Rasik Jankay

Introduction.  Fetal Alcohol Spectrum Disorder (FASD) is a leading cause of preventable intellectual disability which refers to the range of effects that can occur due to prenatal alcohol exposure. Typical manifestations in the child include facial anomalies such as short palpebral fissures, thin vermilion border, and smooth philtrum, as well as abnormal brain growth and neurobehavioral impairment.¹ Studies suggest that alcohol exposure in the developing brain triggers differing DNA methylation patterns in various brain tissue layers causing effects seen in FASD.² In recent years, numerous studies have indicated gestational choline supplementation as a therapy that aids in prevention of global DNA hypomethylation and epigenetic dysregulation.³ Methods. Pregnant mice were separated into controls (chow fed), lcohol fed, and choline fed where relevant. Western blotting was utilized for DNA methylation analysis using 5mC, 5hmC, and MeCP2 as biomarkers. RT-qPCR analysis and in-situ hybridization was used for gene analysis, focusing on Id2 and Rzrβ genes. Additionally, Suok apparatus & Ledge tests were utilized on mice to measure neurobehavioral effects. Results. Alcohol fed mice were found to have reduced expression of 5mC & 5hmC, and increased expression of MeCP2, which is the inverse of controls. Additionally, neuronal epithelium cells were more immature in alcohol fed mice compared to controls across ventricular zone and cortical plate layers of the neocortex.² Increased methylation and subsequent reduced expression of miR-9, which is important for early brain segmentation, neurogenesis and neuronal maturation, was found in alcohol-fed mice. ⁴ Third generation mice descending from the first-generation alcohol fed group exhibited significant increases in falls, missteps, and latency to leave center, indicating major transgenerational effects of FASD.⁵ Choline treated mice showed near correct expression of Id2 and Rzrβ indicating its use as an epigenetic regulator and brain images showed no significant difference in the gene distributions compared to controls despite a significant difference compared to alcohol fed mice. Conclusions. Studies have found that DNA methylation patterns are vital for correct neocortex development and alcohol fed mice have altered gene expression in Id2 and Rzrβ (important for sensorimotor integration), as well as thinner cortical plates, expanded ventricular zones, and immature neuroepithelium. Choline supplementation is shown to prevent further damage from alcohol by working to prevent alterations in Id2 and Rzrβ gene distribution and brain size perturbations in the neocortex, helping reduce the impact of the damaging effects of FASD.

1. Mattson SN, Bernes GA, Doyle LR. Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure. Alcohol Clin Exp Res. 2019 Jun;43(6):1046-1062. doi: 10.1111/acer.14040. Epub 2019 May 2. PMID: 30964197; PMCID: PMC6551289.
2. Öztürk NC, Resendiz M, Öztürk H, Zhou FC. DNA Methylation program in normal and alcohol-induced thinning cortex. Alcohol. 2017;60:135-147. doi:10.1016/j.alcohol.2017.01.006
3. Bottom RT, Abbott CW 3rd, Huffman KJ. Rescue of ethanol-induced FASD-like phenotypes via prenatal co-administration of choline. Neuropharmacology. 2020;168:107990. doi:10.1016/j.neuropharm.2020.107990
4. Burrowes SG, Salem NA, Tseng AM, et al. The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus. Alcohol. 2017;60:149-158. doi:10.1016/j.alcohol.2017.01.003
5. Abbott CW, Rohac DJ, Bottom RT, Patadia S, Huffman KJ. Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD. Cereb Cortex. 2018;28(8):2908-2921. doi:10.1093/cercor/bhx168