Prediction of non-genotoxic carcinogenesis in rats using changes in gene expression following acute dosing

• Published in: Chemico-biological interactions Vol. 172; no. 3; pp. 206 - 215
• Main Authors: Nioi, Paul, Pardo, Ingrid D.R., Sherratt, Philip J., Snyder, Ronald D.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.04.2008
• Subjects: 2-Year bioassay; Animals; Biological Assay - methods; Biomarkers - analysis; Carcinogenicity Tests; Carcinogens - toxicity; Dose-Response Relationship, Drug; Gene expression changes; Gene Expression Regulation, Neoplastic - genetics; Gene signature; Male; Non-genotoxic carcinogenesis; Polymerase Chain Reaction; Predictive Value of Tests; Rats; Rats, Sprague-Dawley; Risk Assessment; Short-term dosing; Time Factors; Gene expression changes; Gene signature; Short-term dosing; 2-Year bioassay; Non-genotoxic carcinogenesis
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2008.01.009

Non-genotoxic carcinogenicity of chemicals is currently routinely evaluated in 2-year rodent bioassays. Therefore, the development of early biomarkers for non-genotoxic carcinogenesis would result in substantial savings in time and expense. The current study investigates whether early changes in gene expression may be developed as markers for cancer. Animals were treated for 1 or 5 days with either non-genotoxic carcinogens (NGTCs) or non-carcinogens and gene expression was analyzed by quantitative PCR (qPCR). We tested two gene signatures previously reported to detect non-genotoxic carcinogens. Using one gene signature it was confirmed that 3/3 non-genotoxic carcinogens and 2/2 non-carcinogens are correctly identified with data from 1 or 5 days of dosing. In contrast an alternative signature correctly identified 0/3 and 2/3 non-genotoxic carcinogens at 1 and 5 days of treatment, respectively and 2/2 non-carcinogens at both time-points. Additionally, we evaluated a novel panel of putative biomarker genes, from the literature, many of which have roles in cell growth and division, including myc, cdc2 and mcm6. These genes were significantly induced by non-genotoxic carcinogens and not by non-carcinogens. Using the average fold-induction across this panel, 2/3 non-genotoxic carcinogens were detected at both 1 and 5 days. These data support the idea that acute changes in gene expression may provide biomarkers for non-genotoxic carcinogenesis but also highlight interesting differences in the sensitivities of distinct gene signatures.