Mechanistic analysis of welding aerosol toxicity using Ingenuity Pathway Analysis (IPA)

Details

• Personal Author:
  Antonini JM ; Erdely A ; Kashon ML ; Ng N ; Tugendreich S ; Zeidler-Erdely PC
• Description:
  Welding involves occupational exposure to an aerosol containing gases and metal-rich particulates that induce adverse physiological effects including inflammation, immunosuppression, and cardiovascular dysfunction. To develop a deeper mechanistic understanding of these adverse effects, mice were exposed by inhalation to gas metal arc-stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 5 d a week for 2 weeks followed by gene expression analysis of whole blood cells, aorta, and lung at 4 hr and 28 d post-exposure. New features in Ingenuity Pathway Analysis (IPA) were used to analyze the expression data. The analysis results establish the importance of interferons and the IRF-family of transcription factors, predicting that they are activated at 4 hours and maintained through 28 days in both blood and lung. The IPA Upstream Regulator Analysis also predicted involvement of several toxicants, such as nickel and ozone, which have been detected in welding aerosol thereby highlighting the utility of Upstream Regulator Analysis for toxicogenomics applications. In addition, as an important drug discovery tool, IPA predicted several compounds that might be useful to ameliorate the inflammatory phenotype. One such compound was LY294002, a PI3K inhibitor that has already been shown to be efficacious in a mouse model of asthma. The new Mechanistic Network Analysis in IPA was used to computationally construct a plausible hypothesis that TRIM24 inactivation may lead to activation of IRF7 and STAT1 and other upstream regulators to drive the gene expression profile after the first exposure. Finally, Downstream Effects Analysis in IPA predicted large increases in proliferation, chemotaxis, and trafficking of immune cells in the lung after 4 hours. In summary, IPA has a unique new set of capabilities to enhance the mechanistic understanding of toxicological datasets and to provide support for new hypotheses that can be tested in the lab. [Description provided by NIOSH]
• Subjects:
  Aerosols Air Pollutants, Occupational Blood Cardiovascular Diseases Cardiovascular System Chemistry Environmental Monitoring Genetics Immune System Laboratories Lung Metals Nickel Occupational Health Particulate Matter Respiratory System Safety Toxicology Welding

  More +
• Keywords:
  Aerosol-particles Analytical-instruments Analytical-models Arc-welding Blood-cells Cardiovascular-function Cardiovascular-system-disorders Cell-alteration Cell-function Cellular-reactions Chemical-indicators Dose-response Exposure-assessment Exposure-levels Fumes Gas-welders Gases Gene-mutation Genes Genotoxic-effects Heart Immune-reaction Immunotoxins Laboratory-animals Laboratory-techniques Laboratory-testing Lung-cells Metal-compounds Metal-fumes Nickel-compounds Particulates Physiological-effects Pulmonary-system Stainless-steel

  More +
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 6 ; OSHA Region 9 ; Texas ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  132
• Issue:
  1
• NIOSHTIC Number:
  nn:20042435
• Citation:
  Toxicologist 2013 Mar; 132(1):347
• CAS Registry Number:
  Nickel (CAS RN 7440-02-0) ; Ozone (CAS RN 10028-15-6) ; Stainless Steel (CAS RN 12597-68-1)
• Federal Fiscal Year:
  2013
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0bc88595366ca3c4d9372969a78341a8250657827de8852c958cb2664f755b5c60ba8cc34f09783ead95488eb223e2b8e5f64f5e4d2bb3f3a4b547688987e72e
• Download URL:
  https://stacks.cdc.gov/view/cdc/194660/cdc_194660_DS1.pdf
• File Type:
  [PDF - 576.19 KB ]