Toxiology of Particulate Cr(VI)in Human Lung Cells

人肺细胞中颗粒 Cr(VI) 的毒理学

• 批准号: 6910834
• 负责人: John Pierce Wise
• 金额: $ 28.43万
• 依托单位: UNIVERSITY OF SOUTHERN MAINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910834
• 关键词: DNA damage; bronchus; cell cycle; cell line; chemical carcinogenesis; chromium; environmental exposure; environmental toxicology; lung neoplasms; mass spectrometry; particle; respiratory epithelium; transmission electron microscopy

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.

Cr(VI) 盐，特别是不溶性化合物，是公认的人类致癌物，会影响肺部支气管细胞。 尚无研究研究颗粒 Cr(VI) 的研究，只有一项研究研究人类支气管细胞中可溶性 Cr(VI) 的研究。因此，本研究的目的是了解 Cr(VI) 诱导人支气管细胞致癌的机制。 指导这一提议的一般假设是，颗粒状 Cr(VI) 比可溶性 Cr(VI) 是一种更有效的致癌物质，因为它可以在基因毒性剂量下逃避细胞周期停滞。 该项目的具体目标是建立人类支气管细胞模型来研究这些机制。 将测试三个假设：1) Cr(VI) 对人类支气管细胞具有遗传毒性。 2) 颗粒状 Cr(VI) 化合物比可溶性 Cr(VI) 化合物是更有效的致癌物，因为它们提供慢性细胞外 Cr(VI) 暴露并逃避细胞周期延迟。 3) 颗粒 Cr(VI) 盐由于其二价抗衡离子而避免了细胞周期延迟。 这些假设将通过以下内容进行测试：1) Cr(VI) 诱导的遗传毒性将通过彗星测定和中期染色体扩散中产生的损伤量来测量。 结果将提供有关完整 Cr(VI) 颗粒对其靶细胞的致癌和基因毒性影响的第一批数据。 2) 颗粒吸收将用透射电子显微镜测量，离子吸收将用电感耦合等离子体质谱法测量。 3）。细胞周期效应将通过有丝分裂指数、荧光自动细胞分选和 cDNA 表达阵列来测量。 结果将首次报告 Cr(VI) 在其靶细胞中的毒性，首次报告 Cr(VI) 与细胞周期相互作用的详细信息，并将提供关于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) 更好地评估接触颗粒物或可溶性 Cr(VI) 的相对风险的基本信息； 3) 用于进一步研究 Cr(VI)、其他金属和肺癌的人类支气管细胞模型。

项目成果

Airborne particulates and asthma: a Maine case study.

空气中的颗粒物和哮喘：缅因州的案例研究。

• DOI: 10.1191/0748233705th218oa
• 发表时间: 2005
• 期刊: Toxicology and industrial health
• 影响因子: 1.9
• 作者: Langley-Turnbaugh,SamanthaJ;Gordon,NancyR;Lambert,Thomas
• 通讯作者: Lambert,Thomas

Human lung cell growth is not stimulated by lead ions after lead chromate-induced genotoxicity.

铬酸铅引起的基因毒性后，铅离子不会刺激人肺细胞的生长。

• DOI: 10.1007/s11010-005-8217-0
• 发表时间: 2005
• 期刊: Molecular and cellular biochemistry
• 影响因子: 4.3
• 作者: Wise,SandraS;Holmes,AmieL;Moreland,JonathanA;Xie,Hong;Sandwick,SarahJ;Stackpole,MeganM;Fomchenko,Elena;Teufack,Sonia;MayJr,AlfredJ;Katsfis,SpirosP;WiseSr,JohnPierce
• 通讯作者: WiseSr,JohnPierce

Comparison of two particulate hexavalent chromium compounds: Barium chromate is more genotoxic than lead chromate in human lung cells.

两种颗粒六价铬化合物的比较：铬酸钡对人体肺细胞的遗传毒性比铬酸铅更大。

• DOI: 10.1002/em.20044
• 发表时间: 2004
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Wise,SandraS;Schuler,JulieHC;Holmes,AmieL;Katsifis,SpirosP;Ketterer,MichaelE;Hartsock,WendyJ;Zheng,Tongzhang;WiseSr,JohnPierce
• 通讯作者: WiseSr,JohnPierce

XRCC1 protects cells from chromate-induced chromosome damage, but does not affect cytotoxicity.

XRCC1 保护细胞免受铬酸盐诱导的染色体损伤，但不影响细胞毒性。

• DOI: 10.1016/j.mrgentox.2006.06.010
• 发表时间: 2006
• 期刊: Mutation research
• 作者: Grlickova-Duzevik,Eliza;Wise,SandraS;Munroe,RayC;Thompson,WDouglas;WiseSr,JohnPierce
• 通讯作者: WiseSr,JohnPierce

XRCC1 protects against particulate chromate-induced chromosome damage and cytotoxicity in Chinese hamster ovary cells.

XRCC1 可防止中国仓鼠卵巢细胞中颗粒铬酸盐诱导的染色体损伤和细胞毒性。

• DOI: 10.1093/toxsci/kfj183
• 发表时间: 2006
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Grlickova-Duzevik,Eliza;Wise,SandraS;Munroe,RayC;Thompson,WDouglas;WiseSr,JohnPierce
• 通讯作者: WiseSr,JohnPierce