Our earlier studies found supportive evidence for a tumorigenic effect of carcinogenic metal-containing welding fume in A/J mice. A/J mice are genetically predisposed to spontaneous and/or chemically-induced lung tumors while C57BL/6J (B6) mice are resistant. This genetic disparity provides a unique scenario to identify molecular mechanisms associated with the lung response to welding fume at the transcriptome level. Mice were exposed four times by pharyngeal aspiration to 5mg/kg mild steel (MS) fume, stainless steel (SS) fume, or saline vehicle. Mice were necropsied 28 days after the last exposure and whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done. Ingenuity pathway analysis (cutoffs: p<0.05; fold change >1.3) of the microarray data revealed the top global molecular network involved in the A/J response to MS fume was behavior, nervous system development and function, and gene expression. In contrast, the connective tissue disorders, immunological disease, inflammatory disease network was most significant in the B6 strain. In the A/J, 75% of the focus molecules that met the cutoff were up-regulated as compared to 40% in the B6. Six genes were common between the strains such as KLF2, KLF4 and MARCO. SS fume exposure in the A/J induced genes primarily involved in connective tissue disorders, immunological disease, and inflammatory disease. Genes regulating cellular movement, hematological system development and function, and immune response were most involved in the B6 response. Of the significant focus molecules, 88% were up-regulated in the A/J compared to 45% in the B6. Only five common genes were found between the strains such as HSPH1, MMP12 and CTSK. Overall, these data confirm our previous observation that strain-dependent differences in response to welding fume occur in the A/J and B6 lung. Also, in contrast to the B6, the A/J strain exhibited a persistent up-regulation of welding fume-induced gene transcription suggesting that chronic lung cell activation may play a role in the tumorigenic effects of welding fume.
Biological-effects; Biological-factors; Carcinogenesis; Carcinogenicity; Exposure-assessment; Exposure-levels; Exposure-methods; Genetic-factors; Inhalation-studies; Laboratory-animals; Lung-disorders; Lung-function; Lung-irritants; Microscopic-analysis; Microscopy; Metal-fumes; Particulates; Pulmonary-system-disorders; Pulmonary-disorders; Pulmonary-function-tests; Particle-aerodynamics; Particulate-dust; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Statistical-analysis; Welders-lung; Welding-industry
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland