Pathways identified by toxicogenomics analysis reveal the size and dose independency of silica particles-induced toxicity in mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE30861 | GEO | 2011/08/01
SECONDARY ACCESSION(S): PRJNA146149
REPOSITORIES: GEO
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Project description:Using a macrophage cell line, we demonstrate the ability of amorphous silica particles to stimulate inflammatory protein secretion and induce cytotoxicity. Whole genome microarray analysis of early gene expression changes induced by 10nm and 500nm particles showed that the magnitude of change for the majority of genes correlated more tightly with particle surface area than either particle mass or number. Gene expression changes that were size-specific were also identified, however the overall biological processes represented by all gene expression changes were nearly identical, irrespective of particle diameter. Our results suggest that on an equivalent nominal surface area basis, common biological modes of action are expected for nano- and supranano-sized silica particles. Experiment Overall Design: RAW 264.7 mouse macrophage cells were treated with two sizes of amorphous silica particles at three doses each for 2 hours. Cells were exposed to 10nm silica at 5 (low), 20 (mid), or 50 (high) ug/ml or 500nm silica at 250 (low), 500 (mid), or 1000 (high) ug/ml in serum-free medium.
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Project description:Previous studies have shown that smoking induces oxidative stress and inflammation, known factors that coincide with the development and progression of silicosis. Nevertheless, the precise role of cigarette smoke exposure in silicosis and the underlying mechanisms are not clearly understood. Therefore, the objective of the present study was to determine the effect of smoking, if any, on silica-induced pulmonary response and the underlying mechanisms. Pulmonary toxicity and lung gene expression profiles were determined in male Fischer 344 rats exposed to air, crystalline silica, cigarette smoke or cigarette smoke plus crystalline silica. Silica exposure resulted in significant pulmonary toxicity which was further exacerbated by cigarette smoke exposure in the rats. Significant differences in the gene expression profiles were detected in the lungs of the rats exposed to cigarette smoke, silica or a combination of both compared with the control rats.
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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.
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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.
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Project description:This SuperSeries is composed of the following subset Series: GSE30178: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (rat lungs) GSE30180: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (A549 cells dataset 1) GSE30200: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (A549 cells dataset 2) GSE30213: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (A549 cells dataset 3) GSE30214: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (A549 cells dataset 4) GSE30215: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling (A549 cells dataset 5) Refer to individual Series
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