DNA Methylation of the Leptin Gene Promoter is Altered by Chronic Alcohol Exposure in an Animal Model for Alcohol Dependence

Rhein, Mathias; Hillemacher, Thomas; Lichtinghagen, Ralf; Hoppe, Viktoria; Müschen, Lars Hendrik; Glahn, Alexander; Frieling, Helge; Muschler, Marc

doi:10.1159/000496111

Cited by 7 publications

(2 citation statements)

References 32 publications

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“…It has been revealed a notable reduction in DNA methylation levels in the leptin promoter region of animals consuming alcohol compared to those who had not been exposed to alcohol. However, after a period of 6 days without alcohol consumption, this disparity in methylation levels ceased to exist [50]. Adolescent intermittent ethanol (AIE) exposure has been found to cause significant alterations in DNA methylation mechanisms within the amygdaloid circuitry.…”

Section: Animal Studiesmentioning

confidence: 99%

Alcohol: Epigenome Alteration and Transgenerational Effect

Heidari¹,

Hajikarim-Hamedani²,

Heidari³

et al. 2023

Preprint

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While DNA serves as the fundamental genetic blueprint for an organism, it is not a static entity. Gene expression, the process by which genetic information is utilized to create functional products like proteins, can be modulated by a diverse range of environmental factors. Epigenetic mechanisms, encompassing DNA methylation, histone modification, and microRNAs, play a pivotal role in mediating the intricate interplay between the environment and gene expression. Intriguingly, alterations in the epigenome have the potential to be inherited across generations. Ethanol abuse poses significant health issues worldwide. Ethanol has the capability to induce changes in the epigenome, which can be inherited by offspring, thus impacting them even in the absence of direct ethanol exposure. This review article reviewed the alterations caused by ethanol on the epigenome. We thoroughly gathered all relevant papers investigating the behavioral and molecular consequences of parental ethanol exposure on their offspring. In conclusion, the comprehensive analysis of the literature supports the notion that ethanol exposure induces lasting epigenetic alterations, which can influence the behavior and health of future generations. This knowledge emphasizes the significance of addressing the potential transgenerational effects of ethanol and highlights the importance of preventive measures to minimize the adverse impact on offspring.

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Section: Animal Studiesmentioning

confidence: 99%

Alcohol: Epigenome Alteration and Transgenerational Effect

Heidari¹,

Hajikarim-Hamedani²,

Heidari³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to the heterogeneity in outcomes seen, studies have also suggested that methylation levels in some regions due to alcohol cease to exist after a particular period making understanding the duration of these changes important (Wieting et al, 2019). Nevertheless, as we have demonstrated, the effects of PPAC can occur in offspring born to sires who were not exposed to alcohol for 8 weeks before mating and the next step is to identify the changes which support epigenetic inheritance through the male germline.…”

Section: Mechanisms Of Ppacmentioning

confidence: 84%

Transgenerational Hangovers: A Rat Model for Behavioural and Epigenetic Changes Across Generations due to Paternal Preconceptual Alcohol Consumption

Hussain

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Alcohol is the most harmful drug of abuse, making alcoholism a major economic and public health crisis. Unsurprisingly, this has led to the majority of neurobiological research on alcohol focussing on its direct effects on an individual. This includes those affected by foetal alcohol spectrum disorders (FASDs). However, research has shown that heavy paternal drinking predicts earlier and heavier adolescent drinking in the offspring, accompanied with other behavioural and molecular changes. While alcohol use disorder (AUD) is highly heritable, research on genetic variants alone does not sufficiently account for its risk and the FASDs like symptoms seen in the offspring of alcoholic fathers. Recently, there has been an increase in appreciation of the importance of epigenetic mechanisms of inheritance, which transfer changes due to parental experiences through the germline. This thesis aimed to assess both the inter and transgenerational impacts of preconceptual paternal alcohol consumption (PPAC) using a rat model. Sprague Dawley male rats (F0) underwent chronic voluntary ethanol intake and at the end of the drinking paradigm were kept for one spermatogenesis cycle before being mated with ethanol naïve females. The litters and matched controls were behaviourally assessed, and a cohort of F1 males mated to observe a F2 generation.PPAC caused behavioural changes in both the F1 and F2 generations, including altering litter sizes and delaying development. The F1 also show a reduction in sensitivity to the motor impairing effects of ethanol compared to controls. Sexually dimorphic effects of PPAC were seen with female offspring having a reduced preference to ethanol in both the F1 and F2, while tolerance to ethanol in motor coordination was again seen in the F2 females but not F2 males. Likewise, F1 males presented reductions in locomotor activity but these effects did not persist in the F2.Analysis of liver mitochondrial DNA copy number (mtDNA-CN) found that drinking F0 fathers had reduced mtDNA-CN at the end of the ethanol intake paradigm and 12 weeks post-drinking relative to controls. The livers of F1 showed lower mtDNA-CN in the offspring of ethanol sired rats compared to offspring of non-drinkers after undergoing ethanol consumption, suggesting differences in liver metabolism. Finally, livers of F0 drinkers had reduced expression of Peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1a), relating to mitochondrial biogenesis, and methyl-CpG-binding protein 2 (Mecp2), indicating putative changes in methylation signalling, together suggesting epigenetic inheritance of changes due to xenotoxic stress.The findings show PPAC induces developmental delays, causes transgenerational changes in drinking behaviour, ethanol sensitivity and liver mitochondrial function in a sexually dimorphic manner. These changes may be protective to the female offspring of PPAC to modify their ethanol intake. The alterations in F1 liver mtDNA-CN demonstrate potential far-reaching consequences for the metabolism of xenotoxic substances extending beyond ethanol and provides evidence to support behavioural and epigenetic changes across generations due to PPAC.

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