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

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2017
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Klaus, Valentina
Damme, Katja
Collins, Leonard B
Frötschl, Roland
Benda, Norbert
Lutter, Dominik
Ellinger-Ziegelbauer, Heidrun
Swenberg, James A.
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Archives of toxicology. 2017, 91(10), pp. 3427-3438. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-1953-6
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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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ISO 690KLAUS, Valentina, Heinke BASTEK, Katja DAMME, Leonard B COLLINS, Roland FRÖTSCHL, Norbert BENDA, Dominik LUTTER, Heidrun ELLINGER-ZIEGELBAUER, James A. SWENBERG, Daniel R. DIETRICH, Kerstin STEMMER, 2017. Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats. In: Archives of toxicology. 2017, 91(10), pp. 3427-3438. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-1953-6
BibTex
@article{Klaus2017Timem-40629,
  year={2017},
  doi={10.1007/s00204-017-1953-6},
  title={Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats},
  number={10},
  volume={91},
  issn={0340-5761},
  journal={Archives of toxicology},
  pages={3427--3438},
  author={Klaus, Valentina and Bastek, Heinke and Damme, Katja and Collins, Leonard B and Frötschl, Roland and Benda, Norbert and Lutter, Dominik and Ellinger-Ziegelbauer, Heidrun and Swenberg, James A. and Dietrich, Daniel R. and Stemmer, Kerstin}
}
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