You are here:
Activation Levels of MIE Transcriptional Biomarkers Identify Liver Tumorigenic Dose Levels
Citation:
Corton, C. Activation Levels of MIE Transcriptional Biomarkers Identify Liver Tumorigenic Dose Levels. Environmental Mutagenesis and Genomics Society (EGMS) and 13th International Conference on Environmental Mutagens (ICEM), Ottawa, N/A, CANADA, August 27 - September 01, 2022. https://doi.org/10.23645/epacomptox.23280206
Impact/Purpose:
Invited presentation to the 53rd Environmental Mutagenesis and Genomics Society (EGMS) and 13th International Conference on Environmental Mutagens (ICEM) conference August 2022. Traditional data sources for cancer hazard assessment are resource-intensive, retrospective, and not feasible for the vast majority of chemicals. Transcriptional biomarkers provide a clear example of viable opportunities for immediate use driven by imminent changes in ICH S1 carcinogenicity testing guidance for pharmaceuticals, and analogous changes evolving for evaluating industrial and agrochemicals. The availability of quantitative, predictive transcriptional biomarkers predictive of changes in cancer-outcome AOPs will have many applications in risk assessment in both the pharmaceutical and chemical sectors. This talk will provide examples of how gene expression biomarkers are built and used in short-term (≤ 28d) testing of the ability of chemicals to induce liver tumors.
Description:
Traditional data sources for cancer hazard assessment are resource-intensive, retrospective, and not feasible for the vast majority of chemicals. Transcriptional biomarkers provide a clear example of viable opportunities for immediate use driven by imminent changes in ICH S1 carcinogenicity testing guidance for pharmaceuticals, and analogous changes evolving for evaluating industrial and agrochemicals. The availability of quantitative, predictive transcriptional biomarkers predictive of changes in cancer-outcome AOPs will have many applications in risk assessment in both the pharmaceutical and chemical sectors. This talk will provide examples of how gene expression biomarkers are built and used in short-term (≤ 28d) testing of the ability of chemicals to induce liver tumors. Six transcriptional biomarkers have been built that predict the major molecular initiating events (MIEs) of liver tumor induction including genotoxicity, cytotoxicity, and activation of the xenobiotic receptors aryl hydrocarbon receptor (AhR), constitutive activated receptor (CAR), estrogen receptor (ER), and peroxisome proliferator-activated receptor α (PPARα). Using full-genome microarrays, these biomarkers can be used to identify chemicals that activate these events with accuracy of 91-98%. Chemical-independent activation levels for the individual biomarkers that are associated with tumor induction could accurately (up to 100%) identify chemical doses that were tumorigenic. These results show that a MIE-directed approach using only chemical-induced transcriptional changes and biomarker tumorigenic activation levels could be applied to short-term assays to identify chemicals and their doses that cause tumors. (This abstract does not reflect EPA policy.)
URLs/Downloads:
DOI: Activation Levels of MIE Transcriptional Biomarkers Identify Liver Tumorigenic Dose Levels
CORTON_CANCER_NAM_EMGS_08_27_22V4.PDF (PDF, NA pp, 3069.299 KB, about PDF)