, 10, and 15 MNU-treated rats, mature cat aracts were constantly seen 7, 14, 14, and 30 days after dosing, respective ly. In the day 20 MNU-treated rats, only subcapsular cataract was seen 30 d ays after dosing. Therefore, the rats exposed to MNU at an earlier age caus ed cataract more rapidly and severely. In the day 0 MNU-treated rats, 7-met hyldeoxyguanosine DNA adduct was detected in the lens epithelial nuclei 12 hours after MNU dosing, followed by apoptosis, which was confirmed by morph ology, by TUNEL signals, and by DNA ladder and peaked 3 days after MNU dosi ng. In the apoptosis cascade, upregulation of Bar, downregulation of Bcl-2, and increased CPP32 protease (caspase-3) activity were seen 12 hours after MNU dosing. Therefore, the pathogenesis of MNU-induced cataract was associ ated with DNA adduct formation in the lens epithelial cell nuclei leading t o apoptosis by upregulation of Bar protein, downmodulation of Bcl-2 protein , and activation of caspase-3.