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War-related Trauma and Its Impact on the Epigenome



In light of the events currently unfolding in Palestine, there’s no denying the psychological and physiological impact that these brutalities are causing civilians. With food and water shortages, lack of access to healthcare, unsanitary living conditions, and the loss of many loved ones, the effect this has on individuals currently is of grave concern [1].  A potential long-term impact that can result from this is post-traumatic stress disorder (PTSD) [2]. PTSD symptoms include recurring flashbacks of traumatic incidents, psychological distress when exposed to something that may remind the individual of the event, sleep disturbances, disassociation, etc [3]. However, there may be outcomes of such trauma that go beyond what can be externally observed.  


Having PTSD can impact individuals at a deep level, including changes at the molecular level in their bodies. This occurs through alterations of the epigenome, which consists of chemical modifications to genes that change the way they function. These modifications include DNA methylation, the process by which a methyl group is attached to a DNA molecule, restricting access to a particular gene and inhibiting expression [4]. In patients with lifetime PTSD, there is a notable decrease in methylation at the promoter region of the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene [5]. This gene is responsible for coding the glucocorticoid receptor (GR), which the hormone cortisol binds to. Cortisol is responsible for helping the body respond to stress and plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis, the main stress response system of the body. Dysregulation of the HPA axis is highly associated with PTSD [6]. Since the reduction of methylation makes the promoter region of NR3C1 more accessible, an increased number of GRs are seen in individuals with PTSD [7]. This increase in receptors can make the body more sensitive to stress, a key feature of PTSD. 


Another important player in the HPA axis is the FK506 binding protein 5 (FKBP5), a gene that plays an inhibitory role on signaling of the GR [8]. For individuals who were exposed to early trauma, there was decreased methylation of FKBP5 [9]. This means GR activity is not regulated normally in these individuals, which can have a detrimental effect on stress response. This is imperative to note as nearly half of Gaza’s population consists of children under the age of 18 [10], and early exposure to such atrocities can lead to chronic dysregulation of important physiological mechanisms. Overall, FKB5 and NR3C1 are both important epigenetic markers that can be used to predict how severe symptoms of PTSD are and what treatments are most effective for individuals, as it helps explain how the disorder can vary person to person.  


So far, the epigenetic impacts discussed have been on a singular level. But these modifications have been observed to transmit generationally [11]. This implies that the effects of war and trauma have a transgenerational impact on even those who have never been exposed to it. For instance, if both parents suffer from PTSD, offspring show significantly reduced methylation in the NR3C1 promoter region, which is commonly exhibited in those with the disorder [12]. In a study by Yehuda et al., children of holocaust survivors with PTSD showed an increased risk of developing PTSD themselves [13]. Mothers who are pregnant at the time of exposure to stressors such as war can have a direct impact on the child prenatally. High levels of cortisol in the fetal environment are associated with an increased risk of impaired neurodevelopment and psychiatric disorders later in life [14]. Infants of mothers who experienced the September 11 attacks gave birth to children with lower birth weights and more severe depressive symptoms [15]. If a pregnant mother is exposed to war or rape, there is higher DNA methylation of the NR3C1 promoter region in newborns [16]. The prenatal environment is extremely susceptible to maternal stress and this can cause lifelong impacts to the brain development and psychological health of children. Currently in Gaza, an estimated 52 000 women are pregnant [1], indicating around this many children may already be affected by the situation before they’re even born.  


Overall, there is much research that still needs to be done to completely understand the mechanisms of epigenetics and the complexity of these effects. What is important to take away from this is what we are seeing transpire will have impacts beyond even our lifetimes. This affects not only individuals, but generations. If nothing is done to stop this, the outcomes may become even more dire. However, epigenetic modifications differ from modifications of actual genomic data, as they are reversible. The severity of this decimation and its potential aftermath can be lessened if only there is intervention and the proper care, attention, research, and effort put into it.  


 


References:

  1. Hunger, lack of medical care claim lives of dozens of people in northern Gaza [en/ar] - occupied Palestinian territory [Internet]. Euro-Med Monitor; 2023 [cited 2024 Feb 17]. Available from: https://reliefweb.int/report/occupied-palestinian-territory/hunger-lack-medical-care-claim-lives-dozens-people-northern-gaza-enar 

  1. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995: 52(12):1048–60.  

  1. DSM-V: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th edn). APA, 2013. 

  1. Bernstein BE, Meissner A, Lander ES. The Mammalian Epigenome. Cell. 2007 Feb;128(4):669–81. 

  1. Young DA, Inslicht SS, Metzler TJ, Neylan TC, Ross JA. The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Psychiatry Research. 2018 Dec;270:961–6. 

  1. Bremner JD. Traumatic stress: effects on the brain. Dialogues in Clinical Neuroscience. 2006 Dec 31;8(4):445–61. 

  1. Yehuda R, Boisoneau D, Mason JW, Giller EL. Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders. Biological Psychiatry. 1993 Jul;34(1–2):18–25. 

  1. Young DA, Inslicht SS, Metzler TJ, Neylan TC, Ross JA. The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Psychiatry Research. 2018 Dec;270:961–6. 

  1. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat Neurosci. 2013 Jan;16(1):33–41. 

  1. Palestinian Central Bureau of Statistics (PCBS) Presents the Conditions of the Palestinian Population on the Occasion of the World Population Day,. Palestinian Central Bureau of Statistics; 2023. 

  1. Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, et al. Epigenetic Transmission of the Impact of Early Stress Across Generations. Biological Psychiatry. 2010 Sep;68(5):408–15. 

  1. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, et al. Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring. AJP. 2014 Aug;171(8):872–80. 

  1. Yehuda R, Bell A, Bierer LM, Schmeidler J. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. Journal of Psychiatric Research. 2008 Oct;42(13):1104–11. 

  1. Talge NM, Neal C, Glover V, the Early Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health. Antenatal maternal stress and long‐term effects on child neurodevelopment: how and why? Child Psychology Psychiatry. 2007 Mar;48(3–4):245–61. 

  1. Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS. Transgenerational Effects of Posttraumatic Stress Disorder in Babies of Mothers Exposed to the World Trade Center Attacks during Pregnancy. The Journal of Clinical Endocrinology & Metabolism. 2005 Jul;90(7):4115–8. 

  1. Mulligan C, D’Errico N, Stees J, Hughes D. Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics. 2012 Aug 18;7(8):853–7. 

 

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