Carbon Nanotube and Asbestos Exposures Induce Overlapping but Distinct Profiles of Lung Pathology in Non-Swiss Albino CF-1 Mice

Abstract

Carbon nanotubes (CNTs) are emerging as important occupational and environmental toxicants owing to their increasing prevalence and potential to be inhaled as airborne particles. CNTs are a concern because of their similarities to asbestos, which include fibrous morphology, high aspect ratio, and biopersistence. Limitations in research models have made it difficult to experimentally ascertain the risk of CNT exposures to humans and whether these may lead to lung diseases classically associated with asbestos, such as mesothelioma and fibrosis. In this study we sought to comprehensively compare profiles of lung pathology in mice following repeated exposures to multi-wall CNTs or crocidolite asbestos (CA). We show that both exposures resulted in granulomatous inflammation and increased interstitial collagen, CA exposures caused predominantly bronchoalveolar hyperplasia whereas CNT exposures caused alveolar hyperplasia of type II pneumocytes (T2Ps). T2Ps isolated from CNT-exposed lungs were found to have upregulated proinflammatory genes, including IL-1ß, in contrast to those from CA-exposed. Immunostaining in tissue showed that while both toxicants increased IL-1ß protein expression in lung cells, T2P-specific IL-1ß increases were greater following CNT exposure. These results suggest related but distinct mechanisms of action by CNTs versus asbestos which may lead to different outcomes in the two exposure types.

Review of toxicity studies of carbon nanotubes

“…One 13-week inhalation study 14) showed that MWCNT exposure induced hyperplasia of epithelial cells after certain observation periods when the concentration of MWCNTs was high. Frank et al (2016) 46) found that the oropharyngeal aspiration of CNT caused alveolar hyperplasia of type 2 pneumocytes at 5 weeks after the end of exposure, although that was not in the bronchoalveolar area, that is the origin of lung cancer. The carcinogenicity of CNTs has been observed in the case of long needle-like structures of CNTs, but If the fiber is shorter, the carcinogenicity of CNTs will be attenuated.…”

“…Two intratracheal instillation studies of MWCNTs showed lung injury 45,46) . One study using proliferating cell nuclear antigen (PCNA) immunolabeling showed that exposure to pristine or functionalized MWCNTs stimulated the proliferation of alveolar and bronchiolar epithelial cells, although the observation period (16 days) was not long enough to evaluate the persistency of hyperplasia.…”

Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks

“…Another study (Wang et al, 2012) documented a decrease in the ability of CNTs to elicit TGF-β in vivo when using a related surfactant (Pluronic F108) as a dispersant. While there has been increasing adoption of BSA/phosphocholine dispersants in CNT aspiration studies, we opted to use Pluronic in this instance in the interest of contiguity with our previously published work (Frank et al, 2015, 2016) using this material. Although we find these dispersion and aspiration methods adequate to illustrate the comparisons captured in the current study, it should be noted that attempts to accurately model human exposures (i.e., for risk analysis) should use true inhalation exposures appropriately adjusted for interspecies differences in respiratory tract dosimetry.…”

“…; De Volder et al, 2013). CNTs are high aspect ratio nanofibers which have been experimentally reported to cause chronic inflammation, hyperplasia, and fibrosis of lung tissue (Bonner et al, 2013; Frank et al, 2016; Mercer et al, 2011). Existing literature indicates that CNTs are poorly cleared from the lung in experimental models using inhaled or aspirated exposure doses (Elgrabli et al, 2008; Muller et al, 2005).…”

The Advances in Biomedical Applications of Carbon Nanotubes

“…Some studies demonstrated that CNTs, even in low concentrations, are able to trigger inflammation in the respiratory system of animals [168]. In addition to inflammation, it was revealed that CNTs are also capable of inducing the modulation of proliferation of lung cells as a result of direct injury [169], fibrosis [170], DNA damage [171], and lung cancer [172,173].…”