title: Transcriptomics analysis of lungs and peripheral blood of crystalline silica-exposed rats.
abstract: Minimally invasive approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. The potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity was investigated. Rats were exposed by inhalation to crystalline silica (15 mg/m(3), 6 h/day, 5 days) and pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined at 32 weeks following termination of exposure. A significant elevation in bronchoalveolar lavage fluid lactate dehydrogenase activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 levels in the lungs showed pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression [>1.5-fold change and false discovery rate (FDR) p < 0.01] of 520 and 537 genes, respectively, in the lungs and blood of the 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 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.
authors.affiliation: Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health (NIOSH), Morgantown, WV 26505, USA.
authors.forename: Rajendran
authors.initials: R
authors.lastname: Sellamuthu
authors.forename: Christina
authors.initials: C
authors.lastname: Umbright
authors.forename: Jenny R
authors.initials: JR
authors.lastname: Roberts
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chapman
authors.forename: Shih-Houng
authors.initials: SH
authors.lastname: Young
authors.forename: Diana
authors.initials: D
authors.lastname: Richardson
authors.forename: Jared
authors.initials: J
authors.lastname: Cumpston
authors.forename: Walter
authors.initials: W
authors.lastname: McKinney
authors.forename: Bean T
authors.initials: BT
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Frazer
authors.forename: Shengqiao
authors.initials: S
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Kashon
authors.forename: Pius
authors.initials: P
authors.lastname: Joseph
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D020869:Gene Expression Profiling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011791:Quartz / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D011791:Quartz; D007770:L-Lactate Dehydrogenase