Raw Single-Wall Carbon Nanotubes Induce Oxidative Stress and Activate MAPKs, AP-1, NF-κB, and Akt in Normal and Malignant Human Mesothelial Cells

TL;DR: The cellular and molecular findings reported here suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies.

Abstract: By 2015, the worldwide market for products with nanotechnology components will reach an estimated $1 trillion (Roco 2005). The unique behavior and properties of nanoscale materials have revolutionized technology, producing an estimated 1,300 materials either in use or being tested for potential commercial applications. Enhanced physical and chemical properties associated with the nanosize of these materials have been exploited to produce a wide variety of new products. In addition, nanoparticles are being explored for several treatment modalities, including early detection of tumors and other clinical applications (Gwinn and Vallyathan 2006). With these applications come unprecedented avenues of human exposure to nanomaterials. Engineered single-wall carbon nanotubes (SWCNTs) are a class of nanoparticles being actively evaluated for myriad industrial and biomedical applications (Dresselhaus et al. 2004). Exponential growth in the use of SWCNTs potentially can cause exposure to a large number of workers (Maynard 2007). SWCNTs have been reported to have many adverse cellular and animal toxicity reactions, which may be predictive of detrimental human health effects upon exposures (Lam et al. 2004; Shvedova et al. 2005). The likely widespread industrial application of SWCNTs in several consumer products and medical applications may pose an emerging human health concern (Donaldson et al. 2006; Maynard 2007). It has been suggested that inhaled SWCNTs and other nanoparticles are likely to evade phagocytosis, penetrate lung tissue, and translocate to other organs to cause systemic cell toxicity and injury (Gwinn and Vallyathan 2006; Oberdorster et al. 2005). Therefore, toxicity studies of nanoparticles should not be limited to a single lung cell or only to the lung, but should involve other systemic targets. Preliminary cellular and animal exposure investigations on toxicity and pathogenicity of SWCNTs have demonstrated biological interactions, including toxicity, inflammatory reactions, oxidative stress, and fibroproliferative response (Lam et al. 2004; Mercer et al. 2008; Shvedova et al. 2005). SWCNTs are biopersistent and have the ability to distribute to subpleural areas after pharyngeal aspiration (Mercer et al. 2008). These earlier investigations compelled the present studies of potential interactions of SWCNTs with mesothelial cells. Epidemiologic, animal, and cellular studies indicate that exposure to crocidolite asbestos (crocidolite) can cause pulmonary fibrosis, lung cancer, and malignant mesothelioma (Manning et al. 2002). Data indicate that mesothelioma in 80–90% of individuals is associated with crocidolite as the primary cause. Because mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used well-characterized SWCNTs with a known concentration of metal catalyst contamination to investigate the alterations in molecular signaling in response to SWCNT exposure in normal mesothelial (NM) and malignant mesothelial (MM) cells. We used this form of SWCNTs because SWCNTs with different redox-sensitive iron contents have displayed diverse redox potentials, with iron-rich SWCNTs causing a significant loss of glutathione and increased lipid peroxidation in alveolar macrophages (Kagan et al. 2006). In this study we examined the toxicity and alterations in molecular signaling pathways in mesothelial cells exposed to raw SWCNTs with significant metal contamination. We compared some results with known effects of crocidolite in cultured mesothelial cells.