Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts

人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学

基本信息

批准号：
10359325
负责人：
John Pierce Wise
金额：
$ 10.51万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359325
关键词：
Address Affect Animals Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Automobile Driving BRCA2 gene Beets Betaine Biological Markers Breast Cancer Cell Cancer Etiology Carcinogens Cell Death Cells Cessation of life Chromium Compounds Chromosomal Instability DNA DNA Double Strand Break Data Double Strand Break Repair Endothelial Cells Environment Epithelial Cells Event Exposure to Fibroblasts Filament Food Funding Goals Hazardous Substances Health Benefit Heritability Human Inflammasome Inflammation Inflammatory Inflammatory Response Investments Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metals Molecular Mus National Institute of Environmental Health Sciences Natural Products Neoplastic Cell Transformation Nucleoproteins Outcome Particulate Pathway interactions Property Proteins Public Health RAD51C gene Rattus Regulatory Pathway Reporting Research Risk Risk Assessment Risk Management Role Signal Transduction Structure of parenchyma of lung Testing Toxicology Translating Umbilical vein United States Work Workplace XRCC2 gene anti-cancer arm cancer cell carcinogenesis carcinogenicity chromium hexavalent ion genotoxicity homologous recombination improved in vivo insight neoplastic neoplastic cell novel strategies parent grant potential biomarker prevent response targeted biomarker therapeutic target tumor tumor progression

项目摘要

PROJECT SUMMARY OF THE FUNDED PARENT GRANT Lung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combating it is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major public health concern because exposure to it is common in the workplace and in the general environment. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. In particular, this work focuses on the particulate Cr(VI) compounds, because they are the most potent Cr(VI) carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells to evade DNA double strand break repair, which are hallmarks of human lung cancer. Thus, this research focuses on how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosome instability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts the effector arm of homologous recombination (HR repair), disrupting RAD51 nucleoprotein filament formation, loss of which can cause chromosome instability. Therefore, the goal of this research is to characterize this impact on HR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is: particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivating HR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test this hypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 to disrupt RAD51 nucleoprotein filament formation in human lung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation in human lung cells neoplastically transformed by Cr(VI), and the protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impact of Cr(VI) on protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in the lungs and lung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of the interactions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the first characterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers. Results will also show which changes are transient and depend on exposure and which changes persist in cells that escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1) An understanding of Cr(VI)’s carcinogenic mechanism; 2) Essential information to better assess exposure risk to particulates; and 3) A mechanistic approach for further study of Cr(VI), other metals and lung cancer in general.

资助的家长补助金项目摘要肺癌仍然是美国癌症死亡的主要原因，这是对抗肺癌的关键策略之一六价铬[Cr(VI)]是主要公众肺癌致癌物。健康问题，因为在我们的研究中，接触它在工作场所和一般环境中很常见。重点研究目前尚不清楚的 Cr(VI) 诱导致癌机制。特别是，这项工作重点关注颗粒 Cr(VI) 化合物，因为它们是最有效的 Cr(VI) 最近的研究表明颗粒 Cr(VI) 会导致染色体不稳定并导致细胞逃避DNA双链断裂修复，这是人类肺癌的标志，因此，本研究的重点是。关于颗粒 Cr(VI) 如何诱导细胞逃避导致染色体的 DNA 双链断裂修复我们的数据显示，长期接触颗粒 Cr(VI) 特别会影响同源重组效应臂（HR 修复），破坏 RAD51 核蛋白丝形成、丢失因此，本研究的目标是表征这种对染色体的影响。为了了解所涉及的机制，HR 修复和潜在的变化我们的假设是：颗粒 Cr(VI) 破坏 RAD51 核蛋白丝形成失活的潜在机制 Cr(VI) 诱导的 DNA 断裂的 HR 修复导致 CIN 和肿瘤转化。我们将对此进行测试。通过三个相互关联的具体目标的假设将确定 Cr(VI) 如何影响 BRCA2、DSS1、 RAD51B、RAD51C、RAD51D、RPA 和 XRCC2 可破坏人类 RAD51 核蛋白丝的形成目标 2 确定肺细胞中 RAD51 细丝形成中断的持久性和细胞遗传力。 Cr(VI)肿瘤转化的人肺细胞，以及BRCA2、DSS1、RAD51B、人类 Cr(VI) 工人肺部肿瘤中的 RAD51C、RAD51D、RPA 和 XRCC2 确定了影响。 Cr(VI) 对肺中 BRCA2、DSS1、RAD51B、RAD51C、RAD51D、RPA 和 XRCC2 蛋白水平的影响 Cr(VI) 暴露动物的肺部肿瘤的结果将导致有关详细信息的第一份报告。 Cr(VI) 与 HR 修复效应臂在细胞和分子水平上的相互作用以及第一个肿瘤结局中这些方面的特征，包括接触六价铬工人的肿瘤。结果还将显示哪些变化是短暂的并且取决于暴露，哪些变化在细胞中持续存在这项研究意义重大，因为它提供了：1) 了解 Cr(VI) 的致癌机制；2) 更好地评估暴露风险的基本信息； 3) 进一步研究 Cr(VI)、其他金属和肺癌的机制方法。