Editor's Highlight: Collaborative Cross Mouse Population Enables Refinements to Characterization of the Variability in Toxicokinetics of Trichloroethylene and Provides Genetic Evidence for the Role of PPAR Pathway in Its Oxidative Metabolism

Trichloroethylene (TCE) is a known carcinogen in humans and rodents. Previous studies of inter-strain variability in TCE metabolism were conducted in multi-strain panels of classical inbred mice with limited genetic diversity to identify gene-environment interactions associated with chemical exposur...

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Bibliographic Details
Published in:Toxicological sciences 2017-07, Vol.158 (1), p.48-62
Main Authors: Venkatratnam, Abhishek, Furuya, Shinji, Kosyk, Oksana, Gold, Avram, Bodnar, Wanda, Konganti, Kranti, Threadgill, David W, Gillespie, Kevin M, Aylor, David L, Wright, Fred A, Chiu, Weihsueh A, Rusyn, Ivan
Format: Article
Language:English
Subjects:
Alcohol Dehydrogenase - biosynthesis
Aldehyde Dehydrogenase - biosynthesis
Animals
Dose-Response Relationship, Drug
Enzyme Induction
Female
Gene-Environment Interaction
Kidney - drug effects
Liver - drug effects
Liver - enzymology
Liver - metabolism
Male
Mice
Oxidation-Reduction
Peroxisome Proliferator-Activated Receptors - genetics
Peroxisome Proliferator-Activated Receptors - metabolism
Quantitative Trait Loci
Revealing Role of PPAR in Trichloroethylene Toxicity Using the Collaborative Cross
Species Specificity
Toxicokinetics
Trichloroethylene - blood
Trichloroethylene - pharmacokinetics
Trichloroethylene - toxicity
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Summary:Trichloroethylene (TCE) is a known carcinogen in humans and rodents. Previous studies of inter-strain variability in TCE metabolism were conducted in multi-strain panels of classical inbred mice with limited genetic diversity to identify gene-environment interactions associated with chemical exposure. To evaluate inter-strain variability in TCE metabolism and identify genetic determinants that are associated with TCE metabolism and effects using Collaborative Cross (CC), a large panel of genetically diverse strains of mice. We administered a single oral dose of 0, 24, 80, 240, or 800 mg/kg of TCE to mice from 50 CC strains, and collected organs 24 h post-dosing. Levels of trichloroacetic acid (TCA), a major oxidative metabolite of TCE were measured in multiple tissues. Protein expression and activity levels of TCE-metabolizing enzymes were evaluated in the liver. Liver transcript levels of known genes perturbed by TCE exposure were also quantified. Genetic association mapping was performed on the acquired phenotypes. TCA levels varied in a dose- and strain-dependent manner in liver, kidney, and serum. The variability in TCA levels among strains did not correlate with expression or activity of a number of enzymes known to be involved in TCE oxidation. Peroxisome proliferator-activated receptor alpha (PPARα)-responsive genes were found to be associated with strain-specific differences in TCE metabolism. This study shows that CC mouse population is a valuable tool to quantitatively evaluate inter-individual variability in chemical metabolism and to identify genes and pathways that may underpin population differences.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfx065