Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model

PLoS One. 2015 May 13;10(5):e0124931. doi: 10.1371/journal.pone.0124931. eCollection 2015.


The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / genetics
  • Alcohol Drinking / metabolism*
  • Alcohol Drinking / pathology
  • Animals
  • Bone Marrow / drug effects
  • CpG Islands
  • DNA Methylation / drug effects*
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Ethanol / pharmacology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Genome
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Immunoglobulin Light Chains, Surrogate / genetics
  • Immunoglobulin Light Chains, Surrogate / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Neurulation / drug effects
  • Neurulation / genetics
  • Olfactory Bulb / drug effects
  • Olfactory Bulb / pathology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prenatal Exposure Delayed Effects / pathology
  • Receptors, Odorant / genetics
  • Receptors, Odorant / metabolism


  • Histones
  • Immunoglobulin Light Chains, Surrogate
  • MicroRNAs
  • Receptors, Odorant
  • pre-B lymphocyte gene 2 protein, mouse
  • Ethanol

Grants and funding

This work was supported by the Academy of Finland (258304), Päivikki and Sakari Sohlberg Foundation, The Finnish Foundation for Alcohol Studies, Finnish Cultural Foundation, Orion-Farmos Research Foundation and Paulo Foundation to N.J.K., The Finnish Foundation for Alcohol Studies and Finnish Cultural Foundation to H.M.M., Academy of Finland (275453) and Finnish Cultural Foundation to A.S. and Biocentrum Helsinki to S.K.H. The funders had no role in study design, data collection and analysis, decisions to publish, or preparation of the manuscript.