Department of Biology, Queen's University, Kingston, ON, Canada.
Aquat Toxicol. 2011 Jan 17;101(1):165-74. doi: 10.1016/j.aquatox.2010.09.016. Epub 2010 Oct 30.
In the embryo-larval stages of fish, alkylphenanthrenes such as retene (7-isopropyl-1-methylphenanthrene) produce a suite of developmental abnormalities typical of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including pericardial and yolk sac edema, cardiovascular dysfunction, and skeletal deformities. To investigate the mechanism and target tissue of retene toxicity, we used observational, histological, and protein knockdown techniques in zebrafish (Danio rerio) embryos. The primary overt signs of toxicity are pericardial edema and reduced blood flow, first observed at 36 h post-fertilization (hpf). The most pronounced effects at this stage are a reduced layer of cardiac jelly in the atrium and reduced diastolic filling. Conversely, an increased layer of cardiac jelly is observed at 72 hpf in retene-exposed embryos. Induction of cytochrome P4501A (CYP1A) is apparent in a subset of cardiomyocytes by 48 hpf suggesting that early cardiac effects may be due to AhR activation in the myocardium. Myocardial CYP1A induction is transient, with only endocardial induction observed at 72 hpf. Knockdown of cyp1a by morpholino oligonucleotides does not affect retene toxicity; however, ahr2 knockdown prevents toxicity. Thus, the mechanism of retene cardiotoxicity is AhR2-mediated and CYP1A-independent, similar to TCDD; however, the onset and proximate signs of retene toxicity differ from those of TCDD. Retene cardiotoxicity also differs mechanistically from the cardiac effects of non-alkylated phenanthrane, illustrating that alkyl groups can alter toxic action. These findings have implications for understanding the toxicity of complex mixtures containing alkylated and non-alkylated polycyclic aromatic hydrocarbons.
在鱼类的胚胎-幼虫阶段，烷基菲（例如，苊烯，7-异丙基-1-甲基菲）会产生一系列发育异常，这些异常与暴露于 2,3,7,8-四氯二苯并对二恶英（TCDD）相似，包括心包和卵黄囊水肿、心血管功能障碍和骨骼畸形。为了研究苊烯毒性的机制和靶组织，我们使用了斑马鱼（Danio rerio）胚胎的观察、组织学和蛋白质敲低技术。毒性的主要明显迹象是心包水肿和血流减少，最早在受精后 36 小时（hpf）观察到。在这个阶段，最明显的影响是心房中心脏果冻层变薄和舒张期充盈减少。相反，在暴露于苊烯的胚胎中，在 72 hpf 时观察到心脏果冻层增加。48 hpf 时，CYP1A 的诱导在一部分心肌细胞中明显，表明早期心脏效应可能是由于 AhR 在心肌中的激活。心肌 CYP1A 的诱导是短暂的，仅在 72 hpf 时观察到心内膜诱导。通过 morpholino 寡核苷酸敲低 cyp1a 不会影响苊烯毒性；然而，ahr2 敲低可预防毒性。因此，苊烯心脏毒性的机制是 AhR2 介导和 CYP1A 非依赖性的，类似于 TCDD；然而，苊烯毒性的发作和近似迹象与 TCDD 不同。苊烯的心脏毒性在机制上也与非烷基化菲的心脏效应不同，这表明烷基基团可以改变毒性作用。这些发现对于理解含有烷基化和非烷基化多环芳烃的复杂混合物的毒性具有重要意义。
