The green tea polyphenol EGCG alleviates maternal diabetes-induced neural tube defects by inhibiting DNA hypermethylation.
The green tea polyphenol EGCG alleviates maternal diabetes-induced neural tube defects by inhibiting DNA hypermethylation.
复制标题
绿茶多酚EGCG通过抑制DNA高甲基化来减轻母体糖尿病引起的神经管缺损。
DOI：
10.1016/j.ajog.2016.03.009
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发表时间：
2016-09
影响因子：
9.8
通讯作者：
Yang P
中科院分区：
文献类型：
--
作者：
Zhong J;Xu C;Reece EA;Yang P
母亲糖尿病会增加后代神经管缺陷的风险。我们以前的研究表明，绿色茶多酚，表没食子儿茶素没食子酸酯，抑制高糖诱导的神经管缺陷培养胚胎。然而，表没食子儿茶素没食子酸酯对母体糖尿病引起的神经管缺陷的治疗作用仍不清楚。我们的目的是检查表没食子儿茶素没食子酸酯治疗是否可以减少母体糖尿病诱导的DNA甲基化和神经管缺陷。非糖尿病和糖尿病妊娠小鼠在胚胎5.5天给予饮用水与或不与1或10 μM表没食子儿茶素没食子酸酯。在胚胎第8.75天，从卵黄囊解剖胚胎，测量DNA甲基转移酶的水平和活性、整体DNA甲基化水平和神经管闭合必需基因启动子CpG岛的甲基化。检查胚胎10.5天胚胎的神经管缺陷发生率。表没食子儿茶素没食子酸酯处理不影响胚胎发育，因为用表没食子儿茶素没食子酸酯处理的非糖尿病母鼠的胚胎没有表现出任何神经管缺陷。用1 μM表没食子儿茶素没食子酸酯处理没有显著减少母体糖尿病诱导的神经管缺陷。与未接受表没食子儿茶素没食子酸酯处理的胚胎相比，接受10 μM表没食子儿茶素没食子酸酯处理的糖尿病母鼠胚胎的神经管缺陷发生率显著降低。表没食子儿茶素没食子酸酯将神经管缺陷率从29.5%降低到2%，这一发生率与非糖尿病母鼠的胚胎相当。10微摩尔的表没食子儿茶素没食子酸酯治疗阻断了母体糖尿病增加的DNA甲基转移酶3a和3b表达及其活性，从而抑制了整体DNA超甲基化。此外，10 μM表没食子儿茶素没食子酸酯消除了母体糖尿病增加的神经管闭合必需基因（包括Grhl3，Pax3和Tulp3）CpG岛中的DNA甲基化。表没食子儿茶素没食子酸酯减少母体糖尿病诱导的神经管缺陷形成，并阻断DNA甲基转移酶的增强表达和活性，从而抑制DNA超甲基化并恢复神经管闭合必需基因的表达。这些观察结果表明，表没食子儿茶素没食子酸酯补充剂可以减轻高血糖对发育中的胚胎的致畸作用，并防止糖尿病诱导的神经管缺陷。
Maternal diabetes increases the risk of neural tube defects in offspring. Our previous study demonstrated that the green tea polyphenol, Epigallocatechin gallate, inhibits high glucose-induced neural tube defects in cultured embryos. However, the therapeutic effect of Epigallocatechin gallate on maternal diabetes–induced neural tube defects is still unclear. We aimed to examine whether Epigallocatechin gallate treatment can reduce maternal diabetes–induced DNA methylation and neural tube defects. Nondiabetic and diabetic pregnant mice at embryonic day 5.5 were given drinking water with or without 1 or 10 μM Epigallocatechin gallate. At embryonic day 8.75, embryos were dissected from the visceral yolk sac for the measurement of the levels and activity of DNA methyltransferases, the levels of global DNA methylation, and methylation in the CpG islands of neural tube closure essential gene promoters. embryonic day 10.5 embryos were examined for neural tube defect incidence. Epigallocatechin gallate treatment did not affect embryonic development because embryos from nondiabetic dams treated with Epigallocatechin gallate did not exhibit any neural tube defects. Treatment with 1 μM Epigallocatechin gallate did not reduce maternal diabetes–induced neural tube defects significantly. Embryos from diabetic dams treated with 10 μM Epigallocatechin gallate had a significantly lower neural tube defect incidence compared with that of embryos without Epigallocatechin gallate treatment. Epigallocatechin gallate reduced neural tube defect rates from 29.5% to 2%, an incidence that is comparable with that of embryos from nondiabetic dams. Ten micromoles of Epigallocatechin gallate treatment blocked maternal diabetes–increased DNA methyltransferases 3a and 3b expression and their activities, leading to the suppression of global DNA hypermethylation. Additionally, 10 μM Epigallocatechin gallate abrogated maternal diabetes–increased DNA methylation in the CpG islands of neural tube closure essential genes, including Grhl3, Pax3, and Tulp3. Epigallocatechin gallate reduces maternal diabetes–induced neural tube defects formation and blocks the enhanced expression and activity of DNA methyltransferases, leading to the suppression of DNA hypermethylation and the restoration of neural tube closure essential gene expression. These observations suggest that Epigallocatechin gallate supplements could mitigate the teratogenic effects of hyperglycemia on the developing embryo and prevent diabetes–induced neural tube defects.