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Schistosoma mansoni: reversible destruction of testes by procarbazine
1Department of Health Research and Policy, Stanford University School of Medicine, California 94305.
Abstract:
1. The anticancer drug procarbazine is profoundly damaging to the testes of Schistosoma mansoni when administered at 200 mg/kg or more to the mouse host. Somatic tissues appear entirely unaffected. 2. Within 2 days the meiotic process is disrupted, and primary and secondary spermatocytes and spermatids are destroyed and replaced by amorphous granular material. 3. The testes regenerate within about 15 days, apparently from surviving spermatogonial resting cells near the germinal epithelium of the testis. 4. Livers of mice treated once 7 weeks earlier have numerous egg granulomas and give rise to many miracidia, suggesting that full testis function is regained. 5. Male worms given the drug at 200 mg/kg at 19 days of age and fixed 7 weeks later have on average one testis less than control worms, indicating that about 15% of immature testes are unable to regenerate, whereas mature worms given the drug regenerate the normal number of testes. 6. The drug did not have significant antispermatogenic effects when male worms were incubated for a week with various concentrations in vitro, suggesting that a host metabolite is the active agent.
Insights
The anticancer drug procarbazine severely damages Schistosoma mansoni testes in mice, but the parasites regenerate functional testes within 15 days. Immature worms show incomplete regeneration, suggesting a host-dependent mechanism.
Area of Science:
- Parasitology
- Drug Discovery
- Reproductive Biology
Background:
- Schistosoma mansoni is a parasitic flatworm causing schistosomiasis.
- Anticancer drugs can have unintended effects on non-target organisms.
- Understanding drug toxicity in parasites is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of the anticancer drug procarbazine on the testes of Schistosoma mansoni.
- To determine if the drug's effects are reversible and if regeneration occurs.
- To explore the mechanism of action, specifically the role of host metabolites.
Main Methods:
- Administration of procarbazine (≥200 mg/kg) to infected mice.
- Microscopic examination of Schistosoma mansoni testes at various time points post-treatment.
- In vitro incubation of male worms with procarbazine to assess direct effects.
- Evaluation of testis regeneration and fertility in treated worms.
Main Results:
- Procarbazine at ≥200 mg/kg profoundly damaged Schistosoma mansoni testes, disrupting meiosis and destroying germ cells.
- Testes regenerated within approximately 15 days, originating from spermatogonial resting cells.
- Mature worms showed complete testis regeneration, while ~15% of immature testes failed to regenerate.
- In vitro studies indicated a host metabolite, not the drug itself, is the active antispermatogenic agent.
Conclusions:
- Procarbazine exhibits potent, reversible toxicity to Schistosoma mansoni testes, primarily affecting the meiotic process.
- The host's metabolic system appears essential for procarbazine's antispermatogenic activity.
- Regeneration capacity varies with parasite maturity, highlighting potential vulnerabilities in immature worms.