ROLE OF IRON IN ASBESTOS-INDUCED DNA DAMAGE

这项拟议研究的假设是，铁与 矿物纤维的致癌作用。纤维可以含有固有的铁， 例如青石棉，或者可以获得结合在表面上的铁。要么 固有的或后天获得的铁在表面可能是活跃的，但动员 可能会增加铁与产生氧自由基的反应活性， 会导致毒性和癌症。体外实验将重点放在 两种铁离子对溶液或培养巨噬细胞铁结合的影响 含铁量高的石棉、青石棉和铁石棉，以及 含铁很少或不含铁的致癌矿物，埃里奥石。四个参数 将被监测：表面成分和地形，表面 氧化还原活性，螯合剂动员铁的速率，以及 诱导铁催化的DNA单链断裂的能力。表面 成分和形貌将用X射线光电子进行表征 光谱学、俄歇电子能谱和扫描力显微镜。 表面氧化还原活性铁的量将使用介体， 薄层电池循环伏安法。药物在细胞内的分布 中子活化青石棉中的~(55)Fe在人肺上皮和肺组织中的分布 间皮细胞将与来自[55Fe]转铁蛋白的细胞进行比较。 无毒的铁源，和有毒的铁源[55Fe]NTA。这个 免疫沉淀中10,000×g上清液中55Fe的含量 铁蛋白，在血红素中，在10,000 mW组分(LMW)中，在亚细胞中 细胞器将被确定。低分子螯合剂的性质将是 激光解吸飞行时间质谱仪测定质子 核磁共振和高效液相色谱仪。 从中子活化到低分子形式的铁动员的量 青石棉、铁石棉或铁榴石，卸载或装载铁，将被 比较它们与细胞毒性和铁蛋白合成的关系。

The hypothesis for the proposed research is that iron is responsible for the carcinogenicity of mineral fibers. Fibers can have intrinsic iron, e.g. crocidolite, or can acquire iron which binds to the surface. Either intrinsic or acquired iron may be active at the surface, but mobilization may increase the reactivity of the iron with O2 generating radicals that can cause toxicity and cancer. The in vitro experiments will focus on the effects of iron binding from solution or from cultured macrophages by two forms of asbestos of high iron content, crocidolite and amosite, and a carcinogenic mineral with little or no iron, erionite. Four parameters will be monitored: the surface composition and topography, the surface redox activity, the rate of iron mobilization by chelators, and the ability to induce iron-catalyzed DNA single-strand breaks. The surface composition and topography will be characterized by X-ray photoelectron spectroscopy, Auger electron spectroscopy, and scanning force microscopy. The amount of surface redox active iron will be determined using mediated, thin-layer cell cyclic voltammetry. The intracellular distribution of 55Fe from neutron activated crocidolite in human lung epithelial and mesothelial cells will be compared with that from [55Fe]transferrin, a nontoxic source of iron, and [55Fe]NTA, a toxic source of iron. The amounts of 55Fe in the 10,000 x g supernatant, in immunoprecipitated ferritin, in heme, in <10,000 MW fraction (LMW), and in subcellular organelles will be determined. The nature of the LMW chelator will be determined using laser desorption time-of-flight mass spectrometry, proton nuclear magnetic resonance, and high performance liquid chromatography. The amounts of iron mobilized into the LMW form from neutron-activated crocidolite, amosite, or erionite, unloaded or loaded with iron, will be compared for their relationship with cytotoxicity and ferritin synthesis.