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Pulmonary toxicity and global gene expression changes in response to subchronic inhalation exposure to crystalline silica in rats.

Joseph-P; Sellamuthu-R; Roberts-JR; Young-S; Richardson-D; McKinney-W; Chen-BT; Frazer-DG; Gu-J; Kashon-ML; Umbright-C
Toxicologist 2014 Mar; 138(1):450
Exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. An understanding of the mechanism(s) underlying the silica-induced pulmonary toxicity is critical for the intervention and/or prevention of adverse health effects. Rats were exposed by inhalation to silica at a concentration of 15 mg/ m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. Pulmonary toxicity and global gene expression changes were determined in the lungs of the control (air) and silica exposed rats at the end of each exposure period. Pulmonary toxicity, as evidenced by an increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid, was seen in the rats depending on the silica exposure duration. The most severe histological changes, seen in the 12-week exposure group, consisted of chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis. In addition, 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 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 crystalline silica in rats. 1715 An Imaging-Based RNAi Screen Identifies Novel Regulators of Nrf2 Activation S. Hiemstra,
Toxicology; Exposure-levels; Health-hazards; Silicosis; Silica-dusts; Cancer; Toxins; Toxic-effects; Pulmonary-function; Pulmonary-system; Pulmonary-system-disorders; Respiration; Respiratory-system-disorders; Animals; Laboratory-animals; Genes; Lung; Lung-cells; Lung-disorders; Lung-fibrosis; Lung-tissue; Blood-cells; Analytical-processes
14808-60-7; 7631-86-9
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The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona