Raw single-walled carbon nanotube-induced cytotoxic effects in human bronchial epithelial cells: comparison to asbestos.
Pacurari-M; Schwegler-Berry-D; Friend-S; Leonard-SS; Mercer-RR; Vallyathan-V; Castranova-V
Toxicol Environ Chem 2011 May; 93(5):1045-1072
Single-walled carbon nanotubes (SWCNT) are being developed to be used in many industrial and biomedical applications. However, SWCNT's durability and likely fibrous morphology have raised health concerns. The present investigations were focused on understanding the cellular and molecular mechanisms induced by raw SWCNT (SWCNT) in human bronchial-epithelial cells (BEAS-2B). Asbestos (crocidolite) was used as a positive control. Exposure of BEAS-2B cells to SWCNT induced apoptosis, DNA damage, and oxidative stress. The generation of hydroxyl radical (*OH) and increase of superoxide dismutase (SOD) activity were concentration-dependent. The increase in apoptosis was associated with activation of caspase-3, caspase-7, and poly (ADP-ribose) polymerase-1 (PARP-1). A short recovery period of 6h of cells from SWCNT exposure resulted in reversal of caspase-3 and caspase-7, and a partial reversal of PARP-1 activation. The activation of PARP-1, caspase-3, and caspase-7 was only partially diminished after a recovery of 6h from the exposure to crocidolite. Exposure of BEAS-2B cells to SWCNT resulted in the phosphorylation of protein p42/44 (p42/44) and protein p38 (p38). SWCNT did not induce protein serine-threonine kinase (AKT) phosphorylation. For all the above end points, crocidolite induced a greater response compared to SWCNT. SWCNT induced a significant activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB), and the effect was inhibited by mitogen-activated protein kinase (MAPK) inhibitors. SWCNT also induced significant increase in the expression levels of c-Jun, ßIGH3, and CD44 genes. The results of this study show that the molecular mechanism for raw SWCNT-mediated toxicity in BEAS-2B cells is through the activation of caspase-3, caspase-7, and PARP-1. Furthermore, the mechanism of AP-1 and NF-kB activation is through MAPK. This bioactivity of raw SWCNT is associated with the generation of oxidative stress and DNA damage. Considering the role of airway epithelium as a critical barrier for normal pulmonary function and focal point for tumor development, this study demonstrates that raw SWCNT activate molecular events which may be linked to adverse biological responses implicated in pulmonary diseases.
Biological-distribution; Biological-effects; Biological-monitoring; Biological-systems; Biomedical-engineering; Cell-biology; Cell-morphology; Cytotoxic-effects; Exposure-levels; Fibrous-bodies; Immunotoxins; Inhalation-studies; Lung-cells; Lung-disorders; Lung-irritants; Molecular-biology; Molecular-structure; Nanotechnology; Oxidative-metabolism; Oxidative-processes; Physiological-effects; Pulmonary-disorders; Pulmonary-system; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-infections; Respiratory-irritants; Respiratory-system-disorders; Statistical-analysis; Toxic-effects;
Author Keywords: poptosis; carbon nanotubes; AKT; caspase 3/7; cytotoxicity; crocidolite; gene expression; MAPK; molecular mechanism; PARP
Vincent Castranova, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505
Toxicological and Environmental Chemistry