Pulmonary inflammation and tumor induction in lung tumor susceptible A/J and resistant C57BL/6J mice exposed to welding fume

Abstract

Background: Welding fume has been categorized as "possibly carcinogenic" to humans. Our objectives were to characterize the lung response to carcinogenic and non-carcinogenic metal-containing welding fumes and to determine if these fumes caused increased lung tumorigenicity in A/J mice, a lung tumor susceptible strain. We exposed male A/J and C57BL/6J, a lung tumor resistant strain, by pharyngeal aspiration four times (once every 3 days) to 85 mug of gas metal arc-mild steel (GMA-MS), GMA-stainless steel (SS), or manual metal arc-SS (MMA-SS) fume, or to 25.5 mug soluble hexavalent chromium (S-Cr). Shams were exposed to saline vehicle. Bronchoalveolar lavage (BAL) was done at 2, 7, and 28 days post-exposure. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 48 and 78 weeks post-exposure.

Results: BAL revealed notable strain-dependent differences with regards to the degree and resolution of the inflammatory response after exposure to the fumes. At 48 weeks, carcinogenic metal-containing GMA-SS fume caused the greatest increase in tumor multiplicity and incidence, but this was not different from sham. By 78 weeks, tumor incidence in the GMA-SS group versus sham approached significance (p = 0.057). A significant increase in perivascular/peribronchial lymphoid infiltrates for the GMA-SS group versus sham and an increased persistence of this fume in lung cells compared to the other welding fumes was found.

Conclusion: The increased persistence of GMA-SS fume in combination with its metal composition may trigger a chronic, but mild, inflammatory state in the lung possibly enhancing tumorigenesis in this susceptible mouse strain.

Figure 1

Effect of S-Cr or MMA-SS welding fume on lavage protein levels and whole lung gene expression of IFN-γ (A&B) and IL-6 (C&D) at 2 days post-exposure in A/J and C57BL/6J mice. The dotted line represents the assay sensitivity for each protein and mean lines (–) are shown for each group. Gene expression data are presented as fold change from sham controls (dotted line). Values are mean ± SE (n = 4–7 per group). *-Significantly different from corresponding sham. #-Significantly different between strains of the same exposure group Note: Portions of this figure have been previously published [42].

Figure 2

Effect of S-Cr or MMA-SS welding fume on lavage protein levels and whole lung gene expression of MCP-1 (A&B) and TNF-α (C&D) at 2 days post-exposure in A/J and C57BL/6J mice. The dotted line represents the assay sensitivity for each protein and mean lines (–) are shown for each group. Gene expression data are presented as fold change from sham controls (dotted line). Values are mean ± SE (n = 4–7 per group). *-Significantly different from corresponding sham. Note: Portions of this figure have been previously published [42].

Figure 3

Effect of GMA welding fumes on lavage protein levels of MCP-1 (A&B) and TNF-α (C&D) at 2 and 28 days post-exposure in A/J and C57BL/6J mice. The dotted line represents the assay sensitivity for each inflammatory protein and mean lines (–) are shown for each group (n = 5–7).

Figure 4

Photomicrographs of lung tissue from welding fume-exposed A/J mice. Preneoplastic lesions (panel A) and adenomas (panel B) were the most common lung lesions observed in all exposed and sham groups. These representative low magnification photomicrographs were captured at 48 weeks post-exposure to GMA-SS fume. Panel C is a high magnification photomicrograph showing the presence of GMA-SS fume (brown-black granular pigmented areas) at 48 weeks post-exposure. An increased persistence in the lung was observed for GMA-SS fume compared to the GMA-MS or MMA-SS fume. At 78 weeks post-exposure, the presence of GMA-SS fume is still observed in the lung and an increased lymphohistiocytic infiltrate was associated with this fume (panel D).