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Maricica Pacurari,¹ Xuejun J. Yin,² Jinshun Zhao,¹ Ming Ding,¹ Steve S. Leonard,¹ Diane Schwegler-Berry,¹ Barbara S. Ducatman,² Deborah Sbarra,³ Mark D. Hoover,³ Vincent Castranova,¹ and Val Vallyathan¹

¹Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA; ²Department of Pathology, School of Medicine, West Virginia University, Morgantown, West Virginia, USA; ³Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA

Abstract
Background: Single-wall carbon nanotubes (SWCNTs) , with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells.

Objective: Exposure to asbestos is the primary cause of malignant mesothelioma in 80–90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT.

Methods: In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1) , stimulation of extracellular signal-regulated kinase (ERKs) , Jun N-terminal kinases (JNKs) , protein p38, and activation of activator protein-1 (AP-1) , nuclear factor κB (NF-κB) , and protein serine-threonine kinase (Akt) .

Results: Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-κB, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure.

Conclusions: The cellular and molecular findings reported here do 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.

Key words: asbestos, cancer, carbon nanotubes, cell injury, DNA damage, mesothelioma, nanoparticles. Environ Health Perspect 116:1211–1217 (2008) .  doi:10.1289/ehp.10924 available via http://dx.doi.org/ [Online 16 May 2008]

Address correspondence to V. Vallyathan, NIOSH/CDC, 1095 Willowdale Rd., Morgantown, WV 26505 USA. Telephone: (304) 285-5770. Fax: (304) 285-5938. E-mail: vav1@cdc.gov

Supplemental Material is available online at http://www.ehponline.org/members/2008/10924/suppl.pdf

We thank M. Postek (Precision Engineering Division, National Institute of Standards and Technology, Gaithersburg, MD) for providing the single-wall carbon nanotube samples used in this study.

This study was supported by the National Institute for Occupational Safety and Health.

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

The authors declare they have no competing financial interests.

Received 26 September 2007 ; accepted 14 May 2008.