Long-term epigenetic changes in offspring mice exposed to alcohol during gestation and lactation

Background: Alcohol exposure impairs brain development and leads to a range of behavioural and cognitive dysfunctions, termed as foetal alcohol spectrum disorders. Although different mechanisms have been proposed to participate in foetal alcohol spectrum disorders, the molecular insights of such effects are still uncertain. Using a mouse model of foetal alcohol spectrum disorder, we have previously shown that maternal binge-like alcohol drinking causes persistent effects on motor, cognitive and emotional-related behaviours associated with neuroimmune dysfunctions. Aims: In this study, we sought to evaluate whether the long-term behavioural alterations found in offspring with early exposure to alcohol are associated with epigenetic changes in the hippocampus and prefrontal cortex. Methods: Pregnant C57BL/6 female mice underwent a model procedure for binge alcohol drinking throughout both the gestation and lactation periods. Subsequently, adult offspring were assessed for their cognitive function in a reversal learning task and brain areas were extracted for epigenetic analyses. Results: The results demonstrated that early binge alcohol exposure induces long-term behavioural effects along with alterations in histone acetylation (histone H4 lysine 5 and histone H4 lysine 12) in the hippocampus and prefrontal cortex. The epigenetic effects were linked with an imbalance in histone acetyltransferase activity that was found to be increased in the prefrontal cortex of mice exposed to alcohol. Conclusions: In conclusion, our results reveal that maternal binge-like alcohol consumption induces persistent epigenetic modifications, effects that might be associated with the long-term cognitive and behavioural impairments observed in foetal alcohol spectrum disorder models.

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Histone deacetylases inhibitor trichostatin A reverses anxiety-like symptoms and memory impairments induced by maternal binge alcohol drinking in mice

Journal of Psychopharmacology ◽

10.1177/0269881119857208 ◽

2019 ◽

Vol 33 (12) ◽

pp. 1573-1587 ◽

Cited By ~ 5

Author(s):

Sandra Montagud-Romero ◽

Lídia Cantacorps ◽

Olga Valverde

Keyword(s):

Alcohol Consumption ◽

Alcohol Drinking ◽

Histone Deacetylases ◽

Trichostatin A ◽

Alcohol Exposure ◽

Brain Regions ◽

Activity Levels ◽

Wide Range ◽

Spectrum Disorders ◽

Foetal Alcohol Spectrum Disorders

Background:Alcohol exposure during development has detrimental effects, including a wide range of physical, cognitive and neurobehavioural anomalies known as foetal alcohol spectrum disorders. However, alcohol consumption among pregnant woman is an ongoing latent health problem.Aim:In the present study, the effects of trichostatin A (TSA) on emotional and cognitive impairments caused by prenatal and lactational alcohol exposure were assessed. TSA is an inhibitor of class I and II histone deacetylases enzymes (HDAC), and for that, HDAC4 activity was determined. We also evaluated mechanisms underlying the behavioural effects observed, including the expression of brain-derived neurotrophic factor (BDNF) in discrete brain regions and newly differentiated neurons in the dentate gyrus (DG).Methods:C57BL/6 female pregnant mice were used, with limited access to a 20% v/v alcohol solution as a procedure to model binge alcohol drinking during gestation and lactation. Male offspring were treated with TSA during the postnatal days (PD28–35) and behaviourally evaluated (PD36–55).Results:Early alcohol exposure mice presented increased anxiogenic-like responses and memory deterioration – effects that were partially reversed with TSA. Early alcohol exposure produces a decrease in BDNF levels in the hippocampus (HPC) and prefrontal cortex, a reduction of neurogenesis in the DG and increased activity levels of the HDAC4 in the HPC.Conclusions:Such findings support the participation of HDAC enzymes in cognitive and emotional alterations induced by binge alcohol consumption during gestation and lactation and would indicate potential benefits of HDAC inhibitors for some aspects of foetal alcohol spectrum disorders.

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Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress

Genes ◽

10.3390/genes12111773 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1773

Author(s):

Alexandre A. Lussier ◽

Tamara S. Bodnar ◽

Michelle Moksa ◽

Martin Hirst ◽

Michael S. Kobor ◽

...

Keyword(s):

Dna Methylation ◽

Prefrontal Cortex ◽

Prenatal Alcohol Exposure ◽

Alcohol Exposure ◽

Epigenetic Changes ◽

Specific Effects ◽

Prenatal Alcohol ◽

Related Stress ◽

Physiological Systems

Prenatal adversity or stress can have long-term consequences on developmental trajectories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional implications. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. As these insults can have sex-specific effects on biological outcomes, we analyzed epigenome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may reflect the sex-specific effects of prenatal insults on long-term functional and health outcomes and have important implications for understanding possible mechanisms underlying fetal alcohol spectrum disorder and other neurodevelopmental disorders.

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Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders

Frontiers in Genetics ◽

10.3389/fgene.2014.00161 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 31

Author(s):

Morgan L. Kleiber ◽

Eric J. Diehl ◽

Benjamin I. Laufer ◽

Katarzyna Mantha ◽

Aniruddho Chokroborty-Hoque ◽

...

Keyword(s):

Fetal Alcohol Spectrum Disorders ◽

Prenatal Alcohol Exposure ◽

Alcohol Exposure ◽

Fetal Alcohol ◽

Prenatal Alcohol ◽

Spectrum Disorders ◽

Fetal Alcohol Spectrum

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Long-term alterations to DNA methylation as a biomarker of prenatal alcohol exposure: From mouse models to human children with fetal alcohol spectrum disorders

Alcohol ◽

10.1016/j.alcohol.2016.11.009 ◽

2017 ◽

Vol 60 ◽

pp. 67-75 ◽

Cited By ~ 27

Author(s):

Benjamin I. Laufer ◽

Eric J. Chater-Diehl ◽

Joachim Kapalanga ◽

Shiva M. Singh

Keyword(s):

Dna Methylation ◽

Mouse Models ◽

Fetal Alcohol Spectrum Disorders ◽

Prenatal Alcohol Exposure ◽

Alcohol Exposure ◽

Fetal Alcohol ◽

Prenatal Alcohol ◽

Spectrum Disorders ◽

Fetal Alcohol Spectrum

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Socio-emotional development of children with foetal alcohol spectrum disorders in long-term foster family care: a qualitative study

Nordic Social Work Research ◽

10.1080/2156857x.2013.766234 ◽

2013 ◽

Vol 3 (1) ◽

pp. 38-58 ◽

Cited By ~ 11

Author(s):

Anne M. Koponen ◽

Mirjam Kalland ◽

Ilona Autti-Rämö ◽

Ritva Laamanen ◽

Sakari Suominen

Keyword(s):

Qualitative Study ◽

Emotional Development ◽

Family Care ◽

Foster Family ◽

Spectrum Disorders ◽

Foetal Alcohol Spectrum Disorders

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Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

10.1101/726307 ◽

2019 ◽

Author(s):

Jessica L. Hoffman ◽

Sara Faccidomo ◽

Michelle Kim ◽

Seth M. Taylor ◽

Abigail E. Agoglia ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Alcohol Use ◽

Entorhinal Cortex ◽

Alcohol Drinking ◽

Alcohol Exposure ◽

The United States ◽

The Impact ◽

Behavioral Pathology

ABSTRACTAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that non-dependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, 2-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wildtype mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer’s pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

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Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking

Translational Psychiatry ◽

10.1038/s41398-021-01728-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daria Piacentino ◽

Silvia Grant-Beurmann ◽

Carlotta Vizioli ◽

Xiaobai Li ◽

Catherine F. Moore ◽

...

Keyword(s):

Amino Acids ◽

Alcohol Use ◽

Alcohol Drinking ◽

Gut Microbiome ◽

Alcohol Exposure ◽

Primate Model ◽

Fecal Microbiome ◽

Excessive Alcohol ◽

Human Primate

AbstractA relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p’s < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p’s < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

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Enhanced synaptic properties of the prefrontal cortex and hippocampus after learning a spatial working memory task in adult male mice

10.1101/339432 ◽

2018 ◽

Cited By ~ 1

Author(s):

Vasiliki Stavroulaki ◽

Vasileios Ioakeimidis ◽

Xanthippi Konstantoudaki ◽

Kyriaki Sidiropoulou

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Dendritic Spine ◽

Memory Task ◽

Long Term Potentiation ◽

Learning Task ◽

Spine Density ◽

Dendritic Spine Density ◽

Term Potentiation

AbstractWorking memory (WM) is the ability to hold on-line and manipulate information. The prefrontal cortex (PFC) is a key brain region involved in WM, while the hippocampus is also involved, particularly, in spatial WM. Although several studies have investigated the neuronal substrates of WM in trained animals, the effects and the mechanisms underlying learning WM tasks have not been explored. In our study, we investigated the effects of learning WM tasks in mice on the function of PFC and hippocampus, by training mice in the delayed alternation task for 9 days (adaptive group). This group was compared to naïve mice that stayed in their homecage (naïve) and mice trained in the alternation procedure only (non-adaptive). Following training, a cohort of mice (Experiment A) was tested in the left-right discrimination task and the reversal learning task, while another cohort (Experiment B) was tested in the attention set- shifting task (AST). The adaptive group performed significantly better in the reversal learning task (Experiment A) and AST (Experiment B), compared to non-adaptive and naïve groups. At the end of the behavioral experiments in Experiment A, field excitatory post-synaptic potential (fEPSP) recordings were performed in PFC and hippocampal brain slices. The adaptive group had enhanced the long-term potentiation (LTP) in the PFC, compared to the other groups. In the hippocampus, both the adaptive and the non-adaptive groups exhibited increased fEPSP compared to the naive group, but no differences in LTP. In Experiment B, the dendritic spine density was measured, which, in the PFC, was found increased in the adaptive group, compared to the non-adaptive and naive groups. In the hippocampus, there was an increase in mature dendritic spine density in the adaptive group, compared to the other two groups. Our results indicate a role for long-term potentiation and dendritic spine density in learning WM tasks.Significance statementWorking memory (WM) allows for transient storage and manipulation of information and has a central role in cognition. While a great number of research studies have investigated the mechanisms underlying the ‘memory’ part of WM in well-trained animals, the mechanisms that underlie learning WM tasks are not known. Studies have indicated that learning a WM tasks alters and enhances neuronal firing during the delay period, suggesting that long-term plasticity mechanisms could be involved. Our results in this study suggest that learning a working memory task primarily increases long-term potentiation and dendritic spine density in the prefrontal cortex, providing evidence for a role of long-term plasticity processes in learning working memory tasks. Furthermore, learning working memory tasks enhances cognitive flexibility.

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Social Development in Children with Foetal Alcohol Spectrum Disorders

Children Australia ◽

10.1017/cha.2013.16 ◽

2013 ◽

Vol 38 (3) ◽

pp. 124-128

Author(s):

Samantha Parkinson ◽

Sara McLean

Keyword(s):

Social Development ◽

Social Information Processing ◽

Prenatal Alcohol Exposure ◽

Peer Pressure ◽

Alcohol Exposure ◽

Social Problem Solving ◽

Out Of Home Care ◽

Spectrum Disorders ◽

Social Skills Deficits ◽

Foetal Alcohol Spectrum Disorders

Foetal Alcohol Spectrum Disorders (FASD) develop when unborn children are exposed to alcohol prenatally. As a result of this exposure, children with FASD exhibit a range of social, behavioural, cognitive and even physical deficits that can impede their life-long development. These deficits can be influenced by maltreatment and the instability resulting from being placed into out-of-home care, and/or multiple foster-care placement breakdowns. The aim of this article is to increase awareness amongst child welfare professionals of how prenatal alcohol exposure impacts on children's social development. Social deficits include problems with social cognition and social information processing, which result in issues in social problem solving, processing social cues, social judgement, and developing and maintaining relationships. These deficits leave children with a FASD vulnerable to victimisation, exploitation, peer pressure and, as a result, interaction with the criminal justice system. Deficits are life-long and become more pronounced with age, although early detection and intervention appears to improve social skills deficits. Such interventions need to be explored further as they could potentially mitigate some of these deficits by capitalising on the neuroplasticity of a child's developing brain and pave a more positive trajectory for these children's future.

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