QTL mapping of TCE toxicokinetic and toxicodynamic phenotypes. Log transformed liver TCA (A-B) and Acox1 (C-D) transcript levels measured at 24-hr time point in CC mice administered with a single oral dose of TCE (800 mg/kg) were mapped to the mouse genome polymorphisms among CC strains. Panels A and C show logarithmic odds ratio (LOD) scores across the whole mouse genome (chromosomes 1 through X). The red line represents a permutation-based significance threshold (n=1000 permutations). Plots B and D show the effect of the CC founder strain alleles on chromosome 2 (top) and a zoom-in on the significant regions with corresponding LOD scores.
Venkatratnam et al used a Collaborative Cross mouse population to increase the precision of estimates for the extent of inter-individual variability in TCE (trichloroethylene) metabolism. TCE is a known carcinogen in humans and rodents. Among the metabolites of TCE, trichloroacetic acid (TCA) is the prevalent oxidative metabolite and a known peroxisome proliferator-activated receptor alpha (PPARα) agonist that is thought to be one of the key drivers of TCE toxicity. A novel outcome of this study was the identification of candidate genes at Quantitative Trait Loci (QTLs) associated with TCE metabolism to TCA. Among several protein-coding genes in the locus significantly associated with liver TCA levels among strains, Acot8 and Fitm2 were identified as candidate genes and were significantly correlated with TCA levels. These results are intriguing as Acot8 and Fitm2 are PPAR-responsive genes, suggesting the role of PPAR signaling in TCE metabolism, in addition to the role of TCE metabolites in peroxisome proliferation.
(Venkatratnam et al., 2017)
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