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

Abstract

The placenta is vital for proper embryonic development and successful pregnancy. Preimplantation alcohol exposure can negatively impact embryonic development and lead to fetal alcohol spectrum disorder. We and others have demonstrated the adverse effects of preimplantation alcohol exposure on embryo morphology and molecular profiles at late gestation, but studies on the placenta are markedly lacking. Here, we used an established preclinical mouse model to assess the impact of preimplantation (8-cell stage) binge-like alcohol exposure on the morphology, DNA methylation, and gene expression patterns in male and female late-gestation placentas. While overall placental morphology was not affected, we uncovered numerous differentially methylated regions (DMRs;n=991 in males;n=1309 in females) and differentially expressed genes (DEGs;n=1046 in males;n=340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Using LASSO regression, we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas. Importantly, it reveals a placental DNA methylation signature that can detect prenatal alcohol exposure and provide appropriate support to prevent eventual impact.GRAPHICAL ABSTRACT