Abstract
BackgroundPrenatal 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.ResultsUsing a pre-clinical in vivo mouse model, we show that a binge-like alcohol exposure during pre-implantation at the 8-cell stage leads to surge in morphological brain defects and adverse developmental outcomes during fetal life. 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).ConclusionThese findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.
Highlights
Fetal Alcohol Spectrum Disorder (FASD) encompasses the range of lifelong cognitive and physical disabilities observed in children born to mothers who consumed alcohol during pregnancy [1,2,3,4]
Upstream key regulator of MGE-derived GABAergic interneurons [52,53,54], Nkx2.1 did not show expression alterations (Additional file 1: Fig. S8B), downstream transcription factors such as Sox6 (DMR in gene body; males), and Arx, DMR in promoter; females) showed small but significant gene expression alteration (Sox6; males and females, Arx; males) (Additional file 1: Fig. S8A). These results indicate that alcohol exposure in pre-implantation embryos in conjunction with epigenetic reprogramming leads to variable levels of sex-specific alterations, with male embryonic forebrains being more prone to DNA methylation alterations
We showed that pre-implantation alcohol exposure is detrimental for normal development and leads to a broad spectrum of adverse outcomes that closely replicate clinical facets observed in children with FASD
Summary
Fetal Alcohol Spectrum Disorder (FASD) encompasses the range of lifelong cognitive and physical disabilities observed in children born to mothers who consumed alcohol during pregnancy [1,2,3,4]. An increasing body of evidence indicates that alcohol exposure during fetal brain development triggers lasting epigenetic alterations, including DNA methylation, in offspring long after the initial insult, supporting the role of epigenetics in FASD phenotypes [16,17,18,19]. Prenatal 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) etiol‐ ogy. 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
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