title: Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: liver effects.
abstract: Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of interindividual variability in TCE metabolism and toxicity, especially in the liver. A hypothesis was tested that amounts of oxidative metabolites of TCE in mouse liver are associated with hepatic-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] in serum and liver, and various hepatic toxicity phenotypes. In subacute study, interstrain variability in TCE metabolite amounts was observed in serum and liver. No marked induction of Cyp2e1 protein levels in liver was detected. Serum and hepatic levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1 but not with degree of induction in hepatocellular proliferation. In subchronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Hepatic protein levels of CYP2E1, ADH, and ALDH2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE.
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: Svitlana
authors.initials: S
authors.lastname: Shymonyak
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
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: D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D049109:Cell Proliferation; D003545:Cysteine / Q000031:analogs & derivatives / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012997:Solvents / Q000493:pharmacokinetics / Q000633:toxicity; D014238:Trichloroacetic Acid / Q000097:blood; D014241:Trichloroethylene / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D002273:Carcinogens; C512110:Cyp4a10 protein, mouse; D012997:Solvents; 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