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ORIGINAL RESEARCH article

Front. Mol. Neurosci.

Sec. Molecular Signalling and Pathways

Regional and temporal dynamics of DNA methylation and epigenetic gene regulation in response to binge-like alcohol exposure in the adolescent mouse brain

Provisionally accepted
Amine CherifAmine Cherif1Amine BourzamAmine Bourzam1,2Zeineb FridhiZeineb Fridhi1Hanani BoukhawiyeHanani Boukhawiye1Clement GuillouClement Guillou3Pascal CosettePascal Cosette3Sami ZekriSami Zekri1,4Jérôme LEPRINCEJérôme LEPRINCE2David VaudryDavid Vaudry2,5Olfa Masmoudi-KoukiOlfa Masmoudi-Kouki1*
  • 1University Tunis El Manar, Faculty of Sciences of Tunis, LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomelcules Valorisation, 2092, Tunis, Tunis, Tunisia
  • 2Neuroendocrine Endocrine and Germinal Differentiation Communication, Mont-Saint-Aignan, France
  • 3Inserm US 51, CNRS UAR 2026, HeRacLeS PISSARO, F-76000 Rouen, France, ROUEN, France
  • 4Confocal Microscopy Unit, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia
  • 5Univ Rouen Normandie, Inserm U1245, Normandie Univ, F-76000 Rouen, France, Rouen, France

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Abstract Adolescence is a critical late phase of the neurodevelopment, characterized by marked brain plasticity and increased vulnerability to environmental challenges such as alcohol exposure.This study examined the impact of binge-like alcohol exposure in male swiss webster mice, focusing on oxidative damage, epigenetic and transcriptional alterations in key brain regions, such as the prefrontal cortex, cerebellum, striatum and hippocampus. Our results demonstrated that acute alcohol exposure during adolescence induces oxidative damage with significant alterations in global DNA methylation and gene expression involved in epigenetic regulation with distinct temporal and anatomical profiles. In the prefrontal cortex binge-like alcohol exposure exhibited persistent upregulation of genes associated with DNA methylation and histone deacetylation, consistent with prolonged transcriptional silencing that may impair executive functions and decision-making. The hippocampus appeared particularly sensitive, exhibiting marked decreases in DNA methylation and gene expression changes associated with an open chromatin state leading potentially linked to cognitive impairments in memory and learning impairments in memory and learning. In the striatum, binge-like alcohol exposure induced active DNA demethylation and transient modulation of histone methyltransferases, reflecting a dynamic compensatory response to alcohol-induced transcriptional repression, with implications for reward processing and impulse control. Similarly the cerebellum displayed a biphasic transcriptional pattern suggesting adaptive or homeostatic mechanisms aimed at maintaining cellular and synaptic balance. Collectively, these findings, accompanied by alterations in behavioral tests, highlight the regional specificity of epigenetic remodeling induced by excessive alcohol exposure during adolescence and offer new insights into the molecular mechanisms underlying increased neurodevelopmental vulnerability during this period

Keywords: Adolescent, Behavior, binge-like alcohol exposure, epigenetic, Methylation, Oxidative Stress

Received: 30 Sep 2025; Accepted: 28 Nov 2025.

Copyright: © 2025 Cherif, Bourzam, Fridhi, Boukhawiye, Guillou, Cosette, Zekri, LEPRINCE, Vaudry and Masmoudi-Kouki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Olfa Masmoudi-Kouki

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