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首页> 外文期刊>Aquatic Toxicology >Polycyclic aromatic hydrocarbons and dibutyl phthalate disrupt dorsal-ventral axis determination via the Wnt/ beta -catenin signaling pathway in zebrafish embryos.
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Polycyclic aromatic hydrocarbons and dibutyl phthalate disrupt dorsal-ventral axis determination via the Wnt/ beta -catenin signaling pathway in zebrafish embryos.

机译：多环芳烃和邻苯二甲酸二丁酯通过斑马鱼胚胎中的Wnt /β-catenin信号传导途径破坏背腹轴的测定。

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摘要

The canonical Wnt/ beta -catenin signaling pathway is critical during early teleost development for establishing the dorsal-ventral axis. Within this pathway, GSK-3 beta , a key regulatory kinase in the Wnt pathway, regulates beta -catenin degradation and thus the ability of beta -catenin to enter nuclei, where it can activate expression of genes that have been linked to the specification of the dorsal-ventral axis. In this study, we describe the morphological abnormalities that resulted in zebrafish embryos when axis determination was disrupted by environmental contaminants. These abnormalities were linked to abnormal nuclear accumulation of beta -catenin. Furthermore, we demonstrated that the developmental abnormalities and altered nuclear beta -catenin accumulation occurred when embryos were exposed to commercial GSK-3 beta inhibitors. Zebrafish embryos were exposed to commercially available GSK-3 inhibitors (GSK-3 Inhibitor IX and 1-azakenpaullone), or common environmental contaminants (dibutyl phthalate or the polycyclic aromatic hydrocarbons phenanthrene and fluorene) from the 2 to 8-cell stage through the mid-blastula transition (MBT). These embryos displayed morphological abnormalities at 12.5 h post-fertilization (hpf) that were comparable to embryos exposed to lithium chloride (LiCl) (300 mM LiCl for 10 min, prior to the MBT), a classic disruptor of embryonic axis determination. Whole-mount immunolabeling and laser scanning confocal microscopy were used to localize beta -catenin. The commercial GSK-3 Inhibitors as well as LiCl, dibutyl phthalate, fluorene and phenanthrene all induced an increase in the levels of nuclear beta -catenin throughout the embryo, indicating that the morphological abnormalities were a result of disruption of Wnt/ beta -catenin signaling during dorsal-ventral axis specification. The ability of environmental chemicals to directly or indirectly target GSK-3 beta was assessed. Using Western blot analysis, the ability of these chemicals to affect enzymatic inhibitory phosphorylation at serine 9 on GSK-3 beta was examined, but no change in the serine phosphorylation state of GSK-3 beta was detected in exposed embryos. Furthermore, polycyclic aromatic hydrocarbons and dibutyl phthalate had no direct effect on the in vitro kinase activity of GSK-3 beta . While developmental abnormalities resulting from these axis-disrupting contaminants were linked to beta -catenin accumulation in nuclei, the details of the disruption of this signaling pathway remain unknown. Since phenanthrene and fluorene as well as other hydrocarbons have been shown to disrupt axial development in sea urchin embryos, and since axis determination and the Wnt/ beta -catenin signaling pathway are highly conserved, we propose that these environmental contaminants may impact embryo development through a similar mechanism across phyla.
机译：典型的Wnt /β-catenin信号通路在早期硬骨发展中对于建立背腹轴至关重要。在该途径中，Wnt途径中的关键调节激酶GSK-3 beta调节β-catenin的降解，从而调节β-catenin进入细胞核的能力，在该细胞中，它可以激活已与β-catenin规格相关的基因的表达。背腹轴。在这项研究中，我们描述了当轴确定被环境污染物破坏时，导致斑马鱼胚胎的形态异常。这些异常与β-catenin的异常核积累有关。此外，我们证明了当胚胎暴露于商品化的GSK-3 beta抑制剂时，发育异常和改变的核β-catenin积累发生了。斑马鱼的胚胎从2到8个细胞阶段一直接触到市售的GSK-3抑制剂（GSK-3抑制剂IX和1-氮杂paullone）或常见的环境污染物（邻苯二甲酸二丁酯或多环芳烃菲和芴）。囊胚过渡（MBT）。这些胚胎在受精后12.5 h（hpf）表现出形态异常，与暴露于氯化锂（LiCl）（MBT之前300 mM LiCl 10分钟，MBT）的胚胎相当，这是胚胎轴测定的经典干扰物。整个安装的免疫标记和激光扫描共聚焦显微镜用于定位β-连环蛋白。商业化的GSK-3抑制剂以及LiCl，邻苯二甲酸二丁酯，芴和菲都诱导整个胚胎中的核β-连环蛋白水平增加，表明形态异常是Wnt /β-连环蛋白信号转导破坏的结果。在背腹轴规范中。评估了环境化学品直接或间接靶向GSK-3 beta的能力。使用蛋白质印迹分析，检查了这些化学物质影响GSK-3β丝氨酸9处酶促抑制性磷酸化的能力，但在裸露的胚胎中未检测到GSK-3β丝氨酸磷酸化状态的变化。此外，多环芳烃和邻苯二甲酸二丁酯对GSK-3β的体外激酶活性没有直接影响。虽然由这些破坏轴的污染物导致的发育异常与细胞核中的β-catenin积累有关，但该信号通路破坏的细节仍然未知。由于已显示菲和芴以及其他碳氢化合物会破坏海胆胚胎的轴向发育，并且由于轴的确定和Wnt /β-catenin信号通路高度保守，因此我们建议这些环境污染物可能通过整个门系的机制相似。

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