Genotoxic Potential of Mixed Dust Exposures

混合粉尘暴露的潜在遗传毒性

• 批准号: 7312099
• 负责人: Agnes B Kane
• 金额: $ 24.42万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312099
• 关键词: DNA damage; air pollution; asbestos; dust; environmental exposure; environmental toxicology; gene expression profiling; iron; laboratory mouse; mutagen testing; oxidation reduction reaction; technology /technique development; tissue /cell culture; toxicant interaction; toxicant screening

Dusts generated during demolition of buildings, remediation, and construction may be contaminated with toxic particulates including metals and asbestos fibers. Three forms of asbestos are on the CERCLA Priority List of Hazardous Substances and it is a common contaminant at former industrial sites and military bases. However, the potential adverse health effects resulting from inhalation of mixed dusts from these asbestos-contaminated sites are unknown. The availability of transition metals, especially iron, to participate in redox cycling leading to generation of free radicals has been hypothesized to play an important role in asbestos-induced lung diseases. It is hypothesized that contamination with iron and asbestos fibers will potentiate the toxicity of mixed dust exposures due to enhanced iron mobilization, redox cycling, and generation of reactive oxygen species. The ultimate goal of this project is to develop a panel of cellular and molecular endpoints that can be integrated into a short-term screening strategy to identify toxic mixed dusts. The Specific Aims to achieve this goal are: a) To generate and characterize model dust samples composed of inert particles, metal-contaminated particles, and asbestos fibers; b) To assess mobilization of transition metals and redox activity of these model dust samples in vitro; c) To develop a gene expression profile that will differentiate between nontoxic and toxic dusts; d) To explore the mechanisms of mixed dust-fiber toxicity using short-term in vitro assays; and e) To validate this testing strategy in a chronic carcinogenicity assay.

建筑物拆除、修复和施工过程中产生的粉尘可能受到金属和石棉纤维等有毒颗粒的污染。 CERCLA 危险物质优先清单中包含三种形式的石棉，它是前工业场地和军事基地的常见污染物。然而，吸入这些受石棉污染的混合粉尘会对健康产生潜在的不利影响。 站点未知。过渡金属（尤其是铁）参与氧化还原的可用性 据推测，导致自由基产生的循环在石棉引起的肺部疾病中发挥着重要作用。据推测，由于铁的动员、氧化还原循环和活性氧物质的产生增强，铁和石棉纤维的污染将增强混合粉尘暴露的毒性。该项目的最终目标是开发一组细胞和分子端点，可以将其集成到短期筛选策略中以识别有毒混合粉尘。实现这一目标的具体目标是： a) 生成并表征由惰性颗粒、金属污染颗粒和石棉纤维组成的模型粉尘样本； b) 评估这些模型粉尘样品的体外过渡金属动员和氧化还原活性； c) 开发区分无毒和有毒粉尘的基因表达谱； d) 使用短期体外试验探索混合粉尘-纤维毒性的机制； e) 在慢性致癌性测定中验证该测试策略。