Inhibition of transmethylation disturbs neurulation in chick embryos
Inhibition of transmethylation disturbs neurulation in chick embryos
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DOI：
10.1016/j.devbrainres.2005.06.002
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发表时间：
2005-08-08
期刊：
影响因子：
--
通讯作者：
van Straaten, HW
中科院分区：
文献类型：
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作者：
Afman, LA;Blom, HJ;van Straaten, HW
围孕期补充叶酸可以减少神经管缺陷的发生。叶酸水平较低会导致同型半胱氨酸 (Hcy) 向蛋氨酸的再甲基化减少，从而导致 Hey 水平升高。事实上，有报道称患有神经管缺陷的儿童的母亲体内的 Hey 浓度升高。在我们之前的研究中，我们在体外模型中表明，用 Hey 处理鸡胚胎会导致神经管闭合延迟。在本研究中，我们检查了 Hey 的这种作用是否是由于通过提高 S-腺苷高半胱氨酸 (AdoHcy) 抑制转三乙基化所致。转甲基化涉及通过提供 S-腺苷甲硫氨酸 (AdoMet) 的甲基对 DNA、RNA 和蛋白质进行甲基化。在应用S-腺苷高半胱氨酸水解酶和甲硫氨酸腺苷转移酶抑制剂后，观察到前神经孔闭合延迟，与Hey治疗后观察到的情况相当。 AdoMet 和 AdoHcy 浓度的变化分别证实了 S-腺苷高半胱氨酸水解酶或甲硫氨酸腺苷转移酶的抑制，并且在所有情况下 AdoMet/AdoHcy 比率均下降，表明三乙基化减少。此外，用蛋氨酸预处理可以防止蛋氨酸腺苷转移酶的抑制。因此，这项研究表明，Hcy 诱导的神经管闭合延迟是通过提高 AdoHcy 水平和降低 AdoMet/AdoHcy 比率来抑制转甲基化引起的。 (c) 2005 Elsevier B.V. 保留所有权利。
Periconceptional folic acid supplementation can reduce the occurrence of neural tube defects. A low folate status will result in reduced remethylation of homocysteine (Hcy) to methionine and, subsequently, in a rise of Hey levels. Indeed, elevated Hey concentrations have been reported in mothers of children with neural tube defects. In our previous study, we showed that treatment of chick embryos with Hey resulted in a delay of neural tube closure in an in vitro model. In the present study, we examined whether this effect of Hey is due to inhibition of transtriethylation via elevation of S-adenosylhomocysteine (AdoHcy). Transmethylation involves methylation of DNA, RNA and proteins by donation of a methyl group from S-adenosylmethionine (AdoMet). After application of inhibitors of S-adenosylhomocysteine hydrolase and of methionine adenosyltransferase, a delay of anterior neuropore closure, comparable to that observed after Hey treatment, was observed. The changes in AdoMet and AdoHcy concentrations confirmed the inhibition of S-adenosylhomocysteine hydrolase or methionine adenosyltransferase, respectively, and the AdoMet/AdoHcy ratio was decreased in all cases, indicating reduced transtriethylation. Moreover, the inhibition of methionine adenosyltransferase was prevented by pretreatment with methionine. This study, therefore, indicates that the Hcy-induced delay of the neural tube closure is caused by the inhibition of transmethylation via elevation of AdoHcy levels and a reduction of the AdoMet/AdoHcy ratio. (c) 2005 Elsevier B.V. All rights reserved.