Editor’s Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes

Autor: 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, Nathaniel Rothman
Rok vydání: 2017
Předmět:
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
Zdroj: Toxicological Sciences. 160:111-120
ISSN: 1096-0929
1096-6080
DOI: 10.1093/toxsci/kfx159
Popis: 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.
Databáze: OpenAIRE
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