Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic.
Mutat Res. 2011 Sep 1;714(1-2):53-62. doi: 10.1016/j.mrfmmm.2011.06.011. Epub 2011 Jul 5.
Many of the toxic and carcinogenic effects of urban air pollution have been linked to polycyclic aromatic hydrocarbons (PAHs) adsorbed to airborne particulate matter (PM). The carcinogenic properties of PAHs in complex organic mixtures derived from PM have been chiefly attributed to their mutagenicity. Nevertheless, PAHs are also potent activators of the aryl hydrocarbon receptor (AhR), which may contribute to their nongenotoxic effects, including tumor promotion. As the genotoxicity of carcinogenic PAHs in complex mixtures derived from urban PM is often inhibited by other mixture constituents, the AhR-mediated activity of urban PM extracts might significantly contribute to the carcinogenic activity of such mixtures. In the present study, we used an organic extract of the urban dust standard reference material, SRM1649a, as a model mixture to study a range of toxic effects related to DNA damage and AhR activation. Both the organic extract and its neutral aromatic fraction formed a low number of DNA adducts per nucleotide in the liver epithelial WB-F344 cells model, without inducing DNA damage response, such as tumor suppressor p53 activation and apoptosis. In contrast, we found that this extract, as well as its neutral and polar fractions, were potent inducers of a range of AhR-mediated responses, including induction of the AhR-mediated transcription, such as cytochrome P450 1A1/1B1 expression, and the AhR-dependent cell proliferation. Importantly, these toxic events occurred at doses one order of magnitude lower than DNA damage. The AhR-mediated activity of the neutral fraction was linked to PAHs and their derivatives, as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls were only minor contributors to the overall AhR-mediated activity. Taken together, our data suggest that more attention should be paid to the AhR-dependent nongenotoxic events elicited by urban PM constituents, especially PAHs and their derivatives.
城市空气污染中的许多有毒和致癌作用都与吸附在空气颗粒物（PM）上的多环芳烃（PAHs）有关。PM 衍生的复杂有机混合物中 PAHs 的致癌特性主要归因于其致突变性。然而，PAHs 也是芳烃受体（AhR）的有效激活剂，这可能导致其非遗传毒性作用，包括肿瘤促进作用。由于城市 PM 衍生的复杂混合物中致癌 PAHs 的遗传毒性通常被其他混合物成分所抑制，因此城市 PM 提取物的 AhR 介导的活性可能会显著促进此类混合物的致癌活性。在本研究中，我们使用城市灰尘标准参考物质 SRM1649a 的有机提取物作为模型混合物，研究与 DNA 损伤和 AhR 激活相关的一系列毒性作用。有机提取物及其中性芳香族馏分在肝上皮 WB-F344 细胞模型中每个核苷酸形成的 DNA 加合物数量较少，不会诱导 DNA 损伤反应，如肿瘤抑制因子 p53 激活和细胞凋亡。相比之下，我们发现该提取物及其中性和极性馏分是一系列 AhR 介导的反应的有效诱导剂，包括诱导 AhR 介导的转录，如细胞色素 P450 1A1/1B1 的表达，以及 AhR 依赖性细胞增殖。重要的是，这些毒性事件发生在 DNA 损伤剂量低一个数量级的剂量下。中性馏分的 AhR 介导活性与 PAHs 及其衍生物有关，因为多氯二苯并对二恶英、二苯并呋喃和联苯只是整体 AhR 介导活性的次要贡献者。总之，我们的数据表明，应更加关注城市 PM 成分引起的 AhR 依赖性非遗传毒性事件，特别是 PAHs 及其衍生物。
