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Testicular toxicity of WIN 18446 in the laboratory mouse
1Centre of Advanced Study in Zoology, Banaras Hindu University, Uttar Pradesh, India.
Abstract:
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.
Insights
The laboratory mouse testis experienced significant damage from N,N'=bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446), a drug impacting germ cell development and causing sustained spermatogenesis impairment.
Area of Science:
- Reproductive Toxicology
- Experimental Pathology
Background:
- The study investigates the toxicological effects of WIN 18446 on male reproductive organs.
- Understanding the impact of chemical agents on spermatogenesis is crucial for reproductive health research.
Purpose of the Study:
- To evaluate the effects of oral WIN 18446 administration on the testis of Parkes (P) strain laboratory mice.
- To determine the duration-dependent toxicity and recovery patterns of spermatogenesis following WIN 18446 exposure.
Main Methods:
- Parkes (P) strain mice were administered WIN 18446 orally at 200 mg/kg/day for up to 30 days.
- Testicular weight, seminiferous tubule morphology, and germ cell development were assessed.
- Recovery was evaluated up to 75 days post-drug withdrawal.
Main Results:
- WIN 18446 caused significant reduction in testicular weight and severe atrophic changes in seminiferous tubules.
- A duration-dependent effect was observed, initially affecting spermatids, then spermatocytes, leading to the Sertoli cell-spermatogonia syndrome.
- Drug withdrawal resulted in incomplete recovery of spermatogenesis in 15-20% of tubules even after 75 days.
Conclusions:
- WIN 18446 induces sustained impairment of spermatogenesis, potentially through direct action on spermatogonia or Sertoli cell damage.
- The drug's effects include germ cell exfoliation, multinucleated giant cell formation, and Sertoli cell nuclear displacement.
- Leydig cells remained unaffected, suggesting a specific toxicity to the germinal epithelium.