Previously, at comparable doses, we observed a greater inflammatory potency of inhaled versus aspirated gas metal arc-stainless steel (GMA-SS) welding fume in C57BL/6J (B6) mice. Also, aspiration of GMA-SS fume provoked a transient inflammation which resolved by 7d while inhalation resulted in a mounting response that remained unresolved at 28d post-exposure. Furthermore, we found by 28d after aspiration, lung gene expression was down-regulated which confirmed that inflammation was resolved. Here, we examined the lung transcriptional response after inhalation of GMA-SS fume and used gene network-based analysis to compare with previous aspiration data. Mice were exposed to GMA-SS fume at 40mg/m3 x 3hr/d for 10d. Necropsy was done at 28d after the last exposure and whole lung microarray was performed. A core analysis in IPA 8.7 was done on the inhalation data (p<0.05; fold change >1.5) followed by a core comparison analysis of the inhalation and aspiration datasets. We found that inhalation of GMA-SS welding fume was associated with activation of complement (C2, C3, C1QA-C, C4B), type 1 interferon pathways and increased expression of monocyte and lymphocyte chemotactic genes such as CCL2, CCL7 and CCL8. In addition, genes encoding the expression of molecules involved in T lymphocyte and natural killer cell regulation were increased (CD86 and CD69). Upon comparison of the datasets, a greater number of genes were changed with inhalation versus aspiration exposure. Involvement of IL1B as a central mediator to the lung response was apparent between the different exposure regimes as well as increased expression of MMP12. Transcriptional regulation of the lung response to GMA-SS aspiration involved FOS, EGR1, FOSB. In contrast, IRF7 and 9 as well as STAT1 and 2 were involved with inhalation. Overall, gene expression was reflective of the unresolved inflammation at 28d after inhalation of GMA-SS fumes. With the exception of a few molecules, differences in gene network signatures are apparent between aspiration and inhalation of GMASS welding fume in B6 mice.
Biological-effects; Cell-biology; Exposure-methods; Fumes; Gas-welders; Inhalants; Inhalation-studies; Laboratory-animals; Laboratory-testing; Lung-cells; Lung-function; Lung-irritants; Mathematical-models; Molecular-biology; Pulmonary-function; Pulmonary-system; Respiratory-gas-analysis; Respiratory-hypersensitivity; Respiratory-irritants; Statistical-analysis; Toxic-effects; Welding-industry
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC