Molecular Activation of Activator Protein-1 in Silica and Asbestos-Induced Carcinogenesis

Details

• Personal Author:
  Castranova, Vincent ; Ding M ; Shi X ; Vallyathan V
• Description:
  Occupational exposures to asbestos and crystalline silica have been implicated in causing lung cancer and other pulmonary diseases in humans. Despite intensive research during the last decade on pulmonary carcinogenesis induced by these minerals, the exact molecular mechanisms involved in carcinogenesis are still unknown. Chronic inflammation and enhanced production of reactive oxygen species (ROS) generated by these particulates have been implicated in the development of tumors. In an attempt to understand the molecular basis of carcinogenesis induced by these particles, we investigated the potential activation of activator protein-1 (AP-1) by crocidolite and freshly fractured or aged crystalline silica in a JB6 P + cell line stably transfected with AP-1-luciferase reporter plasmid (in vitro) and in AP-1-luciferase reporter transgenic mice (in vivo). This transcription factor governs the expression of target genes that are involved in encoding cytokines, chemokines, growth factors, cell adhesion molecules, and acute-phase proteins that regulate inflammation, cell proliferation, and apoptosis. Results of our studies suggest that asbestos and silica activate AP-1 through generation of ROS. In in vitro studies, crocidolite asbestos caused a dose- and time-dependent AP-1 activation in JB6+ cells, which persisted for at least 72 h. In transgenic mice exposed to crocidolite asbestos, AP-1 activation increased significantly by 10-fold in lung tissue and 22-fold in bronchial tissue. This induction of AP-1 activation by crocidolite appears to be mediated through the influence of mitogen-activated protein kinase (MAPK) family members, specifically extracellular signal-regulating protein kinase, ERK 1, and ERK 2 (data not presented). Similarly, freshly fractured silica caused an 8-fold increase in AP-1 activation in JB6 P+cells and 22-fold increase in transgenic mice. The activation of AP-1 by freshly fractured silica was mediated through ERK1, ERK2, and p38 kinase. Activation of AP-1 by asbestos or silica was inhibited in both in vitro and in vivo systems by aspirin, which exhibits OH radical scavenging properties. It is proposed from these studies that asbestos and crystalline silica may promote carcinogenesis through specific mechanistic pathways stimulated by ROS. [Description provided by NIOSH]
• Subjects:
  Aluminum Silicates Asbestos Carcinogens Dust Inorganic Chemicals Lung Lung Diseases Neoplasms Occupational Exposure Occupational Health Particulate Matter Respiratory System Respiratory Tract Diseases Safety Silicon Dioxide

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• Keywords:
  Asbestos Dust Asbestosis Carcinogenesis Carcinogenicity In Vitro Studies In Vivo Studies Lung Cancer Occupational Exposure Particulate Dust Particulates Pulmonary System Disorders Respiratory System Disorders Silica Dusts Silicates Tumors

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• ISSN:
  0895-8378
• 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:
  353-357
• Volume:
  12
• NIOSHTIC Number:
  nn:20020838
• Citation:
  Inhal Toxicol 2000 Sep; 12(Suppl 3):353-357
• Contact Point Address:
  Val Vallyathan, PhD, NIOSH, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  vav1@cdc.gov
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4) ; Quartz (SiO2) (CAS RN 14808-60-7)
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Inhalation Toxicology
• Supplement:
  3
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b17e3f11a1d924996315c6ba726441357a108c66b749e959b8b74bc60cf6aab4c4217bf17dc4f5ac229312c21f567159dcda480469abd37d1d1a1980293ae8bd
• Download URL:
  https://stacks.cdc.gov/view/cdc/198499/cdc_198499_DS1.pdf
• File Type:
  [PDF - 266.27 KB ]