Hard-metal (WC-Co) particles trigger a signaling cascade involving p38 MAPK, HIF-1α, HMOX1, and p53 activation in human PBMC

Arch Toxicol. 2013 Feb;87(2):259-68. doi: 10.1007/s00204-012-0943-y. Epub 2012 Sep 28.


Hard-metals are made of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties. While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC-Co particle mixture was shown to increase the risk of lung cancer in exposed workers. We have previously shown that WC-Co specifically induces a burst of reactive oxygen species (ROS) and in vitro mutagenic/apoptogenic effects in human peripheral blood mononucleated cells (PBMC) used as a validated experimental model. In the present study, PBMCs were treated during a short period (15 min) to focus on the very rapid ROS burst induced by WC-Co. We investigated by microarray the response to WC-Co versus Co(2+) ions (CoCl(2)) after 15 min exposure and found that the oxidative stress response HMOX1 gene was highly expressed in WC-Co-treated samples. This result was confirmed by qRT-PCR, and western blotting was carried out to analyze translational and post-translational regulation of genes belonging to the HMOX1 pathway. We show here that WC-Co, and metallic Co particles although with slower kinetics, but not CoCl(2) or WC alone, induced a temporally ordered cascade of events. This cascade implies p38/MAP kinase activation, HIF-1α stabilization, HMOX1 transcriptional activation, and ATM-independent p53 stabilization. These events, and in particular HIF-1α stabilization, could contribute to the carcinogenic activity of WC-Co dusts.

MeSH terms

  • Cobalt / metabolism
  • Cobalt / toxicity*
  • Dust
  • Gene Expression / drug effects
  • Gene Expression Profiling / methods
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Inhalation Exposure
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Occupational Exposure
  • Oligonucleotide Array Sequence Analysis / methods
  • Particulate Matter / toxicity*
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tungsten Compounds / metabolism
  • Tungsten Compounds / toxicity*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Dust
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Particulate Matter
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Tungsten Compounds
  • tungsten carbide
  • Cobalt
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • p38 Mitogen-Activated Protein Kinases
  • cobaltous chloride