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Toxicologic Pathology
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Cataractogenesis in Neonatal Sprague-Dawley Rats by N-Methyl-N-Nitrosourea

Katsuhiko Yoshizawa

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan, Department of Pathology, Toxicology Research Laboratories, Fujisawa Pharmaceutical Co Ltd, 2-1-6, Kashima, Yodogawa, Osaka, 532-8514, Japan

Yuji Oishi

Department of Pathology, Toxicology Research Laboratories, Fujisawa Pharmaceutical Co Ltd, 2-1-6, Kashima, Yodogawa, Osaka, 532-8514, Japan

Hiroyuki Nambu

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan, Department of Ophthalmology, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Daigo Yamamoto

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Jihong Yang

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Hideto Senzaki

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Hirohiko Miki

Department of Ophthalmology, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Airo Tsubura

Department of Pathology IP, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan

Cataract was induced by a single intraperitoneal injection of 100 mg/kg N-methyl-N-nitrosourea (MNU) to 0-, 5-, 10-, 15-, or 20-day-old male and female Sprague-Dawley rats. In day 0, 5, 10, and 15 MNU-treated rats, mature cataracts were constantly seen 7, 14, 14, and 30 days after dosing, respectively. In the day 20 MNU-treated rats, only subcapsular cataract was seen 30 days after dosing. Therefore, the rats exposed to MNU at an earlier age caused cataract more rapidly and severely. In the day 0 MNU-treated rats, 7-methyldeoxyguanosine DNA adduct was detected in the lens epithelial nuclei 12 hours after MNU dosing, followed by apoptosis, which was confirmed by morphology, by TUNEL signals, and by DNA ladder and peaked 3 days after MNU dosing. In the apoptosis cascade, upregulation of Bax, 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 associated with DNA adduct formation in the lens epithelial cell nuclei leading to apoptosis by upregulation of Bax protein, downmodulation of Bcl-2 protein, and activation of caspase-3.

Key Words: N-Methyl-N-nitrosourea • cataract • apoptosis • lens epithelium • neonatal rats • 7-methyldeoxyguanosine • Bax • Bcl-2 • caspase-3

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Toxicologic Pathology, Vol. 28, No. 4, 555-564 (2000)
DOI: 10.1177/019262330002800408
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