Institute of Environmental Medicine and Toxicology, Research Center of Environmental Science and Engineering, Shanxi University, Taiyuan, China.
Inhal Toxicol. 2010 Mar;22(4):322-9. doi: 10.3109/08958370903341891.
Concurrent exposure to SO(2) and benzo(a)pyrene (B(a)P) resulted in an increased incidence of lung tumors in rodents compared to exposure to B(a)P alone. A synergistic effect on the expression of c-fos and c-jun between SO(2) and B(a)P was observed in lungs after SO(2) and B(a)P exposure. However, tumorigenesis occurs by multiple events that may involve the activation of more than one oncogene, as well as the functional loss of the tumor suppressor gene. In order to further investigate the interactions between SO(2) and B(a)P, male Wistar rats were exposed via intratracheal instillation of B(a)P (3 mg) or SO(2) (56 mg/m(3)) inhalation, alone or together. The mRNA and protein levels of oncogenes (c-myc and H-ras) and tumor suppressor genes (p53, p16, and Rb) were analyzed in lungs by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The results showed that all treatments increased mRNA and protein expression levels of c-myc, H-ras, and p53, and reduced expression levels of p16 and Rb. In general, the combination of SO(2) and B(a)P was more effective in influencing these expression levels than either agent alone, except for H-ras expression. These findings indicate that multiple cell cycle regulatory proteins play key roles in the toxicity of SO(2) and B(a)P. It might involve the activation of c-fos, c-jun, c-myc, and p53. And the p16-Rb pathway might also participate in the progress. Elucidating the expression patterns of those factors after SO(2) and B(a)P exposure may be critical to understanding the mechanisms of SO(2) cocarcinogenesis and helpful for therapeutic intervention.
二氧化硫（SO2）和苯并[a]芘（B(a)P）同时暴露会导致啮齿动物的肺癌发生率增加，高于单独暴露于 B(a)P。在 SO2 和 B(a)P 暴露后，观察到 SO2 和 B(a)P 之间在肺中 c-fos 和 c-jun 的表达有协同作用。然而，肿瘤发生是由多个事件引起的，这些事件可能涉及到一个以上癌基因的激活，以及肿瘤抑制基因的功能丧失。为了进一步研究 SO2 和 B(a)P 之间的相互作用，雄性 Wistar 大鼠通过气管内滴注 B(a)P（3mg）或 SO2（56mg/m3）吸入，单独或联合暴露。通过实时逆转录-聚合酶链反应（RT-PCR）和 Western blot 分别分析肺中癌基因（c-myc 和 H-ras）和肿瘤抑制基因（p53、p16 和 Rb）的 mRNA 和蛋白水平。结果表明，所有处理均增加了 c-myc、H-ras 和 p53 的 mRNA 和蛋白表达水平，降低了 p16 和 Rb 的表达水平。总的来说，SO2 和 B(a)P 的联合作用比单独使用任何一种药物更能影响这些表达水平，除了 H-ras 的表达。这些发现表明，多种细胞周期调节蛋白在 SO2 和 B(a)P 的毒性中起关键作用。这可能涉及 c-fos、c-jun、c-myc 和 p53 的激活。p16-Rb 途径也可能参与其中。阐明 SO2 和 B(a)P 暴露后这些因素的表达模式可能对理解 SO2 协同致癌作用的机制至关重要，并有助于治疗干预。
