Metabolism and toxicity of trichloroethylene in epididymis and testis.
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.
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada, K7L 3N6. forkertp@post.queensu.ca
Poh-Gek
PG
Forkert
Lawrence H
LH
Lash
Veronique
V
Nadeau
Robert
R
Tardif
Andrea
A
Simmonds
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D002697:Chloral Hydrate / Q000031:analogs & derivatives* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000378:metabolism; D004822:Epididymis / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000652:urine; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D016273:Occupational Exposure; D013737:Testis / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D014238:Trichloroacetic Acid / Q000652:urine; D014241:Trichloroethylene / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*
D014241:Trichloroethylene; D002697:Chloral Hydrate; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D019392:Cytochrome P-450 CYP2E1; C021100:trichloroacetaldehyde