Archives of Toxicology

, Volume 91, Issue 10, pp 3427–3438 | Cite as

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

  • Valentina Klaus
  • Heinke Bastek
  • Katja Damme
  • Leonard  B. Collins
  • Roland Frötschl
  • Norbert Benda
  • Dominik Lutter
  • Heidrun Ellinger-Ziegelbauer
  • James A. Swenberg
  • Daniel R. Dietrich
  • Kerstin StemmerEmail author
Genotoxicity and Carcinogenicity


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.


Methylazoxymethanol acetate DNA adducts Kidney cancer Eker rat Biomarkers of effect Biomarkers of exposure 



The authors thank Tanja Lampertsdoerfer, Gudrun von Scheven, Evelyn O’Brien and Alexandra Heussner for their skillful assistance during the animal experiment and Paul Pfluger for critically reading the manuscript. This work was supported by the Federal Ministry of Education and Research (BMBF: 0313024). The UNC Biomarker Mass Spectrometry Facility is partially supported by NIEHS grant P30-ES010126.

Supplementary material

204_2017_1953_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1547 KB)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Valentina Klaus
    • 1
  • Heinke Bastek
    • 2
  • Katja Damme
    • 3
  • Leonard  B. Collins
    • 3
  • Roland Frötschl
    • 4
  • Norbert Benda
    • 4
  • Dominik Lutter
    • 1
  • Heidrun Ellinger-Ziegelbauer
    • 5
  • James A. Swenberg
    • 3
  • Daniel R. Dietrich
    • 2
  • Kerstin Stemmer
    • 6
    Email author
  1. 1.Computational Discovery Research, Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD)Helmholtz Zentrum MünchenNeuherbergGermany
  2. 2.Human and Environmental ToxicologyUniversity of KonstanzKonstanzGermany
  3. 3.Department of Environmental Sciences and EngineeringUniversity of North Carolina at Chapel HillChapel HillUnited States
  4. 4.Federal Institute for Drugs and Medical DevicesBonnGermany
  5. 5.Investigational Toxicology, DD-ED-Toxicology, Bayer AGWuppertalGermany
  6. 6.Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD)Helmholtz Zentrum MünchenNeuherbergGermany

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