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Evidence for Trichloroethylene Bioactivation and Adduct Formation in the Rat Epididymis and Efferent Ducts¹

Department of Environmental Toxicology, University of California, Davis, California 95616

Recent studies indicate that trichloroethylene (TCE) may be a male reproductive toxicant. It is metabolized by conjugation with glutathione and cytochrome P450-dependent oxidation. Reactive metabolites produced along both pathways are capable of forming protein adducts and are thought to be involved in TCE-induced liver and kidney damage. Similarly, in situ bioactivation of TCE and subsequent binding of metabolites may be one mechanism by which TCE acts as a reproductive toxicant. Cysteine-conjugate ß-lyase (ß-lyase) bioactivates the TCE metabolite dichlorovinyl cysteine (DCVC) to a reactive intermediate that is capable of binding cellular macromolecules. In the present study, Western blot analysis indicated that the soluble form of ß-lyase, but not the mitochondrial form, was present in the epididymis and efferent ducts. Both forms of ß-lyase were detected in the kidney. When rats were dosed with DCVC, no protein adducts were detected in the epididymis or efferent ducts, although adducts were present in the proximal tubule of the kidney. Trichloroethylene can also be metabolized and form protein adducts through a cytochrome P450-mediated pathway. Western blot analysis detected the presence of cytochrome P450 2E1 (CYP2E1) in the efferent ducts. Immunoreactive proteins were localized to efferent duct and corpus epididymis epithelia. Metabolism of TCE was demonstrated in vitro using microsomes prepared from untreated rats. Metabolism was inhibited 77% when efferent duct microsomes were preincubated with an antibody to CYP2E1. Dichloroacetyl adducts were detected in epididymal and efferent duct microsomes exposed in vitro to TCE. Results from the present study indicate that the cytochrome P450-dependent formation of reactive intermediates and the subsequent covalent binding of cellular proteins may be involved in the male reproductive toxicity of TCE.

¹ This research was partially supported by grant/cooperative agreement R825325 from the U.S. Environmental Protection Agency; S.B.D. was supported by the NIEHS Training Grant in Environmental Toxicology ES07072. Although the research described in this article has been funded in part by the U.S. Environmental Protection Agency, it has not been subjected to the Agency's required peer and policy review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred.

² Correspondence: Marion G. Miller, Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, California, 95616. FAX: 530 752 3394; gmiller{at}ucdavis.edu