Chronic Ethanol Exposure Alters DNA Methylation in Neural Stem Cells: Role of Mouse Strain and Sex

  • Shayan Amiri
  • James R. Davie
  • Mojgan RastegarEmail author


Prenatal alcohol exposure (PAE) is considered as a risk factor for the development of fetal alcohol spectrum disorders (FASD). Evidence indicates that PAE affects epigenetic mechanisms (such as DNA methylation) and alters the normal differentiation and development of neural stem cells (NSC) in the fetal brain. However, PAE effects depend on several factors such as sex and strain of the studied subjects. Here, we investigated whether murine sex and strain contribute to the effects of chronic ethanol exposure on DNA methylation machinery of differentiating NSC. Further, the effects of PAE on glial lineage (including both astrocytes and oligodendrocytes) in a sex- and strain-dependent manner have not been studied yet. To examine the effects of chronic ethanol exposure on gliogenesis, we exposed differentiating NSC to glio-inductive culture conditions. Applying a standard in vitro model system, we treated male and female differentiating NSC (obtained from the forebrain of CD1 and C57BL/6 embryos at embryonic day 14.5) with chronic ethanol exposure (70 mM) for 8 days. We show that ethanol induces global DNA hypomethylation, while altering the expression of DNA methylation-related genes in a sex- and strain-specific manner. The observed change in cellular DNA methylation levels was associated with altered expression of glial markers CNPASE, GFAP, and OLIG2 in CD1 (but not C57BL/6) cells. We conclude that the impact of ethanol effect on DNA methylation is dependent on cellular sex and strain. Also, ethanol impact on neural stem cell fate commitment was only detected in cells isolated from CD1 mouse strain, but not in C57BL/6 cells. The results of the current study provide evidence that sex and strain of rodents (C57BL/6 and CD1) during gestation are important factors, which affect alcohol effects on NSC differentiation and DNA methylation. Results of this study may also help in interpreting data on the developmental toxicity of many compounds during the gestational period.


DNA methylation Epigenetics Alcohol FASD Neural stem cells Gliogenesis 



The authors would like to thank Mr. Carl Olson from Rastegar Lab for the help with some male–female embryonic dissections and images of male–female embryos.

Authors’ Contributions

SA and MR designed the experiments and analysis. SA and MR performed embryonic dissections, NSC isolation, culture, and differentiation. SA harvested differentiated cells, performed molecular experiments, and prepared the figures. SA and MR wrote the manuscript. JRD provided scientific insight. All authors read and approved the final version of the manuscript.

Funding Information

This research is supported by funds from a CIHR (Canadian Institutes of Health Research) Team Grant (TEC-128094) to MR (Co-PI), JRD (Team Leader), and other team members; and from the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant 2016-06035 to MR.

Compliance with Ethical Standards

All the experimental procedures used in this study were done in accordance with the standards of the Canadian Council on Animal Care with the approval of the Office of Research Ethics of University of Manitoba and under approved and peer-reviewed animal protocol B2016-031/1/2 (AC11190).

Competing Interests

The authors declare that they have no competing interest.

Supplementary material

12035_2019_1728_MOESM1_ESM.docx (47 kb)
ESM 1 (DOCX 46 kb)


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Authors and Affiliations

  1. 1.Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health SciencesUniversity of ManitobaWinnipegCanada
  2. 2.Regenerative Medicine Program, Max Rady College of Medicine, Rady Faculty of Health SciencesUniversity of ManitobaWinnipegCanada

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