Epigenetics and Prenatal care: A Study on The Contributors of Neurodevelopmental Disorders

Overview

This review provides insights into the prenatal origins of neurological disorders particularly attention-deficit/hyperactivity disorder (ADHD), cerebral palsy, autism spectrum disorder (ASD), and fetal alcohol syndrome (FAS) which may pave the way for personalized interventions that promote optimal fetal neurodevelopment and further elucidate how current treatments can further advance to target these diseases.

Epigenetics

Epigenetics is the study of reversible changes in gene expression or phenotype that are not caused by alterations in the DNA sequence itself. These changes are heavily influenced by environmental factors and play a critical role in regulating gene activity during development and in response to environmental cues. These include diet, stress, drugs most commonly alcohol and nicotine, hormone exposure, or chemicals in the environment that an individual is in.

DNA methylation is an epigenetic alteration in which a methyl group is added to the cytosine base of DNA molecules. This covalent modification is typically associated with gene silencing, as it can alter chromatin structure and reduce the accessibility of certain gene regions to transcriptional machinery, thus regulating gene expression without altering the underlying DNA sequence.

Histone modifications are reversible chemical changes done to histone proteins, which are essential components of chromatin, the DNA and protein complex that makes up chromosomes. Acetylation, methylation, and phosphorylation are examples of these alterations, and they can change the shape of chromatin, altering how genes are expressed. Depending on the precise alteration or location, histone modifications may either promote or hinder gene transcription.

Placental Health

The placenta, often known as the afterbirth, is a tissue disc that links a mother's uterus to the umbilical cord, playing a vital role in providing nutrients and oxygen to the developing fetus. Several factors play a role in marking a placenta as "healthy."

A healthy placenta is free from signs of infection or inflammation, as these can adversely affect fetal development and overall pregnancy health. Fetal oxygen deficiency occurs when a newborn is deprived of oxygen before birth, and might experience difficulty breathing after delivery, has excessive acid in body fluids, has brain damage, or damaged organs.

From a biological perspective, if diet is not under proper care a critical nutrient that a mother can lack that contributes to the stunted growth of the brain and spinal cord of the fetus is choline. Choline is a methyl donor in various biochemical reactions, including the methylation of DNA and histones. It is important to note amniotic fluid volume. This fluid pushes the air sacs in the lungs open and helps them grow. The fetus' lungs grow the most in the middle of the second trimester (16 to 24 weeks). In oligohydramnios, the amniotic fluid is too low during this time, lung tissue may not develop properly which affects proper oxygen exchange which is crucial for neurodevelopment. 

Synaptogenesis, connections between neurons, occurs during pregnancy and continues until early life. The formation of synapses allows communication between neurons and is essential for learning and memory. Toxins in the circulatory system of the mother can interfere with the development of synaptogenesis, reducing the total oxygenation given to the fetus.

The intrauterine environment, including substance exposure such as illicit drugs, alcohol, or certain prescriptions, might influence brain development and possibly lead to neurodevelopmental problems.

Attention-deficit/hyperactivity disorder (ADHD) 

ADHD is a neurodevelopmental condition characterized by persistent patterns of inattention, impulsivity, and hyperactivity that severely impede daily functioning and developmentally unusual behavior. It usually appears in infancy and might last throughout adolescence and maturity. ADHD is caused by a complex and multifaceted combination of genetic, environmental, and neurological factors.

A study conducted by Plomin et al. (2013) examined specific cognitive abilities and other aspects of psychopathology, such as autism and hyperactivity. The dopamine transport gene (DAT1) and dopamine receptor gene (DRD4), which codes for a dopamine receptor involved in attention and reward processes, were involved in the risk for ADHD which codes for a dopamine receptor involved in attention and reward processes. DNA methylation patterns in individuals with ADHD and discovered differential methylation at several genomic loci associated with neural development and brain function. 

 A study on mice was conducted to investigate alterations of histone modifications in the hippocampus of rats exposed to various doses of lead, along with concomitant behavioral deficits (Lou et al., 2014). Western blotting assays revealed that chronic lead exposure significantly increased the levels of histone acetylation in the hippocampal tissues. Additionally, while the transcriptional level of p300 was dramatically enhanced with higher-dose Pb exposure, the increased level of histone acetylation may have been caused by the enzymatic activity of p300, a typical histone acetyltransferase. Thus, this potentially identifies the epigenetic process at the histone modification level that connects the environmental effect (Pb) and the disease itself (ADHD), opening possibilities of thorough knowledge of ADHD etiology.

Cerebral Palsy

Cerebral palsy (CP) is a group of permanent movement and posture disorders that are caused by non-progressive disturbances in the developing fetal or infant brain. It affects muscle coordination and body movement, often leading to difficulties with motor skills, muscle tone, and posture. CP can vary widely in its severity and the specific impairments it causes, as well as the underlying brain areas affected.

One study analyzed the epigenetic changes in monozygotic twins discordant for CP (Lussier et al., 2018). They performed a genome-wide DNA methylation analysis on 15 sets of twins who later developed CP. This analysis identified 33 differentially methylated probes (DMPs) and two differentially methylated regions (DMRs) associated with CP. The DMPs were linked to genes involved in immune signaling pathways and genes previously associated with conditions like epileptic encephalopathy. Pathway analysis revealed an enrichment of inflammatory signaling pathways and immune-related processes. Two DMRs were identified, one related to tumor necrosis factor-beta (TNF-β) associated with inflammation and brain development, and another linked to an inflammatory pathway. Overall, this study suggests a potential role of immune dysfunction in the development of CP caused by alteration in DNA methylation, implicated in processes related to brain development and plasticity. 

Autism spectrum disorder (ASD)

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by a range of challenges in social communication, repetitive behaviors, and restricted interests. It is considered a spectrum disorder because it manifests differently in individuals, ranging from mild to severe. Genome-wide DNA methylation analysis in multiple brain regions of individuals with ASD and neurotypical controls.

Researchers conducted a study "Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants,” 200 ASD-risk genes have been identified, no single gene variant explains more than 1% of ASD cases. This study explored the role of epigenetic mechanisms in ASD by investigating genome-wide DNA methylation (DNAm) patterns in blood samples from individuals with ASD, those with 16p11.2 deletions, and individuals with pathogenic variants in the CHD8 gene. The study found that DNA patterns did not clearly distinguish ASD cases of heterogeneous, undefined etiology from controls. These signatures also effectively classified other 16p11.2del and CHD8 variants as pathogenic or benign. Importantly, the genes targeted by these DNAm signatures are related to critical biological pathways, such as neural development, underscoring their functional relevance. This research highlights the potential significance of epigenetic mechanisms in understanding and classifying genetic variants associated with ASD. These differences were observed in genes related to neurodevelopmental processes, synaptic function, and neuronal communication.

Fetal Alcohol Syndrome (FAS)

Fetal Alcohol Syndrome (FAS) is a medical condition that arises from prenatal exposure to alcohol. It is a constellation of physical, behavioral, and cognitive abnormalities that can occur in offspring when a pregnant individual consumes alcohol during pregnancy.

"DNA Methylation Program in Developing Hippocampus and Its Alteration by Alcohol” (Khalife et al., 2012) investigated the epigenetic effects of prenatal alcohol exposure. In this study, researchers examined DNA methylation patterns in infants born to mothers who had consumed varying levels of alcohol during pregnancy. According to the findings, drinking alcohol caused the hippocampal development to be delayed by around one day, which resulted in significantly smaller hippocampi than in the control groups. The group that was exposed to alcohol had an enlarged lateral ventricle, with levels of particular DNA methylation markers (5mC and 5hmC) decreased and the thickness of undifferentiated neural epithelial layers increased. Along with changes in DNA methylation intensity, alcohol exposure also caused slight reductions in cell migration in certain zones. In contrast to the usual decline seen during neuronal development, the generated stratum pyramidale was thinner in the alcohol-exposed group, and greater levels of certain DNA methylation marks were identified in the CA1 area.

Prior research has shown that inhibiting DNA methylation with 5-azacytidine or having a choline deficiency can hinder embryonic growth and memory function, but choline supplementation can alleviate developmental deficits in the hippocampus. 

Reversing effects

Demethylating agents are chemicals that may remove or decrease the insertion of methyl groups (CH3) into DNA molecules. These agents can restore normal gene expression patterns by demethylating particular sections of DNA, possibly restoring aberrant DNA methylation linked with a variety of illnesses, including cancer and some neurodevelopmental disorders.

5-Azacytidine is one of the first demethylating agents developed and is approved for the treatment of myelodysplastic syndromes (MDS), a group of bone marrow disorders. It functions by incorporating itself into DNA during replication, leading to the inhibition of DNA methyltransferases, enzymes that serve the role of adding methyl groups to DNA. By inhibiting DNA methylation, 5-azacytidine can reactivate silenced genes.

Epigallocatechin-3-gallate (EGCG) is a natural compound found in green tea that has demethylating properties. It can prevent DNA methyltransferases, hence changing DNA methylation patterns and possibly gene expression. This can have an impact on fetal health due to maternal activity. Prenatal alcohol exposure (PAE) in mice has been demonstrated to have a detrimental effect on fetal growth, placental development, and neurodevelopment, according to research (Almeida-Toledano et al., 2021). The antioxidant EGCG has shown success in lowering alcohol-induced oxidative stress, which may help to alleviate the symptoms of FASD. 

Some drugs that influence histone acetylation are Histone Deacetylase Inhibitors (HDAC Inhibitors). These are drugs designed to inhibit histone deacetylases- enzymes responsible for the removal of acetyl groups from histone proteins. By inhibiting HDACs, these drugs increase histone acetylation, resulting in a more open chromatin structure and enhanced gene expression.

Conclusion and Future Implications

Levels of DNA methylation patterns and histone modifications can cause interference in embryonic development. This can include indirect influence when myelin sheaths are damaged and insufficient deliverance of cord blood or oxygen in an intrauterine environment due to environmental factors such as lead or alcohol that ultimately lead to neurodevelopmental disorders such as ADHD; proper development of brain regions that are responsible for memory that can develop neurodegenerative disorders.

The discovery of particular epigenetic markers in the placenta linked to neurodevelopmental diseases may lead to the development of early diagnostic tools. These tests may aid healthcare practitioners in identifying high-risk pregnancies and enabling early treatments to enhance embryonic neurodevelopment. 

The development of epigenetic-based therapeutics may become a reality. This includes reversing aberrant DNA Methylation. If DNA methylation patterns are found to be significantly altered in individuals with neurodevelopmental disorders, therapeutic agents could be developed to normalize these patterns. 

Long-term follow-up studies may be conducted to examine the outcomes of people whose placental epigenetic profiles were assessed during pregnancy. This can be useful in determining the predictive potential of epigenetic markers. Expectant mothers may receive guidance on maintaining a healthy lifestyle during pregnancy to support placental health and, in turn, fetal neurodevelopment. The study of epigenetic markers in the placenta and their relationship to neurodevelopmental diseases has the potential to improve prenatal care, early diagnosis, and individualized therapies.  

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Chameli Mallik is currently a high school senior from Florida. Her passion for medicine and biology all started after her autoimmune diagnosis. Her interest in the dynamics of biology and neuroscience expanded when she started interning and volunteering, handling patients diagnosed with cancer and neurological conditions. In her free time, she likes to draw hyperrealism, sing karaoke, and read her anatomy book that displays case studies of unusual pathologies. In the future, she hopes to conduct further research on those very diseases.

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