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. 2018 Jul/Aug;37(4):276-284.
doi: 10.1177/1091581818779038. Epub 2018 Jun 19.

Similar and Differential Canonical Pathways and Biological Processes Associated With Multiwalled Carbon Nanotube and Asbestos-Induced Pulmonary Fibrosis: A 1-Year Postexposure Study

Julian M Dymacek  1   2 , Brandi N Snyder-Talkington  1 , Rebecca Raese  1 , Chunlin Dong  1 , Salvi Singh  1 , Dale W Porter  3 , Barbara Ducatman  1   4 , Michael G Wolfarth  3 , Michal E Andrew  3 , Lori Battelli  3 , Vincent Castranova  5 , Yong Qian  3 , Nancy L Guo  1   6
Affiliations

Similar and Differential Canonical Pathways and Biological Processes Associated With Multiwalled Carbon Nanotube and Asbestos-Induced Pulmonary Fibrosis: A 1-Year Postexposure Study

Julian M Dymacek et al. Int J Toxicol. 2018 Jul/Aug.

Abstract

Respiratory exposure to multiwalled carbon nanotubes (MWCNT) or asbestos results in fibrosis; however, the mechanisms to reach this end point may be different. A previous study by our group identified pulmonary effects and significantly altered messenger RNA (mRNA) signaling pathways following exposure to 1, 10, 40, and 80 µg MWCNT and 120 µg crocidolite asbestos on mouse lungs over time at 1-month, 6-month, and 1-year postexposure following pulmonary aspiration. As a continuation to the above study, this current study took an in-depth look at the signaling pathways involved in fibrosis development at a single time point, 1 year, and exposure, 40 µg MWCNT, the lowest exposure at which fibrosis was pathologically evident. The 120 µg asbestos exposure was included to compare MWCNT-induced fibrosis with asbestos-induced fibrosis. A previously validated computational model was used to identify mRNAs with expression profiles matching the fibrosis pathology patterns from exposed mouse lungs. mRNAs that matched the pathology patterns were then input into ingenuity pathway analysis to determine potential signaling pathways and physiological disease functions inherent to MWCNT and asbestos exposure. Both MWCNT and asbestos exposure induced changes in mouse lungs regarding gene expression, cell proliferation, and survival, while MWCNT uniquely induced alterations in pathways involved in oxidative phosphorylation, mitochondrial dysfunction, and transcription. Asbestos exposure produced unique alterations in pathways involved in sustained inflammation. Although typically considered similar due to scale and fiber-like appearance, the different compositional properties inherent to either MWCNT or asbestos may play a role in their ability to induce fibrosis after pulmonary exposure.

Keywords: asbestos; lung fibrosis; multiwalled carbon nanotubes; nonnegative matrix factorizations; pathway analysis; toxicogenomics.

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Conflict of interest statement

Conflicts of Interest

The authors declare that they have no conflicts of interest. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.

Figures

Figure 1
Figure 1
Study overview.
Figure 2
Figure 2
Left lung trichrome and Sirius red pathology staining at 1 year. Lung sections were evaluated by visualization of collagen at 4× magnification. (A) DM (negative control) trichrome staining; (B) mild fibrosis with focal emphysema, 40 μg MWCNT, trichrome staining; (C) mild fibrosis with focal emphysema, 80 μg MWCNT, trichrome staining; (D) mild fibrosis, 120 μg asbestos, Sirius red staining.
Figure 3
Figure 3
Top 5 IPA pathways associated with mRNA expression concordant with the MWCNT 40 μg pathology pattern versus the asbestos pathology pattern.
Figure 4
Figure 4
Top 5 IPA pathways associated with mRNA expression concordant with the asbestos pathology pattern versus the MWCNT 40 μg pathology pattern.
Figure 5
Figure 5
Top 5 canonical pathways associated with mRNA expression concordant with both the MWCNT 40 μg and asbestos pathology patterns.
See this image and copyright information in PMC

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