System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses

Details

• Personal Author:
  Castranova, Vincent ; Denvir J ; Dymacek J ; Guo NL ; Mercer RR ; Pacurari M ; Porter DW ; Qian Y ; Snyder-Talkington BN ; Wolfarth MG
• Description:
  The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80µg MWCNT at 1, 7, 28, or 56days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. [Description provided by NIOSH]
• Subjects:
  Animals Fibrosis Genetics Laboratories Lung Occupational Health Particulate Matter Pathology Respiratory System Safety
• Keywords:
  Author Keywords: Multi-walled Carbon Nanotubes Biological-effects Computational Toxicology Exposure-levels Fibrous-bodies Genes In Vivo Studies Laboratory-animals Lung-fibrosis Nanotechnology Signaling Pathways

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• ISSN:
  0041-008X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  476-489
• Volume:
  272
• Issue:
  2
• NIOSHTIC Number:
  nn:20043048
• Citation:
  Toxicol Appl Pharmacol 2013 Oct; 272(2):476-489
• Contact Point Address:
  Yong Qian, Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505-2888
• Email:
  yaq2@cdc.gov
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology and Applied Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2b3e67156f0f35957bea5f499406527168040e424a12ab68c9ed82c05708c7ded146d7b5104c322eefeced1250142085e0f2a82f373e6b7e65180dcf71165e15
• Download URL:
  https://stacks.cdc.gov/view/cdc/195070/cdc_195070_DS1.pdf
• File Type:
  [PDF - 3.01 MB ]