Epigenetic pathways linking prenatal alcohol exposure to fetal alcohol spectrum disorder

Fetal Alcohol Spectrum Disorder (FASD) presents a profound global health burden, yet clinical diagnosis remains severely hindered by phenotypic heterogeneity and the lack of objective biomarkers. Emerging evidence reveals that the pathogenesis of prenatal alcohol exposure (PAE) is heavily driven by fetal programming via epigenetic modifications. In this narrative review, we synthesize data from human cohorts and advanced preclinical models to conceptualize FASD as a dynamic epigenetic trajectory rather than a static teratogenic insult. Ethanol disrupts the epigenome systemically, perturbing one-carbon metabolism, oxidative stress pathways, non-coding RNAs, and the placenta-brain axis. Furthermore, postnatal environmental factors, particularly early-life stress, interact with PAE to shape neuroimmune vulnerability and sexually dimorphic outcomes. While stable peripheral DNA methylation "episignatures" offer significant promise for future risk stratification, we highlight the critical translational challenge of correlating these peripheral markers with central neuropathology. Although AI-assisted screening and targeted epigenetic interventions (e.g., choline supplementation) represent exciting translational avenues, they remain investigational. Ultimately, transitioning FASD toward precision medicine will require longitudinal, single-cell multi-omic studies to validate tissue-specific biomarkers, address ethical and algorithmic biases, and pave the way for biologically grounded, early interventions.