Ethanol-induced limb defects in mice: effect of strain and Ro15-4513.
Ethanol-induced limb defects in mice: effect of strain and Ro15-4513.
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乙醇引起的小鼠肢体缺陷：菌株和 Ro15-4513 的影响。
DOI：
10.1002/tera.1420410410
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Collins,MD
中科院分区：
文献类型：
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作者：
Zimmerman,EF;ScottJr,WJ;Collins,MD
现在认为，乙醇通过与γ-氨基丁酸（GABA）受体相互作用在CNS中发挥其许多行为效应，并且已显示苯二氮卓类反向激动剂Ro 15 -4513逆转乙醇产生的一些CNS效应。通过确定Ro 15 - 4513是否逆转C57 BL/6小鼠中乙醇诱导的前肢缺指畸形，检验了乙醇通过与假定的胚胎GABA受体相互作用发挥其致畸作用的假设。首先，在妊娠第10天，对妊娠C57 BL/6母鼠腹腔注射乙醇（2.9 g/kg体重，间隔4 h）两次：49%的胎仔吸收或死亡，46%的存活胎仔显示前肢缺指。相反，当SWV小鼠用乙醇处理时，胚胎死亡率仅为11.9%，并且未观察到前肢缺指。在第二个实验中，当向C57 BL/6小鼠给予乙醇（2.6 g/kg × 2）时，观察到34%的吸收和31%的前肢缺指。乙醇引起的缺指主要是前肢和轴后。乙醇产生了不寻常的前肢缺陷，在少数情况下，有轴后autopod还原缺陷加上轴前zeugopod还原缺陷。Ro 15 - 4513单独给药（50 mg/kg × 2）在C57 BL/6小鼠中既无胚胎致死性也无致畸性。为了尝试逆转乙醇的致畸作用，与仅用乙醇处理的胚胎相比，在每次乙醇给药前5分钟注射Ro 15 - 4513（0.5、1、2.5、5、10 mg/kg，两次）的母鼠的前肢缺指频率没有显著变化。然而，5和10 mg/kg Ro 15 - 4513剂量组的吸收率显著增加至77%和62%。因此，Ro 15 - 4513与乙醇似乎存在胚胎致死相互作用。然而，由于Ro 15 - 4513不能逆转乙醇诱导的致畸作用，这些结果不支持乙醇的致畸机制是通过假定的胚胎GABA受体介导的假设。
It is now thought that ethanol exerts many of its behavioral effects in the CNS by interaction with the γ‐aminobutyric acid (GABA) receptor, and it has been shown that the benzodiazepine reverse agonist Ro15–4513 reverses some of the CNS effects produced by ethanol. The hypothesis was tested that ethanol exerts its teratogenic effects through interaction with a putative embryonic GABA receptor by determining whether Ro15‐4513 reverses ethanol‐induced forelimb ectrodactyly in C57BL/6 mice. First, pregnant C57BL/6 dams were injected twice i.p. with ethanol (2.9 g/kg body weight, 4 hr apart) on day 10 of gestation: 49% of the fetuses were resorbed or dead and 46% of the survivors showed forelimb ectrodactyly. In contrast, when SWV mice were treated with ethanol, embryolethality was only 11.9% and no forelimb ectrodactyly was observed. In a second experiment, when ethanol (2.6 g/kg × 2) was administered to C57BL/6 mice, 34% resorptions and 31% forelimb ectrodactyly were observed. Ectrodactyly induced by ethanol was primarily of the forelimb and exclusively postaxial. Ethanol produced an unusual forelimb defect in a small number of instances where there was a postaxial autopod reduction defect coupled with a preaxial zeugopod reduction defect. Ro15‐4513 administered alone (50 mg/kg × 2) was neither embryolethal nor teratogenic in C57BL/6 mice. To attempt to reverse the teratogenic effect of ethanol, dams that were injected 5 min before each ethanol administration with Ro15‐4513 (0.5, 1, 2.5, 5, 10 mg/kg twice) showed no significant change in frequency of forelimb ectrodactyly compared to embryos treated with ethanol alone. However, resorptions increased significantly to 77% and 62% with the 5 and 10 mg/kg doses of Ro15‐4513. Thus there appears to be an embryolethal interaction of Ro15‐4513 with ethanol. Nevertheless, since Ro15‐4513 did not reverse the teratogenic effect induced by ethanol, these results donotsupport the hypothesis that the teratogenic mechanism of ethanol is mediated through a putative embryonic GABA receptor.