Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
For over a decade, folic acid (FA) supplementation has been widely prescribed to pregnant women to prevent neural tube closure defects in newborns. Although neural tube closure occurs within the first trimester, high doses of FA are given throughout pregnancy, the physiological consequences of which are unknown. FA can cause epigenetic modification of the cytosine residues in the CpG dinucleotide, thereby affecting gene expression. Dysregulation of crucial gene expression during gestational development may have lifelong adverse effects or lead to neurodevelopmental defects, such as autism. We have investigated the effect of FA supplementation on gene expression in lymphoblastoid cells by whole-genome expression microarrays. The results showed that high FA caused dysregulation by ≥ four-fold up or down to more than 1000 genes, including many imprinted genes. The aberrant expression of three genes (FMR1, GPR37L1, TSSK3) was confirmed by Western blot analyses. The level of altered gene expression changed in an FA concentration-dependent manner. We found significant dysregulation in gene expression at concentrations as low as 15 ng/ml, a level that is lower than what has been achieved in the blood through FA fortification guidelines. We found evidence of aberrant promoter methylation in the CpG island of the TSSK3 gene. Excessive FA supplementation may require careful monitoring in women who are planning for, or are in the early stages of pregnancy. Aberrant expression of genes during early brain development may have an impact on behavioural characteristics.
十多年来，叶酸（FA）补充剂已广泛用于孕妇，以预防新生儿神经管缺陷。尽管神经管闭合发生在妊娠早期，但高剂量的 FA 会在整个孕期给予，其生理后果尚不清楚。FA 可以引起胞嘧啶残基在 CpG 二核苷酸中的表观遗传修饰，从而影响基因表达。妊娠发育过程中关键基因表达的失调可能会产生终身的不良影响，或导致神经发育缺陷，如自闭症。我们通过全基因组表达微阵列研究了 FA 补充对淋巴母细胞系基因表达的影响。结果表明，高 FA 导致超过 1000 个基因的表达失调，倍数≥4，包括许多印记基因。Western blot 分析证实了三个基因（FMR1、GPR37L1、TSSK3）的异常表达。改变的基因表达水平随 FA 浓度呈依赖性变化。我们发现，即使在浓度低至 15ng/ml 时，也会出现显著的基因表达失调，这一浓度低于通过 FA 强化指南在血液中达到的水平。我们发现 TSSK3 基因启动子 CpG 岛存在异常的甲基化。在计划怀孕或处于妊娠早期的女性中，过度补充 FA 需要仔细监测。早期大脑发育过程中基因的异常表达可能会对行为特征产生影响。
