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Schematic representation of DNA methylation. The process starts with the covalent addition of a methyl group to form 5-methylcytosine (5-mC). This process is catalyzed by a family of DNA methyltransferases (DNMTs)—DNMT1, DNMT3A and DNMT3B. The majority of DNA methylation usually occurs at CpG sites and CpG islands nearby a gene to regulate related gene expression. DNA methylation is an epigenetic mechanism and required fine tuning for proper regulation.
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Ethanol is well known as a teratogenic factor that is capable of inducing a wide range of developmental abnormalities if the developing fetus is exposed to it. Duration and dose are the critical parameters of exposure that affect teratogenic variation to the developing fetus. It is suggested that ethanol interferes with epigenetic processes especia...
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Background: Risk of fetal alcohol spectrum disorder (FASD) is not based solely on the timing and level of prenatal alcohol exposure (PAE). The effects of teratogens can be modified by genetic differences in fetal susceptibility and resistance. This is best illustrated in twins.
Objective: To compare the prevalence and magnitude of pairwise discord...
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... EtOH causes several epigenetic modifications, which have been associated with its embryopathic mechanism [14][15][16]. The effect of EtOH on histone acetylation patterns depends on the EtOH treatment paradigm, timing of exposure and brain regions examined, with varying results even within a region [16,32,33]. ...
Oxoguanine glycosylase 1 (OGG1) is widely known to repair the reactive oxygen species (ROS)-initiated DNA lesion 8-oxoguanine (8-oxoG), and more recently was shown to act as an epigenetic modifier. We have previously shown that saline-exposed Ogg1 -/- knockout progeny exhibited learning and memory deficits, which were enhanced by in utero exposure to a single low dose of ethanol (EtOH) in both Ogg1 +/+ and -/- progeny, but more so in Ogg1 -/- progeny. Herein, OGG1-deficient progeny exposed in utero to a single low dose of EtOH or its saline vehicle exhibited OGG1- and/or EtOH-dependent alterations in global histone methylation and acetylation, DNA methylation and gene expression (Tet1 (Tet Methylcytosine Dioxygenase 1), Nlgn3 (Neuroligin 3), Hdac2 (Histone Deacetylase 2), Reln (Reelin) and Esr1 (Estrogen Receptor 1)) in fetal brains, and behavioural changes in open field activity, social interaction and ultrasonic vocalization, but not prepulse inhibition. OGG1- and EtOH-dependent changes in Esr1 and Esr2 mRNA and protein levels were sex-dependent, as was the association of Esr1 gene expression with gene activation mark histone H3 lysine 4 trimethylation (H3K4me3) and gene repression mark histone H3 lysine 27 trimethylation (H3K27me3) measured via ChIP-qPCR. The OGG1-dependent changes in global epigenetic marks and gene/protein expression in fetal brains, and postnatal behavioural changes, observed in both saline- and EtOH-exposed progeny, suggest the involvement of epigenetic mechanisms in developmental disorders mediated by 8-oxoG and/or OGG1. Epigenetic effects of OGG1 may be involved in ESR1-mediated gene regulation, which may be altered by physiological and EtOH-enhanced levels of ROS formation, possibly contributing to sex-dependent developmental disorders observed in Ogg1 knockout mice. The OGG1- and EtOH-dependent associations provide a basis for more comprehensive mechanistic studies to determine the causal involvement of oxidative DNA damage and epigenetic changes in ROS-mediated neurodevelopmental disorders.
... Prenatal alcohol exposure can often lead to fetal alcohol spectrum disorders (FASD) that include fetal alcohol syndrome (FAS) [69,70]. Epigenetic dysregulation of DNA methylation, histone modifications, and miR-NAs may cause fetal abnormalities such as defects in cell cycle gene expression neurodevelopment, neuronal connectivity, and cortical deficits, as well as deficits in learning, memory, social interaction, and motivation behavior [71][72][73]. Changes in histone methylation contribute to the silencing of genes related to developmental processes during gestation. This has been shown in multiple rodent models of FASD [50]. ...
Currently, and globally, we are facing the worst epidemic of psychoactive drug abuse resulting in hundreds of thousands of lives annually. Besides alcohol and opioid use and misuse, there has been an increase in illicit abuse of psychostimulants. Epigenetics is a relatively novel area of research that studies heritable alterations in gene expression. Long-term administration of psychoactive drugs may lead to transcriptional changes in brain regions related to drug-seeking behaviors and rewards that can be passed down transgenerationally. Epigenetic biomarkers such as DNA methylation and histone modifications contribute to disease diagnoses. This review aims to look at the epigenetic modifications brought forth by psychoactive drug abuse.
... Early life exposure to unhealthy environmental factors and maternal risk factors [49][50][51][52][53] are linked to an increased risk for elevated BP in children in various African settings. These factors, discussed in the next few paragraphs include among others, hypertension, hypertensive disorders of pregnancy, hyperglycaemia, smoking, alcohol use, overweight/obesity, physical inactivity, and low socioeconomic status [49][50][51][52][53]. Exposure to adverse maternal factors such as smoking, alcohol consumption, and micronutrient deficiency may have a detrimental effect on cardiovascular system development through DNA methylation [54][55][56]. ...
Purpose of Review: To review recent evidence on childhood hypertension across Africa, identifying knowledge gaps, challenges and priorities, and highlight clinical perspectives in managing primary hypertension.
Recent Findings: Only 15 of the 54 African countries reported on absolute blood pressure (BP) measures, elevated BP, pre and/or hypertension. The reported hypertension prevalence ranged between 0.0 and 38.9%, while elevated BP and/or prehypertension ranged from 2.7 to 50.5%. Childhood BP nomograms are lacking across Africa and the rates of hypertension were based on guidelines developed in countries with the lowest to no number of children from African ancestry. The recent studies across Africa also showed little to no detail when reporting BP specific methodology. No recent data informing the use or effectiveness of antihypertensive agents in children and adolescents are available.
Summary: Childhood hypertension is on the rise, while data from Africa remains vastly under-represented. Collaborative research, resources, and policies need to be strengthened in addressing the growing public health concern of childhood onset hypertension on this continent.
... Alcohol use can reduce bioavailability of many nutrients including folate and vitamin B12 [42][43][44][45][46] as well as dysregulate one-carbon metabolism pathways [47][48][49][50] and DNA methylation mechanisms. [51][52][53][54] During pregnancy, women are vulnerable to deficiencies in methyl donor nutrients as maternal metabolic demand for these nutrients increases to support fetal and placental development. [55][56][57] Consequently, many women do not consume the recommended dietary intake for several of these methyl donor nutrients during pregnancy. ...
Fetal alcohol exposure at any stage of pregnancy can lead to fetal alcohol spectrum disorder (FASD), a group of life‐long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8‐cell stage) fetal alcohol exposure (2 × 2.5 g/kg ethanol with a 2h interval) in mice leads to long‐term FASD‐like morphological phenotypes (e.g. growth restriction, brain malformations, skeletal delays) in late‐gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol‐induced morphological defects without altering DNA methylation status of imprinting control regions and regulation of associated imprinted genes. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizes the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.
... Последнее время проводится активное изучение влияния различных экзогенных факторов окружающей среды на изменение экспрессии генов, активно транскрибирующихся в развивающемся и взрослом мозге и играющих ключевую роль в поддержании гомеостатического состояния организма [12,24,37]. Ранее было показано влияние пренатальной алкоголизации на процесс метилирования генов в мозге [18,20,22], что может быть косвенным подтверждением стойких долговременных эффектов пренатальной алкоголизации на уровень транскрипционной активности генов в мозге. ...
Disruption of normal epigenetic reprogramming during the prenatal period under the influence of exogenous factors affects fetus development and adult phenotype formation. The mechanisms through which determinants, such as maternal alcohol intake, contribute to the formation of an alcohol-vulnerable phenotype later in life still remain unclear. In this paper, we suggest that alteration in the reinforcing properties of ethanol in prenatally alcohol-exposed subjects may be associated with transcriptional dysregulation of the brain opioid receptor genes. We compared voluntary alcohol intake and levels of mRNA coding for μ- (MOP) and κ-opioid (KOP) receptors in the mesolimbic areas of adult male offspring of the female Wistar rats having received 10% ethanol as the only source of liquid throughout pregnancy or water (control). We found that prenatally alcohol exposed rats had higher alcohol preference on PND60 (free-choice paradigm) and lower mRNA expression for both MOP and KOP in the midbrain compared to the control. This suggests a potential link between prenatal alcohol, dysfunction of the brain opiate system and adult vulnerability for alcohol use disorder.
... cytochrome CYP26 inhibition with consequent retinoic acid increase for azoles and with minor affinity for VPA; 2. histone deacetylase HDAC inhibition with consequent chromatin decondensation for VPA) and a number of KEs (Fig. 5). Literature on Eth-related pathogenic pathway leading to craniofacial defects describes some events already mentioned in our azole/VPA AOP (Fig. 5): (i) chromatin remodeling leading to altered epigenetic regulation (Liu et al. 2009;Mandal et al. 2017;Wallén et al. 2021), (ii) increased retinoic acid (Kane et al. 2010), (iii) neural crest cell specification-migration-differentiation disrupted (for a review see Smith et al. 2014), (iv) branchial arch dysmorphology (Giavini et al. 1992;van Maele-Fabry et al. 1995). We propose the involvement of Eth in enhancing one or more steps of the previously proposed AOP. ...
The prenatal exposure to ethanol (Eth), fluconazole (FLUCO) and sodium valproate (VPA) is related to effects on development, producing characteristic syndromic pictures. Among embryotoxic effects described for the three molecules, the alteration on craniofacial morphogenesis is a common feature in humans and animal models, including rodent embryos developed in vitro. The aim of the present work is to evaluate the developmental effects of low Eth serum concentration (17 mM, corresponding to the legal limit to drive in UK, USA, Canada, and many other countries) in mixture with increasing realistic concentrations of the antifungal drug FLUCO (62.5–500 µM) or with increasing realistic concentrations of the antiepileptic drug VPA (31.25–250 µM). Groups exposed to Eth alone (17–127.5 mM), FLUCO alone (62.5–500 µM) or VPA alone (31.25–750 µM) were also included. The chosen alternative animal model was the post-implantation rat whole embryo culture (WEC). E9.5 embryos were exposed in vitro to the test molecules during the whole test period (48 h, corresponding to the developmental stages characteristics of any vertebrate, for human embryos post-fertilization days 23–31). Data were statistically analyzed and processed for modelling applying the benchmark dose (BMD) and relative potency factor (RPF) approaches. Concentration-related effects on facial outcomes were observed in all experimental groups, with a significant enhancement in the groups co-exposed with Eth in comparison to the single exposures. Data obtained by the present work suggest an additional alert for the assumption of even low levels of alcohol in pregnant women during FLUCO or VPA therapy.
... Choline is involved in many cellular processes [14]; one potential area of interest is methylation changes in the epigenetic signature [64]. Indeed, studies in both individuals with FASD and animal models have demonstrated disruptions in the epigenetic signature with PNEE [65][66][67][68][69]. As choline is a methyl donor within the one-carbon metabolism cycle, it is perhaps unsurprising that postnatal choline supplementation has influenced methylation indices [31,70,71]. ...
Prenatal ethanol exposure (PNEE) is a leading cause of neurodevelopmental impairments, yet treatments for individuals with PNEE are limited. Importantly, postnatal supplementation with the essential nutrient choline can attenuate some adverse effects of PNEE on cognitive development; however, the mechanisms of action for choline supplementation remain unclear. This study used an animal model to determine if choline supplementation could restore hippocampal synaptic plasticity that is normally impaired by prenatal alcohol. Throughout gestation, pregnant Sprague Dawley rats were fed an ethanol liquid diet (35.5% ethanol-derived calories). Offspring were injected with choline chloride (100 mg/kg/day) from postnatal days (PD) 10–30, and then used for in vitro electrophysiology experiments as juveniles (PD 31–35). High-frequency conditioning stimuli were used to induce long-term potentiation (LTP) in the medial perforant path input to the dentate gyrus of the hippocampus. PNEE altered synaptic transmission in female offspring by increasing excitability, an effect that was mitigated with choline supplementation. In contrast, PNEE juvenile males had decreased LTP compared to controls, and this was rescued by choline supplementation. These data demonstrate sex-specific changes in plasticity following PNEE, and provide evidence that choline-related improvements in cognitive functioning may be due to its positive impact on hippocampal synaptic physiology.
... Further studies are definitely needed to understand the correlation in detail between fetal alcohol spectrum disorder and epigenetic changes [165]. ...
Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. Epigenetic mechanisms in pregnancy are a dynamic phenomenon that responds both to maternal–fetal and environmental factors, which can influence and modify the embryo-fetal development during the various gestational phases. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders.
... One possibility is the action of ethanol on the epigenetic enzymatic machinery, which could trigger global changes in gene expression. Epigenetic modifications, which can occur through DNA methylation, histone modifications, microRNAS, and other mechanisms, have been proposed as triggering mechanisms for ethanol-induced cellular and molecular dysregulation (Basavarajappa and Subbanna, 2016;Chastain et al., 2019;Mandal et al., 2017;Ungerer et al., 2013). The effect of ethanol in modulating the epigenetic enzymatic machinery, specifically in brain ECs, is an interesting target for investigation. ...
Ethanol consumption during pregnancy or lactation permanently impairs the development of the central nervous system (CNS), resulting in the spectrum of fetal alcohol disorders (FASD). FASD is a general term that covers a set of deficits in the embryo caused by gestational alcohol exposure, with fetal alcohol syndrome (FAS) considered the most serious. The clinical features of FAS include facial abnormalities, short stature, low body weight, and evidence of structural and/or functional damage to the central nervous system (CNS). The prevalence of FAS carriers worldwide is about 15 for every 10,000 live births (about 119,000 children with APS born per year). Epidemiological data in the US show that the incidence of FAS exceeds other congenital syndromes such as Down syndrome and spina bifida. The deleterious effects of ethanol appear in different brain regions, varying according to the dose and period of neural development when the embryo was exposed, and include: 1) microcephaly; 2) abnormalities in cortical development, with a significant decrease in gyrification; 3) agenesis or hypoplasia of the corpus callosum; and 4) cognitive and behavioral deficits (such as impaired memory and learning, speech difficulties, and hyperactivity). Current evidence indicates that CNS blood vessels are particularly affected by teratogenic ethanol. The CNS vasculature is composed of specialized endothelial cells that establish intimate interactions with astrocytes, pericytes, and microglia, constituting the neurovascular unit of the blood-brain barrier (BBB). Together with the fact that BBB exert protective function, it can prevent the passage of substances and drugs to treat diseases that affect the CNS. Pathological changes in the BBB, such as drug abuse during pregnancy, congenital infections, or ageing processes can drastically alter the molecular structure and vascular stability, disrupting the BBB and aggravating certain neurodegenerative and neurological diseases. In this review, we address the effects of alcohol exposure on the formation of the BBB, specifically describing the cellular and molecular events induced by ethanol in the physiology of endothelial cells and glial cells, as well as their interaction during CNS development.
... Moreover, Liu et al. [67] found that alcohol gestational exposure in mice caused neural tube defects through the alteration of DNA methylation (both hypomethylation and hypermethylation). Alcohol-mediated changes in DNA methylation, for-runner signs of DNA mutation were associated with impaired differentiation and subsequent cellular death, commonly found in neurodegenerative diseases [68]. These data help explain the increased incidence of neurodevelopmental disorders associated with fetal alcohol syndrome disorders. ...
The molecular and cellular mechanisms by which alcohol produces its deleterious effects on neuronal networks are only now beginning to be understood. This review focused on alcohol-induced neurobiological alterations on neuronal network components underlying information processing, for further understanding of intellectual disability related to FASD. Abnormal neurodevelopmental events related to alcohol-damaged fetal brain included neurogenesis inhibition, aberrant migration, impaired differentiation, exacerbated apoptosis, impaired axon outgrowth and branching altering synaptogenesis and synaptic plasticity, abnormal GABAergic interneurons triggering synaptic inhibitory/excitatory imbalance, reduced myelinogenesis causing injured white matter in prefrontal lobe and atrophied corpus callosum compromising interhemispheric information transfer, the whole compromising neuronal network scaffolding which may lead to biased information processing with deficits in executive function. Added to these abnormalities are smaller gray matter and reduced hippocampus resulting in cognition and memory failures. As a whole, these developmental disorders may underlie intellectual disability related to FASD. In rodents, these neuronal network components matured mainly during the second and third trimesters equivalents of human gestation. Transferability of results from animal to human was also discussed. It was hoped that understanding of alcohol-induced neuronal networks failure mechanisms during the developing brain may lay a foundation for prospective new treatments and interventions
