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

• 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
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfx065

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.