1. Editor’s Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes
- Author
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Chris D. Vulpe, Jun Nakamura, Alex Loguinov, Jonathan B. Asfaha, Michael Fasullo, Lee E. Moore, Vanessa Y. De La Rosa, Luoping Zhang, Martyn T. Smith, Peng Li, Ghislaine Scelo, James A. Swenberg, and Nathaniel Rothman
- Subjects
0301 basic medicine ,DNA Repair ,DNA repair ,Metabolite ,Saccharomyces cerevisiae ,Computational biology ,Biology ,Functional Genomics of Tce Metabolites Genotoxicity ,Toxicology ,medicine.disease_cause ,Risk Assessment ,Toxicogenetics ,Cell Line ,Birds ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Species Specificity ,Gene Expression Regulation, Fungal ,Databases, Genetic ,medicine ,Animals ,Humans ,DNA, Fungal ,Mode of action ,Gene ,Genetic Association Studies ,Genetics ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Computational Biology ,High-Throughput Nucleotide Sequencing ,RNA, Fungal ,Trichloroethylene ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Environmental Pollutants ,Transcriptome ,Homologous recombination ,Toxicogenomics ,Functional genomics ,Genotoxicity - Abstract
Trichloroethylene (TCE), an industrial chemical and environmental contaminant, is a human carcinogen. Reactive metabolites are implicated in renal carcinogenesis associated with TCE exposure, yet the toxicity mechanisms of these metabolites and their contribution to cancer and other adverse effects remain unclear. We employed an integrated functional genomics approach that combined functional profiling studies in yeast and avian DT40 cell models to provide new insights into the specific mechanisms contributing to toxicity associated with TCE metabolites. Genome-wide profiling studies in yeast identified the error-prone translesion synthesis (TLS) pathway as an import mechanism in response to TCE metabolites. The role of TLS DNA repair was further confirmed by functional profiling in DT40 avian cell lines, but also revealed that TLS and homologous recombination DNA repair likely play competing roles in cellular susceptibility to TCE metabolites in higher eukaryotes. These DNA repair pathways are highly conserved between yeast, DT40, and humans. We propose that in humans, mutagenic TLS is favored over homologous recombination repair in response to TCE metabolites. The results of these studies contribute to the body of evidence supporting a mutagenic mode of action for TCE-induced renal carcinogenesis mediated by reactive metabolites in humans. Our approach illustrates the potential for high-throughput in vitro functional profiling in yeast to elucidate toxicity pathways (molecular initiating events, key events) and candidate susceptibility genes for focused study.
- Published
- 2017