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Metabolism and toxicity of trichloroethylene in epididymis and testis
Poh-Gek Forkert1, Lawrence H Lash, Veronique Nadeau
1Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada, K7L 3N6. forkertp@post.queensu.ca
Abstract:
The widespread occupational exposure to trichloroethylene (TCE) led us to test the hypothesis that TCE causes toxicity in the male reproductive system. We also investigated mechanisms mediating the potential cytotoxic response. Mice were exposed to TCE (1000 ppm) by inhalation for 6 h/day for 5 days/week for a total of 19 days. Exposure after the first week was interspersed by a "weekend." To estimate internal exposure, we measured the TCE metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCOH), in urine at Days 4, 9, 14, and 19. Urinary excretion of TCOH was significantly higher than TCA; levels of TCOH and TCA significantly increased by the second and third week, respectively. Cytochrome P450 2E1 (CYP2E1), an enzyme involved in TCE metabolism, was localized in the epididymal epithelium and testicular Leydig cells, and was found at higher levels in the former than the latter. Immunoblotting confirmed that CYP2E1 protein was present in greater amounts in epididymis than in testis. p-Nitrophenol hydroxylation, a CYP2E1 catalytic activity, was also higher in the epididymis than in the testis. Chloral, a major TCE metabolite, was generated in microsomal incubations at significantly higher levels in epididymis than in testis. Antibody inhibition of CYP2E1 reduced chloral formation, which was more pronounced in epididymis than in testis. After 4 weeks of TCE exposure, damage to the epididymis was manifested as sloughing of epithelial cells. These results indicated that TCE is metabolized in the male reproductive tract, leading to adverse effects that are more severe in the epididymis than in the testis.
Insights
Trichloroethylene (TCE) exposure causes male reproductive toxicity, particularly in the epididymis. TCE is metabolized within the reproductive tract, leading to cellular damage and adverse effects.
Area of Science:
- Toxicology
- Reproductive Biology
- Occupational Health
Background:
- Widespread occupational exposure to trichloroethylene (TCE) necessitates understanding its reproductive health impacts.
- Investigating the mechanisms of TCE-induced male reproductive toxicity is crucial for risk assessment.
Purpose of the Study:
- To test the hypothesis that TCE causes toxicity in the male reproductive system.
- To investigate the mechanisms mediating TCE's potential cytotoxic response in male reproductive organs.
Main Methods:
- Mice were exposed to TCE (1000 ppm) via inhalation for 19 days.
- Urinary TCE metabolites (TCA, TCOH) were measured to estimate internal exposure.
- Cytochrome P450 2E1 (CYP2E1) levels, activity, and metabolite formation were assessed in reproductive tissues.
Main Results:
- Urinary TCOH and TCA levels increased significantly during TCE exposure.
- CYP2E1 was localized and found at higher levels in the epididymis than the testis.
- TCE metabolism and subsequent chloral formation were more pronounced in the epididymis, correlating with epithelial cell damage.
Conclusions:
- TCE is metabolized within the male reproductive tract.
- Adverse effects of TCE exposure are more severe in the epididymis compared to the testis.
- CYP2E1 plays a significant role in mediating TCE toxicity in the male reproductive system.
