Fetal Alcohol Syndrome Disorder: How Maternal Alcohol Consumption Affects Neurobehavior, Neurodevelopment, and Alters Gene Methylation

Introduction

Fetal Alcohol Syndrome Disorder (FASD) is characterized by a set of behaviors that are brought on by fetal alcohol exposure during utero, causing an abnormal neurodevelopmental process [3]. Despite it being preventable, approximately 2% to 5% of United States schoolchildren are impacted by prenatal alcohol exposure (PAE), with 6-9 out of 1,000 actually being diagnosed with this disorder [1,2,3]. Severe consequences of fetal ethanol exposure consist of miscarriages, stillbirths, and premature delivery [2]. Viable repercussions are subject to intellectual and behavioral problems that onset during childhood, with neurodevelopmental deficits being the underlying cause [2,3]. The developing central nervous system (CNS) is significantly impacted by the presence of ethanol [4]. The hindrance is caused by ethanol crossing the placenta and later being swallowed by the fetus as it accumulates in the amniotic fluid and is infused with the xenobiotics excreted by the fetus's kidneys [4]. It is ethanol’s crossing over that underlies the mechanistic alterations in FASD and PAE, like the hypomethylation of genes responsible for behavior and neurodevelopmental delays, along with changes in brain volume, cerebral cortex, and other structures that will be later addressed [4,5,6].

This review is not only written for those interested in how ethanol plays a mechanistic role in the development of a fetus and later life, but also to acknowledge that only a few modifications can be touched on because of a lack of research in this field; hence, much remains unknown. The scarcity of information on how maternal alcohol consumption alters fetal development serves to highlight that more efforts in research and expanding knowledge on how alcohol mechanistically affects the proper development of the brain are vital. The understanding of these modifications will further help us understand how genetic and developmental alterations lead to the traits associated with FASD. In this literature review, I will talk about how the consumption of alcohol during pregnancy impacts the developing fetus via neurodevelopment and behavioral alterations through adolescence, and DNA methylation modifications that alter gene expression. 

The Role of Epigenetics In Alcohol’s Effect on Neurodevelopment

Ethanol plays a vast role in influencing the methylation of the brain, leading to structural changes and dysregulations. C57BL/6J mice models were used in a research experiment to understand the effects alcohol exposure has on fetuses, in terms of gene regulation [6]. This mouse species is commonly used for biomedical research and intakes alcohol on a voluntary basis, exhibiting a high preference for ethanol, compared to other inbred strains [13]. Based on these models, it was discovered that ethanol accumulation in utero leads to the hypomethylation of genes associated with histone methylation [6]. Since hypomethylation relieves the tight coil in which DNA is wound up, it confers accessibility for a protein to bind to the promoter region and kickstart the increased expression of particular genes. Alcohol's hypomethylating characteristic primarily targets those genes of importance for brain function and formation [6] which corresponds with the increase in cerebral and regional volume, alongside amplified regional surface area, which is displayed in those with prenatal alcohol exposure [5,6].

Hypermethylation of genes responsible for neuroactive ligand-receptor interactions and chemokine signaling was also discovered [6]. Hypermethylation makes DNA coils even tighter, prohibiting genes from being expressed. Decreased expression of genes associated with neuroactive ligand-receptors helps understand that people with FASD and PAE display deficits in brain and behavioral processing, because ethanol prohibits neurotransmitter receptors from being produced in an adequate amount for normal brain functioning. Neurotransmitter receptors will become desensitized to their ligand as there continues to be a lack of their expression. Receptor desensitization will then drive delayed cellular responses and, consequently, delayed behavioral responses, as the receptors will not easily sense the neurotransmitters, despite their presence. An increase in promoter methylation is distinctively detected in the hippocampus [6]. In particular, mouse model studies exhibited hypermethylation in the hippocampus specifically, which can be by virtue of an alcohol-induced reactive oxygen species (ROS)-dependent mechanism [7]. ROS mechanisms influence the activity of the enzyme DNA methyltransferases, with a possibility of increasing enzymatic activity, giving rise to the hypermethylation of genes [7]. The stated outcome is largely observed in genes associated with neurodegeneration, axon guidance, and neuron excitability [14]. This leads to a reduction in gray matter, which will be the cause for future neurobehavioral issues that will be assessed later in the review [4]. 

Furthermore, alcohol not only has adverse effects on gene expression, but also on the creation of new cells within the nervous system and how they operate. In response to the presence of teratogenic alcohol, the Central Nervous System (CNS) will be faced with a surge of oxidative stress [4]. The increase in reactive oxygen species will further result in impaired neurogenesis and negative alterations to functional connectivity and executive control networks of the brain [4,5]. Neurons are a crucial component of the nervous system, for they are where information and memories are electrically and chemically transmitted. The foundation of electrical and chemical transmission, rooted in neurons, makes proper connections between them and the constant formation of new ones substantially necessary for one to be able to fully understand and interact with new information. The deficiency in neuronal connectivity that is caused by alcohol exposure in utero aids in understanding why people with FASD and PAE have trouble processing new information and how to best control their behavior. With that said, the connection disruption neurons face between one another in the presence of alcohol will only bring an array of neurodevelopmental issues. The rise of neurodevelopmental disorders is rooted in the elimination of brain plasticity as a result of disrupted neuron connections, hindering the learning process and the travel distance of action potentials. The stated fetal development modifications will also pose developmental neurobehavior and emotion barriers, like deficits and impulsiveness [6], that will later be discussed in this review.

Modified Hippocampal Neurological Formation Caused Via Hypermethylation 

As previously discussed, fetal alcohol exposure influences the development of the hippocampus by hypermethylating various promoters, tightening the chromatin coils and inhibiting gene expression. In the research experiment where C57BL/6J mice models were used, a surge of promoter methylation was particularly observed in the cytosines of the Peroxisome Proliferator-Activated Receptor alpha (PPAR-α) gene, Eif4g1, and Myo6 [6,9]. C57BL/6J mice were bred and housed with access to unlimited food and water, with experimental female mice groups having free access to ethanol-infused water [6]. For female mice, the concentration of ethanol in their water was gradually increased prenatally and after mating, with 10% ethanol being the maximum concentration [6]. After giving birth, males were immolated via carbon dioxide asphyxiation to dissect their hippocampus and analyze the DNA promoter regions in their hippocampus [6].

Eif4g1 is an initiation factor for eukaryotic translation, Myo6 is an actin filament motor protein that transports intracellular cargo, and PPAR-α transcribes a factor necessary for lipid metabolism [6,9]. Myo6 and PPAR-α are both essential for appropriate behavior maturation [6,9]. These genes are vital for proper neurobehavior development and are found within the hippocampus. Behavior maturation refers to the process of proper brain development and structural formation of regions that are responsible for critically executing actions contextually, socially, or physiologically, in response to a stimulus. The prohibition of these genes from being adequately expressed highlights that one modification leads to a cascade of issues because without the expression of Eif4g1, proteins cannot be produced, and without Myo6, cellular components in vesicles can not be moved around. Impurities in PPAR-α protein factors specifically drive the onset of impaired behaviors like impulsivity, aggression, attention deficits, and overall greater psychopathology [5,9]. The issues that are brought on by the hypermethylation of promoters, like abnormal behaviors, protein production inhibition, and vesicle immobility, highlight how mechanistic alterations due to the presence of alcohol also influence the behaviors displayed by people with FASD and PAE. A fetus's interaction with ethanol not only results in the hypermethylation of various hippocampal promoters but also prevents PPAR-α, Eif4g1, and Myo6 from being expressed later, which underlie the abnormal behaviors associated with Fetal Alcohol Syndrome Disorder. Hence, the stated modifications highlight the extent to which ethanol exposure will continue to play a role in the lives of those who faced this teratogen in utero.

Neurobehavioral Response to Hippocampal Malformation 

The mechanistic hippocampal alterations associated with PAE and FASD that were previously touched upon lead to a plethora of neurobehaviors that are typically associated with this disorder. PPAR-α deficiency causes increased oxidative stress, neurodegenerative diseases via defective angiogenesis and neurogenesis, and neuroinflammation [4,9]. The vast impact PPAR-α has on multiple processes demonstrates the degree to which prenatal alcohol exposure not only affects the genetic aspect of neurodevelopment but also influences the modifications of other factors, like neuron and blood vessel death. Ethanol’s ability to disrupt the expression of behavioral gene regulators like PPAR-α foreshadows attitudes associated with anxiety, stress-related disorders, and PTSD [8,9]. Anxiety is the most heightened disorder and poses daily barriers amongst people with FASD and PAE [8]. With that said, the behaviors that characterize Fetal Alcohol Syndrome Disorder are rooted in the early death of neurons and blood vessels that occur in the presence of alcohol as a result of PPAR-α being inhibited to some degree in utero. The abnormal deficiency of gene regulators further prevents the proper regulation of factors that are likely responsible for the psychopathological issues that occur in FAS. This demonstrates how early exposure to alcohol in a fetus produces a cascade of neuropsychiatric disorders, brought by a lack of hippocampal PPAR-α expression via a hypermethylation mechanism. 

Similarly, adolescents who experienced maternal alcohol consumption in utero experience intensified levels of anxiety, which contributes to their refusal to socialize and engage in community activities [8]. Their decision to refrain from interacting with others is one of the many atypical neurobehaviors that people with Prenatal Alcohol Exposure and FASD face, which is associated with the lack of gene-regulating factors like PPAR-α. Brought by ethanol-induced gene hypermethylation. Alcohol-modified PPAR-α in the hippocampus also causes individuals to have trouble in fully controlling their emotions, aiding in understanding why it may be difficult to lower heightened anxiety levels. In addition, the way anxiety greatly influences the life choices of these individuals provides insight into how minor hippocampal malformations caused by alcohol lead to heightened atypical neurobehaviors.

Alcohol’s Impact on Cerebral Cortex Establishment

The cerebral cortex is among the structures where the effects of alcohol on fetal development can be visually distinguishable, due to its influence on the formation of anatomical structures. Decreased surface area and brain volume in the frontal domain of the brain, alongside increased intracranial volume in the brainstem and bilateral cortex, leading to the rise of impaired cerebellar cortex activity, as observed in those with PAE and FASD [10,11,12]. Decreased brain volume, but increased intracranial volume, implies that teratogenic alcohol affects various regions of the cerebrum simultaneously. As one area is increasing in volume, the other is decreasing, highlighting the neuroimbalances brought on by ethanol exposure in utero. The inverse growth demonstrates how alcohol-induced pathophysiology continues to arise as a result of multiple region-specific modifications that accumulate over time. Gene expression prohibition via hypermethylation influences decreased brain volume since fewer biological products will be produced. Further atypical development can be observed in the form of neurobehaviors. This altered behavior is also connected to the increased gray matter in the parietal and temporal lobes and increased surface area, which is observed amongst those with Prenatal Alcohol Exposure [5,11]. Alcohol-induced neurodevelopment reconstruction yields cortex and interneuron dysfunctions attributable to the brain's plasticity in pathology [7,10]. As the brain continues to develop in people with PAE and FASD, plasticity pathology, the ability for the brain to be modified in a manner that will give rise to dysfunctional cortical regions, will also increase. Learning and acquiring new information surrounding this is also impeded by abnormal changes in cerebral volume and surface area.

Conclusion

Fetal Alcohol Syndrome disorder continues to remain prevalent because ethanol's toll on proper fetal neuro-behavior and development is not widely spread enough due to a lack of pertinent research in this field. Alcohol's impairment of formal methylation, yielding the prohibition of genes like PPAR-α from being expressed, along with those that are vital for the proper development of neurobehaviors, characterizes the rise of psychopathological disorders. Not only are genes unable to be expressed due to hypermethylation, but this barrier also prevents the proper evolution of fetal brain volume and surface area associated with the cerebral cortex, temporal, and parietal lobes. The way in which the brain is mechanistically impacted by ethanol and the consequences it brings remains greatly ambiguous because of a lack of effort to continue discovering alcohol's role within structural and proper neurodevelopment and neurobehaviours expressed. In return, only a sliver of alcohol induced abnormalities were touched on because much remains unknown. Thus, efforts to better understand how ethanol mechanistically alters neurodevelopment and its role in foreshadowing psychopathological neurobehaviors must be immensely increased to reiterate the extent to which this alcohol poses harm to a fetus in utero and spread awareness of this recurring issue.

Author’s Note

I wrote this piece because, as someone who aspires to join the medical field, I believe it is vital for physicians to explain to their patients why they should follow their recommendations by describing what is occurring within their bodies. Specifically, medical providers always reiterate the idea to avoid alcohol consumption during pregnancy, but rarely explain why it should be avoided. Let alone its biological mechanistic impact on the fetus. As my passion for neuroscience and chemistry continuously grows, so does my curiosity for how ethanol specifically impacts proper fetal development at a mechanistic level and how these issues foreshadow future complications. I also realized that there must be others like me who are interested in this scarce information, but are troubled with finding outdated sources. This issue also led me to choose this topic because it allows me to gather as much recent information as possible to not only educate myself, but also those who are interested in how alcohol alters fetal development in multiple aspects. As my readers approach the end of my literature review, I hope they walk away with a better understanding of how ethanol biochemically alters fetal neurodevelopment and gene methylation. Leaving them inspired and with the efforts necessary to continue researching how alcohol plays a systemically teratogenic role in utero. 

References

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