title: Finding transcriptomics biomarkers for in vivo identification of (non-)genotoxic carcinogens using wild-type and Xpa/p53 mutant mouse models.
abstract: The carcinogenic potential of chemicals and pharmaceuticals is traditionally tested in the chronic, 2 year rodent bioassay. This assay is not only time consuming, expensive and often with a limited sensitivity and specificity but it also causes major distress to the experimental animals. A major improvement in carcinogenicity testing, especially regarding reduction and refinement of animal experimentation, could be the application of toxicogenomics. The ultimate aim of this study is to demonstrate a proof-of-principle for transcriptomics biomarkers in various tissues for identification of (subclasses of) carcinogenic compounds after short-term in vivo exposure studies. Both wild-type and DNA repair-deficient Xpa(-/-)/p53(+/-) (Xpa/p53) mice were exposed up to 14 days to compounds of three distinct classes: genotoxic carcinogens (GTXC), non-genotoxic carcinogens (NGTXC) and non-carcinogens. Subsequently, extensive transcriptomics analyses were performed on several tissues, and transcriptomics data were screened for potential biomarkers using advanced statistical learning techniques. For all tissues analyzed, we identified multigene gene-expression signatures that are, with a high confidence, predictive for GTXC and NGTXC exposures in both mouse genotypes. Xpa/p53 mice did not perform better in the short-term bioassay. We were able to achieve a proof-of-principle for the identification and use of transcriptomics biomarkers for GTXC or NGTXC. This supports the view that toxicogenomics with short-term in vivo exposure provides a viable tool for classifying (geno)toxic compounds.
authors.affiliation: MicroArray Department and Integrative Bioinformatics Unit, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martijs J
authors.initials: MJ
authors.lastname: Jonker
authors.forename: Oskar
authors.initials: O
authors.lastname: Bruning
authors.forename: Maarten
authors.initials: M
authors.lastname: van Iterson
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: Schaap
authors.forename: Tessa V
authors.initials: TV
authors.lastname: van der Hoeven
authors.forename: Harry
authors.initials: H
authors.lastname: Vrieling
authors.forename: Rudolf B
authors.initials: RB
authors.lastname: Beems
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Vries
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Timo M
authors.initials: TM
authors.lastname: Breit
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D002273:Carcinogens; D005819:Genetic Markers; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D012313:RNA