Biological effects of inhaled hydraulic fracturing sand dust in rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE148255 | GEO | 2020/10/01
REPOSITORIES: GEO
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Project description:The projected increase in the production and use of nanomaterials is expected to result in a corresponding increase in human exposure, potentially resulting in significant morbidity and mortality. Currently, the lung toxicity of multi-walled carbon nanotubes (MWCNT), a prototype nanomaterial, was investigated in a rat model. The rats were exposed by whole-body inhalation to air (controls) or MWCNT (6 hours/day, 3 days) to result in cumulative doses of 180, 90, 45, 22.5, or 11.25 mg/m3. Lung toxicity and gene expression profiles were determined in the lungs of the control and MWCNT exposed rats one day following termination of the exposures. Moderate lung histological changes, indicative of toxicity, were detected in rats exposed to MWCNT at doses > 45 mg/m3. Changes in toxicity parameters including, lactate dehydrogenase (LDH) activity, oxidant production, cell counts of phagocytes, and cytokine levels were detected in the bronchoalveolar lavage of rats exposed to > 22.5 mg/m3 MWCNT, compared with the air controls. Lung gene expression profiling detected differences in transcript levels (fold change >1.5 and FDR p<0.05) of several genes in the rats exposed to >22.5 mg/m3 MWCNT, compared with the controls. The changes in lung toxicity and gene expression profiles exhibited a dose-response to the MWCNT administered in the rats.
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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.
2014-07-01 | E-GEOD-49144 | biostudies-arrayexpress
Project description:The present research aimed to investigate peripheral blood gene expression profiling as a minimally invasive surrogate approach to study silica-induced pulmonary toxicity. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days). Pulmonary damage and blood gene expression profiles were determined at various latency periods (0 - 16 weeks). Silica exposure resulted in pulmonary toxicity and this was evidenced by histological changes in the lungs and elevation of LDH activity, and total protein and albumin contents in the bronchoalveolar lavage fluid (BALF) of the rats. Microarray analysis of global gene expression profiles in the blood of the rats identified genes that were differentially expressed in response to silica exposure and toxicity. The number of significantly differentially expressed genes in the blood of silica exposed rats correlated with the severity of silica-induced pulmonary toxicity. Genes involved in biological functions such as inflammatory response, cancer, pulmonary damage, oxidative stress, energy metabolism, fibrosis, etc, were found differentially expressed in the blood of the silica exposed rats compared with the controls. Induction of pulmonary inflammation in the silica exposed rats, as suggested by differential expression of inflammatory response genes in the blood, was supported by significant increases in the number of macrophages and infiltrating neutrophils as well as the activity of pro-inflammatory chemokines M-bM-^@M-^S MCP1 and MIP2, observed in the BALF of the silica exposed rats. A silica-responsive blood gene expression signature developed using the gene expression data predicted with significant accuracy the exposure of rats to lower concentrations (1 and 2 mg/m3) of silica. Taken together our findings suggest the potential application of peripheral blood gene expression profiling as a minimally invasive and efficient surrogate approach to detect and study silica-induced pulmonary toxicity. 96 samples were analyzed in this experiment. The RNA from rat blood samples was isolated for gene expression studies. Rats (48) were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days) and air (24). Blood gene expression profiling was performed using rat blood samples, 8 each for silica exposed and 4 each for air exposed controls at various post-exposure time periods (0, 1, 2, 4, 8, and 16 weeks). A silica-responsive blood gene expression signature was developed using the gene expression data obtained from the 0 week post-exposure group and the control rats. The signature was tested for predicting silica exposure and resulting toxicity in the rats exposed to lower concentrations (1 and 2 mg/m3) of silica (8 rats per group) and air (8 rats).
2011-12-02 | E-GEOD-27023 | biostudies-arrayexpress
Project description:The present research aimed to investigate peripheral blood gene expression profiling as a minimally invasive surrogate approach to study silica-induced pulmonary toxicity. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days). Pulmonary damage and blood gene expression profiles were determined at various latency periods (0 - 16 weeks). Silica exposure resulted in pulmonary toxicity and this was evidenced by histological changes in the lungs and elevation of LDH activity, and total protein and albumin contents in the bronchoalveolar lavage fluid (BALF) of the rats. Microarray analysis of global gene expression profiles in the blood of the rats identified genes that were differentially expressed in response to silica exposure and toxicity. The number of significantly differentially expressed genes in the blood of silica exposed rats correlated with the severity of silica-induced pulmonary toxicity. Genes involved in biological functions such as inflammatory response, cancer, pulmonary damage, oxidative stress, energy metabolism, fibrosis, etc, were found differentially expressed in the blood of the silica exposed rats compared with the controls. Induction of pulmonary inflammation in the silica exposed rats, as suggested by differential expression of inflammatory response genes in the blood, was supported by significant increases in the number of macrophages and infiltrating neutrophils as well as the activity of pro-inflammatory chemokines – MCP1 and MIP2, observed in the BALF of the silica exposed rats. A silica-responsive blood gene expression signature developed using the gene expression data predicted with significant accuracy the exposure of rats to lower concentrations (1 and 2 mg/m3) of silica. Taken together our findings suggest the potential application of peripheral blood gene expression profiling as a minimally invasive and efficient surrogate approach to detect and study silica-induced pulmonary toxicity.
2011-12-02 | GSE27023 | GEO
Project description:From an occupational standpoint, exposure to silica can have devastating consequences. An estimated 2.3 million workers in the U.S. are exposed to dust containing crystalline silica, annually. In addition, of the 140 million people over the age of 20, employed in the U.S., 30% are obese. If and how diet-induced obesity modifies silica-induced pulmonary toxicity is unknown. Therefore, the objective of this study was to determine the effect of diet-induced obesity, if any, on silica induced pulmonary toxicity. Rats (Fischer 344, male) were fed either a regular-fat diet (RFD; 18% kcal as fat) (Envigo, Indianapolis, IN) or a high-fat diet (HFD; 60% kcal as fat) (Envigo, Indianapolis, IN) and exposed by whole-body inhalation to either air or crystalline silica (15 mg/m3, 6 hours/day, 5 days). At designated post-exposure time intervals (1, 3, 6, and 9 months), pulmonary toxicity was determined. Silica inhalation resulted in pulmonary toxicity, which progressed across all post-exposure time points, as evidenced by enhanced neutrophil infiltration, increased LDH levels, enhanced oxidant production, and increased inflammatory cytokine levels. The incidence and severity of silica-induced lung pathology was similar between the two diet groups up to 6 months post-exposure. However, by 9 months post-exposure, silica-induced pathology tended to be slightly more severe in animals fed an RFD compared to those fed an HFD. Lung gene expression profiles were then determined in the rats euthanized at the 3- and 9-month post-silica exposure time intervals by RNA sequencing to identify transcript differences between the two timepoints.
2022-12-31 | GSE142446 | GEO
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.
2012-12-31 | E-GEOD-36208 | biostudies-arrayexpress
Project description:The lung response to inhalation exposure to oil vapor particles was investigated in a rat model. Adult male Sprague-Dawley rats were exposed by whole-body inhalation to air or an aerosol containing oil vapor particles at concentrations of 300 ppm, 6 hours/day for 1 day (shot-term) or 300 ppm, 6 hours/day, 4 days/week for 4 weeks (long-term). The control and oil vapor exposed rats were euthanized at post-exposure time intervals of 1 and 28 days and lung toxicity determined. Analysis of bronchoalveolar lavage parameters of toxicity such as lactate dehydrogenase activity, oxidant generation, and inflammation did not reveal any significant lung toxicity in the oil vapor exposed rats. Approximately 50 genes each were found significantly differentially expressed in both the short- and long-term exposure groups of the rats at the one-day post-exposure time interval. The data obtained from the present study demonstrated that oil vapor inhalation exposure, under the exposure conditions employed in the present study, did not result in any significant lung toxicity in the rats despite the gene expression changes detected.
2022-12-31 | GSE152187 | GEO
Project description:Previous studies in our laboratory identified a correlation between silica-induced pulmonary toxicity and SLC26A4 transcript levels in the lungs of rats. To determine the role of the SLC26A4 gene product, pendrin (Pds) in silica-induced pulmonary toxicity, pendrin wild type (WT) and knockout (KO) mice were employed. All mice were exposed to either air or crystalline silica (15 mg/m3, 6 hours/day, 4 days) and pulmonary toxicity and lung gene expression profiles determined at post-exposure time intervals of 1-day, 3-months, and 9-months. Silica exposure resulted in the induction of pulmonary toxicity in both the WT and KO mouse strains, compared to corresponding air exposed controls. However, there were significant differences (p<0.05) in the measured pulmonary toxicity parameters between silica exposed WT and KO groups being more severe in the WT compared with the KO mice. Significant differences in the gene expression profiles were also detected in the WT and KO mice in response to their exposure to crystalline silica.
2022-10-23 | GSE139287 | GEO
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/m³, 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.
2012-06-29 | E-GEOD-32147 | biostudies-arrayexpress