Mount Desert Island Biological Laboratory, PO Box 35, Salisbury Cove, Maine 04672, USA.
Chem Res Toxicol. 2010 Mar 15;23(3):480-7. doi: 10.1021/tx9003165.
Vertebrate jaw development can be disrupted by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-a potent activator of the aryl hydrocarbon receptor (AHR) transcription factor required for transducing the toxic effects of TCDD. We used zebrafish (Danio rerio) embryos to investigate transcriptional responses to TCDD with the goal of discovering novel, jaw-specific genes affected by TCDD exposure. Our results uncovered a novel target of TCDD-activated Ahr belonging to the evolutionarily conserved family of forkhead box transcription factors. Quantitative real-time polymerase chain reaction analysis demonstrated that FoxQ1b was upregulated by TCDD 7- and 10-fold at 24 and 48 h postfertilization (hpf), respectively. The rate of TCDD-induced FoxQ1b expression was more rapid than that of Cyp1a, a known direct target of TCDD-activated Ahr. TCDD-mediated induction of FoxQ1b was suppressed in the presence of an Ahr antagonist, alpha-naphthoflavone, as well as following knockdown of Ahr2 expression using an Ahr2-specific morpholino antisense oligonucleotide. In situ hybridization analysis of FoxQ1b expression at 48 hpf demonstrated that FoxQ1b is specifically expressed in the jaw primordium where it discretely outlines a developing jaw structure known as Meckel's cartilage--a conserved structure in all jawed vertebrates that develops abnormally in the presence of TCDD. These results identify a novel target of TCDD-activated Ahr and suggest that FoxQ1b may play a role in craniofacial abnormalities induced by developmental exposure to TCDD.
脊椎动物的颌骨发育可能会因暴露于 2,3,7,8-四氯二苯并对二恶英（TCDD）而受到干扰，TCDD 是一种有效的芳烃受体（AHR）转录因子激活剂，该转录因子对于传递 TCDD 的毒性作用是必需的。我们使用斑马鱼（Danio rerio）胚胎研究了 TCDD 引起的转录反应，目的是发现受 TCDD 暴露影响的新的、特异性颌骨基因。我们的研究结果揭示了 AHR 激活的 TCDD 的一个新靶标，属于叉头框转录因子的进化保守家族。定量实时聚合酶链反应分析表明，FoxQ1b 在受精后 24 和 48 小时（hpf）分别被 TCDD 上调了 7 倍和 10 倍。TCDD 诱导 FoxQ1b 表达的速度快于 Cyp1a，后者是 AHR 激活的 TCDD 的已知直接靶标。Ahr 拮抗剂α-萘黄酮以及使用 Ahr2 特异性的 morpholino 反义寡核苷酸敲低 Ahr2 表达均可抑制 TCDD 介导的 FoxQ1b 诱导。在 48 hpf 时进行的 FoxQ1b 表达的原位杂交分析表明，FoxQ1b 特异性地在颌骨原基中表达，在那里它清晰地勾勒出一个正在发育的颌骨结构，称为 Meckel 软骨——这是所有有颌脊椎动物的保守结构，在 TCDD 存在的情况下会异常发育。这些结果确定了 AHR 激活的 TCDD 的一个新靶标，并表明 FoxQ1b 可能在发育暴露于 TCDD 引起的颅面异常中发挥作用。
