Testicular toxicity of WIN 18446 in the laboratory mouse.

The effect of oral administration of N,N'=bis (dichloroacetyl)-1, 8-octamethylenediamine (WIN 18446) (200 mg/kg body weight/day, up to 30 days) on the testis of the Parkes (P) strain laboratory mouse was studied. The drug caused reduction in testicular weight and severe atrophic changes in the seminiferous tubules. A duration-dependent effect of the drug was observed on the germ cells. The drug had its initial impact on spermatids followed by spermatocytes, ultimately culminating in the Sertoli cell-spermatogonia syndrome. The drug-induced changes included exfoliation of germ cells, formation of multinucleated giant cells, and vacuolization of cytoplasm and displacement (towards the lumina of the tubules) of Sertoli cell nuclei. Even 75 days after drug withdrawal, testicular weight remained depressed and in 15 to 20% of the tubules there was incomplete recovery of spermatogenesis. Our data indicate that WIN 18446 induces sustained impairment of spermatogenesis by a direct action on spermatogonia or indirectly by affecting the integrity of the Sertoli cells. The Leydig cells remained unaffected in WIN 18446-treated mice.