The role of DNA methylation in alcohol-mediated neurodevelopmental toxicity.

Alcohol induces neurodevelopmental toxicity through multiple biological processes, including DNA methylation and histone modifications in epigenetic regulation. Epigenetic mechanisms involving DNA chemical modifications represent crucial molecular pathways that regulate gene expression during neurodevelopment, exhibiting high sensitivity to adverse lifestyle factors such as alcohol consumption, smoking, and stress. Prenatal alcohol consumption is a primary cause of fetal neurodevelopmental disorders. Alcohol alters DNA methylation and histone modification levels in the brain, which in turn disrupts the expression levels of related genes. This review focuses on how alcohol mediates neurodevelopmental toxicity by disrupting DNA methylation mechanisms. First, alcohol affects DNA methylation through the following pathways: (1) Inhibiting folate metabolism reduces the production of the methyl donor S-adenosylmethionine (SAM), thereby decreasing DNA methyltransferase (DNMTs) activity; (2) Induces oxidative stress, where reactive oxygen species (ROS) disrupt methylation status at CpG sites; (3) Directly alters the activity of DNMTs and TETs, leading to hypermethylation or hypomethylation in gene promoter regions. These abnormal methylation patterns significantly impact the differentiation neural stem cells (NSCs), neuronal migration and synapse formation, as well as the function of glial cells. Methylation abnormalities in neurodevelopment-related genes can trigger neuronal migration defects and synaptic plasticity disorders. Alcohol-induced methylation-related changes exhibit brain region specificity, involving areas such as the hippocampus, prefrontal cortex, and hypothalamus. Regarding intervention strategies, prenatal supplementation with methyl donors like folate and choline partially reverses alcohol-induced abnormal DNA methylation and improves neurodevelopmental outcomes. This study highlights the role of DNA methylation in alcohol-mediated neurotoxicity, providing a theoretical basis for elucidating the molecular mechanisms of FASD and developing targeted epigenetic therapeutic strategies.