Mechanisms of particulate chromium lung carcinogenesis

说明(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质。主要的环境健康问题源于工业废物中铬的沉积，或者以溶解的铬酸盐化合物的形式释放到地表水中，或者以用于垃圾填埋场的铬酸盐炉渣的形式沉积。铬作为一种大气污染物在铬铁生产、矿石精炼、焊接和各种类型的焚烧过程中产生。六价铬酸盐，即铬(VI)，目前是美国环境保护局(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，铬酸盐化合物被美国国家职业安全与健康研究所(NIOSH)列为职业性肺癌的主要原因之一。虽然关于铬(VI)在细胞培养中的遗传毒性已有相当多的信息，但铬(VI)在体内引起肺损伤和致癌的机制仍不清楚。一个主要的缺点是缺乏一种合适的动物模型来再现铬暴露在人类体内引起的肺组织微环境。一个关键的问题是，为什么在职业和环境环境中被证明是最有效的遗传毒剂之一的铬(VI)，除了在非常特殊的情况下，未能在实验动物中诱导致癌。我们认为，大多数动物模型对吸入铬(VI)的反应未能诱导肿瘤的发展，因为它们缺少一个关键的促成因素：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一种新的铬(VI)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生的贡献，该模型包括慢性肺组织炎症反应。在我们建议的研究中，我们将使用BALB/c小鼠模型进行六价碱性铬酸锌(ZnCrO44Zn(OH)2)的鼻腔给药，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，也是城市地区铬铁生产设施周围的环境大气污染物。将检验以下两个工作假说：1)铬(VI)介导的肿瘤发生与组织炎症、损伤/修复和细胞生存失调的顺序变化有关；2)炎症过程是通过铬(VI)暴露导致肺癌发生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铬(VI)暴露模型，可以用来分析吸入铬(VI)导致肺癌的机制。这些研究的结果将有额外的好处，为潜在的干预性或预防性治疗确定分子靶点。拟议研究的意义的一个重要方面是使用一种与职业和环境有关的颗粒铬(VI)作为一种纯化合物，具有模拟人类暴露的输送系统。这一发现也将与其他导致伤害和癌症的肺部颗粒物相关。 与公共健康相关：某些颗粒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，而环境和职业接触铬酸盐仍然是一个重大的公共健康问题。这项提议将采用一种新的小鼠模型，复制人类暴露于铬引起的肺组织微环境。这些研究将为铬致癌过程的复杂病因学提供有价值的新见解，并为评价炎症环境和生存信号通路在铬致癌中的作用提供一种手段。

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.