title: Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: kidney effects.
abstract: Trichloroethylene (TCE) is a well-known environmental and occupational toxicant that is classified as carcinogenic to humans based on the epidemiological evidence of an association with higher risk of renal-cell carcinoma. A number of scientific issues critical for assessing human health risks from TCE remain unresolved, such as the amount of kidney-toxic glutathione conjugation metabolites formed, interspecies and interindividual differences, and the mode of action for kidney carcinogenicity. It was postulated that TCE renal metabolite levels are associated with kidney-specific toxicity. Oral dosing with TCE was conducted in subacute (600 mg/kg/d; 5 d; 7 inbred mouse strains) and subchronic (100 or 400 mg/kg/d; 1, 2, or 4 wk; 2 inbred mouse strains) designs. The quantitative relationship was evaluated between strain-, dose, and time-dependent formation of TCE metabolites from cytochrome P-450-mediated oxidation (trichloroacetic acid [TCA], dichloroacetic acid [DCA], and trichloroethanol) and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione], and various kidney toxicity phenotypes. In subacute study, interstrain differences in renal TCE metabolite levels were observed. In addition, data showed that in several strains kidney-specific effects of TCE included induction of peroxisome proliferator-marker genes Cyp4a10 and Acox1, increased cell proliferation, and expression of KIM-1, a marker of tubular damage and regeneration. In subchronic study, peroxisome proliferator-marker gene induction and renal toxicity diminished while cell proliferative response was elevated in a dose-dependent manner in NZW/LacJ but not C57BL/6J mice. Overall, data demonstrated that renal TCE metabolite levels are associated with kidney-specific toxicity and that these effects are strain dependent.
authors.affiliation: a Department of Environmental Sciences and Engineering , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.
authors.forename: Hong Sik
authors.initials: HS
authors.lastname: Yoo
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shymonyak
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Bodnar
authors.forename: Louise M
authors.initials: LM
authors.lastname: Ball
authors.forename: Avram
authors.initials: A
authors.lastname: Gold
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000378:metabolism; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000378:metabolism; D014241:Trichloroethylene / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D002273:Carcinogens; C512110:Cyp4a10 protein, mouse; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D047493:PPAR alpha; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; C039961:S-(1,2-dichlorovinyl)cysteine; D005023:Ethylene Chlorohydrin; D003577:Cytochrome P-450 Enzyme System; C041464:S-(1,2-dichlorovinyl)glutathione; D003999:Dichloroacetic Acid; C005849:2,2,2-trichloroethanol; D005978:Glutathione; D003545:Cysteine