Comparative dose-response analysis of liver and kidney transcriptomic effects of trichloroethylene and tetrachloroethylene in B6C3F1 mouse. Mus musculus

Purpose: Trichloroethylene (TCE) and tetrachloroethylene (PCE) are ubiquitous environmental contaminants and occupational health hazards. The goals of this study were to establish the common and differing transcriptional effects of TCE and PCE. This study examined liver and kidney effects of TCE and PCE in a dose-response study design. Methods: Equi-molar doses of TCE (24, 80, 240, 800 mg/kg) or PE (30, 100, 300, 1,000 mg/kg) were administered by gavage in aqueous vehicle to male B6C3F1/J mice. Tissues were collected 24 hrs after exposure. Trichloroacetic acid (TCA), a major oxidative metabolite of both compounds, was measured and RNA sequencing was performed on liver and kidney samples, with ~30 samples for each organ (29 after QC). Results: Most dose-responsive pathways were common among chemicals/tissues, with the strongest effect on peroxisomal beta-oxidation. Effects on liver and kidney mitochondria-related pathways were notably unique to PCE. Tissue-specific acute transcriptional effects of TCE and PCE occurred at human equivalent doses comparable to those for apical effects. Conclusions: Our study is the first RNA-Seq transcriptional study of TCE vs. PCE in both liver and kidney, enabling a detailed comparison of the chemicals and effects on different organs. Our results show strong commonalities of effects, although PCE shows stronger transcriptional responses than TCE for the same equimolar doses. Overall design: Male B6C3F1/J mice were subjected to equi-molar doses of TCE or PCE by gavage in aqueous vehicle, with liver and kidney samples sequenced in triplicate using Illumina HiSeq-2000 for each dose and with a larger number of sequenced reads for control and the highest concentration in liver, to maximize discoveries of differential exon usage.