Courter Lauren A, Luch Andreas, Musafia-Jeknic Tamara, Arlt Volker M, Fischer Kay, Bildfell Robert, Pereira Cliff, Phillips David H, Poirier Miriam C, Baird William M
Department of Environmental and Molecular Toxicology, Oregon State University, Agricultural and Life Sciences 1007, Corvallis, OR 97331, USA.
Cancer Lett. 2008 Jun 28;265(1):135-47. doi: 10.1016/j.canlet.2008.02.017. Epub 2008 Mar 18.
The carcinogenic effects of individual polycyclic aromatic hydrocarbons (PAH) are well established. However, their potency within an environmental complex mixture is uncertain. We evaluated the influence of diesel exhaust particulate matter on PAH-induced cytochrome P450 (CYP) activity, PAH-DNA adduct formation, expression of certain candidate genes and the frequency of tumor initiation in the two-stage Sencar mouse model. To this end, we monitored the effects of treatment of mice with diesel exhaust, benzo[a]pyrene (BP), dibenzo[a,l]pyrene (DBP), or a combination of diesel exhaust with either carcinogenic PAH. The applied diesel particulate matter (SRM(1975)) altered the tumor initiating potency of DBP: a statistically significant decrease in overall tumor and carcinoma burden was observed following 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA), compared with DBP exposure alone. From those mice that were treated at the beginning of the observation period with 2 nmol DBP all survivors developed tumors (9 out of 9 animals, 100%). Among all tumors counted at the end, nine carcinomas were detected and an overall tumor incidence of 2.6 tumors per tumor-bearing animal (TBA) was determined. By contrast, co-treatment of DBP with 50mg SRM(1975) led to a tumor rate of only 66% (19 out of 29 animals), occurrence of only three carcinomas in 29 animals and an overall rate of 2.1 tumors per TBA (P=0.04). In contrast to the results with DBP, the tumor incidence induced by 200 nmol BP was found slightly increased when co-treatment with SRM(1975) occurred (71% vs. 85% after 25 weeks). Despite this difference in tumor incidence, the numbers of carcinomas and tumors per TBA did not differ statistically significant between both treatment groups possibly due to the small size of the BP treatment group. Since bioactivation of DBP, but not BP, predominantly depends on CYP1B1 enzyme activity, SRM(1975) affected PAH-induced carcinogenesis in an antagonistic manner when CYP1B1-mediated bioactivation was required. The explanation most likely lies in the much stronger inhibitory effects of certain PAHs present in diesel exhaust on CYP1B1 compared to CYP1A1. In the present study we also found molecular markers such as highly elevated AKR1C21 and TNFRSF21 gene expression levels in tumor tissue derived from animals co-treated with SRM(1975) plus DBP. Therefore we validate microarray data as a source to uncover transcriptional signatures that may provide insights into molecular pathways affected following exposure to environmental complex mixtures such as diesel exhaust particulates.
单个多环芳烃（PAH）的致癌作用已得到充分证实。然而，它们在环境复杂混合物中的效力尚不确定。我们评估了柴油废气颗粒物对PAH诱导的细胞色素P450（CYP）活性、PAH-DNA加合物形成、某些候选基因的表达以及两阶段Sencar小鼠模型中肿瘤起始频率的影响。为此，我们监测了用柴油废气、苯并[a]芘（BP）、二苯并[a,l]芘（DBP）或柴油废气与致癌性PAH的组合处理小鼠的效果。所应用的柴油颗粒物（SRM(1975)）改变了DBP的肿瘤起始效力：在用12-O-十四酰佛波醇-13-乙酸酯（TPA）促进25周后，与单独暴露于DBP相比，观察到总体肿瘤和癌负担有统计学意义的下降。在观察期开始时用2 nmol DBP处理的那些小鼠中，所有存活者都发生了肿瘤（9只动物中的9只，100%）。在最后统计的所有肿瘤中，检测到9例癌，每只荷瘤动物（TBA）的总体肿瘤发生率为2.6个肿瘤。相比之下，DBP与50mg SRM(1975)联合处理导致肿瘤发生率仅为66%（29只动物中的19只），29只动物中仅出现3例癌，每只TBA的总体发生率为2.1个肿瘤（P = 0.04）。与DBP的结果相反，当与SRM(1975)联合处理时，发现200 nmol BP诱导的肿瘤发生率略有增加（25周后为71%对85%）。尽管肿瘤发生率存在这种差异，但由于BP处理组规模较小，两个处理组之间每只TBA的癌和肿瘤数量在统计学上没有显著差异。由于DBP而非BP的生物活化主要依赖于CYP1B1酶活性，当需要CYP1B1介导的生物活化时，SRM(1975)以拮抗方式影响PAH诱导的致癌作用。最可能的解释是，与CYP1A1相比，柴油废气中存在的某些PAH对CYP1B
