title: Identification of specific mRNA signatures as fingerprints for carcinogenesis in mice induced by genotoxic and nongenotoxic hepatocarcinogens.
abstract: Long-term rodent carcinogenicity studies for evaluation of chemicals and pharmaceuticals concerning their carcinogenic potential to humans are currently receiving critical revision. Additional data from mechanistic studies can support cancer risk assessment by clarifying the underlying mode of action. In the course of the IMI MARCAR project, a European consortium of EFPIA partners and academics, which aims to identify biomarkers for nongenotoxic carcinogenesis, a toxicogenomic mouse liver database was generated. CD-1 mice were orally treated for 3 and 14 days with 3 known genotoxic hepatocarcinogens: C.I. Direct Black 38, Dimethylnitrosamine and 4,4'-Methylenedianiline; 3 nongenotoxic hepatocarcinogens: 1,4-Dichlorobenzene, Phenobarbital sodium and Piperonyl butoxide; 4 nonhepatocarcinogens: Cefuroxime sodium, Nifedipine, Prazosin hydrochloride and Propranolol hydrochloride; and 3 compounds that show ambiguous results in genotoxicity testing: Cyproterone acetate, Thioacetamide and Wy-14643. By liver mRNA expression analysis using individual animal data, we identified 64 specific biomarker candidates for genotoxic carcinogens and 69 for nongenotoxic carcinogens for male mice at day 15. The majority of genotoxic carcinogen biomarker candidates possess functions in DNA damage response (eg, apoptosis, cell cycle progression, DNA repair). Most of the identified nongenotoxic carcinogen biomarker candidates are involved in regulation of cell cycle progression and apoptosis. The derived biomarker lists were characterized with respect to their dependency on study duration and gender and were successfully used to characterize carcinogens with ambiguous genotoxicity test results, such as Wy-14643. The identified biomarker candidates improve the mechanistic understanding of drug-induced effects on the mouse liver that result in hepatocellular adenomas and/or carcinomas in 2-year mouse carcinogenicity studies.
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kossler
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium katja.matheis@boehringer-ingelheim.com.
authors.forename: Katja A
authors.initials: KA
authors.lastname: Matheis
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Ostenfeldt
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Bach Toft
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dhalluin
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deschl
authors.affiliation: *Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany, H. Lundbeck A/S, 2500 Valby, Denmark and UCB Pharma S.A., 1070 Brussels, Belgium.
authors.forename: Arno
authors.initials: A
authors.lastname: Kalkuhl
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics; D002273:Carcinogens / Q000145:classification / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics*; D012737:Sex Factors; D013997:Time Factors; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger
keywords: biomarker candidates; genotoxic carcinogens; individual animal fold changes; mouse liver; nongenotoxic carcinogens; toxicogenomics