You are here:
Establishing Genomic Biomarkers for the Assessment of Chemical Tumorigenicity Risk
Citation:
Mitchell, C., C. Corton, P. Bushel, H. Ellinger-Ziegelbauer, H. Estrella, M. Gosink, E. McDermott, P. Shankar, R. Hao, A. Podtelezhnikov, J. van der Laan, F. Sistare, AND K. Tanis. Establishing Genomic Biomarkers for the Assessment of Chemical Tumorigenicity Risk. Society of Toxicology 62nd Annual Meeting and ToxExpo 2023, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.25883944
Impact/Purpose:
Presentation to the Society of Toxicology 62nd Annual Meeting and ToxExpo March 2023
Description:
Genomic biomarkers have the potential to reduce the need for conventional rodent cancer bioassays when used in a weight-of-evidence manner together with other classical and mechanistic information from shorter term studies. In a cross-sector initiative, our goal is to develop genomic biomarkers for the measurement of molecular initiating events (MIEs) for hazard identification in short-term rat studies, associated with threshold scores for doses known to induce liver tumors in longer term rat studies. To derive the genomic biomarkers, publicly available transcriptomic data (microarrays, RNA-Seq) from rat livers were collected, quality-controlled, and harmonized resulting in 394 compounds associated with gene expression data, many with multiple doses and time points. These compounds with existing transcriptomic data were then annotated for the MIEs they activate that are known to lead to tumorigenicity in rats (AhR (11 compounds), CAR (13), cytotoxicity (9), ER (5), genotoxicity (10), PPARα (13), and PXR (3)). Annotations were based on pharmacology or reported responses for the pathways of interest (e.g., receptor binding, knockout studies, known target gene responses for specific MIEs, or positive result mutagenicity assays, amongst others). The gene expression data from each set of annotated compounds are being used to build consensus biomarker gene sets derived via multiple statistical approaches. To identify activation levels (thresholds) for tumorigenic risk, MIE biomarker response scores are being compared to rat tumor incidence data compiled from reported 2-year rat bioassays. Biomarkers will be refined with experimental work exposing wildtype (WT) and MIE-specific knockout (KO) rats to reference compounds for each MIE. Future work will include defining the applicability domain for each biomarker by testing them with new and existing sets of rat gene expression data. (This abstract does not represent US EPA or MEB policy.)
URLs/Downloads:
DOI: Establishing Genomic Biomarkers for the Assessment of Chemical Tumorigenicity Risk
SOT2023_HESICARCIGENOMICS_TO_PRINT.PDF (PDF, NA pp, 1751.807 KB, about PDF)