Multi-walled carbon nanotube-induced gene expression in the mouse lung: Association with lung pathology

Abstract

Due to the fibrous shape and durability of multi-walled carbon nanotubes (MWCNT), concerns regarding their potential for producing environmental and human health risks, including carcinogenesis, have been raised. This study sought to investigate how previously identified lung cancer prognostic biomarkers and the related cancer signaling pathways are affected in the mouse lung following pharyngeal aspiration of well-dispersed MWCNT. A total of 63 identified lung cancer prognostic biomarker genes and major signaling biomarker genes were analyzed in mouse lungs (n = 80) exposed to 0, 10, 20, 40, or 80 μg of MWCNT by pharyngeal aspiration at 7 and 56 days post-exposure using quantitative PCR assays. At 7 and 56 days post-exposure, a set of 7 genes and a set of 11 genes, respectively, showed differential expression in the lungs of mice exposed to MWCNT vs. the control group. Additionally, these significant genes could separate the control group from the treated group over the time series in a hierarchical gene clustering analysis. Furthermore, 4 genes from these two sets of significant genes, coiled-coil domain containing-99 (Ccdc99), muscle segment homeobox gene-2 (Msx2), nitric oxide synthase-2 (Nos2), and wingless-type inhibitory factor-1 (Wif1), showed significant mRNA expression perturbations at both time points. It was also found that the expression changes of these 4 overlapping genes at 7 days post-exposure were attenuated at 56 days post-exposure. Ingenuity Pathway Analysis (IPA) found that several carcinogenic-related signaling pathways and carcinogenesis itself were associated with both the 7 and 11 gene signatures. Taken together, this study identifies that MWCNT exposure affects a subset of lung cancer biomarkers in mouse lungs.

MDSC and TGFβ Are Required for Facilitation of Tumor Growth in the Lungs of Mice Exposed to Carbon Nanotubes

“…Many studies have reported that CNT can induce apoptosis, DNA damage, and activation of major regulatory pathways - MAPKs, AP-1, NF-κB, and Akt - all of which recapitulate key molecular events involved in asbestos-induced lung cancer (31, 35). Moreover, Pacurari et al reported that MWCNT exposure affects a subset of lung cancer prognostic biomarkers in mouse lungs (36) and Wang et al showed that chronic exposure to SWCNT in vitro caused malignant transformation of human lung epithelial cells (37). …”

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

“…Finally, change of gene expression signatures in the mouse lungs following pharyngeal aspiration MWCNTs were associated with human lung cancer risk and progression signatures [148,149].…”

Acute pulmonary dose–responses to inhaled multi-walled carbon nanotubes

“…A recent report used morphometry to determine that the average thickness of connective tissue in the alveolar septa was increased over vehicle control by 45% in the 40 mg and 73% in the 80 mg exposure groups at 56 days postexposure, demonstrating that MWCNT have the potential to produce a progressive, fibrotic response in the alveolar tissues of the lungs (Mercer et al 2011). Also, using Ingenuity Pathway Analysis (IPA), we determined that MWCNT exposure affects a subset of lung cancer biomarkers and identified several carcinogenic-related signalling pathways that may be involved in the response (Pacurari et al 2011). These studies, when considered together, provide compelling evidence that MWCNT may pose a significant human health risk.…”