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Intergenerational Effects of PTSD on Offspring Glucocorticoid Receptor Methylation

  • Mallory E. Bowers
  • Rachel YehudaEmail author
Chapter
Part of the Epigenetics and Human Health book series (EHH)

Abstract

Posttraumatic stress disorder is precipitated by the experience of extreme stress in a subset of vulnerable individuals. Data now suggest that PTSD in parents confers vulnerability to PTSD in offspring. This is underlined by the observation that offspring born to individuals with PTSD exhibit low baseline cortisol levels, a neuroendocrine risk factor for PTSD. Several mechanisms have been proposed to mediate intergenerational inheritance of PTSD, including genetics and social learning. However, there is also the possibility that biological changes associated with PTSD in parents directly impact offspring, potentially via changes to gametes, fetuses in utero, or via changes in early postnatal care. The exact mechanism of this form of “intergenerational transmission” is unknown; however changes in epigenetic signatures, including DNA methylation, provide an appealing candidate. Animal studies have prompted investigation into methylation of the NR3C1 promoter, which regulates transcription of the glucocorticoid receptor gene. Here, we review evidence of NR3C1 methylation alterations in offspring of parents exposed to extreme stress and offspring of parents who developed PTSD in response to extreme stress. We propose several hypotheses based on the current evidence and suggest future directions related to these interpretations.

Keywords

PTSD CpG island Glucocorticoid receptor Stress Offspring Methylation 

References

  1. American Psychiatric Association, American Psychiatric Association. DSM-5 Task Force (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association, Washington, DCGoogle Scholar
  2. Bandura A (1977) Social learning theory. Prentice Hall, Englewood CliffsGoogle Scholar
  3. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci USA 95:5335–5340CrossRefPubMedPubMedCentralGoogle Scholar
  4. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ (2013) The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8:1321–1329. doi: 10.4161/epi.26634 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Daskalakis NP, Yehuda R (2014) Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: systematic review of contributing factors. Front Neurosci 8:369. doi: 10.3389/fnins.2014.00369 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Delahanty DL, Raimonde AJ, Spoonster E (2000) Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol Psychiatry 48:940–947CrossRefPubMedGoogle Scholar
  7. Dias BG, Ressler KJ (2014) Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 17:89–96. doi: 10.1038/nn.3594 CrossRefPubMedGoogle Scholar
  8. Dias BG, Maddox SA, Klengel T, Ressler KJ (2015) Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci 38:96–107. doi: 10.1016/j.tins.2014.12.003 CrossRefPubMedGoogle Scholar
  9. Feil R, Fraga MF (2011) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109. doi: 10.1038/nrg3142 Google Scholar
  10. Field NP, Om C, Kim T, Vorn S (2011) Parental styles in second generation effects of genocide stemming from the Khmer Rouge regime in Cambodia. Attach Hum Dev 13:611–628. doi: 10.1080/14616734.2011.609015 CrossRefPubMedGoogle Scholar
  11. Flory JD, Bierer LM, Yehuda R (2011) Maternal exposure to the holocaust and health complaints in offspring. Dis Markers 30:133–139. doi: 10.3233/DMA-2011-0748 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Franklin TB, Russig H, Weiss IC et al (2010) Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68:408–415. doi: 10.1016/j.biopsych.2010.05.036 CrossRefPubMedGoogle Scholar
  13. Gangi S, Talamo A, Ferracuti S (2009) The long-term effects of extreme war-related trauma on the second generation of Holocaust survivors. Violence Vict 24:687–700CrossRefPubMedGoogle Scholar
  14. Gapp K, Jawaid A, Sarkies P et al (2014) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17:667–669. doi: 10.1038/nn.3695 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hompes T, Izzi B, Gellens E et al (2013) Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J Psychiatr Res 47:880–891. doi: 10.1016/j.jpsychires.2013.03.009 CrossRefPubMedGoogle Scholar
  16. Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492. doi: 10.1038/nrg3230 CrossRefPubMedGoogle Scholar
  17. Klengel T, Pape J, Binder EB, Mehta D (2014) The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology 80:115–132. doi: 10.1016/j.neuropharm.2014.01.013 CrossRefPubMedGoogle Scholar
  18. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97. doi: 10.1016/j.tibs.2005.12.008 CrossRefPubMedGoogle Scholar
  19. Labonte B, Azoulay N, Yerko V, Turecki G, Brunet A (2014) Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Transl Psychiatry 4, e368. doi: 10.1038/tp.2014.3 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Lam LL, Emberly E, Fraser HB, Neumann SM, Chen E, Miller GE, Kobor MS (2012) Factors underlying variable DNA methylation in a human community cohort. Proc Natl Acad Sci USA 109(Suppl 2):17253–17260. doi: 10.1073/pnas.1121249109 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lehrner A, Bierer LM, Passarelli V et al (2014) Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. Psychoneuroendocrinology 40:213–220. doi: 10.1016/j.psyneuen.2013.11.019 CrossRefPubMedGoogle Scholar
  22. McFarlane AC (1987) Family functioning and overprotection following a natural disaster: the longitudinal effects of post-traumatic morbidity. Aust N Z J Psychiatry 21:210–218CrossRefPubMedGoogle Scholar
  23. Mulligan CJ, D’Errico NC, Stees J, Hughes DA (2012) Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 7:853–857. doi: 10.4161/epi.21180 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Nieratschker V, Massart R, Gilles M et al (2014) MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD. Transl Psychiatry 4, e429. doi: 10.1038/tp.2014.75 CrossRefPubMedPubMedCentralGoogle Scholar
  25. O’Connor TG, Heron J, Golding J, Beveridge M, Glover V (2002) Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br J Psychiatry 180:502–508CrossRefPubMedGoogle Scholar
  26. O’Connor TG, Bergman K, Sarkar P, Glover V (2013) Prenatal cortisol exposure predicts infant cortisol response to acute stress. Dev Psychobiol 55:145–155. doi: 10.1002/dev.21007 CrossRefPubMedGoogle Scholar
  27. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106CrossRefPubMedGoogle Scholar
  28. Perroud N, Rutembesa E, Paoloni-Giacobino A et al (2014) The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry 15:334–345. doi: 10.3109/15622975.2013.866693 CrossRefPubMedGoogle Scholar
  29. Pineles SL, Rasmusson AM, Yehuda R, Lasko NB, Macklin ML, Pitman RK, Orr SP (2013) Predicting emotional responses to potentially traumatic events from pre-exposure waking cortisol levels: a longitudinal study of police and firefighters. Anxiety Stress Coping 26:241–253. doi: 10.1080/10615806.2012.672976 CrossRefPubMedGoogle Scholar
  30. Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, Elbert T (2011) Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry 1, e21. doi: 10.1038/tp.2011.21 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ressler KJ, Mercer KB, Bradley B et al (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470:492–497. doi: 10.1038/nature09856 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Smallwood SA, Kelsey G (2012) De novo DNA methylation: a germ cell perspective. Trends Genet 28:33–42. doi: 10.1016/j.tig.2011.09.004 CrossRefPubMedGoogle Scholar
  33. Smith AK, Kilaru V, Klengel T et al (2015) DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet B Neuropsychiatr Genet 168B:36–44. doi: 10.1002/ajmg.b.32278 CrossRefPubMedGoogle Scholar
  34. Solomon Z, Kotler M, Mikulincer M (1988) Combat-related posttraumatic stress disorder among second-generation Holocaust survivors: preliminary findings. Am J Psychiatry 145:865–868CrossRefPubMedGoogle Scholar
  35. Spiegelman A (1991) Maus II: a survivor’s tale: and here my troubles began. Pantheon Books, New YorkGoogle Scholar
  36. Turner JD, Muller CP (2005) Structure of the glucocorticoid receptor (NR3C1) gene 5’ untranslated region: identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol 35:283–292. doi: 10.1677/jme.1.01822 CrossRefPubMedGoogle Scholar
  37. Van den Bergh BR, Van Calster B, Smits T, Van Huffel S, Lagae L (2008) Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology 33:536–545. doi: 10.1038/sj.npp.1301450 CrossRefPubMedGoogle Scholar
  38. van der Knaap LJ, Riese H, Hudziak JJ, Verbiest MM, Verhulst FC, Oldehinkel AJ, van Oort FV (2014) Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Transl Psychiatry 4, e381. doi: 10.1038/tp.2014.22 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Vassoler FM, White SL, Schmidt HD, Sadri-Vakili G, Pierce RC (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42–47. doi: 10.1038/nn.3280 CrossRefPubMedGoogle Scholar
  40. Walsh K, Nugent NR, Kotte A et al (2013) Cortisol at the emergency room rape visit as a predictor of PTSD and depression symptoms over time. Psychoneuroendocrinology 38:2520–2528. doi: 10.1016/j.psyneuen.2013.05.017 CrossRefPubMedGoogle Scholar
  41. Wankerl M, Miller R, Kirschbaum C, Hennig J, Stalder T, Alexander N (2014) Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles. Transl Psychiatry 4, e402. doi: 10.1038/tp.2014.37 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Weaver IC, Cervoni N, Champagne FA et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854. doi: 10.1038/nn1276 CrossRefPubMedGoogle Scholar
  43. Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schubeler D (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39:457–466. doi: 10.1038/ng1990 CrossRefPubMedGoogle Scholar
  44. Yehuda R, Bierer LM (2008) Transgenerational transmission of cortisol and PTSD risk. Prog Brain Res 167:121–135. doi: 10.1016/S0079-6123(07)67009-5 CrossRefPubMedGoogle Scholar
  45. Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr, Mason JW (1990) Low urinary cortisol excretion in patients with posttraumatic stress disorder. J Nerv Ment Dis 178:366–369CrossRefPubMedGoogle Scholar
  46. Yehuda R, Southwick SM, Krystal JH, Bremner D, Charney DS, Mason JW (1993) Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. Am J Psychiatry 150:83–86CrossRefPubMedGoogle Scholar
  47. Yehuda R, Schmeidler J, Wainberg M, Binder-Brynes K, Duvdevani T (1998) Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. Am J Psychiatry 155:1163–1171CrossRefPubMedGoogle Scholar
  48. Yehuda R, Bierer LM, Schmeidler J, Aferiat DH, Breslau I, Dolan S (2000) Low cortisol and risk for PTSD in adult offspring of holocaust survivors. Am J Psychiatry 157:1252–1259CrossRefPubMedGoogle Scholar
  49. Yehuda R, Halligan SL, Bierer LM (2001) Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring. J Psychiatr Res 35:261–270CrossRefPubMedGoogle Scholar
  50. Yehuda R, Halligan SL, Bierer LM (2002) Cortisol levels in adult offspring of Holocaust survivors: relation to PTSD symptom severity in the parent and child. Psychoneuroendocrinology 27:171–180CrossRefPubMedGoogle Scholar
  51. Yehuda R, Halligan SL, Golier JA, Grossman R, Bierer LM (2004) Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder. Psychoneuroendocrinology 29:389–404CrossRefPubMedGoogle Scholar
  52. Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS (2005) Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 90:4115–4118. doi: 10.1210/jc.2005-0550 CrossRefPubMedGoogle Scholar
  53. Yehuda R, Blair W, Labinsky E, Bierer LM (2007) Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring. Am J Psychiatry 164:163–166. doi: 10.1176/appi.ajp.164.1.163 CrossRefPubMedGoogle Scholar
  54. Yehuda R, Bell A, Bierer LM, Schmeidler J (2008) Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J Psychiatr Res 42:1104–1111. doi: 10.1016/j.jpsychires.2008.01.002 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Yehuda R, Daskalakis NP, Lehrner A et al (2014) Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 171:872–880. doi: 10.1176/appi.ajp.2014.13121571 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Zhang TY, Meaney MJ (2010) Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol 61(439–466):C431–C433. doi: 10.1146/annurev.psych.60.110707.163625 Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Departments of PsychiatryIcahn School of Medicine at Mount SinaiBronxUSA
  2. 2.James J. Peters Veterans Affairs Medical CenterBronxUSA
  3. 3.Departments of NeuroscienceIcahn School of Medicine at Mount SinaiBronxUSA

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