The role of the aryl hydrocarbon receptor pathway in mediating synergistic developmental toxicity of polycyclic aromatic hydrocarbons to zebrafish
The role of the aryl hydrocarbon receptor pathway in mediating synergistic developmental toxicity of polycyclic aromatic hydrocarbons to zebrafish
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DOI：
10.1093/toxsci/kfl011
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发表时间：
2006-08-01
影响因子：
3.8
通讯作者：
Di Giulio, Richard T.
中科院分区：
文献类型：
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作者：
Billiard, Sonya M.;Timme-Laragy, Alicia R.;Di Giulio, Richard T.
平面卤代芳烃类化合物2，3，7，8-四氯二苯并对二恶英(Dioxin)与芳香烃受体(AHR)具有很强的亲和力，是细胞色素P4501A(CyP1A)的有效诱导剂。人们普遍认为，二恶英的毒性在很大程度上是由AHR介导的；然而，CYP1A活性在导致这种毒性中的作用尚不清楚。另一类日益受到关注的AHR激动剂是多环芳烃(PAHs)，因为它们在环境中已知的毒性和普遍存在。与二恶英一样，一些多环芳烃也会对脊椎动物的早期生命阶段造成毒性。症状包括心血管功能障碍增加、心包和卵黄囊水肿、皮下出血、头面部畸形、生长减慢和死亡率增加。虽然这两种类型的AHR激动剂的发育效应是相似的，但AHR和CyP1A活性在多环芳烃毒性中的作用尚不清楚。正如在以前对斑马鱼(Fundulus Herocltes)的研究中所观察到的那样，我们在这里证明了斑马鱼(Danio Rerio)胚胎与PAH型AHR激动剂β-萘黄酮(BNF)和细胞色素P1a抑制剂α-萘黄酮(ANF)共同暴露于单一化合物暴露时的毒性显著增强。为了阐明AHR途径在介导多环芳烃混合物对早期生命阶段的协同毒性中的作用，我们使用吗啡诺方法下调斑马鱼AHR2和CYP1A蛋白在发育过程中的表达。我们观察到，虽然AHR2基因的敲除降低了BNF和ANF对斑马鱼胚胎的心脏毒性，但CyP1A基因敲除显著增强了BNF单独和BNF+ANF联合暴露的毒性。这些数据支持早期的化学诱导剂/抑制剂研究，也表明PAH型AHR激动剂的发育毒性机制不同于PHAHs。确定涉及多环芳烃毒性的途径将为单一化合物和复杂环境混合物的风险评估提供更强大的、基于机械的工具。
Planar halogenated aromatic hydrocarbons (pHAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), show strong binding affinity for the aryl hydrocarbon receptor (AHR) and are potent inducers of cytochrome P4501A (CYP1A). It is widely accepted that dioxin toxicity is largely AHR mediated; however, the role of CYP1A activity in causing that toxicity is less clear. Another class of AHR agonists of increasing concern because of their known toxicity and ubiquity in the environment is the polycyclic aromatic hydrocarbons (PAHs). Like dioxin, some PAHs also cause toxicity to early life stages of vertebrates. Symptoms include increased cardiovascular dysfunction, pericardial and yolk sac edemas, subcutaneous hemorrhages, craniofacial deformities, reduced growth, and increased mortality rates. Although developmental effects are comparable between these two types of AHR agonists, the roles of both the AHR and CYP1A activity in PAH toxicity are unknown. As observed in previous studies with killifish (Fundulus heteroclitus), we demonstrate here that coexposure of zebrafish (Danio rerio) embryos to the PAH-type AHR agonist beta-naphthoflavone (BNF) and the CYP1A inhibitor alpha-naphthoflavone (ANF) significantly enhanced toxicity above that observed for single-compound exposures. In order to elucidate the role of the AHR pathway in mediating synergistic toxicity of PAH mixtures to early life stages, we used a morpholino approach to knock down expression of zebrafish AHR2 and CYP1A proteins during development. We observed that while knock down of AHR2 reduces cardiac toxicity of BNF combined with ANF to zebrafish embryos, CYP1A knockdown markedly enhanced toxicity of BNF alone and BNF + ANF coexposures. These data support earlier chemical inducer/inhibitor studies and also suggest that mechanisms underlying developmental toxicity of PAH-type AHR agonists are different from those of pHAHs. Identifying the pathways involved in PAH toxicity will provide for more robust, mechanistic-based tools for risk assessment of single compounds and complex environmental mixtures.