2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo:: Local circulation failure in the dorsal midbrain is associated with increased apoptosis
2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo:: Local circulation failure in the dorsal midbrain is associated with increased apoptosis
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DOI：
10.1093/toxsci/69.1.191
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发表时间：
2002-09-01
影响因子：
3.8
通讯作者：
Hiraga, T
中科院分区：
文献类型：
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作者：
Dong, W;Teraoka, H;Hiraga, T
研究了2，3，7，8-四氯二苯并对二恶英（TCDD）对斑马鱼胚胎发育早期中脑局部循环和细胞凋亡的影响。胚胎在28.5 ℃的水中从受精后24小时（hpf）开始暴露于TCDD，直到观察。TCDD减少了中脑静脉的血流量，中脑静脉是胚胎中脑背侧的唯一灌注血管。在50 hpf时，该血管中的血流量最大程度地减少，并在60 hpf时逐渐恢复到对照水平。相比之下，在躯干和其他血管的胚胎头部的血流没有显着变化，直到72 hpf。此外，TCDD暴露引起细胞凋亡在中脑在60 hpf，和TCDD剂量反应关系，这种效果是类似的，在中脑静脉血流量减少在50 hpf。TCDD对中脑细胞凋亡的影响，但不对血流量，被取消Z-VAD-FMK，一般的半胱天冬酶抑制剂。TCDD对两个终点的影响被β-萘酮（BNF），一种芳香烃受体（AHR）激动剂，模仿，并几乎取消了同时暴露于TCDD和α-萘酮（ANF），AHR拮抗剂。同时暴露于TCDD和细胞色素P450抑制剂（SKF 525 A或咪康唑）或抗氧化剂（N-乙酰半胱氨酸或抗坏血酸）抑制TCDD的这些作用。在这些不同的治疗和分级TCDD暴露浓度后，中脑细胞凋亡的发生率与该脑区的血流量呈负相关（r = -0.91）。相同范围的TCDD暴露浓度，减少血流量和增加中脑细胞凋亡大大增强CYP 1A mRNA的表达和免疫反应性在50 hpf的血管内皮细胞，包括中脑静脉和心脏，但不是脑实质。总而言之，这些结果表明，TCDD诱导局部循环衰竭引起的斑马鱼胚胎中脑细胞凋亡，这可能与AHR激活、CYP 1A诱导和氧化应激有关。
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on local circulation and apoptosis in the midbrain were investigated in zebrafish (Danio rerio) embryos during early development. Embryos were exposed to TCDD from 24 h post fertilization (hpf) until observation, in water maintained at 28.5degreesC. TCDD decreased blood flow in the mesencephalic vein, the only vessel perfusing the dorsal midbrain of the embryo. At 50 hpf, blood flow was maximally reduced in this vessel and gradually returned to the control level at 60 hpf. In contrast, blood flows in the trunk and in other vessels of the head of the embryo did not significantly change until 72 hpf. Furthermore, TCDD exposure caused apoptosis in the midbrain at 60 hpf, and the TCDD dose response relationship for this effect was similar to that for reduced blood flow in the mesencephalic vein at 50 hpf. The effects of TCDD on apoptosis in the midbrain, but not on blood flow, were abolished by Z-VAD-FMK, a general caspase inhibitor. TCDD effects on both endpoints were mimicked by beta-naphthoflavone (BNF), an aryl hydrocarbon receptor (AHR) agonist, and almost abolished by concomitant exposure to TCDD and alpha-naphthoflavone (ANF), an AHR antagonist. Concomitant exposure to TCDD and either an inhibitor of cytochrome P450 (CYP) (SKF525A or miconazole) or an antioxidant (N-acetylcysteine or ascorbic acid) inhibited these effects of TCDD. The incidence of apoptosis in the midbrain was inversely related to blood flow in this brain region following these various treatments and graded TCDD exposure concentrations (r = -0.91). The same range of TCDD exposure concentrations that reduced blood flow and increased apoptosis in the midbrain greatly enhanced CYP1A mRNA expression and immunoreactivity at 50 hpf in endothelial cells of blood vessels including the mesencephalic vein and the heart, but not the brain parenchyma. Taken together, these results suggest that TCDD induces apoptosis in the midbrain of the zebrafish embryo secondary to local circulation failure, which could be related to AHR activation, induction of CYP1A, and oxidative stress.