Dose-response modeling of 3-nitrobenzanthrone-induced alterations of the energy metabolism in urothelial cells

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Bladder cancer is one of the most prevalent cancers and is often linked with exposure to certain chemicals. Besides the known carcinogens such as 2-naphthylamine, polycyclic aromatic hydrocarbons are increasingly discussed as risk factors. In addition, a positive association has been observed between exposure to diesel engine exhaust and cancer of the urinary bladder. A powerful mutagenic and clastogenic compound of diesel exhaust is the nitrated polycyclic aromatic hydrocarbon 3-nitrobenzanthrone (3-NBA). 3-NBA is reduced to reactive intermediates and produced the highest score ever reported in the Ames-test. It is carcinogenic in rats causing lung tumors and was classified as possible carcinogenic to humans by the IARC.Adducts and an increased mutant frequency were detected in various organs as lung, kidney and bladder. The main metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), was found in the urine of salt mine workers occupationally exposed to diesel emissions. It can therefore be assumed that the bladder is also a target organ of toxicity. As most studies have so far only partially investigated the underlying mechanism predominant in lung cells, the proposed project will highlight the cellular response to 3-NBA in urothelial cells. Recently, cancer biology has recalled Otto Warburgs description of the switch to glycolysis in cancer cells (1956) and started to elucidate the metabolic reprogramming in cancer. While the importance of metabolism in cancer is becoming increasingly apparent, our comprehension of the metabolic response to xenobiotic exposure lags behind other areas of toxicological research. The energy metabolism plays a fundamental role in the anti-oxidant defense and DNA repair by activating pathways such as the pentose phosphate pathway. From a toxicological point of view the threshold above which the cell cannot successfully manage the maintenance of the homeostasis by the switch in energy metabolism would be of particular interest. This threshold may serve as a point where cell transition from stress adaptation to stress-related adversity takes place. Therefore, in the proposed project, the dose response relationship in the energy metabolism with regard to anti-oxidative defense and DNA repair will be investigated. In addition, the changes will be linked to posttranslational modifications of p53 which is being reported to regulate central aspects of energy metabolism, anti-oxidant defense and DNA repair. Finally, the underlying biochemical control network pathways will be mathematically modelled with the objective of simulating the dose response curve in the low-dose region. This approach might allow examining the issue of threshold response.