Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic.
Department of Cell Biology and Genetics, Faculty of Science, Šlechtitelů 11, Palacký University, 78371 Olomouc, Czech Republic.
Environ Pollut. 2018 Jun;237:473-486. doi: 10.1016/j.envpol.2018.02.067. Epub 2018 Mar 15.
The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.
空气中低氯代多氯联苯同系物（LC-PCBs）产生毒性的机制仍未得到充分描述。我们使用报告基因检测以及其他功能细胞生物测定法，评估了室内和室外空气中存在的环境 LC-PCBs（PCB 4、8、11、18、28 和 31）以及选择的 PCB 8、11 和 18 的羟基代谢物的体外毒性。我们专注于与内分泌干扰、肿瘤促进和/或控制代谢内源化合物和外源性化合物的转录因子调节相关的过程。测试的 LC-PCBs 被发现是高效的抗雄激素（纳摩尔-微摩尔范围内）和雌激素（微摩尔浓度）化合物，以及在微摩尔浓度下抑制缝隙连接细胞间通讯（GJIC）的化合物。发现 PCB 8、28 和 31 部分抑制芳烃受体（AhR）介导的活性。测试的 LC-PCBs 也是部分组成型雄激素受体（CAR）和孕烷 X 受体（PXR）激动剂，其中 PCB 4、8 和 18 是最活跃的化合物。它们对其他核受体（如维生素 D 受体、甲状腺受体 α、糖皮质激素受体或过氧化物酶体增殖物激活受体 γ）无活性。我们发现只有 PCB 8 会导致氧化应激的产生，而所有测试的 LC-PCBs 都会在人肺上皮细胞中诱导花生四烯酸释放（尽管没有进一步调节花生四烯酸代谢）。重要的是，LC-PCBs 的羟基代谢物（4-OH-PCB 8、4-OH-PCB 11 和 4'-OH-PCB 18）的雌激素效应高于母体 PCB，而它们的其他毒性效应仅略有改变或受到抑制。这表明代谢可能以受体特异性方式改变 LC-PCBs 的毒性特征。总之，抗雄激素和雌激素活性、GJIC 的急性抑制和 AhR 介导的活性的抑制被认为是空气中 LC-PCBs 最相关的作用模式，尽管它们也部分影响了其他细胞靶标。
