Nutrition Innovation Centre for Food and Health and Genomic Medicine Group, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom.
Genomic Medicine Group, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom.
Am J Clin Nutr. 2018 Apr 1;107(4):566-575. doi: 10.1093/ajcn/nqx069.
Emerging evidence suggests that maternal folate status can impact cognitive development in childhood. Folate-dependent DNA methylation may provide a biological mechanism to link folate status during pregnancy with cognition in the offspring.
The objective was to investigate the effect of continued folic acid (FA) supplementation beyond the first trimester of pregnancy on DNA methylation in cord blood of epigenetically controlled genes related to brain development and function.
Using available cord blood samples (n = 86) from the Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) trial in pregnancy, we applied pyrosequencing techniques to analyze cord blood DNA at 9 candidate loci known to be regulated by methylation, including some previously implicated in observational studies: the widely dispersed retrotransposon long interspersed nuclear element-1 (LINE-1) and 8 single-copy loci (RBM46, PEG3, IGF2, GRB10, BDNF, GRIN3B, OPCML, and APC2).
The newborns of mothers who received ongoing FA (400 µg/d) through the second and third trimesters, compared with placebo, had significantly lower overall DNA methylation levels at LINE-1 (56.3% ± 1.7% compared with 57.2% ± 2.1%; P = 0.024), IFG2 (48.9% ± 4.4% compared with 51.2% ± 5.1%; P = 0.021), and BDNF (2.7% ± 0.7% compared with 3.1% ± 0.8%; P = 0.003). The effect of FA treatment on DNA methylation was significant only in female offspring for IGF2 (P = 0.028) and only in males for BDNF (P = 0.012). For GRB10 and GRIN3B, we detected no effect on overall methylation; however, individual cytosine-phosphate-guanine sites showed significant DNA methylation changes in response to FA.
Continued supplementation with FA through trimesters 2 and 3 of pregnancy results in significant changes in DNA methylation in cord blood of genes related to brain development. The findings offer a potential biological mechanism linking maternal folate status with neurodevelopment of the offspring, but this requires further investigation using a genome-wide approach. This trial was registered at www.isrctn.com as ISRCTN19917787.
新出现的证据表明，母体叶酸状态可能会影响儿童期的认知发育。叶酸依赖性 DNA 甲基化可能为在怀孕期间将叶酸状态与后代认知联系起来提供了一种生物学机制。
本研究旨在探讨在妊娠中期和晚期继续补充叶酸（FA）对与大脑发育和功能相关的基因的脐带血中表观遗传控制的基因的 DNA 甲基化的影响。
我们利用来自妊娠中期和晚期补充叶酸试验（FASSTT）的可用脐带血样本（n=86），应用焦磷酸测序技术分析 9 个候选基因座的脐带血 DNA，这些基因座已知受甲基化调节，包括一些在观察性研究中已涉及的基因：广泛分散的逆转录转座子长散布核元件 1（LINE-1）和 8 个单拷贝基因座（RBM46、PEG3、IGF2、GRB10、BDNF、GRIN3B、OPCML 和 APC2）。
与安慰剂相比，在妊娠第二和第三孕期接受持续 FA（400μg/d）治疗的母亲所生的新生儿，LINE-1（56.3%±1.7%比 57.2%±2.1%；P=0.024）、IGF2（48.9%±4.4%比 51.2%±5.1%；P=0.021）和 BDNF（2.7%±0.7%比 3.1%±0.8%；P=0.003）的整体 DNA 甲基化水平明显较低。FA 治疗对 DNA 甲基化的影响仅在 IGF2 方面在女性后代中具有显著性（P=0.028），而在 BDNF 方面在男性后代中具有显著性（P=0.012）。对于 GRB10 和 GRIN3B，我们没有发现整体甲基化的影响；然而，个别胞嘧啶-磷酸-鸟嘌呤位点显示出对 FA 有明显的 DNA 甲基化变化。
在妊娠中期和晚期继续补充 FA 会导致与大脑发育相关的基因的脐带血中 DNA 甲基化发生显著变化。这些发现提供了一个潜在的生物学机制，将母体叶酸状态与后代的神经发育联系起来，但这需要进一步使用全基因组方法进行研究。该试验在 www.isrctn.com 上注册为 ISRCTN19917787。
