Pre-Implantation Alcohol Exposure Induces Lasting Sex-Specific DNA Methylation Programming Errors in the Developing Forebrain
ABSTRACTPrenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program. Using a pre-clinical in vivo mouse model, we show that pre-implantation alcohol exposure leads to adverse developmental outcomes that replicate clinical characteristics observed in children with FASD. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development). These findings support the contribution of alcohol-induced DNA methylation programming deviations during pre-implantation to the manifestation of neurodevelopmental phenotypes associated with FASD.