The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo
The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo
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DOI：
10.1016/j.canlet.2008.02.017
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发表时间：
2008-06-28
期刊：
影响因子：
9.7
通讯作者：
Baird, William M.
中科院分区：
文献类型：
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作者：
Courter, Lauren A.;Luch, Andreas;Baird, William M.
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是不确定的。我们评估了柴油机排气颗粒物油多环芳烃诱导的细胞色素P450（CYP 450）活性、多环芳烃-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，我们监测了用柴油机废气、苯并[a]芘（BP）、二苯并[a，l]芘（DBP）或柴油机废气与致癌PAH的组合处理小鼠的效果。应用的柴油颗粒物（SRM 1975）改变了DBP的肿瘤引发效力：与单独暴露于DBP相比，在用12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）促进25周后观察到总体肿瘤和癌负荷的统计学显著降低。在观察期开始时用2 nmol DBP处理的小鼠中，所有存活小鼠均发生肿瘤（9/9只动物，100%）。在最后计数的所有肿瘤中，检测到9个癌，并确定所有总体肿瘤发生率为2.6个肿瘤/荷瘤动物（TBA）。相比之下，DBP与50 mg SRM 1975的共治疗导致肿瘤率仅为66%（29只动物中的19只），29只动物中仅发生3例癌，总体发生率为2.1例肿瘤/TBA（P = 0.04）。与DBP的结果相反，当与SRM 1975共同治疗时，发现200 nmol BP诱导的肿瘤发生率略有增加（25周后71% vs. 85%）。尽管肿瘤发生率存在差异，但两个治疗组之间的癌和肿瘤数量/TBA无统计学显著差异，可能是由于BP治疗组规模较小。由于DBP而非BP的生物活化主要取决于CYP 1B 1酶活性，因此当需要CYP 1B 1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。最有可能的解释是，与CYP 1A 1相比，柴油机尾气中存在的某些多环芳烃对CYP 1B 1的抑制作用更强。在本研究中，我们还发现了分子标志物，如高度升高的AKR 1C 21和TNFRSF 21基因表达水平，肿瘤组织来源于SRM 1975加DBP联合治疗的动物。因此，我们验证微阵列数据作为一个来源，以揭示转录签名，可能会提供深入了解分子途径受影响后，暴露于环境复杂的混合物，如柴油机尾气颗粒物。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
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 oil 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 (SRM1975) 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 all overall tumor incidence of 2.6 tumors per tumor-bearing animal (TBA) was determined. By contrast, co-treatment of DBP with 50 mg SRM1975 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 SRM1975 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, SRM1975 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 SRM1975 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.