ArticleToxicological sciences : an official journal of the Society of Toxicology2020
A Set of Six Gene Expression Biomarkers Identify Rat Liver Tumorigens in Short-term Assays.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Comparison of phenotypic and transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and Ppara-null mouse livers.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Progress in toxicogenomics to protect human health.Nature reviews. Genetics · 2025Review
- Adverse Outcome Pathways Mechanistically Describing Hepatotoxicity.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Bridging organ transcriptomics for advancing multiple organ toxicity assessment with a generative AI approach.NPJ digital medicine · 2024Article
- A novel support vector machine-based 1-day, single-dose prediction model of genotoxic hepatocarcinogenicity in rats.Archives of toxicology · 2024Article
- A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.Frontiers in toxicology · 2024Article
- Assessment of the mode of action underlying development of liver lesions in mice following oral exposure to HFPO-DA and relevance to humans.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death.Toxicologic pathology · 2023Article
- Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens.International journal of molecular sciences · 2022Review
- A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology.Regulatory toxicology and pharmacology : RTP · 2021Article
- Benchmark Concentrations for Untargeted Metabolomics Versus Transcriptomics for Liver Injury Compounds in In Vitro Liver Models.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- A Modern Genotoxicity Testing Paradigm: Integration of the High-Throughput CometChip® and the TGx-DDI Transcriptomic Biomarker in Human HepaRG™ Cell Cultures.Frontiers in public health · 2021Article
- A set of six Gene expression biomarkers and their thresholds identify rat liver tumorigens in short-term assays.Toxicology · 2020Article
- Thresholds Derived From Common Measures in Rat Studies Are Predictive of Liver Tumorigenic Chemicals.Toxicologic pathology · 2020Article
- Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Chemical-induced liver cancer occurs in rodents through well-characterized adverse outcome pathways. We hypothesized that measurement of the 6 most common molecular initiating events (MIEs) in liver cancer adverse outcome pathways in short-term assays using only gene expression will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in 2-year bioassays. We tested this hypothesis using transcript data from a rat liver microarray compendium consisting of 2013 comparisons of 146 chemicals administered at doses with previously established effects on rat liver tumor induction. Five MIEs were measured using previously characterized gene expression biomarkers composed of gene sets predictive for genotoxicity and activation of 1 or more xenobiotic receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Because chronic injury can be important in tumorigenesis, we also developed a biomarker for cytotoxicity that had a 96% balanced accuracy. Characterization of the genes in each biomarker set using the unsupervised TXG-MAP network model demonstrated that the genes were associated with distinct functional coexpression modules. Using the Toxicological Priority Index to rank chemicals based on their ability to activate the MIEs showed that chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Balanced accuracies using thresholds derived from either TG-GATES or DrugMatrix data sets to predict tumorigenicity in independent sets of chemicals were up to 93%. These results show that a MIE-directed approach using only gene expression biomarkers could be used in short-term assays to identify chemicals and their doses that cause tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.