Pulmonary toxicity and global gene expression profile in response to crystalline silica exposure in rats.
Sellamuthu-R; Umbright-C; Roberts-JR; Young-S; Richardson-D; McKinney-W; Chen-BT; Frazer-D; Li-S; Kashon-ML; Joseph-P
Toxicologist 2013 Mar; 132(1):203-204
The ability to detect target organ toxicity as well as to determine the molecular mechanisms underlying such toxicity by employing surrogate biospecimens that can be obtained either by a non-invasive or minimally invasive procedure has significant advantage in toxicology. Pulmonary toxicity and global gene expression profiles in the lungs, blood and bronchoalveolar lavage (BAL) cells were determined in rats 44-weeks following inhalation exposure to crystalline silica (15 mg/m3, 6- hours/day, 5 days). A significant elevation in lactate dehydrogenase activity and albumin content in the BAL fluid as well as histological alterations, mainly type II pneumocyte hyperplasia and fibrosis, observed in the lungs suggested silica-induced pulmonary toxicity in the rats. A significant increase in the number of neutrophils and elevated monocyte chemotactic protein 1 in the BAL fluid indicated silica-induced pulmonary inflammation in the rats. Determination of global gene expression profiles in the lungs, BAL cells, and blood of the silica exposed rats identified 175, 273, and 59 significantly differentially expressed genes (SDEGs) (FDR p<0.05 and >1.5 fold change in expression), 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 as the major molecular mechanism underlying the silica-induced pulmonary toxicity. These findings demonstrated the potential application of global gene expression profiling of blood and BAL cells as a valuable minimally invasive approach to study silica-induced pulmonary toxicity.
Toxicology; Laboratory-animals; Exposure-levels; Pulmonary-disorders; Pulmonary-system; Dose-response; Lung-disorders; Immune-reaction; Lung-cells; Alveolar-cells; Cell-function; Cellular-reactions; Molecular-biology; Biological-agents; Genes; Blood-cells; Inhalation-studies; Silica-dusts; Lung-fibrosis; Cytotoxic-effects; Neutrophils; Proteins; Biological-function
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas