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FE(II) AND DUST INDUCED CARCINOGENESIS

FE(II) 和粉尘诱发的致癌作用

基本信息

批准号：
2277873
负责人：
XI HUANG
金额：
$ 4.19万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 1996-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2277873
关键词：
FE II DUST INDUCED CARCINOGENESIS

项目摘要

Increasing evidence demonstrates that an excess of lung cancer and stomach cancer has been observed in workers of iron ore and steel factories. It has been shown that the incidence of cancer is related to the exposure to airborne mineral dusts. However, the active compound(s) responsible for the observed carcinogenicity of mineral dusts has not yet been identified. Although iron oxide (Fe2O3) particles have been tested and found to produce little carcinogenicity, this was likely due to the insolubility of iron oxide in water, even in a slightly low pH medium. Ferrous ion, one of the most abundant elements in polluted industrial environment, is capable of producing reactive oxygen species (ROS), and may play an important role in mineral dust-induced carcinogenesis. Due to the complexity of iron chemistry, previous studies on iron-induced cell transformation did not take into account some important chemical factors. For example, oxidation of Fe(II) to Fe(III) which results in ROS formation is greatly dependent upon the pH of media. Because of the alkaline pH in cell growth medium, oxidation of Fe(II) to Fe(III) takes place quickly in the extracellular medium. Therefore, the short lived ROS resulting from interaction of Fe(II) and O2 may only damage cell membrane which causes cell toxicity. In contrast, when Fe(II) is deposited on a particle, and phagocytized by cells, the released Fe(II) in cells can induce cell transformation. This is relevant to the mineral dust-induced carcinogenesis. The aims of this proposed research are to compare the carcinogenicity of Fe(I) ions in solution and Fe(II)-containing dusts. Different iron compounds will be tested in SHE cell transformation assay. To further determine the mechanism of Fe(II) containing dust-induced carcinogenesis, dichlorofluorescein will be used to estimate oxidant level in cells. 8-oxo-dG and DNA-protein crosslinkings will be measured to detect the DNA damage induced by iron compounds. In addition to SHE cells, we will also investigate the effect of iron compounds on human tracheal epithelial (HTE) cells. Moreover, we will compare the responsiveness of oxidative stress-responsive transcription factors, such as nuclear factor kB and AP-1 to Fe(II) treatment.

越来越多的证据表明，过量的肺癌和胃癌在铁矿石和钢铁厂的工人中发现了癌症。它研究表明，癌症的发病率与接触空气中的矿物粉尘然而，负责治疗的活性化合物矿物粉尘的致癌性尚未确定。尽管已经测试了氧化铁（Fe 2 O3）颗粒，并且发现其几乎没有致癌性，这可能是由于氧化铁在水中，即使在pH值稍低的介质中。亚铁离子，1 污染的工业环境中最丰富的元素，能够产生活性氧（ROS），并可能发挥在矿物粉尘致癌作用中起重要作用。由于铁化学的复杂性，铁诱导细胞的先前研究转化没有考虑一些重要的化学因素。例如，Fe（II）氧化成Fe（III），导致ROS形成这在很大程度上取决于介质的pH值。由于碱性pH值，在细胞生长培养基中，Fe（II）氧化为Fe（III）在细胞外介质。因此，短寿命的ROS产生于 Fe（II）和O2的相互作用可能仅损伤细胞膜，细胞毒性相反，当Fe（II）沉积在颗粒上时，被细胞吞噬后，细胞内释放的Fe（II）可诱导细胞转型这与矿尘引起的致癌作用这项研究的目的是比较溶液和含铁粉尘中Fe（I）离子的致癌性。将在SHE细胞转化试验中测试不同的铁化合物。为进一步确定含Fe（II）粉尘诱发的机理，致癌作用，二氯荧光素将用于估计氧化剂水平在细胞中。将测量8-氧代-dG和DNA-蛋白质交联，检测铁化合物诱导的DNA损伤。除了SHE之外细胞，我们还将研究铁化合物对人体的影响，气管上皮（HTE）细胞。此外，我们将比较氧化应激反应性转录因子的反应性，如如核因子kB和AP-1对Fe（II）处理。