Uptake and Mutagenicity of Moderately Soluble Hexavalent Chromium

中等溶解度六价铬的吸收和致突变性

• 批准号: 7491192
• 负责人: Diane M Stearns
• 金额: $ 18.13万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491192
• 关键词: Anions; Calcium; Cancer Etiology; Carcinogens; Cations; Cell Line; Cells; Chromates; Chromium; Complementary DNA; Complex; Condition; Confocal Microscopy; Coupled; DNA; DNA Damage; DNA lesion; Data; Dose; Electron Microscopy; Epithelial Cells; Foundations; Frequencies; Gene Mutation; Genomics; Goals; Guanine; Human; Hypoxanthine; Hypoxanthines; Induced Mutation; Industry; International; Ions; Laser Scanning Confocal Microscopy; Lung; Mammalian Cell; Mass Spectrum Analysis; Measures; Metals; Mutation; Mutation Spectra; Numbers; Optics; Oxides; Particulate; Plasma; Purpose; Relative (related person); Risk Assessment; Roentgen Rays; Scanning Electron Microscopy; Scanning Transmission Electron Microscopy Procedures; Strontium; Techniques; Testing; Toxic effect; Transferase; Transmission Electron Microscopy; Water; Work; Zinc; barium chromate; calcium chromate(VI); chromium hexavalent ion; emission spectrometry; extracellular; genotoxicity; insight; lead chromate; neoplastic cell; novel; particle; potassium chromate(VI); research study; sodium chromate(VI); strontium chromate; uptake; water solubility; zinc chromate

DESCRIPTION (provided by applicant): Hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Millions of workers are exposed to Cr(VI) worldwide. The most recent paradigm proposes that the chromate compounds that are moderately water-soluble are more carcinogenic than the chromates that are either insoluble or water-soluble; however, it is not understood why this is so. Most of the data on how chromium damages DNA and causes DNA mutations has come from either the insoluble chromates or the water soluble chromates, not from the moderately soluble chromates that may be the most carcinogenic. The moderately soluble chromates are zinc chromate, strontium chromate and calcium chromate. Several crucial pieces of information are lacking regarding the activity of these moderately soluble chromates. No mutagenicity studies have been carried out with these compounds in human lung epithelial cells, which are the target cells for tumor formation. The types of mutations that these compounds cause have not been characterized in any cell line. The relative mutagenic potency of these chromates is not known. The extent to which these compounds dissolve outside of cells or enter cells as particulates is not known. The involvement of the zinc, strontium and calcium counterions in chromate toxicity is not known. The goals of the current proposal are to explain (1) how the moderately soluble Cr(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the soluble and insoluble chromates. The first aim of this proposal will apply the techniques of inductively coupled plasma mass spectrometry, laser scanning confocal microscopy, transmission electron microscopy, and scanning electron microscopy to determine how the moderately soluble chromates enter cells. The second aim of this proposal will measure and characterize mutations at the hypoxanthine (guanine) phosphoribosyl transferase (hprt) locus caused by the moderately soluble chromates in human lung epithelial cells and will compare mutation frequency and identity with mutations caused by the soluble and insoluble chromates. Data from these experiments will determine the relative mutagenic potency of these chromates, and will give insight into mechanisms of action, i.e., involvement of counterion and possible DNA lesions responsible for the mutations. Data from this proposal will provide mode of action information that will be necessary for thorough human risk assessment. The purpose of this work is to determine how chromium(VI) causes cancer. The goals of this proposal are to explain (1) how the moderately soluble chromium(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the less carcinogenic soluble and insoluble chromates. Understanding the mode of action of these chromates will provide a foundation for human risk assessment.

描述（由申请人提供）：六价铬（Cr(VI)）是一种已知的人类肺癌致癌物。全世界数以百万计的工人暴露于铬（六）。最近的范式提出，适度水溶性的铬酸盐化合物比不溶性或水溶性的铬酸盐更具有致癌性；然而，目前还不清楚为什么会这样。大多数关于铬如何破坏DNA并导致DNA突变的数据来自不溶性铬酸盐或水溶性铬酸盐，而不是来自可能最致癌的中溶性铬酸盐。中溶性铬酸盐有铬酸锌、铬酸锶和铬酸钙。关于这些中等可溶性铬酸盐的活性，缺少几个关键的信息。这些化合物尚未在人肺上皮细胞（肿瘤形成的靶细胞）中进行致突变性研究。这些化合物引起的突变类型尚未在任何细胞系中得到表征。这些铬酸盐的相对诱变效力尚不清楚。这些化合物在细胞外溶解或以颗粒形式进入细胞的程度尚不清楚。锌、锶和钙反离子在铬酸盐毒性中的作用尚不清楚。当前提案的目标是解释(1)中溶性铬（VI）化合物如何进入细胞和(2)中溶性铬酸盐引起的突变是否与可溶性和不溶性铬酸盐引起的突变不同。本提案的第一个目标将应用电感耦合等离子体质谱，激光扫描共聚焦显微镜，透射电子显微镜和扫描电子显微镜技术来确定中等可溶性铬酸盐如何进入细胞。本研究的第二个目标是测量和表征中等可溶性铬酸盐在人肺上皮细胞中引起的次黄嘌呤（鸟嘌呤）磷酸核糖基转移酶（hprt）位点上的突变，并将其与可溶性和不溶性铬酸盐引起的突变的频率和特性进行比较。来自这些实验的数据将确定这些铬酸盐的相对诱变效力，并将深入了解作用机制，即反离子的参与和可能导致突变的DNA损伤。该提案的数据将提供行动方式信息，这将是对人类风险进行全面评估所必需的。这项工作的目的是确定铬（VI）是如何致癌的。本提案的目标是解释(1)中溶性铬（VI）化合物如何进入细胞；(2)中溶性铬酸盐引起的突变是否与致癌性较低的可溶性和不溶性铬酸盐引起的突变不同。了解这些铬酸盐的作用方式将为人类风险评估提供基础。