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Klaus, V. ; Bastek, H.* ; Damme, K.* ; Collins, L.B.* ; Frötschl, R.* ; Benda, N.* ; Lutter, D. ; Ellinger-Ziegelbauer, H.* ; Swenberg, J.A.* ; Dietrich, D.R.* ; Stemmer, K.

Time-matched analysis of DNA adduct formationand early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats.

Arch. Toxicol. 91, 3427–3438 (2017)
Postprint DOI PMC
Open Access Green
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 O(6)-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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Biomarkers Of Effect ; Biomarkers Of Exposure ; Dna Adducts ; Eker Rat ; Kidney Cancer ; Methylazoxymethanol Acetate; Cell-proliferation; Alkylating-agents; Risk-assessment; Repair; Damage; Exposure; Cancer; Predisposition; Tumorigenesis; Inhibition
ISSN (print) / ISBN 0340-5761
e-ISSN 1432-0738
Zeitschrift Archives of Toxicology
Quellenangaben Band: 91, Heft: 10, Seiten: 3427–3438 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Heidelberg
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)