Polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (oxy-PAHs), are common environmental pollutants known to cause health effects in humans and wild-life. In particular, vertebrate cardiovascular development and function are sensitive to PACs. However, the interactive effects of PAHs and oxy-PAHs on cardiovascular endpoints have not been well studied. In this study, we used zebrafish embryos (ZFEs) as a model to examine developmental and cardiovascular toxicities induced by the three environmental oxy-PAHs benzo[]fluorenone (BFLO), 4-cyclopenta[]phenanthren-4-one (4H-CPO) and, 6-benzo[]pyren-6-one (6H-BPO), and the PAH benzo[]pyrene (BaP) either as single exposures or binary oxy-PAH + PAH mixtures. 6H-BPO induced developmental and cardiovascular toxicity, including reduced heartbeat rate and blood flow, at lower doses compared to the other compounds. Exposure to binary mixtures generally caused enhanced toxicity and induction of aryl hydrocarbon receptor (AhR)-regulated gene expression ( and ) compared to single compound exposure. This was associated with differential expression of genes involved in cardiovascular development and function including , , and . AhR-knock-down significantly reduced the cardiovascular toxicity of 6H-BPO and its binary mixture with BaP indicating a significant AhR-dependence of the effects. Measurements of internal concentrations showed that the toxicokinetics of BaP and 6H-BPO were altered in the binary mixture compared to the single compound exposure, and most likely due to CYP1 inhibition by 6H-BPO. Altogether, these data support that similar to interactions between PAHs, mixtures of PAHs and oxy-PAHs may cause increased developmental and cardiovascular toxicity in ZFEs through an AhR-dependent mechanism.

中文翻译：

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含氧多环芳烃和苯并[a]芘对斑马鱼胚胎心血管发育和功能的混合影响

多环芳香族化合物 (PAC)，包括多环芳香烃 (PAH) 和含氧 PAH (氧基 PAH)，是已知会对人类和野生动物健康造成影响的常见环境污染物。特别是，脊椎动物心血管的发育和功能对 PAC 很敏感。然而，PAH 和含氧 PAH 对心血管终点的相互作用尚未得到充分研究。在这项研究中，我们使用斑马鱼胚胎（ZFE）作为模型来检查三种环境含氧多环芳烃苯并[]芴酮（BFLO）、4-环戊[]菲-4-酮（4H-CPO）诱导的发育和心血管毒性。 ) 和 6-苯并[]芘-6-酮 (6H-BPO) 和 PAH 苯并[]芘 (BaP) 作为单次曝光或二元氧基-PAH + PAH 混合物。与其他化合物相比，6H-BPO 在较低剂量下会引起发育和心血管毒性，包括心率和血流量降低。与单一化合物暴露相比，暴露于二元混合物通常会导致毒性增强并诱导芳烃受体（AhR）调节的基因表达（和）。这与涉及心血管发育和功能的基因的差异表达有关，包括、、和。 AhR 敲低显着降低了 6H-BPO 及其与 BaP 的二元混合物的心血管毒性，表明该效应具有显着的 AhR 依赖性。内部浓度测量表明，与单一化合物暴露相比，二元混合物中 BaP 和 6H-BPO 的毒代动力学发生了改变，很可能是由于 6H-BPO 对 CYP1 的抑制。总之，这些数据表明，与 PAH 之间的相互作用类似，PAH 和含氧 PAH 的混合物可能通过 AhR 依赖性机制导致 ZFE 的发育和心血管毒性增加。