Epigenetic Mechanism of DNA Methylation in Fetal Alcohol Syndrome
Introduction Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term referring to the adverse health effects of prenatal ethyl alcohol exposure.1 Fetal Alcohol Syndrome (FAS) lies at the severe end of this spectrum and describes a group of characteristics including craniofacial abnormalities, central nervous system damage, and growth deficiencies. Currently, few tools are available for early diagnosis and treatment. In order to develop interventions and achieve better outcomes, it is necessary to understand the underlying mechanisms of fetal alcohol exposure.2 It has been shown that ethanol enters the fetal compartment via the placenta.3 Studies suggest alcohol exposure may then contribute to development of FAS through epigenetic changes. DNA methylation is one of the more researched of these mechanisms.4 Further insights may lead to more specific detection of prenatal alcohol exposure, as well as treatments better suited to target its harmful effects. Methods Buccal epithelial cells of children with FASD and controls were analyzed for genome-wide DNA methylation patterns using the Illumina HumanMethylation450 array.5 Mouse models were given a 4% alcohol liquid diet from embryonic days 7-16 and harvested on day 17. Immunohistochemistry, Western blot, and methyl-DNA assays were then used to assess cortical neuroanatomy, neural phenotypes, and epigenetic markers of methylation in comparison to controls.6 Mice were also injected with saline or ethanol on postnatal days 4 and 7, simulating binge drinking during the neurodevelopmental equivalent of the human third trimester. Microarrays were then performed.7 Immortalized teratocarcinoma-derived murine cells (1C11 cells) were cultured and primary mouse embryonic fibroblasts (MEFs) were prepared using heat shock factor (Hsf1 and Hsf2) knockout mice. They were then exposed to heat shock and ethanol and analyzed with Western blot analysis, immunofluorescence, and for ROS levels.8 Results These studies suggest that there are distinct patterns of DNA methylation associated with prenatal alcohol exposure.5 DNA methylation was found to be disrupted by fetal alcohol exposure, and this disturbance occurred alongside abnormalities in cortical development.6 Free radical scavenging and peroxisome biogenesis were pathways affected, suggesting an interaction between epigenetic mechanisms and oxidative stress mechanisms.7This may be due to alcohol exposure triggering production of ROS, which results in an accumulation of DNMT3A, a DNA methyltransferase protein.8 Conclusions Studies show that there are DNA methylation patterns associated with prenatal alcohol exposure. Alcohol-induced changes in DNA methylation occur alongside cortical abnormalities, and increases in ROS may contribute to the effects of fetal alcohol exposure.
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