Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain

• Published in: Clinical epigenetics Vol. 13; no. 1; p. 164
• Main Authors: Legault, L M, Doiron, K, Breton-Larrivée, M, Langford-Avelar, A, Lemieux, A, Caron, M, Jerome-Majewska, L A, Sinnett, D, McGraw, Serge
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central Ltd 01.12.2021; BioMed Central
• Subjects: Adult; Alcohol Drinking - adverse effects; Animals; Brain; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; DNA; DNA Damage - drug effects; DNA Damage - genetics; DNA methylation; DNA Methylation - drug effects; DNA Methylation - genetics; Effect of alcohol on; Embryonic development; Embryonic Development - drug effects; Embryonic Development - genetics; Embryos; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Ethanol; Etiology; Female; Females; Fetal Alcohol Spectrum Disorders - genetics; Fetal alcohol syndrome; Fetus; Forebrain; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Genetic research; Genomes; Genomics; Humans; Male; Males; Methylation; Mice; Morphology; Phenotype; Phenotypes; Pregnancy; Pregnant women; Prenatal experience; Prenatal Exposure Delayed Effects; Program errors; Prosencephalon - metabolism; Early embryonic development; DNA methylation; Epigenetic reprogramming; Imprinting; Fetal alcohol spectrum disorder; Prenatal exposure
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-021-01151-0

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 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). These findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.