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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues
concentration (approximately150 parts per million [ppm]). Because the mice were exposed during early spermatogenesis and not for a full spermatogenic cycle, the authors concluded that the observed spermatotoxicity occurred during the first or second meiosis or during sperm maturation (spermiogenesis) (Land et al. 1981).
Forkert et al. (2002) used an inhibitory CYP2E1 monoclonal antibody to demonstrate that the enzyme CYP2E1 is involved in trichloroethylene metabolism to chloral in both the testes and epididymides. The extent of chloral formation was higher in the epididymis than in the testis and correlated with the relative levels of CYP2E1 activity present in individual tissues. Exposed mice exhibited damage to the epididymal epithelium, which plays a central role in sperm development and functional maturity during sperm transit from the testis to the cauda epithelium. Because CYP2E1 is localized in the male reproductive tract of mice, monkeys, and humans and trichloroethylene and its P-450-derived metabolites are found in the seminal fluid of exposed humans and in the epididymides of exposed mice (Forkert et al. 2003), the effects on sperm development and functional maturity in rodents are likely to be predictive of outcomes in humans.
DuTeaux et al. (2002) proposed that the epididymis might be toxicologically analogous to the kidney. They found that enzymes involved in nephrotoxic responses (e.g., CYP2E1, soluble epoxide hydrolase, and the cysteine conjugate β-lyase) are present in the epididymis and efferent ducts of rats. The enzymes were present at higher concentrations in the efferent ducts than in the epididymis, suggesting that the proximal excurrent ducts are a potential target for compounds and metabolites that are nephrotoxicants, such as trichloroethylene.
Kumar et al. (2000a,b) also found significant decreases in total epididymal sperm count, motility, and specific activities of the steroidogenic enzymes glucose-6-phosphate dehydrogenase and 17β-hydroxysteroid dehydrogenase, with concomitant decreases in sperm testosterone, in male Wistar rats exposed by inhalation to trichloroethylene at 376 ppm (4 hours/day, 5 days/week, for 12 or 24 weeks). Fertility was reportedly reduced when the males mated with unexposed females (Kumar et al. 2000b). Follow-up investigations of whether testicular steroid precursors (cholesterol and ascorbic acid) or testosterone plays a role in trichloroethylene-induced effects showed that total cholesterol content was greater in the testes of rats exposed to trichloroethylene than in controls (Kumar et al. 2000b). The authors concluded that the findings indicated possible impairment of testicular testosterone biosynthesis, which might explain, at least in part, the reproductive inefficiency initially reported.
Another study by Kumar et al. (2001b) explored the histomorphology of the testes, sperm count and motility, and marker testicular enzymes involved in sperm maturation and spermatogenesis. They found significant