O3 AND MODULATING CR TOXICITY AND THE LUNG

O3 与调节 CR 毒性和肺部

• 批准号: 2730820
• 负责人: Richard B Schlesinger
• 金额: $ 43.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2730820
• 关键词: DNA damage; air pollution; chromium; chromosome aberrations; comorbidity; disease /disorder proneness /risk; environmental contamination; gene expression; laboratory rat; lung neoplasms; occupational health /safety; oncogenes; ozone; pathologic process; pollutant interaction; protein kinase

Most studies of occupationally relevant chemical hazards have involved use of single contaminants, so the biological and safety implications from inhalation of realistic mixtures have commonly been ignored in evaluations related to worker health and safety. In this regard, chromium (Cr) is released with ozone (O3) during welding, and a major health hazard from inhalation exposure to Cr-containing materials is lung cancer; this is likely due largely to the insoluble Cr species in the fumes. However, the contribution from other co-inhalants in modulating Cr-initiated responses is not clear. Co-contaminants may change the pulmonary environment producing conditions which could enhance the formation and survival of Cr- initiated tumors. For example, it has been demonstrated that simultaneously-inhaled O3 increases the pulmonary retention of inhaled insoluble Cr particles; this could be part of a scenario which would ultimately give rise to conditions within the lungs conductive to the formation and survival of Cr-initiated neoplasia. This proposal investigates other mechanisms underlying the elevated lung cancer incidence in welders exposed welding fumes containing both Cr and O3. It is hypothesized that the carcinogenic potential of insoluble Cr(VI) in the lungs of hosts inhaling the Cr/O3 mixture is greater than that in hosts inhaling the Cr alone due to O3-mediated increases in the lung tissue burdens of Cr(VI) and/or augmentation of one or more of the documented genetic/epigenetic mechanisms associated with Cr-induced conversion of normal cells to transformed types (i.e., an enhancement in level of DNA damage, chromosomal aberrations, and/or induced increases in the activity of cell kinases known to regulate the expression of nascent oncogenes) arising from the effects of O3 upon mechanisms utilized for the intracellular of insoluble Cf(VI) particles. The project involves exposure of rats to atmospheres containing carcinogenic Cr(VI), namely calcium chromate, alone and in combination with O3. This study will improve our understanding of the mechanisms underlying the interaction between Cr and O3 in the lungs and the role which mixtures of air contaminants may play in pulmonary disease pathogenesis following exposure to realistic mixed atmospheres of occupational relevance.

大多数与职业相关的化学危害研究都涉及到使用 单一污染物，所以生物和安全的影响 在评估中，对真实混合物的吸入通常被忽略 与工人的健康和安全有关。在这方面，铬(Cr)是 在焊接过程中会释放出臭氧(O3)，而且 吸入含铬物质会导致肺癌；这是 很可能主要是由于烟雾中不溶的铬物种。然而， 其他共吸入剂在调节铬引发的反应中的作用 目前还不清楚。共污染物可能会改变肺部环境 提高铬的形成和存活率的生产条件 引发了肿瘤。例如，已经证明 同时吸入臭氧可增加吸入性肺滞留 不可溶的铬颗粒；这可能是一种情况的一部分， 最终导致肺内的条件传导到 铬诱发的肿瘤的形成和存活。这项建议 研究肺癌升高的其他机制 电焊工接触同时含有铬和臭氧的焊接烟尘的发生率。它 假设不溶性铬(VI)的致癌潜力 吸入铬/O_3混合物的宿主的肺大于宿主 由于臭氧介导的肺组织增加而单独吸入铬 铬(VI)的负担和/或一个或多个已记录的 铬诱导细胞转化的遗传/表观遗传机制 正常细胞向转化类型转化(即DNA水平的提高 损伤、染色体异常和/或导致活性增加 已知可调节新生癌基因表达的细胞激酶) 产生于臭氧对机制的影响 胞内不溶的Cf(VI)颗粒。这个项目涉及到曝光 对含有致癌铬(VI)，即钙的环境的影响 铬酸盐，单独或与臭氧结合使用。这项研究将改善我们的 对铬与铬相互作用机理的理解 肺中的臭氧以及空气污染物混合物可能发挥的作用 暴露在现实混合物中的肺部疾病发病机制 与职业相关的氛围。