Brown D R, Clark B W, Garner L V T, Di Giulio R T
Nicholas School of the Environment, Duke University, Durham, NC 27514, USA.
Comp Biochem Physiol C Toxicol Pharmacol. 2016 Oct;188:45-51. doi: 10.1016/j.cbpc.2016.05.005. Epub 2016 May 20.
High affinity aryl hydrocarbon receptor (AHR) ligands, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, for example benzo[a]pyrene and β-naphthoflavone, are capable of causing similar cardiotoxic effects, particularly when coupled with cytochrome P450 1A (CYP1A) inhibitors (e.g., fluoranthene (FL). Additionally, some weaker AHR agonists (carbaryl, 2-methylindole, 3-methylindole, and phenanthrene) are known to also cause cardiotoxicity in zebrafish (Danio rerio) embryos when coupled with FL; however, the cardiotoxic effects were not mediated specifically by AHR stimulation. This study was performed to determine if binary exposure to weak AHR agonists and FL were also capable of causing cardiotoxicity in Atlantic killifish Fundulus heteroclitus embryos. Binary exposures were performed in both naïve and PAH-adapted killifish embryos to examine resistance to weak agonists and FL binary exposures. Weak agonists used in this study included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. Carbaryl, indigo, and indirubin induced the highest CYP1 activity levels in naïve killifish embryos, but no significant CYP1 induction was observed in the PAH-adapted killifish. Embryos were coexposed to subteratogenic levels of each agonist and 500μg/L FL to assess if binary administration could cause cardiotoxicity. Indigo and indirubin coupled with FL caused cardiac teratogenesis in naïve killifish, but coexposures did not produce cardiac chamber abnormalities in the PAH-adapted population. Knockdown of AHR2 in naïve killifish embryos did not prevent cardiac teratogenesis. The data suggest a unique mechanism of cardiotoxicity that is not driven by AHR2 activation.
高亲和力芳烃受体（AHR）配体，如某些多氯联苯和2,3,7,8-四氯二苯并对二恶英（TCDD），会在鱼类胚胎中导致严重的心脏致畸作用。中等强度的AHR激动剂，例如苯并[a]芘和β-萘黄酮，能够引起类似的心脏毒性作用，尤其是与细胞色素P450 1A（CYP1A）抑制剂（如荧蒽（FL））联合使用时。此外，已知一些较弱的AHR激动剂（西维因、2-甲基吲哚、3-甲基吲哚和菲）与FL联合使用时也会在斑马鱼（Danio rerio）胚胎中引起心脏毒性；然而，心脏毒性作用并非由AHR刺激特异性介导。进行这项研究是为了确定二元暴露于弱AHR激动剂和FL是否也能够在大西洋鳉Fundulus heteroclitus胚胎中引起心脏毒性。在未接触过污染物的和适应多环芳烃的鳉胚胎中进行二元暴露，以检查对弱激动剂和FL二元暴露的抗性。本研究中使用的弱激动剂包括以下几种：西维因、菲、2-甲基吲哚、3-甲基吲哚、靛蓝和靛玉红。西维因、靛蓝和靛玉红在未接触过污染物的鳉胚胎中诱导出最高的CYP1活性水平，但在适应多环芳烃的鳉中未观察到显著的CYP1诱导。胚胎同时暴露于每种激动剂的亚致畸水平和500μg/L的FL，以评估二元给药是否会引起心脏毒性。靛蓝和靛玉红与FL联合使用会在未接触过污染物的鳉中导致心脏致畸，但在适应多环芳烃的群体中同时暴露不会产生心脏腔室异常。在未接触过污染物的鳉胚胎中敲低AHR2并不能预防心脏致畸。数据表明存在一种不由AHR2激活驱动的独特心脏毒性机制。
