Epigenetic Mechanisms Underlying Fetal Alcohol Spectrum Disorders
Alcohol consumption during any stage of pregnancy has been shown to result in a range of congenital and cognitive defects, collectively known as fetal alcohol spectrum disorder (FASD). Alcohol (EtOH) consumed by the mother is readily able to cross the placenta where it remains trapped in the amniotic fluid resulting in prolonged exposure to the fetus, even after the mother’s blood alcohol level has dropped. The severity and particular manifestation of FASD depends on the amount of alcohol consumed, the pattern of consumption (for example few episodes of heavy binge drinking verses light frequent drinking), and stage of pregnancy during which alcohol was consumed. Early alcohol consumption during the first two trimesters can result in congenital defects, while drinking in the later third trimester is more likely to result in abnormalities of the central nervous system.
Epigenetic mechanisms play an important role in programmed fetal development and epigenetic changes in response to environment are well known contributors to developmental disorders. A recent study in Stem Cell Research by Khalid et al. sought to investigate changes in DNA methylation as a result of EtOH exposure. Due to the many ethical issues involved in giving pregnant women alcohol, the group used human embryonic stem cells (hESCs) as their model for EtOH exposure. They treated hESCs with physiological relevant levels of EtOH, equivalent to DUI levels, for 24 in order to mimic the prolonged exposure to the fetus.
Transcriptome profiling in conjunction with Reduced Representation Bisulfite Sequencing (RRBS) was used to investigate the genome wide influences of EtOH exposure. They found that EtOH exposure increased DNA methytlation levels at promoters and decreased levels within CpG islands. Additionally, they noted that these changes were much more significant in undifferentiated cells than in cells that had already differentiated, suggesting that developing cells are much more vulnerable to EtOH. Next the authors correlated EtOH-induced changes in DNA methylation to changes in gene expression. They found that changes in DNA methylation correlated with transcriptional changes seen in both differentiated and undifferentiated cells when treated with EtOH.
Pluripotent (undifferentiated) hESCs are the most abundant in the early stages of embryo development, before implantation. Previous studies have demonstrated that a single dose of alcohol during this time increased the risk of post-implantation fetal death and negatively influenced normal development. Khalid et al. argue that even a small EtOH exposure may have such detrimental effects by altering the pluripotency of the embryo’s hESCs, adversely influencing their differentiation later on down the road. To investigate this, they used immunoflourensence to look at the abundance of stem cell marker proteins. They found that expression of these pluripotent markers were significantly reduced, while Annexin V, a marker for apoptosis, was significantly increased in EtOH-treated cells.
Although there are numerous studies documenting the effects of alchol consumption during pregnancy, this current study by Khalid et al. demonstrates for the first time that a 24 hour low dose of EtOH is able to significantly reduced the pluripotency and differentiation potential of hESCs. They also identified underlying epigenetic mechanisms, showing how EtOH exposure (even in the very early stages of development) is able to induce changes in DNA methylation in regions that may be involved in stem cell maintenance and differentiation, cellular functions which are critical to a developing fetus.
Khalid O, Kim JJ, Kim HS, Hoang M, Tu TG, Elie O, Lee C, Vu C, Horvath S, Spigelman I, & Kim Y (2014). Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells. Stem cell research, 12 (3), 791-806 PMID: 24751885