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REVIEW ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 1  |  Page : 41-49

Epigenetic Modifications Due to Childhood Trauma Causative of Potential Mental and Physical Disorders


Department of Genetic Engineering, Faculty of Engineering and Technology, SRM Institute of Science & Technology, SRM Nagar, Kattankulathur, 603203, Kanchipuram, Chennai, Tamilnadu, India

Date of Submission12-Jul-2020
Date of Decision23-Jul-2020
Date of Acceptance31-Jul-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
J. Megala
Department of Genetic Engineering, Faculty of Engineering and Technology, SRM Institute of Science & Technology, SRM Nagar, Kattankulathur, 603203, Kanchipuram, Chennai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_74_20

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   Abstract 


The early years of life are when brain and behavioral development are most impacted by the environment. Children need to be in a nurturing environment with responsive and sensitive caretakers to ensure normal development. Findings have shown that traumatic events that occur during these stages tend to have lasting effects that extend to adulthood. Epigenetic modifications of the genes and receptors involved in the hypothalamic-pituitary-adrenal (HPA) axis have been shown to be the link between early life adversities (ELAs) and the increased risk of disease in adulthood. In this review, we have discussed the effect of ELAs on child development and its associated disorders in later life. We have also highlighted certain prominent genes involved in the stress response that have been reported to be epigenetically regulated in response to ELAs. As the detrimental mental and physical health consequences of ELAs have been well documented, we have also included reports that validate the hypothesis that ELAs increase the risk of depression and cardiovascular diseases (CVDs) in adulthood. Learning how these epigenetic modifications could occur in early stages, can help us in discovering new therapeutic interventions to reverse these effects by expressing or inhibiting the genes. Also, studying the interrelation between biological and psychological systems will provide an opportunity to improve treatment outcomes.

Keywords: Child neglect, childhood trauma, early life adversity, epigenetic modifications, mental disorders


How to cite this article:
Megala J, Sivakumar D, Jha D, Kundu S, Arora K, Gayathri V. Epigenetic Modifications Due to Childhood Trauma Causative of Potential Mental and Physical Disorders. Int J Nutr Pharmacol Neurol Dis 2021;11:41-9

How to cite this URL:
Megala J, Sivakumar D, Jha D, Kundu S, Arora K, Gayathri V. Epigenetic Modifications Due to Childhood Trauma Causative of Potential Mental and Physical Disorders. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2021 Jul 28];11:41-9. Available from: https://www.ijnpnd.com/text.asp?2021/11/1/41/303907




   Introduction Top


It is well-known that stressful experiences in the early stages of life, when the brain is not fully developed would affect the biological functioning of the system and health outcomes in the later stages of life. Also, research on the developing brain suggests that development and maturation of the early postnatal brain are greatly influenced by genetic factors and environmental input. Children who have been exposed to adverse events such as neglect, poverty, physical, emotional or sexual abuse during this period have been shown to have an increased disease probability in the later stages of their life.

Early life adversities (ELAs) have been associated with many diseases such as cardiovascular diseases (CVDs), diabetes and obesity.[1],[2] D’Argenio et al.[3] reported that exposure to stress or trauma during the first 15 years of one’s life was significantly linked to the increased risk of adult obesity. Childhood maltreatment during the ages 3-11 has also been shown to been associated to the increased level of inflammatory markers even at age 32.[4] Another study reported that the likelihood of having ischemic heart disease is significantly increased with the exposure to adverse experiences such as childhood abuse and neglect during the first 18 years of life.[5] ELAs can also have long lasting detrimental effects on cognitive development and brain function which can lead to many psychiatric disorders such as anxiety, depression, and post-traumatic stress disorder (PTSD).[6],[7]

Studies have shown that the hypothalamic-pituitary-adrenal (HPA) axis, the major stress response pathway, has been the link between ELAs and the increased risk of diseases. Peng et al.[8] reported that the HPA axis functioning in depressed patients with childhood neglect was significantly higher than in depressed patients without childhood neglect. The increased levels of corticotropin-releasing hormone (CRH) resulting from the dysregulation of the HPA axis has also been associated with increased risk of Alzheimer’s.[9]

These findings have revealed that the development and function of the brain are not only determined by genes but is also influenced by the environment. Thus, these interactions result in epigenetic modifications such as DNA methylation and histone modifications and would affect the genomic structure as well as regulate the gene expression without changing the DNA sequence. Epigenetic regulation of the stress response genes would affect the stress response pathways and the downstream pathways that ultimately affect health.[10]


   HPA Axis Top


The HPA axis describes the relationship between the hypothalamus, pituitary gland, and adrenal glands. It is our central stress response system and is involved in the neuroendocrine element of the stress response. The glucocorticoid end product of the HPA axis in humans, which is cortisol, has widespread effects on systems that underlie developmental processes and mental and physical health.

The HPA axis activity is carefully regulated through negative feedback loops to ensure that hormone levels are maintained at a predetermined level. To achieve this, the secretion of CRH, arginine vasopressin (AVP), and adrenocorticotropic hormone (ACTH) are controlled by the negative feedback effects of the glucocorticoids [Figure 1]. Studies carried out in mice have established that there are two different negative feedback responses: fast nongenomic feedback and delayed genomic feedback. The nongenomic feedback involves the glucocorticoids mediated inhibition of CRH and ACTH release from the paraventricular nucleus (PVN) and pituitary gland respectively.[11],[12] The genomic feedback involves the inhibition of CRH expression in the PVN and the suppression of transcription of proopiomelanocortin (POMC) in the pituitary gland.[13]
Figure 1 The HPA axis.

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   Effects of Early Life Adversity Top


Recent advances in brain research have provided a great insight into the growth and development of the brain. Negative early experience can profoundly affect a child’s brain development. Childhood trauma affects children to various extents. Few individuals become more vulnerable, whereas, some are able to get over their trauma. Besides childhood trauma, several factors like environment, genetics and epigenetics will add to the outcome of ELAs. As per the neural diathesis stress model, environmental components and genetic proneness contributes collaboratively to induce mental diseases.[14] Also, it has been shown that adverse early life environment influences human development via disruptions in the stress response system. Experiments done in mice have shown that exposure to ELAs such as prolonged separation of a pup from its mother or exposure of pups to stressed mothers result in the dysregulation of HPA axis, i.e., when the older mice were exposed to stress, there was an immediate change in the stress response system but the effects were not long lasting. The findings showed that there was a particular period during early life where the mice are more sensitive to adverse environmental conditions and thus resulted in long term changes in the stress response system. In this review paper, we have focused on how neglect and socioeconomic status affect child development and the regulation of the HPA axis.


   Developmental Impact of Child Neglect During Early Childhood Top


Neglect is the most common form of maltreatment which has been shown to affect a child’s development. The various forms of child neglect have been shown in [Figure 2]. Early childhood is a critical period for child development and therefore neglect in early childhood is of particular concern. Neglect can have either short term effects such as language and behavioral deficits or long-term effects such as depression or PTSD.[15] Children who have experienced neglect have an increased risk for a number of health and development problems, both physically as well as mentally. They may also face learning problems and socio-emotional issues. Children who have been neglected have shown to have an increased risk for psychiatric disorders, substance use, and serious medical illnesses in adulthood.[16]
Figure 2 Various kinds of child neglect.

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The experimental models of humans and rats have been used to understand the mechanism of how neglect affects the development of the HPA axis. In rats, it has been shown that the amount of licking and grooming (LG) and arched-back nursing (ABN) by rat mothers can affect how the offspring react to stress in their adulthood. Adult offspring of low-LG-ABN mothers tend to be more fearful and exhibit more anxiety-like behavior compared to adult offspring of high-LG-ABN mothers. The offspring of low-LG-ABN mothers showed increased plasma ACTH and corticosterone levels in response to stress, whereas the offspring of high-LG-ABN mothers showed a more modest HPA response.[17]

Callaghan and Richardson[18] studied the effect of neglect by maternal separation experiment on rats where the pups were separated from the mother 3 hours daily from postnatal day (P) 2 through P14. On P17, the pups were trained to fear a conditioned stimulus paired with an aversive unconditioned stimulus. The fear association formed was then tested for the next 55 days. The pups that had undergone maternal separation retained the association for up to 30 days whereas the pups that were not separated typically forgot the associated within 10 days. This shows that maternal separation promotes the retention of fear memories formed in infancy.


   Developmental Impact of Socioeconomic Status During Early Childhood Top


Socioeconomic status (SES) is the social standing of an individual or a group. SES has been shown to be directly or indirectly related with health, both physical as well as mental, development and emotional outcomes in children. The effects of low SES on children was shown in [Figure 3]. Family income and parental education have been shown to be the major aspects of SES that was found to be associated with cognitive development and academic attainment, with education being the strongest association.[19] Nutritional deprivation in low SES families has also been shown to result in growth retardation in children and it may eventually lead to other conditions such as anemia.[20]
Figure 3 Effect of low SES on children.

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Various studies have shown that there is an association between SES and the levels of the child’s socio-emotional development.[21] Socio-emotional development refers to the ability of the child to form positive relationships, experience, manage and express emotions. The major contributing factor leading to the lack of socio-emotional development was the absence of parent-child interaction in low SES families. Children lacking socio-emotional development have been shown to have poor adaptive functioning, depression and delinquent behaviors.[22]

Several studies have found the associations between poverty and dysregulation of stress hormone levels. Experiments on poverty as a causative factor for childhood stress are usually focused on cortisol. Many studies examining the relationship between income and cortisol levels have shown an inverse relation.[23] The difference in the time spent in poverty has also shown to be significant, children who had spent a longer time in poverty had a greater cortisol output which means that they have higher levels of chronic HPA activity.[24]

Chen et al.[25] have studied the cortisol outputs of children aged 9-18 from low and high SES families. In this study, the family’s SES was calculated based on two socioeconomic variables, namely the family savings and home ownership. Based on the percentile of SES, the families at 25th percentile score for SES were considered as low SES and families at 75th percentile score for SES were considered high SES. They have reported that the cortisol levels rose almost twice as much in low-SES children compared with high-SES children over the period of 2 years. This may be due to children from low SES families being more prone to chronic stressful events which makes them vulnerable to negative emotions causing dysregulations of HPA axis.[26] Also, children from low SES families tend to see the world around them differently, for example, they are more likely to interpret ambiguous situations as threatening.

A number of studies have also reported that low SES in early life can lead to cortisol level dysregulation even in adulthood. Gustafsson et al.[27] conducted a study over a period of 27 years where they collected participants SES information when they were 16, 21, 30 and 43. They also collected salivary cortisol samples when participants were at the age of 43. Higher cortisol levels were observed in participants who had a low SES at age 16, independent of their SES later on in life. SES for this study was determined based on the parents’ occupation (when the participants were at the age of 16) and the participant’s occupation (at ages 21, 30 and 43). Non-manual employees and self-employed individuals were considered as high SES, whereas manual workers were considered as low SES. This experiment provides support for the hypothesis that there is a critical period in early life where any SES disadvantage can have long term influences on the regulation of cortisol.


   Epigenetic Modifications in Stress Response Genes Associated with ELAs Top


ELAs have been shown to have a lifelong impact on mental and physical health. It is associated with high risk of mortality, PTSD, anxiety, depression, substance abuse, eating disorders, diabetes (type 2), CVDs, gastrointestinal disorders, obesity and autoimmune diseases.[1],[2],[7],[28],[29],[30],[31],[32],[33]

There have been a number of studies that have investigated the relationship between ELAs and the epigenetic modifications and regulations of several genes that are involved in the stress response.[34],[35],[36] “Epigenetics” essentially indicates “outside of conventional genetics”. Epigenetic regulation of genes, is essentially the turning on and off of the genes, without changing the sequence of DNA. These changes direct the accessibility of the transcription factors to the gene.[10] The epigenetic changes that have been reported in a few genes involved in the stress response pathway are discussed below.

CRH gene

The CRH gene codes for CRH, which is the initiator of the HPA axis stress response. It has been established that people who suffer from depression have an increased amount of CRH mRNA and CRH containing PVN neurons.[9],[37] Studies have shown that rats exposed to ELAs have certain methylation patterns on the CRH gene which causes permanent alteration of gene expression. The rats who were subjected to maternal deprivation were shown to have significantly higher basal levels of CRH mRNA in the hypothalamus compared to controls who were not exposed to maternal deprivation.[38] When methylation analysis was done in order to determine if the increased level of mRNA was related to epigenetic modifications, they found that maternal deprivation was associated with lower methylation percentage at two specific CpG sites located in the CRH promoter. The long-term effects of increased CRH expression may result in the lifelong dysregulation of the stress response in a behavioural, neuroendocrine and molecular aspect.

NR3C1 gene

The nuclear receptor subfamily 3 group C member 1 (NR3C1) gene codes for glucocorticoid receptors (GRs). Studies have shown that childhood trauma and early life stress leads to the increased methylation of this gene. Weaver et al.[39] reported that an increased amount of methylation of the NR3C1 gene was associated with the lack of maternal care in rats. It was also reported by Melas et al.[40] that early parental death was linked to the hypermethylation of the NR3C1 gene. In another study, postmortem hippocampal brain tissue extracted from suicide victims with a past of childhood harm indicated lower expression of GRs and high cytosine methylation of the NR3C1 promoter.[41] It has been shown that the decreased expression of GRs affects the negative feedback mechanism of the HPA axis as glucorticoids are unable to supress to secretion of CRH and ACTH, thus leading to the dysregulation of the HPA axis.

COMT gene

The COMT gene codes for catechol-O-methyltransferase (COMT) which metabolizes catecholamines and neurotransmitters such as adrenaline, noradrenaline and dopamine. This gene is essential to study the epistatic connection between COMT and NR3C1 wherein changes in any one of these will affect the other. COMT promoter methylation encourages change in prefrontal cortical connectivity in schizophrenia and depression.[42],[43] The decreased methylation observed at the promoter region leads to the increased expression of the COMT gene. As a result, metabolic degradation of neurotransmitters such as dopamine occurs, leading to symptoms associated with depression.

BNDF gene

The BNDF gene codes for the brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin, which are a family of proteins that regulate development, functioning and plasticity of neurons. Roth et al.[44] reported that pups exposed to stressed mothers for 30 minutes per day during the first postnatal week caused a significant decrease in BDNF mRNA levels in the prefrontal cortex. They have suggested that the decreased BDNF mRNA levels are due to the fact that childhood maltreatment had resulted in the methylation of the BDNF gene. It has also been reported that individuals with history of childhood trauma seem to have low BNDF serum levels.[45] A sufficient amount of BDNF is required for the maintenance of normal neuronal function and for neuronal plasticity. In response to stress and due to the lack of BDNF in maltreated children, they are unable to reshape the neuronal circuits during periods of chronic stress, thus leading to disorders such as depression.[46]

IL-6 gene

The IL-6 gene encodes the Interleukin-6 protein (IL-6). Variants associated with IL-6 gene have been linked with disorders such as depression and schizophrenia.[47],[48] Munjiza et al.[47] reported that the serum concentrations of IL-6 in patients with major depressive disorder were significantly higher compared to healthy controls. Moreover, their findings suggested that the depressed patients who were abused had higher levels of IL-6. Thus IL-6, a pro-inflammatory cytokine could be a link between childhood trauma and depression. In addition, the more the exposure to childhood trauma, the lesser the DNA methylation at the IL-6 promoter.[49] According to Ting et al.[50] elevated IL-6 may disrupt HPA axis function, reduce levels of neurotrophic factors and even affect neurotransmission.

Oxytocin and OXTR gene

Oxytocin (OT) is a neuropeptide hormone that is involved in labour and breastfeeding. ELAs such as child maltreatment, neglect or parental death can lead to imbalance in the release of the hormone. A study done on 22 females showed that women who were exposed to ELAs showed significantly lower levels of OT in the cerebrospinal fluid.[51] Fujisawa et al.[52] have suggested that hypermethylation of oxytocin receptor (OXTR) gene was seen in individuals with childhood trauma. They have also reported that hypermethylation of OXTR gene had a negative correlation with the grey matter volume in the left orbitofrontal cortex which led to reduced socio-emotional adaptation and social-cognition deficits. Therefore, hypermethylation of OXTR gene disrupts the OT signaling pathway in a way that prevents the typical development of the brain during developmental years.


   The Long-Lasting Effects of ELA Top


It has been well established that children who have experienced ELAs such as neglect, abuse, parental loss, and poverty have a dysfunctional stress response and increased risk of diseases in later life. There have been many studies that spoke about how early life stress can affect the behavioural and cognitive development of a child. There have also been several research papers stating that ELAs have been associated with altered brain structure and function which can lead to mental health issues such as anxiety and depression. Physical health issues other disorders such as CVDs and type 2 diabetes have also been observed.[1],[2] In this review, we have focused on depression and CVDs, as many studies indicated that childhood trauma was significantly involved in the development of these disorders, which are the leading cause of mortality and morbidity worldwide.


   Depression Top


Major depressive disorder (MDD) is a mental disorder that affects more than 265 million people worldwide. Depression is a result of interaction between biological factors and the environment.[53] Changes in brain architecture and chemistry due to excessive stress have been reported to result in anxiety and depression both in animal and human models. There has been compelling evidence from epigenetic studies that have linked depression and dysregulation of HPA axis. Epigenetic modification caused by the exposure to stress can either turn genes off or on, and both conditions have been associated with an increased risk for mental and physical illness. Occurrence of depression and anxiety in adulthood can be due to the exposure of early life stress which leads to permanent changes in the HPA axis.

Saleh et al.[54] have compared the early life stress exposure between depressed and non-depressed individuals. Participants were required to complete a questionnaire and analysis of the responses showed that depressed patients reported more early life stress exposure than the other group. Their findings suggested that emotional abuse, sexual abuse and severe family conflict significantly predicts adult MDD. In another study elevated heart rate, higher cortisol level reactivity, and dysregulated ACTH were reported in depressed women who had experienced sexual or physical abuse in early life.[55]


   Cardiovascular diseases (CVDs) Top


According to the World Health Organization (WHO) CVDs are the leading cause of death globally, taking an estimated 17.9 million lives each year.[56] Some prominent studies have revealed the importance of balanced maternal diet and healthy environmental condition for reducing the risk of CVDs. It has been proved that exposure to stress during different critical stages of development can increase the risk of later cardiovascular dysfunction.

The growing number of clinical trials in the last two decades have proved that exposure to ELAs increases the risk of developing chronic diseases such as CVDs, respiratory diseases, cerebrovascular diseases and genetic disorders.[57],[58] Hamer et al.[59] measured the salivary cortisol of the participants upon exposure to a stressor. They also measured the amounts of coronary artery calcification in these participants. Upon analysis, they concluded that heightened cortisol reactivity was associated with higher levels of coronary artery calcification. This supports the hypothesis that long-term activation of the HPA axis, leading to higher cortisol levels, is a risk factor for CVDs.

It has also been reported that low SES in childhood was associated with an increased risk of CVDs in later life.[60] Children who were raised in environments of low SES and were exposed to stressful events have been shown to have higher blood pressure levels and greater risk of CVDs.[61] Roque et al.[62] conducted experiments on rats by mimicking parental separation in human and it resulted in the increased risk of hypertension and development of CVDs in adulthood.


   Conclusion Top


The childhood trauma faced by an individual causes epigenetic changes that can impact adult life. Children who face traumatic situations like neglect, parental loss, divorce, and socio-economic failures, witness an effect in their behavioural and physiological features in the later stages of adulthood. Though the child might have faced one or many ELAs for a short term, the detrimental effects of stress could pertain throughout the child’s life because of epigenetic changes. Severity of the effects depends on the type, number and intensity of stress-inducing factors, and period of exposure to stress. Stress response is very important; it is a survival mechanism that allows individuals to react quickly when they are under stress or in a traumatic situation. However, prolonged activation of the stress system may have hazardous effects; causing alterations in genes and receptors leading to diseases such as anxiety, depression, and CVDs in later life.

Most of the research on childhood abuse and trauma that have been done are based on questionnaires, interviews, visual observation and simple biochemical tests. Studies with fluorescence recovery after photobleaching assay (FRAP) or nanopore sequencing allows investigation on how epigenetic modifications could dynamically and spatially mould chromosomes, hence impacting cellular functions. These studies establish how quintessential a positive familial environment is, hence, on a common people’s level, it re-enforces good household practices. Also, the studies stand as a proof of the communal belief system of maltreatment of children.

For more proactive interventions, further investigations can be done on a molecular level to study epigenetic modifications and the results brought into clinical practice. Prospects of these studies are that they open new windows for assessing the cause of diseases and can possibly help to troubleshoot by predicting later life effects. If the doctor could ascertain the childhood trauma and find the epigenetic changes, there will be a better chance to prevent the severe later life disorders. Integration of epigenomics, metabolomics and proteomics could connect basic biological processes in response to childhood trauma and thereby produce innovations in mental health. The field of epigenetics opens up an innovative field of study to understand and rectify complicated multilevel ethology of mental disorders which could strengthen the interdisciplinary interaction between fields of neurobiology/genetics with psychology/psychotherapy to their mutual benefit.

Authors’ contributions

DS, DJ, SK, KA, and GV performed the literature search, collected the data and wrote the manuscript. MJ provided critical revision of the article.

Financial support and sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial (or) not-for-profit sectors.

Conflicts of interest

All the authors declare that there are no conflicts of interest.



 
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    Abstract
     Introduction
     HPA Axis
   Effects of Early...
   Developmental Im...
   Developmental Im...
   Epigenetic Modif...
   The Long-Lasting...
     Depression
   Cardiovascular d...
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