Lung Toxicity And Gene Expression Changes In Response To Whole-Body Inhalation Exposure To Cellulose Nanocrystal In Rats

ObjectiveHuman exposure to cellulose nanocrystal (CNC) is possible during the production and/or use of products containing CNC. The objectives of the current study were to determine the lung toxicity of CNC and the underlying molecular mechanisms of the toxicity.MethodsRats were exposed to air or CNC (20 mg/m(3), six hours/day, 14 d) by whole-body inhalation and lung toxicity and global gene expression profile were determined.ResultsSignificant increases in lactate dehydrogenase activity, pro-inflammatory cytokine levels, phagocyte oxidant production, and macrophage and neutrophil counts were detected in the bronchoalveolar lavage cells or fluid from the CNC exposed rats. Mild lung histological changes, such as the accumulation of macrophages and neutrophils, were detected in the CNC exposed rats. Gene expression profiling by next generation sequencing identified 531 genes whose expressions were significantly different in the lungs of the CNC exposed rats, compared with the controls. Bioinformatic analysis of the lung gene expression data identified significant enrichment in several biological functions and canonical pathways including those related to inflammation (cellular movement, immune cell trafficking, inflammatory diseases and response, respiratory disease, complement system, acute phase response, leukocyte extravasation signaling, granulocyte and agranulocyte adhesion and diapedesis, IL-10 signaling, and phagosome formation and maturation) and oxidative stress (NRF2-mediated oxidative stress response, production of nitric oxide and reactive oxygen species in macrophages, and free radical scavenging).ConclusionOur data demonstrated that inhalation exposure of rats to CNC resulted in lung toxicity mediated mainly through the induction of inflammation and oxidative stress.