Mechanisms of particulate chromium lung carcinogenesis

颗粒铬肺癌发生机制

• 批准号: 7990590
• 负责人: SUSAN M CERYAK
• 金额: $ 23.48万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990590
• 关键词: Alveolus; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Biological Markers; Breathing; Carcinogens; Cell Culture Techniques; Cell Death; Cell Survival; Chromates; Chromium; Chromium Compounds; Chronic; Complex; Data; Defect; Deposition; Development; Disease; Dose; Environment; Environmental Health; Environmental and Occupational Exposure; Etiology; Event; Exploratory/Developmental Grant; Exposure to; Fibrosis; Funding; Future; Generations; Goals; Health; Human; Hyperplasia; Inbred BALB C Mice; Incineration; Industrial Waste; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Institution; Knock-out; Lead; Lung; Lung Neoplasms; Lung diseases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mining; Modeling; Molecular; Molecular Target; Monitor; Mus; Mutagens; National Institute for Occupational Safety and Health; Nature; Neoplasms; Occupational; Particulate; Premalignant; Preventive; Process; Production; Public Health; Publishing; Regimen; Research; Risk Assessment; Route; Severities; Signal Pathway; Staging; Structure of parenchyma of lung; Surface; Suspension substance; Suspensions; System; Testing; Time; Tissues; United States Environmental Protection Agency; Water; Welding; Work; Wound Healing; bronchial epithelium; carcinogenesis; chromium hexavalent ion; exposed human population; genotoxicity; improved; in vivo; injury and repair; insight; landfill; lung carcinogenesis; lung injury; lung tumorigenesis; mouse model; neoplastic; pollutant; public health relevance; respiratory; respiratory toxin; response; stem; tool; tumor; tumor progression; tumorigenesis; urban area; zinc chromate

DESCRIPTION (provided by applicant): Certain chromium compounds are well-established human respiratory toxins and carcinogens. Major environmental health concerns stem from the deposition of chromium in industrial waste either in the form of dissolved chromate compounds released to surface waters or chromate slag used in landfills. Chromium is generated as an atmospheric pollutant during ferrochrome production, ore refining, welding, and incinerations of all types. Hexavalent chromate, Cr(VI), is currently one of 33 compounds listed by the Environmental Protection Agency (EPA) to pose the greatest potential health threat in urban areas and chromate compounds are listed by NIOSH (National Institute of Occupational Safety and Health) to be one of the major causes of occupational lung cancer. While considerable information exists regarding Cr(VI) genotoxicity in cell culture, the mechanisms by which Cr(VI) causes lung injury and carcinogenesis in vivo are still unknown. A major drawback has been the lack of a suitable animal model that reproduces the lung tissue microenvironment induced by chromium exposure in humans. One critical question is why Cr(VI), shown to be one of the most potent genotoxic agents in occupational and environmental settings, fails to induce carcinogenesis in experimental animals except in very select cases. We propose that most animal models fail to induce tumor development in response to inhaled Cr(VI) because they are missing a key contributing factor: the appropriate type of chronic tissue inflammation. Thus, the goal of our proposed studies is to directly test the contribution of inflammatory processes to chromate-mediated lung cancer development, using a new mouse model of Cr(VI) respiratory exposure that includes chronic lung tissue inflammatory responses. For our proposed studies we will use the BALB/c mouse model for intranasal delivery of hexavalent basic zinc chromate (ZnCrO44Zn(OH)2), which is an intermediately water soluble chromate typically encountered in mining and chromate production facilities and is also present as an environmental atmospheric contaminant in urban areas surrounding ferrochrome production facilities. The following two working hypotheses will be tested: 1) Cr(VI)-mediated oncogenesis is associated with sequential changes in tissue inflammation, injury/repair and cell survival dysregulation; 2) Inflammatory processes are required for the neoplastic events that lead to lung tumor generation by Cr(VI) exposure. Our long-term goal is to establish a non-human model of Cr(VI) exposure that can be used to dissect the mechanism whereby inhaled Cr(VI) induces lung cancer. Results from these studies will have the added benefit of identifying molecular targets for potential interventional or preventive therapy. An important aspect of the significance of the proposed studies is the use of an occupationally and environmentally relevant form of particulate Cr(VI), as a pure compound, with a delivery system which mimics human exposure. The findings will also be relevant to other lung particulates that induce injury and cancer. PUBLIC HEALTH RELEVANCE: Certain particulate chromium compounds are well established atmospheric pollutants and human respiratory toxins and carcinogens, while environmental and occupational exposure to chromate continues to loom large as a major public health issue. This proposal will employ a new mouse model that reproduces the lung tissue microenvironment induced by chromium exposure in humans. The proposed studies will provide valuable new insights into the complex etiology of the disease process, as well as provide a means to evaluate the contribution of the inflammatory environment and survival signaling pathways to chromium carcinogenesis.

描述（由申请人提供）：某些铬化合物是公认的人类呼吸道毒素和致癌物。主要的环境健康问题源于工业废物中铬的沉积，要么以溶解的铬酸盐化合物的形式释放到地表水中，要么以垃圾填埋场使用的铬酸盐渣的形式存在。铬是在各种类型的铬铁生产、矿石精炼、焊接和焚烧过程中产生的大气污染物。六价铬酸盐 (Cr(VI)) 目前是美国环境保护署 (EPA) 列出的对城市地区构成最大潜在健康威胁的 33 种化合物之一，并且 NIOSH（美国国家职业安全与健康研究所）将铬酸盐化合物列为对城市地区构成最大潜在健康威胁的 33 种化合物之一。是职业性肺癌的主要原因之一。虽然关于细胞培养中 Cr(VI) 基因毒性的大量信息存在，但 Cr(VI) 在体内引起肺损伤和致癌的机制仍不清楚。主要缺点是缺乏合适的动物模型来重现人类铬暴露引起的肺组织微环境。一个关键问题是，为什么六价铬（Cr(VI)）被证明是职业和环境环境中最有效的基因毒性剂之一，除了极少数情况外，却无法在实验动物中诱发致癌作用。我们认为，大多数动物模型未能通过吸入 Cr(VI) 诱导肿瘤发展，因为它们缺少一个关键的影响因素：适当类型的慢性组织炎症。因此，我们提出的研究的目标是使用包括慢性肺组织炎症反应的新的六价铬呼吸暴露小鼠模型，直接测试炎症过程对铬酸盐介导的肺癌发展的贡献。对于我们提出的研究，我们将使用 BALB/c 小鼠模型鼻内输送六价碱性铬酸锌 (ZnCrO44Zn(OH)2)，它是一种中等水溶性的铬酸盐，通常在采矿和铬酸盐生产设施中遇到，也作为一种铬铁生产设施周围城市地区的环境大气污染物。将测试以下两个工作假设：1）Cr（VI）介导的肿瘤发生与组织炎症、损伤/修复和细胞存活失调的连续变化有关； 2) 因接触 Cr(VI) 而导致肺部肿瘤生成的肿瘤事件需要炎症过程。我们的长期目标是建立一个非人类的 Cr(VI) 暴露模型，可用于剖析吸入 Cr(VI) 诱发肺癌的机制。这些研究的结果将具有确定潜在介入或预防性治疗的分子靶点的额外好处。拟议研究的一个重要方面是使用与职业和环境相关的颗粒 Cr(VI)，作为纯化合物，并具有模拟人类暴露的输送系统。这些发现也与其他引起损伤和癌症的肺部颗粒物有关。 公共卫生相关性：某些颗粒铬化合物是公认的大气污染物、人类呼吸道毒素和致癌物，而环境和职业接触铬酸盐仍然是一个重大的公共卫生问题。该提案将采用一种新的小鼠模型，该模型可以重现人类因铬暴露而引起的肺组织微环境。拟议的研究将为疾病过程的复杂病因学提供有价值的新见解，并提供一种评估炎症环境和生存信号通路对铬致癌作用的方法。