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

膀胱癌是最常见的癌症之一，通常与暴露于某些化学物质有关。除了已知的致癌物如2-萘胺，多环芳烃越来越多地被讨论为风险因素。此外，还观察到柴油机废气与膀胱癌之间存在正相关。柴油机尾气中的硝化多环芳烃3-硝基苯并蒽酮（3-NBA）是一种强致突变和致染色体断裂的化合物。3-NBA被还原为活性中间体，并在Ames测试中获得了有史以来最高的分数。在大鼠体内具有致癌性，可导致肺肿瘤，IARC将其归类为可能对人类致癌。在肺、肾和膀胱等多种器官中检测到加合物和突变频率增加。3-氨基苯并蒽酮（3-阿坝）是3-NBA的主要代谢产物。因此，可以假设膀胱也是毒性的靶器官。由于迄今为止大多数研究仅部分研究了肺细胞中占主导地位的潜在机制，因此拟议的项目将突出尿路上皮细胞对3-NBA的细胞反应。最近，癌症生物学回顾了Otto Warburgs对癌细胞中糖酵解转换的描述（1956），并开始阐明癌症中的代谢重编程。虽然代谢在癌症中的重要性越来越明显，但我们对外源性物质暴露的代谢反应的理解落后于毒理学研究的其他领域。能量代谢通过激活戊糖磷酸途径等途径在抗氧化防御和DNA修复中起着重要作用。从毒理学的角度来看，细胞不能成功地通过能量代谢的转换来维持稳态的阈值将是特别感兴趣的。这个阈值可以作为细胞从压力适应到压力相关逆境的过渡点。因此，在拟议的项目中，将研究能量代谢中与抗氧化防御和DNA修复有关的剂量反应关系。此外，这些变化将与p53的翻译后修饰有关，据报道，p53调节能量代谢，抗氧化防御和DNA修复的中心方面。最后，将对潜在的生化控制网络途径进行数学建模，目的是模拟低剂量区的剂量反应曲线。这一办法可能有助于审查最低限度反应问题。

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.