| Title: | Editor's Highlight: Comparative Dose-Response Analysis of Liver and Kidney Transcriptomic Effects of Trichloroethylene and Tetrachloroethylene in B6C3F1 Mouse |
| Author(s): | Zhou YH; Cichocki JA; Soldatow VY; Scholl EH; Gallins PJ; Jima D; Yoo HS; Chiu WA; Wright FA; Rusyn I; |
| Address: | "Department of Biological Sciences. Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina. Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas. Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina. Department of Statistics, North Carolina State University, Raleigh, North Carolina" |
| ISSN/ISBN: | 1096-0929 (Electronic) 1096-6080 (Print) 1096-0929 (Linking) |
| Abstract: | "Trichloroethylene (TCE) and tetrachloroethylene (PCE) are ubiquitous environmental contaminants and occupational health hazards. Recent health assessments of these agents identified several critical data gaps, including lack of comparative analysis of their effects. This study examined liver and kidney effects of TCE and PCE in a dose-response study design. Equimolar doses of TCE (24, 80, 240, and 800 mg/kg) or PCE (30, 100, 300, and 1000 mg/kg) were administered by gavage in aqueous vehicle to male B6C3F1/J mice. Tissues were collected 24 h after exposure. Trichloroacetic acid (TCA), a major oxidative metabolite of both compounds, was measured and RNA sequencing was performed. PCE had a stronger effect on liver and kidney transcriptomes, as well as greater concentrations of TCA. 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. We performed dose-response modeling of the transcriptomic data and compared the resulting points of departure (PODs) to those for apical endpoints derived from long-term studies with these chemicals in rats, mice, and humans, converting to human equivalent doses using tissue-specific dosimetry models. Tissue-specific acute transcriptional effects of TCE and PCE occurred at human equivalent doses comparable to those for apical effects. These data are relevant for human health assessments of TCE and PCE as they provide data for dose-response analysis of the toxicity mechanisms. Additionally, they provide further evidence that transcriptomic data can be useful surrogates for in vivo PODs, especially when toxicokinetic differences are taken into account" |
| Keywords: | "Animals Dose-Response Relationship, Drug Environmental Pollutants/*toxicity Gene Expression Profiling/*methods Gene Expression Regulation Gene Regulatory Networks Kidney/*drug effects/metabolism Liver/*drug effects/metabolism Male Mice Risk Assessment Seq;" |
| Notes: | "MedlineZhou, Yi-Hui Cichocki, Joseph A Soldatow, Valerie Y Scholl, Elizabeth H Gallins, Paul J Jima, Dereje Yoo, Hong-Sik Chiu, Weihsueh A Wright, Fred A Rusyn, Ivan eng F32 ES026005/ES/NIEHS NIH HHS/ P42 ES005948/ES/NIEHS NIH HHS/ P42 ES027704/ES/NIEHS NIH HHS/ Comparative Study 2017/10/04 Toxicol Sci. 2017 Nov 1; 160(1):95-110. doi: 10.1093/toxsci/kfx165" |
