title: Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats.
abstract: Genotoxic carcinogens pose great hazard to human health. Uncertainty of current risk assessment strategies and long latency periods between first carcinogen exposure and diagnosis of tumors have raised interest in predictive biomarkers. Initial DNA adduct formation is a necessary step for genotoxin induced carcinogenesis. However, as DNA adducts not always translate into tumorigenesis, their predictive value is limited. Here we hypothesize that the combined analysis of pro-mutagenic DNA adducts along with time-matched gene expression changes could serve as a superior prediction tool for genotoxic carcinogenesis. Eker rats, heterozygous for the tuberous sclerosis (Tsc2) tumor suppressor gene and thus highly susceptible towards genotoxic renal carcinogens, were continuously treated with the DNA alkylating carcinogen methylazoxymethanol acetate (MAMAc). Two weeks of MAMAc treatment resulted in a time-dependent increase of O6-methylguanine and N7-methylguanine adducts in the kidney cortex, which was however not reflected by significant expression changes of cyto-protective genes involved in DNA repair, cell cycle arrest or apoptosis. Instead, we found a transcriptional regulation of genes involved in the tumor-related MAPK, FoxO and TGF-beta pathways. Continuous MAMAc treatment for up to 6 months resulted in a mild but significant increase of cancerous lesions. In summary, the combined analysis of DNA adducts and early gene expression changes could serve as a suitable predictive tool for genotoxicant-induced carcinogenesis.
authors.affiliation: Computational Discovery Research, Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Klaus
authors.affiliation: Human and Environmental Toxicology, University of Konstanz, Konstanz, Germany.
authors.forename: Heinke
authors.initials: H
authors.lastname: Bastek
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Katja
authors.initials: K
authors.lastname: Damme
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Frötschl
authors.affiliation: Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Benda
authors.affiliation: Computational Discovery Research, Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Investigational Toxicology, DD-ED-Toxicology, Bayer AG, Wuppertal, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Human and Environmental Toxicology, University of Konstanz, Konstanz, Germany.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Dietrich
authors.affiliation: Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany. kerstin.stemmer@helmholtz-muenchen.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D018736:DNA Adducts / Q000032:analysis*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000008:administration & dosage / Q000633:toxicity*; D011922:Rats, Mutant Strains; D013997:Time Factors
chemical_list: D018736:DNA Adducts; D008746:Methylazoxymethanol Acetate; D006147:Guanine; C008450:7-methylguanine; C008449:O-(6)-methylguanine
keywords: Biomarkers of effect; Biomarkers of exposure; DNA adducts; Eker rat; Kidney cancer; Methylazoxymethanol acetate