Mechanisms of particulate chromium lung carcinogenesis

颗粒铬肺癌发生机制

• 批准号: 8125032
• 负责人: SUSAN M CERYAK
• 金额: $ 19.37万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125032
• 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（由申请方提供）：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，无论是以溶解的铬酸盐化合物释放到地表沃茨的形式，还是以用于垃圾填埋的铬酸盐炉渣的形式。铬作为大气污染物在铬铁生产、矿石精炼、焊接和所有类型的焚烧过程中产生。六价铬，Cr（VI），目前是环境保护局（EPA）列出的33种化合物之一，对城市地区造成最大的潜在健康威胁，并且铬酸盐化合物被NIOSH（国家职业安全与健康研究所）列为职业性肺癌的主要原因之一。虽然存在大量关于Cr（VI）在细胞培养中的遗传毒性的信息，但Cr（VI）在体内引起肺损伤和致癌的机制仍然未知。一个主要的缺点是缺乏一个合适的动物模型，再现肺组织微环境诱导的铬暴露在人类。一个关键的问题是，为什么铬（VI），被证明是最有效的遗传毒性剂在职业和环境设置，未能诱导致癌作用的实验动物，除了在非常选择的情况下。我们提出，大多数动物模型未能诱导肿瘤的发展，吸入Cr（VI），因为他们缺少一个关键的贡献因素：适当类型的慢性组织炎症。因此，我们提出的研究的目标是直接测试炎症过程的贡献铬介导的肺癌发展，使用一种新的小鼠模型的Cr（VI）呼吸道暴露，包括慢性肺组织炎症反应。对于我们提出的研究，我们将使用BALB/c小鼠模型鼻内递送六价碱式铬酸锌（ZnCrO 44 Zn（OH）2），这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，也作为环境大气污染物存在于铬铁生产设施周围的城市地区。将检验以下两个工作假设：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顺序变化相关; 2）炎症过程是导致Cr（VI）暴露导致肺肿瘤生成的肿瘤事件所必需的。我们的长期目标是建立一个非人类的Cr（VI）暴露模型，可用于解剖吸入Cr（VI）诱导肺癌的机制。这些研究的结果将有额外的好处，确定潜在的干预或预防性治疗的分子靶点。拟议研究意义的一个重要方面是使用一种职业和环境相关形式的颗粒状Cr（VI），作为一种纯化合物，其输送系统模拟人体接触。这些发现也将与其他导致损伤和癌症的肺部颗粒物有关。 公共卫生相关性：某些颗粒状铬化合物是公认的大气污染物和人类呼吸道毒素和致癌物，而环境和职业暴露于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，该模型再现了人类铬暴露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，并提供一种方法来评估炎症环境和生存信号通路对铬致癌作用的贡献。