Archives of Toxicology

, Volume 73, Issue 4, pp 274–281

Doxorubicin induces male germ cell apoptosis in rats

Authors

  • Kazutoshi Shinoda
    • Pathology Unit, Hita Research Laboratories, Chemicals Inspection and Testing Institute, 3-822 Ishii-machi, Hita-shi, Oita 877-0061, Japan Fax: +81-973-23-9800; Tel.: +81-973-24-7211 e-mail: shinodak@hita.citi.or.jp
  • Kunitoshi Mitsumori
    • Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
  • Kazuo Yasuhara
    • Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
  • Chikako Uneyama
    • Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
  • Hiroshi Onodera
    • Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
  • Masao Hirose
    • Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
  • Masato Uehara
    • Department of Veterinary Anatomy, Tottori University, 4-101 Minami, Koyama-cho, Tottori 680-8553, Japan
GENOTOXICITY

DOI: 10.1007/s002040050617

Cite this article as:
Shinoda, K., Mitsumori, K., Yasuhara, K. et al. Arch Toxicol (1999) 73: 274. doi:10.1007/s002040050617

Abstract

To clarify whether apoptosis is involved in doxorubicin (DXR)-induced testicular toxicity and to identify the target germ cell type, adult Sprague-Dawley rats were treated with a single intravenous dose of DXR (8 or 12 mg/kg) and euthanized at 3, 6, 12, 24, and 48 h subsequently. Histologically, germ cell degeneration was first found 6 h after dosing in meiotically dividing spermatocytes and early round spermatids of seminiferous tubules at stage I, and subsequently observed in spermatogonia at stages I–VI showing ultrastructural characteristics of apoptosis. Coincident with the appearance of morphological changes, degenerating germ cells were shown to be undergoing apoptosis as revealed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The frequency of TUNEL-labeled germ cells increased in a stage- and cell type-specific manner, the peak of frequency gradually progressing from stage I of seminiferous tubules to later stages with time after dosing, suggesting that the damaged germ cells, especially spermatogonia, gradually underwent the processes leading to apoptosis. DNA laddering on gel electrophoresis was apparent 24 and 48 h after dosing. The results demonstrate that apoptosis plays an important role in the induction of testicular toxicity caused by DXR with meiotically dividing spermatocytes and type A and intermediate spermatogonia as highly vulnerable target cells.

Key words DoxorubicinApoptosisTesticular toxicity

Copyright information

© Springer-Verlag Berlin Heidelberg 1999