Norimitsu Takahashi

Toxicological study of etoposide (VP-16) in rats with special emphasis on testicular alteration.

Etoposide (VP-16) was administered intravenously to rats for 3 months. Testicular alterations induced by etoposide (VP-16) at 0.5 and 1.5 mg/kg/d were thoroughly assessed with light and electron microscopy. Light microscopic analyses demonstrated disorganization and moderate depletion of germinal epithelium at 0.5 mg/kg/d, and complete germ cell depopulation at 1.5 mg/kg/d. Ultrastructural studies revealed degenerative changes in spermatogonia and early spermatocytes, appearance of large spermatids with multi-nuclei, and nuclear alterations and cytoplasmic vacuolation in Sertoli cells. Moreover, the basement membrane of the seminiferous tubule showed wavy lamellae and infolding to the seminiferous epithelium. Leydig cells manifested no significant ultrastructural changes. The small intestine and ovaries were not affected. The 2-month recovery period following cessation of treatment led to the recovery of these testicular alterations at the 0.5 mg/kg/d dose, but not at the 1.5 mg/kg/d dose. Judging from these results, etoposide (VP-16) induced damage primarily in spermatogenic cells, followed by Sertoli cells and the basement membrane in seminiferous tubules. Though reversible at intermediate doses, higher doses of VP-16 might produce irreversible testicular lesions.