Transcriptomics Analysis of Lungs and Peripheral Blood of Crystalline Silica Exposed Rats

Non-invasive or minimally invasive surrogate approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. Presently, using a rat model, we have investigated the potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity. Rats were exposed by inhalation to crystalline silica for one week (15 mg/m3, 6-hours/day, 5 days/week). Pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined in the control and silica exposed rats at 32-weeks following termination of silica exposure. A significant elevation in bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated silica-induced pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 (MCP1) level in the lungs suggested silica-induced pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression (>1.5 fold change and FDR p<0.01) of 520 and 537 genes, respectively, in the lungs and blood of the silica exposed rats. Bioinformatics analysis of the differentially expressed genes demonstrated significant similarity in the biological processes, molecular networks, and canonical pathways enriched by silica exposure in the lungs and blood of the rats. Several genes involved in functions relevant to silica-induced pulmonary toxicity such as inflammation, respiratory diseases, cancer, cellular movement, fibrosis, etc, were found significantly differentially expressed in the lungs and blood of the silica exposed rats. The results of this study, in addition to providing molecular insights into the mechanisms underlying silica-induced pulmonary toxicity, suggested the potential application of peripheral blood gene expression profiling as a toxicologically relevant and minimally invasive surrogate approach to study the mechanisms underlying silica-induced pulmonary toxicity. Non-invasive or minimally invasive surrogate approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. Presently, using a rat model, we have investigated the potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity. Rats were exposed by inhalation to crystalline silica for one week (15 mg/m3, 6-hours/day, 5 days/week). Pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined in the control and silica exposed rats at 32-weeks following termination of silica exposure. A significant elevation in bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated silica-induced pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 (MCP1) level in the lungs suggested silica-induced pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression (>1.5 fold change and FDR p<0.01) of 520 and 537 genes, respectively, in the lungs and blood of the silica exposed rats. Bioinformatics analysis of the differentially expressed genes demonstrated significant similarity in the biological processes, molecular networks, and canonical pathways enriched by silica exposure in the lungs and blood of the rats. Several genes involved in functions relevant to silica-induced pulmonary toxicity such as inflammation, respiratory diseases, cancer, cellular无创或微创替代检测方法在靶器官毒性的检测/预测中，在职业毒理学（occupational toxicology）领域具有重要的实际应用价值。本研究以大鼠模型（rat model）为对象，探讨了外周血转录组学（peripheral blood transcriptomics）作为研究二氧化硅诱导肺毒性（silica-induced pulmonary toxicity）机制的实用方法的潜在应用价值。大鼠经吸入方式暴露于结晶二氧化硅（crystalline silica）一周（15 mg/m³，每日6小时，每周5天）。在二氧化硅暴露结束32周后，对对照组与二氧化硅暴露组大鼠的肺毒性，以及肺与外周血的全基因表达谱进行了检测。支气管肺泡灌洗液（BALF）中乳酸脱氢酶（LDH）活性显著升高，肺部出现包括II型肺泡上皮细胞增生与纤维化在内的中度组织学改变，表明大鼠发生了二氧化硅诱导的肺毒性。同样，肺部中性粒细胞显著浸润以及单核细胞趋化蛋白-1（MCP1）水平升高，提示大鼠出现了二氧化硅诱导的肺部炎症。对全基因表达谱进行的微阵列分析（microarray analysis）显示，二氧化硅暴露组大鼠的肺和血液中分别有520个和537个基因出现显著差异表达（倍数变化>1.5倍，假发现率（FDR）p<0.01）。对差异表达基因进行的生物信息学分析（bioinformatics analysis）表明，二氧化硅暴露在大鼠肺和血液中富集的生物学过程、分子网络以及经典通路存在显著相似性。多个与二氧化硅诱导肺毒性相关功能（如炎症、呼吸系统疾病、癌症、细胞迁移、纤维化等）的基因在二氧化硅暴露组大鼠的肺和血液中均出现了显著差异表达。本研究结果不仅为二氧化硅诱导肺毒性的潜在机制提供了分子层面的见解，同时表明外周血基因表达谱可作为毒理学相关且微创的替代方法，用于研究二氧化硅诱导肺毒性的机制。 无创或微创替代检测方法在靶器官毒性的检测/预测中，在职业毒理学领域具有重要的实际应用价值。本研究以大鼠模型为对象，探讨了外周血转录组学作为研究二氧化硅诱导肺毒性机制的实用方法的潜在应用价值。大鼠经吸入方式暴露于结晶二氧化硅一周（15 mg/m³，每日6小时，每周5天）。在二氧化硅暴露结束32周后，对对照组与二氧化硅暴露组大鼠的肺毒性，以及肺与外周血的全基因表达谱进行了检测。支气管肺泡灌洗液中乳酸脱氢酶活性显著升高，肺部出现包括II型肺泡上皮细胞增生与纤维化在内的中度组织学改变，表明大鼠发生了二氧化硅诱导的肺毒性。同样，肺部中性粒细胞显著浸润以及单核细胞趋化蛋白-1水平升高，提示大鼠出现了二氧化硅诱导的肺部炎症。对全基因表达谱进行的微阵列分析显示，二氧化硅暴露组大鼠的肺和血液中分别有520个和537个基因出现显著差异表达（倍数变化>1.5倍，假发现率p<0.01）。对差异表达基因进行的生物信息学分析表明，二氧化硅暴露在大鼠肺和血液中富集的生物学过程、分子网络以及经典通路存在显著相似性。多个与二氧化硅诱导肺毒性相关功能（如炎症、呼吸系统疾病、癌症、细胞）的基因在二氧化硅暴露组大鼠的肺和血液中均出现了显著差异表达。