Department of Environmental and Molecular Toxicology, Oregon State University, USA.
Toxicol Appl Pharmacol. 2012 Nov 1;264(3):377-86. doi: 10.1016/j.taap.2012.08.014. Epub 2012 Aug 23.
The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response with mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by ³²P post-labeling, did not correlate with tumor incidence. PAH-dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and phase 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs).
多环芳烃（PAH）苯并[a]芘（BaP）与二苯并[def，p]chrysene（DBC）以及三种环境 PAH 混合物（煤焦油、柴油颗粒和香烟烟雾冷凝物）的组合在 FVB/N 小鼠皮肤肿瘤模型中进行了比较。DBC（4nmol）最为有效，达到 100%的肿瘤发生率，肿瘤形成潜伏期较短，少于 20 周的 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）促进作用与其他所有治疗方法相比。多发性是 BaP（400nmol）的 4 倍。两种 PAH 主要产生乳头状瘤，随后是鳞状细胞癌和原位癌。柴油颗粒提取物（1mgSRM1650b；混合物 1）与甲苯对照物没有区别，未能引起致癌反应。添加煤焦油提取物（1mgSRM1597a；混合物 2）产生的反应与 BaP 相似。进一步添加 2mg 香烟烟雾冷凝物（混合物 3）并没有改变混合物 2 的反应。在起始后 12 小时通过 ³²P 后标记分析表皮中的 PAH-DNA 加合物，与肿瘤发生率无关。通过微阵列评估起始后 12 小时皮肤中 PAH 依赖性转录组的改变。对 922 个显著改变的基因（p<0.05）进行主成分分析（所有处理的总和），表明 DBC 和 BaP 与 PAH 混合物及其彼此聚类不同。BaP 和混合物上调了 1 期和 2 期代谢酶，而 DBC 则没有。DBC 和两种混合物的致癌性比根据已发表的相对效力因子（RPF）预测的要大得多。
