Role of Epigenetic Modification in the Intergeneration Transmission of War Trauma

Abstract

War trauma has been linked to changes in the neuroendocrine and immunological systems and increases the risk of physical disorders. Traumatic events during the war may have long-term repercussions on psychological and biological parameters in future generations, implying that traumatic stress may have transgenerational consequences. This article addresses how epigenetic mechanisms, which are a key biological mechanism for dynamic adaptation to environmental stressors, may help explain the long-term and transgenerational consequences of trauma. In war survivors, epigenetic changes in genes mediating the hypothalamus–pituitary–adrenal axis, as well as the immune system, have been reported. These genetic modifications may cause long-term changes in the stress response as well as physical health risks. Also, the finding of biomarkers for diagnosing the possibility of psychiatric illnesses in people exposed to stressful conditions such as war necessitates extensive research. While epigenetic research has the potential to further our understanding of the effects of trauma, the findings must be interpreted with caution because epigenetic molecular mechanisms is only one piece of a complicated puzzle of interwoven biological and environmental components.

Introduction

War is an issue that negatively affects various aspects of life and poses many challenges in social, psychological, personal, economic, cognitive, and many other aspects of life. Usually, the families of people who are wounded or killed in the war, even after the war, may not be able to cope with these events and experience severe issues. Some wars have devastating consequences, such as World War I–II, the Iran-Iraq War, the Crusades, the Gulf War, and now Russo-Ukrainian war which led to massive killings of soldiers and civilians and the plunder of wealth and natural resources [1]. For war veterans and civilians in war zones, trauma can be related to difficult combat tasks, being in a dangerous war zone, seeing traumatic scenes, and generally stressful war conditions [2]. Individuals, whether as military personnel and/or non-military civilians, face stressful and traumatic events in wartime that cause many health damages.

In general, war has many physical and psychological consequences for war survivors. It has been shown that there are changes in the immune and endocrine systems, and a higher risk of infection, diabetes, cardiovascular disease, or even cancer in war survivors [3]. Besides, studies indicate that the incidence of mental illness is much higher in war-torn countries. The most common and serious psychological disease that occurs after the war is post-traumatic stress disorder (PTSD), which occurs as a result of confrontation with acute problems related to the war [3]. In the Iran-Iraq war, it is estimated that about 23% and 19% of veterans suffer from major depressive disorder and PTSD, respectively [4]. A recent study on the psychological impact of war on adolescents in Ukraine indicated a higher rate of war trauma and daily stress in adolescents in the Donetsk region of Ukraine. They also had significantly increased risks for PTSD, severe anxiety, and moderate to severe depression [5]. War-induced stress is reported as a devastating factor in the physical and psychological consequences of war [3].

Stress is classified into three categories: “good stress”, “tolerable stress”, and “toxic stress” which have acute, delayed, and long-lasting effects on the body. The body can cope with good stress through physiological compensatory mechanisms and even lead to healthy growth. The body can also overcome tolerable stress through successful interventions that lead to homeostasis. Toxic stress, on the other hand, causes long-term changes and damage to the brain and other organs [6]. The main biological pathway in response to stress is the hypothalamic–pituitary–adrenal (HPA) axis. Research has shown that changes in the HPA axis interfere with the stress management process [7]. Neurotransmitters, including glutamate, serotonin, and γ-aminobutyric acid (GABA), are involved in transmitting stress-induced signals. Nerve signals from the amygdala and locus coeruleus lead to the secretion of neuropeptides such as arginine vasopressin (AVP), and the stress-induced corticotropin-releasing factor/hormone (CRF/H) from the hypothalamus [7]. The CRF receptor 1 is activated in the anterior pituitary gland, leading to the secretion of adrenocorticotropic hormone (ACTH). AVPs participate in the ACTH response with CRH contribution. ACTH affects the adrenal cortex and leads to the release of stress-related hormones, including glucocorticoids (cortisol) and mineralocorticoids (aldosterone) (Fig. 1) [7]. Other neurotrophic factors such as neuropeptide Y, dynorphine, and oxytocin, as well as the brain-derived neurotrophic factor (BDNF), also play a role in the HPA axis and in regulating the stress response [8].

Fig. 1.

The hypothalamic–pituitary–adrenal (HPA) axis is the most important pathway of response to stress and trauma. Stress and trauma are processed by the amygdala and then a stress signal is sent to the hypothalamus. The hypothalamus secretes CRH and AVP, which bind to CRHR1 and AVPR1A receptors, which in turn leads to the secretion of ACTH from the pituitary gland. ACTH triggers the secretion of glucocorticoids (e.g. cortisol) into the bloodstream by acting on the adrenal cortex. After cortisol binds to the corticosteroid receptor, including GR (encoded by NR3C1), the receptor complex is transferred to the nucleus, leading to the expression of various genes. FKBP5 is a co-chaperone of Hsp90 and binds to the GR complex, reducing cortisol receptor affinity. FKBP5 levels increase in response to GR activation. The GR prevents further cortisol secretion through the negative feedback loop

Another important point is that people's reactions to stressful situations are very different, with some showing short-term effects while others may experience longer-lasting effects. The correct answer to these individual differences has not yet been determined [9–11]. In Canada, it is estimated that up to 10% of war zone veterans suffer from PTSD, While others have experienced only some related symptoms [12]. Studies have shown that in addition to individual differences, there are also gender differences in the risk of developing PTSD in war veterans, and women are more likely to develop PTSD following war trauma [13]. It is revealed that these individual and gender differences in war consequences are not only related to exposure to traumatic events but also to other various unknown elements [14].

One of the most challenging debates on war outcomes is the possibility of intergenerational transmission of the psychological consequences of war. In 1864, near the end of the American Civil War, conditions in the POW camps were very difficult. During this time, the mortality rate increased dramatically. For those who survived, these experiences had a devastating effect on their lives. But the impact of these hardships on the people did not end there. This situation also affected the children and grandchildren of the prisoners and was thought to be transmitted through the paternal line of the families. While their sons and grandchildren had not experienced the hardships of a prisoner-of-war camp, they had a higher mortality rate than the general population. These prisoners seemed to pass on elements of their harm to their children. Unlike most inherited traits, intergenerational transmission of war trauma was not caused by a mutation in the genetic code [15].

Therefore, the question arises as to what causes individual and gender differences in the devastating consequences of war trauma. On the other hand, how are the consequences of the war trauma transmitted to the next generation? In this case, researchers are examining the most obscure type of inheritance: how events in a person's life can change the gene expression and how that change can be passed on to the next generation. Some studies have shown that stress and exposure to traumatic conditions can lead to genetic changes and altered gene expression through various mechanisms [16, 17]. It is suggested that epigenetic alterations can solve this mystery of individual differences and the intergenerational transmission of war-induced trauma. Epigenetic is a process in which gene expression is altered without changing the DNA code. Small chemical tags are added to or subtracted from DNA and histone proteins in response to environmental changes [18]. These labels turn genes on or off and are known to be a way to adapt to environmental conditions without causing permanent changes in the genome [19, 20]. Therefore, intergenerational transmission of war-induced trauma by epigenetic mechanisms can have great destructive consequences. Epigenetic changes, including DNA methylation, histone (de) acetylation, and post-transcriptional regulation by non-coding RNAs such as miRNAs, are involved in many neurological diseases [21].

Several studies have proposed that the effects of trauma can be passed on to future generations through epigenetic mechanisms. Life experiences, especially the experiences of severe trauma, have a devastating impact on several generations. On the other hand, studies indicate that early memories of life and environment can affect the epigenetic pattern of individuals, which may cause different responses to critical situations such as war. Therefore, this question arises: can we use the epigenetic signatures to monitor the soldiers who are prone to mental disorders? Epigenetic memory may be the key to predicting, diagnosing, and treating the psychological disorders observed in war survivors. The epigenetic memory may be one piece of the puzzle of the connection between trauma, gender/individual differences, and clinical and health consequences. Therefore, it can be very helpful to have a broad knowledge of epigenetic modifications in war survivors.

Regarding the current global issues, including the war in Ukraine, civil unrest in Iran, upheaval in Afghanistan, conflict in Ethiopia, South Sudan, and Syria (and undoubtably numerous ather yet less widely publicized unrest), it is a necessity to understand the epigenetic impacts of war/conflict trauma that may further contribute to, or drive, psychological and/or physiological complications in order to improve support for vulnerable populations. This study aimed to review studies on epigenetic changes resulting from stress exposure induced by war in childhood and adulthood. We also examined the theory of the involvement of epigenetic changes in the intergenerational transmission of war trauma. Finally, we discussed how epigenetic signatures can be used to predict the development of mental disorders in war survivors and soldiers.

Method

In this study, I reviewed articles related to the effects of war trauma on the epigenetic signature of war survivors and veterans. A systematic search was performed on international medical databases such as Medline, ISI, PubMed, and Scopus. The keyword used in the search was war trauma and the search terms used were war veterans, PTSD, epigenetic modification, childhood trauma, intergeneration transmission, and animal models of trauma. Our main focus was to study the effects of war trauma on the epigenetic signature. We reviewed studies involving indigenous populations and soldiers in war zones. Studies that included chemical weapons were excluded.

Association of Epigenetic Alterations and War Trauma in Children

One in six children globally is growing up where acts of political violence and armed conflict are occurring [22]. Children exposed to wartime conflicts experience a variety of stressors. War-induced childhood injuries are associated with devastating psychological and physical consequences [23]. People who are exposed to various types of childhood trauma have an increased risk of premature mortality, which reduces their lifespan by up to 20 years [24]. Cardiovascular disease, autoimmune disease, gastrointestinal symptoms, obesity, and type 2 diabetes are much more common in children exposed to war [25]. Also, a recent study reported that exposure to war is associated with an increased lifetime risk of high cholesterol and hypertension and that this association is strongly concentrated among cohorts exposed in utero or during early childhood (e.g., before age 8) [26]. Children exposed to war exhibit an increased likelihood of irritable bowel syndrome (IBS), a condition more common in veteran populations [27]. Childhood injuries are also one of the most important risk factors for mental illness. The prevalence of PTSD, insomnia, anxiety, and depression is much higher in children exposed to war [26]. The war in Ukraine puts an estimated 7.5 million children at extreme mental and physical health risk [22].

War-related mental and physical child injuries can be caused in a variety of ways. Response of children to war conflicts is very different; therefore, some children are more vulnerable, while others show a “flexibility” trait [28]. Various elements, such as epigenetic and environmental factors, affect the response of children to wartime conflicts [29]. In recent years, much attention has been directed toward the examination of epigenetic and environmental interactions in the consequences of exposure to childhood trauma. Studies show that children in war-torn areas are affected by trauma even before birth. In a study by A. Kertes et al., it was shown that in the Democratic Republic of the Congo, stressful maternal experiences can be transmitted to the fetus through epigenetic changes in the stress-responsive genes. Samples of umbilical cord blood, placenta, and maternal blood were collected at birth, and the results showed changes in the methylation pattern in several stress-responsive genes. Stress-related DNA methylation alterations are associated with reduced brain growth and lower birth weight. Kertes and colleagues also indicated that stress has destructive long-term effects on the development and growth of children in war-torn areas [30].

Another important point is the separation of children from their parents during wartime. Indeed, separation from parents in childhood during wartime is a kind of stress in early life. Several studies found the alteration of DNA methylation patterns in response to childhood separation from their parents. In a study, alterations of the HPA axis were examined in response to the separation of children from parents during World War II. The results showed that individuals who separated from their fathers during World War II were not significantly different from non-separated individuals. However, plasma cortisol and ACTH concentrations were significantly higher in those separated from both parents compared with the non-separated group. Interestingly, women had higher plasma cortisol and ACTH levels. Also, people who were separated from their parents in early childhood were more affected than children who were separated during infancy or school time. Therefore, it can be concluded that separation from parents in childhood can change the physiology of coping with stress in adulthood by dysregulating of the HPA axis [31]. Besides, a study of 149 monozygotic twins from the Swedish Adoption/Twin Study of the ging sample showed that childhood separation from parents affects the methylation pattern of CpG sites in the oxytocin (OXT) and vasopressin (AVP) genes. DNA methylation alterations lead to changes in the oxytocin-nergic and vasopress-nergic systems that affect stress response. However, the results of these studies need to be interpreted more carefully and cautiously.

A study of samples collected from children of Gulf War veterans showed a high prevalence of HPA-based disorders and increased BDNF Val66Met polymorphism. The BDNF Val66Met polymorphism is associated with a variety of psychological disorders. However, due to the small sample size and the cross-sectional nature of the samples, the study had some limitations [32]. Studies also show an association between changes in the serotonin transporter gene and susceptibility to depression in children exposed to highly stressful situations such as war [33]. Generally, epigenetic changes in HPA axis-function regulating genes have been identified as modulators of trauma responses in children [34]. Several studies have been done on post-mortem human brain tissue. Labonte et al. reported that there were 362 different methylated sites in the hippocampal tissues of those who died by suicide and compared those with or without a history of childhood abuse. Results found that 248 CpG sites were hypermethylated and 114 CpG sites were hypomethylated. Similarly, a bidirectional regulation of methylation in the cingulate cortex has been observed in those with/without childhood trauma who had depression and died by suicide, with the most differential methylation in myelin-related genes. Studies also show that childhood trauma is associated with DNA hypomethylation in peripheral blood samples [35]. In sum, the evidence suggests that childhood exposure to war can lead to epigenetic modification and reprogramming of the HPA axis. Considering the ongoing wars in the world today, it is very important to investigate the long-term effects of epigenetic changes in war-exposed children. The conducted studies have only examined DNA methylation changes, which indicates the need for more research on other epigenetic modifications caused by war in childhood, such as histone acetylation and dysregulation of non-coding RNAs.

Epigenetic Alterations in Combat-Exposed War Veterans

There have been many studies in recent years on the relationship between epigenetic alteration and the prevalence of PTSD in adult war survivors. Several studies found dysregulation in epigenetic molecular mechanisms in PTSD patients that could act as a derivation to other severe complications. Epigenetic alteration plays a key role in the molecular mechanisms of memory formation. Animal studies have shown that inhibition of DNA methyltransferase prevents long-term augmentation and memory stabilization in the hippocampus [36, 37]. The expression level of the DNA-methyltransferase gene increases after the induction of fear [37]. Besides, glucocorticoids, as the main factor in boosting memory, are influenced by emotions and, therefore, play an important role in the manifestations and progression of PTSD [38]. In a study by Vukojevic et al. [39], an association was found between epigenetic changes in the glucocorticoid receptor encoding gene (NR3C1) and healthy memory function as well as intrusive memory symptoms in PTSD patients. Hypomethylation in the promoter of the NR3C1 gene was also associated with intrusive memory symptoms in the men survivors of the Rwandan genocide but not in the women survivors [39]. The molecular mechanism of these sex-linked epigenetic changes in memory formation and the risk of PTSD have not yet been fully elucidated, but it could be an interesting starting point for examining the relationship between epigenetic changes and sex-linked war damage in memory and mental health. As we know, the production of gonadal hormones is regulated by the hypothalamic-pituitary–gonadal (HPG) axis and has been shown to play a role in sex differences in adult HPA function after acute stress. However, no study has been done on the possible effect of sex chromosomes on HPA function. There are also many ambiguities regarding gender differences in HPA function following stress and the essential contribution of sex hormones and sex chromosomes [40].

Evidence suggests that the number of glucocorticoid receptors on lymphocytes increases in veterans with PTSD, and also that cortisol levels in the bloodstream change. There is a theory that epigenetic changes in the promoter of the NR3C1 gene contributed to the observed changes in the glucocorticoid signaling pathway [41]. Yehuda and colleagues also reported decreased methylation of the NR3C1 gene in peripheral blood mononuclear cells of veterans with PTSD. In comparison to the control group, the expression of the glucocorticoid receptor gene was 39% higher in veterans with PTSD. More glucocorticoid receptors in the peripheral blood mononuclear cells of soldiers can be identified as susceptible factors for PTSD [17]. Also, T. Y. Kim et al. investigated DNA methylation at four CpG sites within the BDNF promoter I region in the peripheral blood samples of veterans of the Vietnam War. This study found that veterans with PTSD showed higher DNA methylation at the BDNF promoter compared with those without PTSD. High methylation levels at the BDNF promoter CpG site, high combat exposure, and alcohol problems were significantly associated with a PTSD diagnoses. This study demonstrated an association between higher DNA methylation of the BDNF promoter and PTSD diagnosis in combat-exposed individuals [42]. The authors propose BDNF methylation as a vulnerable biomark of PTSD development after trauma exposure [42, 43]. As mentioned, another common complication following the war is immune system dysfunction, which may be partly related to epigenetic alterations. An examination of methylation changes in more than 14,000 genes among PTSD patients and healthy individuals showed a remarkable epigenetic difference in immune system-related genes in PTSD patients. In this study, it was found that some genes regulating the innate and adaptive immune response had less DNA methylation [44].

A recent study investigated patterns of serum DNA methylation in repetitive genomic elements, LINE-1, and Alu, in US military service members recently deployed in Afghanistan or Iraq with or without PTSD. The results of this study showed that the hypermethylation signatures of LINE-1 in the controls post-deployment and Alu in the post-deployment cases have the potential to be used as biomarkeres of resilience or vulnerability [45]. A panel of methylation changes in immune system-regulating mechanisms in peripheral blood cells of the African American population with PTSD has also been reported. Therefore, these studies show the activation of the chronic immune system in people with PTSD, which is associated with epigenetic modifications. The person's unique epigenetic signature can partially respond to individual differences in psychiatric outcomes after exposure to war trauma [46].

The life expectancy of people exposed to war is significantly shorter than that of other individuals. Studies have shown that there is a relationship between aging and the pattern of DNA methylation, which is called “epigenetic age” and can be considered an indicator of biological age. Biological aging is indexed by several cellular and molecular processes, such as genomic instability, telomere attrition, and mitochondrial dysfunction. A relatively new indicator of biological aging is based on DNA methylation patterns. Numerous studies have shown that PTSD can cause shortened life expectancy. In fact, PTSD can accelerate biological aging. In a recent study, epigenetic age was estimated in 160 male veterans with or without PTSD. In this study, DNA methylation in the genomic DNA of leukocytes was evaluated, and epigenetic age was calculated using Horvath’s epigenetic clock algorithm. The results showed that Δage was lower in war veterans with PTSD compared to those without PTSD. This difference between groups could not be explained by other factors such as race or ethnicity, lifestyle factors, or childhood injuries. On the other hand, in the veterans with PTSD, there was an inverse relationship between Δage and telomerase activity. Studies have shown that veterans with PTSD have a lower epigenetic age than those without PTSD. Studies have shown that the use of current antidepressants can play a role in the epigenetic aging of people with PTSD. Research has shown that changes in glucocorticoid levels are associated with epigenetic changes in PTSD patients. One study found that 85 of 353 CpG sites associated with the epigenetic age pattern were located in glucocorticoid-responsive genes. In fact, cortisol secretion, followed by activation of the glucocorticoid receptor, can cause extensive changes in the methylation pattern of CpG sites in the whole genome, as well as other epigenetic changes [47]. People who have been exposed to war have less methylation in the promoter of the glucocorticoid receptor gene [48]. Evidence also suggests that the use of antidepressants in war survivors may have had direct effects on the epigenetic pattern [49]. Furthermore, a link has also been found between these genetic modifications and changes in some behaviors, such as drinking alcohol in combat-exposed war veterans [50]. It can be suggested that DNA methylation patterns can be considered a way to diagnose and prognosis, although it is not yet fully clear whether DNA methylation changes are related to clinical symptoms or have predictive power. A recent study examined the methylation of the glucocorticoid-related NR3C1 and FKBP51 genes in veterans with PTSD. This study aimed to investigate whether methylation changes in these genes can predict future symptoms. The results show that the epigenetic pattern of some glucocorticoid-related genes is regulated by environmental factors during life. Furthermore, psychotherapy is a form of “environmental regulation” that may alter epigenetic patterns. The results also showed that the DNA methylation pattern has the potential to predict the state of symptoms [51]. Therefore, it can be assumed that it is possible to use the DNA methylation signature to assess the psychological risk factors in soldiers, which represents a promising approach for further research in this area.

Histone modifications, DNA methylation and non-coding RNAs act in concert to orchestrate gene expression in the context of gene-environment interactions [52]. Until now, all studies conducted on the consequences of war trauma on epigenetic regulation mechanisms in war veterans were focused more on the DNA methylation modifications. But, several studies indicated the role of histone (de) acetylation in stress response mechanisms, memory formation, and fear memory learning [53]. Many animal studies used HDAC inhibitors to elucidate the effects of inhibition of these enzymes after trauma or stress. These results provide strong evidence for the role of these enzymes in PTSD in humans. The few clinical studies that exist with HDAC inhibitors also suggest a fundamental role of these enzymes in the neurobiology of the stress response [54]. Also, histon acetylation has been linked to the extinction of fear. Animal model studies found that successful fear extinction correlates with increased H4 acetylation of the BDNF promoter in the prefrontal cortex of mice, which results in enhanced BDNF expression. There is substantial evidence that the mechanisms that orchestrate histone acetylation are involved in fear extinction, and there is indeed further data suggesting a role of epigenetic mechanisms in the pathogenesis of PTSD [55]. Therefore, further study on histone (de) acetylation in war veterans may help to elucidate the neurobiology of war trauma-related pathology and provide a foundation for the prognosis and therapy of psychological complications of war trauma.

Role of Epigenetic Alteration in the Intergeneration Transmission of War Trauma

One of the most important concerns about the consequences of a severe situation such as war is the possibility of transmitting the resulting damage to future generations, which leads to perpetuating the poor economic and social situation of families. Exposing mothers to the stresses induced by instability and turmoil in society, famine, and psychological stress during pregnancy can lead to unhealthy children at birth as well as into adulthood. Unfortunately, the devastating consequences of war trauma can be passed on to future generations. Indeed, war and conflict do not only affect the health of people who have directly experienced them but also potentially have long-term consequences for future generations [56].

The hypothesis of the possibility of intergenerational transmission of trauma through the observation of behavioral and clinical problems was first proposed by Holocaust survivors. The study found that the children of Holocaust survivors showed severe psychological symptoms. However, this initial report faced poor feedback, and the results were highly controversial [57]. After the 1970s, numerous studies aimed to explain clinical observations in children of war survivors in different ways. Furthermore, similar symptoms were reported in children of Vietnam War survivors, which at the time was called secondary trauma, relying more on the traumatic effects of living with the injured parents and with no biological explanation [58]. It was later found that the high risk of developing PTSD was associated with the children of Holocaust survivors whose mothers had PTSD [59]. Similar results were found in studies on the children of Vietnam War survivors [60]. There has been much debate about the intergenerational transmission of historical events such as colonialism, slavery, genocide, ethnic cleansing, and displacement in many societies, including the Native American communities, Cambodians, Armenians, Rwandans, Palestinians, and Yugoslavia. Since the late 1990s, the hypothesis of genetic involvement in intergenerational transmission has emerged. Children of war survivors may have a specific genetic risk factor for PTSD or other psychological disorders. Extensive studies were conducted to find out the potential alteration in the HPA axis in children of war survivors [61]. The children of holocaust survivors were presumed to have changes in the regulatory molecular mechanisms of the stress signaling pathway. The results also showed a change in the HPA axis in the children of Holocaust survivors. In fact, trauma can have long-term effects on the biological signatures associated with the stress signaling pathway [62]. Since then, comprehensive studies have been conducted on the understanding of gene-environment interaction and environmental-induced epigenetic changes in the HPA axis-related genes. Studies showed a significant change in cortisol levels in the children of holocaust survivors [62, 63].

Intergenerational transmission of adverse environmental effects in animal models has been well established. An animal study found that there is an intergenerational effect of odor-related damage. The researchers injected Staffanone (which contains the scent of cherry blossoms) into the cages of adult male mice and at the same time inflicted an electric shock on the male mice. After repeated this several times, these mice found the smell of cherry blossoms to be associated with pain. Shortly afterward, the male mice mated with the female mice. When their offspring smelled the cherry blossoms, they became more nervous and agitated than the offspring of mice whose fathers had not been conditioned. To prevent offspring from recognizing this fear through learning from their parents, they grew up with unrelated mice that had never encountered the odor before. The grandchildren of the injured mice were also more sensitive to the odor. None of the generations was more sensitive to other odors, so inheritance was specific to that particular odor. This sensitivity to the smell of cherry blossoms was associated with epigenetic changes in sperm DNA. These epigenetic changes accrued in the gene encoding an odor receptor in the olfactory bulb of the brain. When the researchers examined the brain tissue of the offspring, they found that there were more neurons in this area of the brain than in the control group. Therefore, there is a molecular relationship between parents and gene function in offspring via epigenetic mechanisms [64].

Epigenetic changes can occur at different stages of life and affect how we respond to stress in critical situations. Studies by Meaney proposed a molecular mechanism for long-term changes in the biological systems of stress response in offspring and also recognized some responsible regions in the glucocorticoid receptor (GR) gene [65]. After observing these results, a study was performed to evaluate the status of GR promoter methylation in peripheral blood mononuclear cells from Holocaust survivors’ offspring. The results showed that there is a link between parents with PTSD and GR methylation in their offspring [66]. Analysis of clinical results has shown that there are different mechanisms for intergenerational impact on children depending on the gender of the parents and the status of PTSD. GR methylation was higher in offspring whose mother did not have PTSD but whose father had PTSD. However, offspring whose mothers had PTSD had lower levels of methylation. Lower GR methylation is associated with greater GR sensitivity [67]. Epigenetic mechanisms are operational throughout life and are highly responsive to environmental disturbances. Stressful experiences such as adult trauma have now been shown to alter GR methylation in the blood cells of offspring, whether inducted with an initial experience or not. It is important to note that the impact of parental behavior should not be combined with the direct inherited effects of biological transmission to the offspring, although both may lead to genetic changes. Epigenetic modifications may occur throughout life depending on the environment, and in this regard, it has been shown that stressful parental experiences such as war can lead to changes in the pattern of GR methylation in children's blood cells. In this context, there are also hypotheses that trauma is transmitted from mother to child through fetoplacental interventions. This hypothesis is consistent with the clinical and epigenetic findings that the gender of the parent with PTSD leads to different psychological and biological outcomes in offspring [68].

Potential Mechanisms of Epigenetic Alteration by Severe Stress and Trauma

Intergenerational transmission of war trauma is a really big issue. The question now is how this mechanism works. A deep understanding of the traumatic mechanisms that lead to war-related psychiatric disorders is also important for the development of effective prevention and treatment strategies. Epidemiological studies indicate a combined contribution of genetic and environmental factors to the risk of war-related mental illness.

The stressful condition can affect the epigenetic pattern through various mechanisms. In mammals, as soon as the sperm enters the oocyte, a rapid decrease in DNA methylation occurs in the set of paternal chromosomes. But there are parts of the genome that do not demethylate. A process called “genome imprinting” protects methylation at certain points in the genome [69]. Evidence has shown that the prenatal environment affects the epigenetic regulation of imprinted genes during fetal development. Maternal stress and cortisol levels during pregnancy are related to the DNA methylation of imprinted genes. Prenatal incompatibility can affect the methylation of the imprinted genes [70]. Post-transcriptional changes in proteins involved in epigenetic modifications are among the most important mechanisms of the long-term effects of stress on gene function. Animal studies have shown that methyl CpG binding protein 2 (MeCP2) affects gene expression in response to neuronal activation. MeCP2 acts as a transcriptional suppressor by binding to methylated DNA but can also activate transcription by interacting with other proteins such as the cAMP binding protein (CREB) [71]. In an animal study of early mother–child separation, it was indicated that a MeCP2-dependent change is involved in the long-term inhibition of AVP gene expression in response to maternal separation in mice [72]. Murgatroyd et al. study showed that early mother–child separation leads to phosphorylation of the MeCP2 protein and consequently detachment from the promoter region of the AVP gene in the nucleus around the ventricles, which leads to demyelination and activation of stable transcription of the AVP gene. In general, phosphorylation and degradation of MeCP2 by stressful conditions can lead to changes in methylation patterns and gene expression. MeCP2 also targets many of the genes involved in the HPA axis. Nuber et al. study indicated the role of MeCP2 in the activity of glucocorticoids in neurons [73]. Therefore, post-transcriptional changes in MeCP2 can lead to changing the expression of a wide range of genes. Also, exposure to stressful conditions can alter the gene expression and activity of epigenetic regulatory enzymes such as DNA methyltransferases (DNMT), histone methyltransferases (HMT), and histone deacetylases (HDAC), leading to a change in the epigenetic profile [74]. On the other hand, these epigenetic changes themselves can affect the binding of transcription factors. Stress also affects the expression of non-coding RNAs such as miRNAs. The altered expression of non-coding RNAs affects the expression of a set of genes [75].

Epigenetic Pattern as a potential Biomarker in the Therapy and Prognosis of Psychological Disorders

At this point, the use of drugs that target epigenetic changes in mental illness is highly controversial. Bilateral regulation of DNA methylation and other epigenetic markers raises the question of whether the use of DNMT regulatory drugs or HDAC inhibitors has the potential to be used in the treatment of psychological disorders. On the other hand, the use of antidepressants such as valproic acid has epigenetic effects [76]. Despite animal and human studies on the involvement of epigenetic changes in the development of diseases, the location and direction of epigenetic changes are very variable, which has challenged the idea of using epigenetic drugs. In addition, specific targeting of epigenetic markers within the genome and even within the gene is critical. The drug must also target the specific cells and area of the brain responsible for the disease. This is one of the challenges facing the use of these drugs. The use of such drugs may be associated with unwanted and severe side effects [77]. In addition to the therapeutic potential, epigenetic changes can be used in predicting diseases in high-risk individuals as well as evaluating treatment methods [78]. For example, the methylation status of the GR gene can be used as a marker to predict the development of mental disorders. At this time, the introduction and discovery of biologically efficient biomarkers in diagnosing the possibility of psychological disorders in individuals exposed to stressful situations like war require comprehensive and detailed studies [79].

Funding

No funds, grants, or other support were received.

Declarations

Conflict of interest

Author certifies that I have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical Approval

Ethical approval was not required as this study was a review paper.

Informed Consent

Consent was not required as this study was a review paper.