Toxiology of Particulate Cr(VI)in Human Lung Cells

Cr（VI）盐，特别是不溶性化合物，是公认的人类致癌物，影响肺的支气管细胞。 没有研究颗粒铬（VI），只有一个研究了可溶性铬（VI）在人支气管细胞。因此，本研究的目的是了解铬（VI）诱导人支气管细胞癌变的机制。 指导这一建议的一般假设是，颗粒状Cr（VI）是一种比可溶性Cr（VI）更有效的致癌物，因为它可以在遗传毒性剂量下逃避细胞周期阻滞。 本项目的具体目标是建立人支气管细胞模型来研究这些机制。 将检验三个假设：1）Cr（VI）在人支气管细胞中具有遗传毒性。2)颗粒状Cr（VI）化合物是比可溶性Cr（VI）化合物更有效的致癌物，因为它们提供慢性细胞外Cr（VI）暴露和逃逸细胞周期延迟。3)颗粒状Cr（VI）盐由于其二价抗衡离子而逃避细胞周期延迟。 这些假设将通过以下方式进行检验：1）Cr（VI）诱导的遗传毒性将通过彗星试验和中期染色体扩散中产生的损伤量进行测量。 结果将提供完整的Cr（VI）颗粒对其靶细胞的致癌性和遗传毒性效应的第一个数据。 2)将采用透射电子显微镜测量颗粒摄取，并采用电感耦合等离子体质谱法测量离子摄取。 3）。将使用有丝分裂指数、荧光自动细胞分选和cDNA表达阵列测量细胞周期效应。 结果将首次报道Cr（VI）在其靶细胞中的毒性，首次详细介绍Cr（VI）与细胞周期相互作用的信息，并将提供有关颗粒和可溶性六价铬之间差异的重要毒理学数据。这项研究意义重大，因为它将提供：1）了解Cr（VI）如何在其靶细胞中引起遗传; 2）更好地评估暴露于颗粒或可溶性Cr（VI）的相对风险的基本信息; 3）人类支气管细胞模型，用于进一步研究Cr（VI），其他金属和肺癌。

Cr(VI) salts, particularly the insoluble compounds, are well-established human carcinogens, affecting the bronchial cells of the lung. No investigations have studied particulate Cr(VI) and only one has studied soluble Cr(VI) in human bronchial cells. Thus the goal of this research is to understand the mechanisms of Cr(VI)-induced carcinogenesis in human bronchial cells. The general hypothesis guiding this proposal is that particulate Cr(VI) is a more potent carcinogen than soluble Cr(VI) because it can escape cell cycle arrest at genotoxic doses. The specific goal of this project is to establish a human bronchial cell model to investigate these mechanisms. Three hypotheses will be tested: 1) Cr(VI) is genotoxic in human bronchial cells. 2) Particulate Cr(VI) compounds are more potent carcinogens than soluble Cr(VI) compounds because they provide chronic extracellular Cr(VI) exposure and escape cell cycle delay. 3) Particulate Cr(VI) salts escape cell cycle delay because of their divalent counter ion. These hypotheses will be tested with the following: 1) Cr(VI)-induced genotoxicity will be measured by the amount of damage produced in the Comet assay, and in metaphase chromosome spreads. Results will provide the first data on the carcinogenic and genotoxic effects of intact Cr(VI) particles to its target cells. 2) Particle uptake will be measured with transmission electron microscopy and ion uptake will be measured with inductively coupled plasma mass spectrometry. 3). Cell cycle effects will be measured with a mitotic index, fluorescent automated cell sorting and cDNA expression arrays. Results will the first reports of Cr(VI) toxicity in its target cells, the first detailed information of the interaction of Cr(VI) with the cell cycle, and will provide important toxicological data on the differences between particulate and soluble hexavalent chromium. This research is significant because it will provide: 1) an understanding of how Cr(VI) causes genetic in its target cells; 2) essential information to better assess the relative risk of exposure to particulate or soluble Cr(VI); 3) models of human bronchial cells for further study of Cr(VI), other metals, and lung cancer in general.