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Testicular germ cell toxicity caused by vinylcyclohexene diepoxide in mice
S B Hooser1, D G DeMerell, D A Douds
1Department of Pharmacology/Toxicology, University of Arizona, Tucson 85721, USA.
Abstract:
Vinylcyclohexene diepoxide (VCD) produces ovarian toxicity in female mice and rats, whereas testicular damage occurs only in mice. The objectives of these studies were to determine the target cell(s) and spermatogonial survival following VCD administration. In addition, the effects of 4-vinylcyclohexene (VCH) and two epoxide metabolites, vinylcyclohexene 1,2-monoepoxide and VCD were compared. Male mice were dosed daily with VCD (320 mg/kg/d, i.p.) and killed at 5, 10, 15, 20, 25, or 30 d. Two groups were dosed daily for 30 d and allowed to recover for 30 or 60 d. Decreases in testis weight began at 5 d and continued to 30 d. These decreases corresponded to progressive necrosis of germ cells. After 5 d of VCD, there was loss of Type I and B spermatogonia in Stages II to VI and of preleptotene spermatocytes in Stages VI to VIII. After 30 d of dosing, seminiferous tubules were devoid of germ cells except for spermatogonial stem cells. Following 30 d of recovery, 100% of the seminiferous tubules were repopulated. Epididymal spermatozoa were present after 60 d of recovery. Increasing doses of VCD (0 to 320 mg/kg/d) resulted in increasing testicular toxicity. Neither VCH (800 mg/kg, i.p.) nor VCM (200 mg/kg, i.p.) caused testicular damage. VCD administration initially results in destruction of spermatogonia and spermatocytes, which are undergoing DNA synthesis and cell replication, followed by loss of maturing cells. Neither VCH nor VCM caused testicular germ cell destruction, although all three compounds destroy germ cells in female mice. Therefore, further investigation will be necessary to understand these differences in chemical-induced toxicity between ovaries and testes.
Insights
Vinylcyclohexene diepoxide (VCD) causes testicular toxicity in male mice by destroying spermatogonia and spermatocytes. However, recovery is possible, with full repopulation of seminiferous tubules observed after 30 days.
Area of Science:
- Toxicology
- Reproductive Biology
- Chemical Safety
Background:
- Vinylcyclohexene diepoxide (VCD) is known to cause ovarian toxicity in rodents.
- Testicular damage from VCD has been observed only in mice, necessitating further investigation into its mechanisms.
Purpose of the Study:
- To identify the specific target cells in the testes affected by VCD.
- To assess spermatogonial survival and seminiferous tubule repopulation after VCD exposure.
- To compare the testicular toxicity of VCD with its precursor, 4-vinylcyclohexene (VCH), and a monoepoxide metabolite.
Main Methods:
- Male mice were administered daily doses of VCD and euthanized at various time points (5-30 days).
- Additional groups received 30-day VCD treatment followed by recovery periods of 30 or 60 days.
- Testis weight, germ cell populations, and tubule morphology were assessed.
Main Results:
- VCD administration led to decreased testis weight and progressive germ cell necrosis starting from day 5.
- Spermatogonia and spermatocytes undergoing DNA synthesis were particularly sensitive to VCD.
- Complete repopulation of seminiferous tubules occurred after 30 days of recovery, with spermatozoa present after 60 days.
- Neither VCH nor its monoepoxide metabolite caused testicular damage in male mice.
Conclusions:
- VCD induces testicular toxicity by targeting actively dividing germ cells, but spermatogonial stem cells survive, allowing for regeneration.
- The differential toxicity between ovaries and testes, and between VCD and its metabolites, requires further research.
- These findings are crucial for understanding VCD's reproductive health risks and developing safety guidelines.