Nathan Child

Introduction. Fetal Alcohol Spectrum Disorder (FASD) is an underdiagnosed condition resulting from alcohol exposure at any point during pregnancy.¹ Estimated to affect 2-5% of individuals in the US and Europe, FASD is characterized by varying degrees of severity of clinical presentations, and there are multiple diagnostic classification systems which make diagnosis difficult.¹ Current treatment approaches vary to accommodate an individual’s specific profile of needs.¹ However, the targets of ethanol toxicity are diverse and poorly understood, and treatment options remain limited.² It is hypothesized that transcription factors that regulate stem/progenitor cell development such as Sox2 are key components in the pathogenesis of FASD.² Methods. A literature search was performed in the PubMed database, selecting articles from reputable journals published after 2017. Review articles and primary research articles were analyzed to aid the understanding of the mechanistic effects of alcohol toxicity in FASD. Zebrafish embryos were exposed to ethanol, and microarray gene analysis was used to identify dysregulated genes.² Synthetic Sox2 mRNA was injected into some of the ethanol exposed embryos, and gastrulation delays were measured.² Hippocampal tissue from human adult donors with severe alcohol abuse was stained for Sox2 and other markers to determine the cell types present after prolonged alcohol exposure.³ Mouse models of intrauterine growth restriction (IUGR) induced by maternal hypertension were subjected to behavioral assays of implicit and explicit memory.⁴ Embryonic brain samples underwent immunofluorescent staining for Sox2, quantitative PCR, and RNA sequencing.⁴ Mouse models of maternal binge-like alcohol drinking during gestation underwent learning acquisition tests and adult brain tissue analysis, assessing for histone acetyltransferase and deacetylase activity with ELISA.⁵ Results. Examination of the articles revealed altered Sox2 function in FASD. There were 521 dysregulated genes, including 61 transcription factors detected in ethanol-exposed embryos.² Sox2 and 52 of its gene targets were also included.² Synthetic Sox2 treatment rescued ethanol exposed embryos from gastrulation delays.² Adult hippocampal samples with prolonged alcohol exposure showed significant decreases in Sox2⁺ neural stem/progenitor cells.³ Mice with IUGR showed abnormal memory with reduced hippocampal volumes and fewer Sox2⁺ cells.⁴ Prenatal alcohol exposure caused increased acetylation of histone 4 at lysine 5 and 12.⁵ Conclusions. Limitations of these results include the differences between adult and fetal stem cells, the types of epigenetic modifications that were not studied, and the application of data from animal models. However, Sox2 may be a target for future FASD research and possible therapeutic interventions.

1. Wozniak JR, Riley EP, Charness ME. Clinical presentation, diagnosis, and management of fetal alcohol spectrum disorder. Lancet Neurol. 2019;18(8):760-770. doi:10.1016/S1474-4422(19)30150-4
2. Sarmah S, Srivastava R, McClintick JN, Janga SC, Edenberg HJ, Marrs JA. Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects. Sci Rep. Mar 3 2020;10(1):3951. doi:10.1038/s41598-020-59043-x
3. Le Maître TW, Dhanabalan G, Bogdanovic N, Alkass K, Druid H. Effects of Alcohol Abuse on Proliferating Cells, Stem/Progenitor Cells, and Immature Neurons in the Adult Human Hippocampus. Neuropsychopharmacology. 2018;43(4):690-699. doi:10.1038/npp.2017.251
4. Brown AS, Wieben M, Murdock S, et al. Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits. eNeuro. Sep-Oct 2021;8(5)doi:10.1523/eneuro.0062-21.2021
5. Cantacorps L, Alfonso-Loeches S, Guerri C, Valverde O. Long-term epigenetic changes in offspring mice exposed to alcohol during gestation and lactation. J Psychopharmacol. Dec 2019;33(12):1562-1572. doi:10.1177/0269881119856001