Stueckle-TA; Mishra-A; Derk-R; Meighan-T; Castranova-V; Rojanasakul-Y; Wang-L
Toxicologist 2013 Mar; 132(1):91
Concern for increased risk of CNT-induced lung cancer has arisen due to asbestos-like high aspect ratio, pulmonary persistence and fibrosis. Our previous study found that chronic in vitro exposure to dispersed single (D-SWCNT) and multi wall CNT (D-MWCNT) resulted in neoplastic transformation in human small airway epithelial cells (SAEC). Genome profiling identified oncogene signaling mechanisms in CNT SAECs that were quite different from asbestos-exposed (ASB) SAEC. Few in vivo studies identified whole lung gene markers associated with MWCNT exposure, but did not compare CNT vs. asbestos genetic response. Here, toxicogenomic profiling with correlation feature selection strategies identified particle-specific, key gene markers from our previous study. D-SWCNT, D-MWCNT, ASB, ultrafine carbon black (UFCB) and control SAEC genome profiles were subjected to comparative marker and class neighbor analyses followed by multistep cross validation to identify genes with highly correlated expression for each treatment. Specific treatment markers and genome profiles were subjected to Ingenuity Pathway and Biomarker Analysis to determine both specific markers performance and identify disease markers. Gene marker subsets and disease markers were validated using rtPCR and protein expression. Here, we present robust SWCNT, MWCNT, ASB and UFCB specific gene marker sets for in vitro chronically exposed SAEC. Matching our original analysis, both D-MWCNT and D-SWCNT markers were associated with lipid metabolism and cancer while ASB and UFCB centered on inflammatory response and senescence, respectively. Biomarker Analysis identified known lung and other cancer markers (MYC, PPARG) in CNT SAECs which differed from inflammation-associated cancer markers (IL-1B) in ASB SAECs. In conclusion, toxicogenomic profiling in a chronic in vitro exposure model identified particle-specific gene markers and known lung cancer markers which can potentially aid in assessing CNT exposure and detection of early disease markers.
Toxicology; Nanotechnology; Lung-cancer; Cancer; Respiratory-system-disorders; Pulmonary-system-disorders; Fibrosis; Lung-fibrosis; Cell-alteration; Neoplastic-transformation; Gene-mutation; Cellular-reactions; Oncogenic-agents; In-vitro-studies; In-vivo-studies; Genotoxic-effects; Biomarkers; Biotransformation; Genes; Proteins; Lipids; Chronic-exposure; Metabolism
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, San Antonio, Texas, March 10-14, 2013