Transcriptomic fingerprints in human peripheral blood mononuclear cells indicative of genotoxic and non-genotoxic carcinogenic exposure

• Published in: Mutation research Vol. 746; no. 2; pp. 124 - 134
• Main Authors: Hochstenbach, K., van Leeuwen, D.M., Gottschalk, R.W., Gmuender, H., Stølevik, S.B., Nygaard, U.C., Løvik, M., Granum, B., Namork, E., van Loveren, H., van Delft, J.H.M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-08-2012; Elsevier BV
• Subjects: Biomarker; biomarkers; Biomarkers - analysis; Biomarkers, Tumor - analysis; Blood; Blood cells; Carcinogens; Carcinogens - toxicity; Cells; DNA microarrays; Gene expression; Gene Expression Profiling; Genomes; Genomics; Genotoxicity; Human; Human exposure; Humans; Leukocytes, Mononuclear - chemistry; Liver; Mutagenesis; Mutagens - toxicity; Non-genotoxic carcinogenicity; Peripheral blood mononuclear cells; Signal Transduction; Toxicity; Transcription factors; Transcriptome; Transcriptomics; Non-genotoxic carcinogenicity; Human; Peripheral blood mononuclear cells; Biomarker; Transcriptomics; Genotoxicity
• ISSN: 1383-5718; 0027-5107; 1879-3592
• DOI: 10.1016/j.mrgentox.2012.01.002

► Existing genotoxicity biomarkers provide limited mechanistic insight. ► Furthermore, they do not allow detection of exposure to non-genotoxic carcinogens. ► Potentially, transcriptomics can overcome these limitations. ► We investigate transcriptomic responses to (non-) genotoxic exposure in human PBMC. ► Profiles indicative of genotoxic and non-genotoxic exposure were identified.
For evaluating genotoxic exposure in human populations a number of biomarkers has been successfully applied over the last 30 years to determine early biological effects due to exposure to carcinogens. Despite their success, these early biological effect markers provide limited mechanistic insight, and do not allow detection of exposure to non-genotoxic carcinogens. Gene expression profiling forms a promising tool for the development of new biomarkers in blood cells to overcome these limitations. The aim of our research was to identify novel genomics-based candidate markers for genotoxic and non-genotoxic carcinogen exposure in human peripheral blood cells (PBMC). Whole genome gene expression changes were investigated following 20h of in vitro exposure to a high and low concentration of eight genotoxic and three non-genotoxic carcinogenic compounds using whole genome microarrays. Per condition, PBMC of five independent donors were exposed, all in the presence of human liver S9. Sets of genes, as well as biological pathways indicative of genotoxic exposure and of non-genotoxic carcinogenic exposure were identified. Furthermore, networks were built using the genotoxic and non-genotoxic gene sets, showing the majority of the genes to be interlinked and revealing distinctive transcription factors for both classes. The identification of these potential candidate marker genes might contribute to the development of genomic based biomarkers of carcinogen exposure.