Molecular Mechanisms of Nitroarene Toxicity

描述（由申请人提供）：癌症是一个通用术语，是指超过一百种不同的疾病，其特征在于不受控制的细胞分裂以及这些细胞侵入和破坏周围正常组织的能力。从病因学上讲，癌症是一种受多种因素影响的缓慢发展的疾病，包括暴露于环境毒素，生活方式，病毒感染和个体遗传组成。增加癌症风险的已知因素包括吸烟，暴露于紫外线或电离辐射，以及摄入空气，水或食物中存在的环境有毒物质。硝基芳烃是在香烟烟雾、粉煤灰和柴油机废气中发现的广泛污染物。这些化合物与细胞DNA反应，形成大的碱基损伤，可导致基因突变，最终引发致癌过程。核苷酸切除修复（NER）系统通过去除大体积DNA损伤和恢复基因组完整性来对抗这些影响。着色性干皮病和Cockayne综合征是由NER缺乏引起的两种遗传疾病，是DNA损伤持续存在对人类健康造成破坏性后果的明显例子。 在这项应用中，我们计划使用多学科的方法来确定介导的3-硝基苯蒽酮（3-NBA），一种流行的环境毒物的毒性的分子机制。我们的建议的指导假设是，3-NBA可以形成加合物，增加DNA的稳定性，而不会扰乱其结构。因此，这些病变逃脱了NER处理，持续存在于DNA中并延长了其毒性作用。我们将通过建立具有来自3-NBA的位点特异性加合物的双链体的溶液结构和热力学参数（目的2）并通过哺乳动物NER系统（目的3）建立其加工来测试我们的假设。作为生物学终点，我们将研究3-NBA加合物的致突变潜力，并建立哺乳动物细胞中跨损伤合成的机制（目的4）。化学合成是我们研究的基础，也是我们提案的一个组成部分（目标1）。我们期望我们的多学科方法将定义3- NBA毒性的相关机制，进而确定环境暴露和疾病风险的更好生物标志物。

DESCRIPTION (provided by applicant): Cancer is a general term that refers to more than a hundred of different diseases characterized by uncontrolled cell division and the capacity of these cells to invade and destroy surrounding normal tissues. Etiologically, cancer is a slow developing condition affected by multiple factors including exposure to environmental toxics, lifestyle, viral infections and individual genetic makeup. Known factors that increase cancer risk include tobacco smoke, exposure to UV or ionizing radiation, and the intake of environmental toxicants present in the air, water or foods. Nitroarenes are widespread pollutants found in cigarette smoke, coal fly ash, and diesel exhaust. These compounds react with cellular DNA forming bulky base lesions that can cause gene mutations and eventually trigger carcinogenic processes. The nucleotide excision repair (NER) system opposes these effects by removing bulky DNA lesions and restoring genome integrity. Xeroderma Pigmentosum and Cockayne syndrome, two genetic diseases caused by NER deficiencies, are flagrant examples of the damaging consequences that the persistence of DNA lesions have for human health. In this application, we plan to use a multidisciplinary approach to determine the molecular mechanisms that mediate the toxicity of 3-nitrobenzanthrone (3-NBA), a prevalent environmental toxicant. The guiding hypothesis of our proposal is that 3-NBA can form adducts that increase DNA stability without perturbing its structure. As a result, these lesions escape NER processing, persisting in DNA and extending their toxic effects. We will test our hypothesis by establishing the solution structure and thermodynamic parameters of duplexes having site specific adducts derived from 3-NBA (aim 2) and establishing their processing by the mammalian NER system (aim 3). As biological end-point, we will investigate the mutagenic potential of 3-NBA adducts and establish the mechanisms of trans-lesion synthesis in mammalian cells (aim 4). Chemical synthesis by which we develop methods for the preparation and site-specific incorporation of these adducts into 2'- oligodeoxynucleotides, is the foundation of our studies and forms an integral part of the proposal (aim 1). We expect that our multidisciplinary approach will define the relevant mechanisms of 3- NBA toxicity and, in turn, identify better biomarkers of environmental exposure and disease risk.