Pre-Implantation Alcohol Exposure Induces Lasting Sex-Specific DNA Methylation Programming Errors in the Developing Forebrain

Abstract

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) 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.

Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

“…Importantly, these ethanol-exposed DMRs and sex-biased regions exhibited distinct CpG distributions based on sex. Notably, we observed a higher proportion of female-specific DMRs located in sex-biased regions in CpG islands and shores than male-specific DMRs located in sexbiased regions 13 . These differentially methylated regions between male and female embryos could help explain the sex-specific changes observed in both DNA methylation and gene expression.…”

“…To evaluate the impact of early preimplantation alcohol exposure on genes crucial for placental development, we analyzed our DNA methylation and gene expression datasets using previously published curated gene lists 13 .…”

“…In a recent study, we discovered genome regions with sex-biaised DNA methylation profiles in control placentas at E18.5 13 . When we compared the DMRs observed following preimplantation alcohol exposure with these sex-biased regions, we found that 115 male DMRs and 188 female DMRs were also sex-biased at late gestation.…”