Ir. A. Paini: Generation of in vitro data to model dose dependent in vivo DNA binding of genotoxic carcinogens and its consequences: -the case of estragole-

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26 mrt 2012 11:00 - 26 mrt 2012 12:30
Locatie: Aula, gebouw 362, Gen. Foulkesweg 1, Wageningen
Organisatie: Wageningen University
Promotor: prof.dr. I.M.C.M Rietjens (Toxicologie)
Promotor: Prof. dr. P.J. van Bladeren
Co-Promotor: G. Scholz

 The present thesis describes a study on the dose-dependent DNA adduct formation and repair in the liver of rat and human exposed to genotoxic carcinogens taking the alkenylbenzene estragole as the model compound. Estragole is present in herbs and spices like for example basil and food product derived thereof like pesto. The thesis describes a quantitative analysis of the level of DNA adduct formation at carcinogenic dose levels for different genotoxic liver carcinogens which reveals that the carcinogenic potential of DNA adducts may vary with the nature of the adduct formed. The thesis also describes the use of in vitro data to extend the physiologically based biokinetic (PBBK) model for bioactivation and detoxification of estragole into a so-called physiologically based biodynamic (PBBD) model, able to predict the dose dependent levels of DNA adduct formation in the liver, the target organ for tumor formation by estragole. In a next step the PBBD model defined and validated for rat is extrapolated to human and this allows prediction of DNA adduct formation in human liver at realistic low dose levels. Omics based changes accompanying the processes of DNA adduct formation and repair were also analysed and provide further insight in the Mode of Action of estragole. All together the results obtained provide better insight in dose-dependent behaviour of an important step in the Mode of Action of a genotoxic carcinogen and are one step closer to in silico models for prediction the ultimate biological effect resulting from exposure to a genotoxic carcinogen, the formation tumors.

Thesis title: Generation of in vitro data to model dose dependent in vivo DNA binding of genotoxic carcinogens and its consequences: -the case of estragole-
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