Antiepileptic drugs and the fetal epigenome

Abstract

SUMMARYAntiepileptic drugs (AEDs) can lower maternal folate and increase maternal homocysteine levels, which are known to affect the methyl cycle and hence DNA methylation levels. The influence of in utero exposure to AEDs on fetal DNA methylation was investigated. Genome-wide fetal epigenomic profiles were determined using the Infinium 27K BeadArray from Illumina (San Diego, CA, U.S.A.). The Infinium array measures approximately 27,000 CpG loci associated with 14,496 genes at single-nucleotide resolution. Eighteen cord blood samples (nine samples from babies exposed to AEDs and nine controls) from otherwise uncomplicated pregnancies were compared. Unsupervised hierarchic clustering was used to compare the calculated methylation profiles. A clear distinction between the methylation profiles of samples from babies exposed to AEDs in utero compared with controls was detected. These data provide evidence of an epigenetic effect associated with antenatal AED and high-dose folate supplementation during pregnancy. The differences in fetal DNA methylation of those exposed to AEDs shows that a genomewide effect of methylation is evident. In addition, the epigenetic changes observed appear to be, in this limited sample, independent of extremes of birth weight centiles. These preliminary data highlight possible mechanisms by which AEDs might influence fetal outcomes and the potential of optimizing AED-specific folate supplementation regimens to offset these effects.

Effects of Antiepileptic Drug Monotherapy on One-Carbon Metabolism and DNA Methylation in Patients with Epilepsy

“…In the present study, we found that the methylation level of LINE-1 showed no significant difference between AED monotherapeutic patients with epilepsy and controls. Our findings were in accordance with a study conducted by Emes et al, which indicated that the levels of LINE-1 methylation in cord blood were not significantly different between the AED and control groups [ 23 ]. We also found that the levels of methylation of MTHFR amplicon in AED-treated patients with epilepsy were significantly lower than that of controls.…”

Contrasting The Effects of Intra-Uterine Smoking and One-Carbon Micronutrient Exposures on Offspring DNA Methylation

“…Although one study [ 48 ] evaluated other nutrients such as betaine, choline and other nutrients involved in one-carbon metabolism, the strongest effects on offspring methylation were observed for maternal folate levels in pregnancy. Sample sizes for the seven studies ranged from 18 neonates of mothers enrolled in a clinical trial [ 46 ] to nearly 2000 mother-offspring pairs in a meta-analysis of two independent European cohorts [ 48 ]. Measures of folate exposure included measurements from maternal serum, plasma or blood samples as well as maternal report of folic acid supplementation.…”

Epigenetic Biomarkers of Preterm Birth and Its Risk Factors

“…Interventions for the fetus may include the anticipation of clinical interventions to limit complications common in preterm infants as well as early participation in developmental enrichment programs [ 1 ]. Over the past several years, the availability of cost-effective methods for assessing the epigenome has led to identification of epigenetic signatures of the intrauterine environment including exposure to medication, stress, gestational length, and smoking [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Evaluation of the genes containing these differentially methylated sites is not only useful for identifying biological pathways regulated in each circumstance, but it may also facilitate identification of clinically informative biomarkers.…”