Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown 26505, USA.
Respir Res. 2010 Jun 3;11(1):70. doi: 10.1186/1465-9921-11-70.
Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at risk population for the development of lung cancer. Recently, we found that exposure to welding fume caused an acutely greater and prolonged lung inflammatory response in lung tumor susceptible A/J versus resistant C57BL/6J (B6) mice and a trend for increased tumor incidence after stainless steel (SS) fume exposure. Here, our objective was to examine potential strain-dependent differences in the regulation and resolution of the lung inflammatory response induced by carcinogenic (Cr and Ni abundant) or non-carcinogenic (iron abundant) metal-containing welding fumes at the transcriptome level.
Mice were exposed four times by pharyngeal aspiration to 5 mg/kg iron abundant gas metal arc-mild steel (GMA-MS), Cr and Ni abundant GMA-SS fume or vehicle and were euthanized 4 and 16 weeks after the last exposure. Whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done.
Overall, we found that tumor susceptibility was associated with a more marked transcriptional response to both GMA-MS and -SS welding fumes. Also, Ingenuity Pathway Analysis revealed that gene regulation and expression in the top molecular networks differed between the strains at both time points post-exposure. Interestingly, a common finding between the strains was that GMA-MS fume exposure altered behavioral gene networks. In contrast, GMA-SS fume exposure chronically upregulated chemotactic and immunomodulatory genes such as CCL3, CCL4, CXCL2, and MMP12 in the A/J strain. In the GMA-SS-exposed B6 mouse, genes that initially downregulated cellular movement, hematological system development/function and immune response were involved at both time points post-exposure. However, at 16 weeks, a transcriptional switch to an upregulation for neutrophil chemotactic genes was found and included genes such as S100A8, S100A9 and MMP9.
Collectively, our results demonstrate that lung tumor susceptibility may predispose the A/J strain to a prolonged dysregulation of immunomodulatory genes, thereby delaying the recovery from welding fume-induced lung inflammation. Additionally, our results provide unique insight into strain- and welding fume-dependent genetic factors involved in the lung response to welding fume.
关于焊接烟尘是否具有致癌性存在争议，但流行病学证据表明，焊工是肺癌发病的高危人群。最近，我们发现，与抗性 C57BL/6J（B6）小鼠相比，接触焊接烟尘会导致易感 A/J 小鼠的肺部炎症反应更剧烈且持续时间更长，并且在接触不锈钢（SS）烟尘后，肿瘤发病率也呈上升趋势。在这里，我们的目的是研究在转录组水平上，致癌（富含铬和镍）或非致癌（富含铁）金属的焊接烟尘引起的肺部炎症反应中，潜在的与菌株相关的差异调节和解决。
通过咽吸法将小鼠暴露于 5mg/kg 富含铁的气体金属电弧-低碳钢（GMA-MS）、富含铬和镍的 GMA-SS 烟尘或载体中，分别在最后一次暴露后 4 周和 16 周处死。使用 Illumina Mouse Ref-8 表达芯片进行全肺微阵列分析。
总的来说，我们发现肿瘤易感性与 GMA-MS 和-GMA-SS 焊接烟尘的转录反应更明显有关。此外，Ingenuity Pathway Analysis 揭示了在暴露后两个时间点，基因调控和表达在菌株之间存在差异。有趣的是，在这两个菌株之间的一个共同发现是，GMA-MS 烟尘暴露改变了行为基因网络。相比之下，GMA-SS 烟尘暴露慢性上调趋化因子和免疫调节基因，如 CCL3、CCL4、CXCL2 和 MMP12，在 A/J 株中。在 GMA-SS 暴露的 B6 小鼠中，在暴露后两个时间点，最初下调细胞运动、血液系统发育/功能和免疫反应的基因参与其中。然而，在 16 周时，发现了一种向中性粒细胞趋化基因上调的转录开关，其中包括 S100A8、S100A9 和 MMP9 等基因。
总的来说，我们的结果表明，肺部肿瘤易感性可能使 A/J 株更容易发生免疫调节基因的长期失调，从而延迟焊接烟尘引起的肺部炎症的恢复。此外，我们的结果为与菌株和焊接烟尘相关的遗传因素提供了独特的见解，这些因素涉及到对焊接烟尘的肺部反应。
