Tugendreich-S; Ng-N; Zeidler-Erdely-PC; Antonini-JM; Kashon-ML; Erdely-A
Toxicologist 2013 Mar; 132(1):347
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.
Toxicology; Laboratory-animals; Laboratory-techniques; Laboratory-testing; Exposure-assessment; Exposure-levels; Aerosols; Aerosol-particles; Gases; Fumes; Metal-fumes; Dose-response; Stainless-steel; Physiological-effects; Cardiovascular-function; Cardiovascular-system-disorders; Immune-reaction; Immunotoxins; Welding; Arc-welding; Gas-welders; Heart; Pulmonary-system; Cell-function; Cellular-reactions; Cell-alteration; Gene-mutation; Genes; Genotoxic-effects; Blood-cells; Lung-cells; Particulates; Chemical-indicators; Analytical-instruments; Analytical-models; Metal-compounds; Nickel-compounds
12597-68-1; 7440-02-0; 10028-15-6
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, San Antonio, Texas, March 10-14, 2013