Project description:Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with occupational exposure to crystalline silica. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 h/day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8, and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5 fold change and <0.01 FDR p value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The various biological functions, canonical pathways, and molecular networks affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved lung inflammation was the single most significant biological response to pulmonary exposure to crystalline silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat and these findings may be useful in future to develop strategies to prevent occupational silicosis. A total of 60 rat lung samples were analyzed in this gene expression experiment. Rats were exposed to crystalline silica at a concentration of 15 mg/mÂ³, 6-hours/day for 5 consecutive days. Rats exposed simultaneously to filtered air served as the controls. The control (n=4) and silica exposed (n=8) rats were sacrificed at post-exposure time intervals of 1, 2, 4, 8, and 16 weeks following termination of silica exposure and lung gene expression profile was determined.

Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats. 36 samples were analyzed in this experiment. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 3 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 6 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 12 weeks. 18 rats served as controls (6 for each 3 week, 6 week, and 12 week exposure) and were exposed to air during treatment times. Lung gene expression profiling was performed using RNA isolated from rat lung samples.

Project description: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 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. A total of 12 rat blood samples were analyzed in this gene expression experiment. Rats were exposed to crystalline silica at a concentration of 15 mg/m3, 6-hours/day for 5 consecutive days. Rats exposed simultaneously to filtered air served as the controls. The control (n=6) and silica exposed (n=6) rats were sacrificed at post-exposure time interval of 32 weeks following termination of silica exposure and blood gene expression profiles were determined.

Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats.

Project description: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 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.

Project description:The capability to detect target organ toxicity as well as to determine the molecular mechanisms underlying such toxicity by employing surrogate biospecimens that can be obtained by a non-invasive or minimally invasive procedure has significant advantage in occupational toxicology. Pulmonary toxicity and global gene expression profile in the lungs, peripheral blood and bronchoalveolar lavage (BAL) cells were determined in rats at 44-weeks following pulmonary exposure to crystalline silica (15 mg/m3, 6-hours/day, 5 days). A significant elevation in lactate dehydrogenase activity and albumin content observed in the BAL fluid suggested the induction of pulmonary toxicity in the silica exposed rats. Similarly, the observation of histological alterations, mainly type II pneumocyte hyperplasia and fibrosis, in the lungs further confirmed silica-induced pulmonary toxicity in the rats. A significant increase in the number of neutrophils and elevated monocyte chemotactic protein 1 level in the BAL fluids suggested silica-induced pulmonary inflammation in the rats. Determination of global gene expression profile in the lungs, BAL cells, and peripheral blood of the silica exposed rats identified 144, 236, and 51 significantly differentially expressed genes (SDEGs), respectively, compared with the corresponding control samples. Bioinformatics analysis of the SDEGs demonstrated a remarkable similarity in the biological functions, molecular networks and canonical pathways that were significantly affected by silica exposure in the lungs, BAL cells and blood of the rats. Induction of inflammation was identified, based on the bioinformatics analysis of the significantly differentially expressed genes in the lungs, blood and BAL cells, as the major molecular mechanism underlying the silica-induced pulmonary toxicity. The findings of our study demonstrated the potential application of global gene expression profiling of peripheral blood and BAL cells as a valuable minimally invasive approach to study silica-induced pulmonary toxicity in rats.

Project description:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 20 samples were analyzed in this experiment. RNA from rat lung samples was isolated for gene expression studies. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days) or air. Lung gene expression profiling was performed using rat lung samples, 8 for silica exposed and 12 for air-exposed controls at 0 weeks post-exposure time period.

Project description:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 20 samples were analyzed in this experiment. Exponentially growing human lung epithelial cells (1.5x10^5 cells) were cultured in 6-well cell culture plates. When the cells were approximately 70% confluent, they were treated with crystalline silica (0, 100, 200 and 400 M-BM-5g/ml) in serum-free medium. Following 6 hours of culturing at 37oC, total RNA was isolated for gene expression studies.

Project description:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 10 samples were analyzed in this experiment. Exponentially growing human lung epithelial cells (1.5x10^5 cells) were cultured in 6-well cell culture plates. When the cells were approximately 70% confluent, they were treated with crystalline silica (0 or 200 M-BM-5g/ml) in serum-free medium. Following 2 hours of culturing at 37oC, total RNA was isolated for gene expression studies.

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Molecular insights into the progression of crystalline silica-induced pulmonary toxicity in rats

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