Shi Q, Fijten R R, Spina D, Riffo Vasquez Y, Arlt V M, Godschalk R W, Van Schooten F J
Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands.
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
Toxicol Appl Pharmacol. 2017 Dec 1;336:8-19. doi: 10.1016/j.taap.2017.09.023. Epub 2017 Oct 5.
Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20μg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity. Ultimately, these changes resulted in higher levels of B[a]P-DNA adducts in the lungs of mice exposed to B[a]P with prior LPS treatment compared to the lungs of mice exposed to B[a]P alone. Using principle component analysis (PCA), we found that of all the genes that were significantly altered in their expression, those that were able to separate the different exposure conditions were predominantly related to immune-response. Moreover, an overall analysis of differentially expressed genes indicated that cell-cell adhesion and cell-cell communication was inhibited in lungs of mice that received both B[a]P and LPS. Our results indicate that pulmonary inflammation increased the genotoxicity of B[a]P via inhibition of both phase I and II metabolism. Therefore, inflammation could be a critical contributor to B[a]P-induced carcinogenesis in humans.
患有炎症性肺病的患者通常还会接触到多环芳烃，如苯并[a]芘，这些患者中苯并[a]芘诱导的基因表达改变可能促成肺癌的发生。给小鼠经鼻内注射脂多糖（LPS，20μg/小鼠）以诱导肺部炎症，随后通过气管内滴注使其接触苯并[a]芘（0.5mg/小鼠）。通过RNA微阵列分析小鼠肺中的基因表达变化。对已知参与细胞对苯并[a]芘反应的基因分析表明，LPS显著抑制了与苯并[a]芘代谢相关的各种酶的基因表达，这通过酶活性的表型分析得到了证实。最终，与仅接触苯并[a]芘的小鼠肺相比，预先经LPS处理后再接触苯并[a]芘的小鼠肺中苯并[a]芘-DNA加合物水平更高。使用主成分分析（PCA），我们发现，在所有表达显著改变的基因中，那些能够区分不同暴露条件的基因主要与免疫反应相关。此外，对差异表达基因的全面分析表明，同时接受苯并[a]芘和LPS的小鼠肺中细胞间粘附和细胞间通讯受到抑制。我们的结果表明，肺部炎症通过抑制I期和II期代谢增加了苯并[a]芘的遗传毒性。因此，炎症可能是人类中苯并[a]芘诱导致癌作用的关键促成因素。
