Psychosocial Impact of Epigenetics in Pediatrics

  • Xiaoming Gong
  • Lewis P. RubinEmail author
Reference work entry


Psychosocial stress has pervasive influences on our lives. Both human and experimental animal studies demonstrate that psychosocial stressor exposures experienced during early (prenatal and infant) life can modify risks for health deterioration and disease in later life. In many cases, adapting to stress can lead to resilience and strengthen the organism, but chronic or severe stress often has harmful, maladaptive consequences. Chronic malnutrition, changes in social conditions, and adverse early life experiences can program phenotypes and contribute to long-lasting disease risk. A growing body of evidence indicates that epigenetic mechanisms play a major role in the biological response to psychosocial stresses. In this chapter, we summarize current knowledge on epigenetic changes in response to psychosocial stressors in the pediatric age group. We focus on epigenetic mechanisms, in particular DNA methylation, as molecular mechanisms that link psychosocial stress and health consequences, and discuss common epigenetic effector pathways during psychosocial stressors at different stages in development.


Epigenetic modification Early life stress Prenatal stress Postnatal stress HPA axis DNA methylation microRNAs 

List of Abbreviations


Allostatic load


Brain-derived neurotrophic factor


Corticotropin-releasing hormone


Developmental origins of health and disease


FK506 binding protein 5




Glucocorticoid receptor




Low birth weight


Noncoding RNAs


Nuclear receptor subfamily 3 group C member 1


Posttraumatic stress disorder


Socioeconomic status


  1. Aizer A, Currie J (2014) The intergenerational transmission of inequality: maternal disadvantage and health at birth. Science 344:856–861CrossRefGoogle Scholar
  2. Alt SR, Turner JD, Klok MD, Meijer OC, Lakke EA, Derijk RH, Muller CP (2010) Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed. Psychoneuroendocrinology 35:544–556CrossRefGoogle Scholar
  3. Anacker C, O’Donnell KJ, Meaney MJ (2014) Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function. Dialogues Clin Neurosci 16:321–333PubMedPubMedCentralGoogle Scholar
  4. Ben-Shlomo Y (2007) Rising to the challenges and opportunities of life course epidemiology. Int J Epidemiol 36:481–483CrossRefGoogle Scholar
  5. Blumenshine P, Egerter S, Barclay CJ, Cubbin C, Braveman PA (2010) Socioeconomic disparities in adverse birth outcomes a systematic review. Am J Prev Med 39:263–272CrossRefGoogle Scholar
  6. Bockmuhl Y, Patchev AV, Madejska A, Hoffmann A, Sousa JC, Sousa N, Holsboer F, Almeida OFX, Spengler D (2015) Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress. Epigenetics 10:247–257CrossRefGoogle Scholar
  7. Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, Hertzman C, Power C, Szyf M (2012) Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol 41:62–74CrossRefGoogle Scholar
  8. Braithwaite EC, Kundakovic M, Ramchandani PG, Murphy SE, Champagne FA (2015) Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics 10:408–417CrossRefGoogle Scholar
  9. Braveman P (2009) A health disparities perspective on obesity research. Prev Chronic Dis 6:A91PubMedPubMedCentralGoogle Scholar
  10. Brent DA, Silverstein M (2013) Shedding light on the long shadow of childhood adversity. JAMA 309:1777–1778CrossRefGoogle Scholar
  11. Caldji C, Diorio J, Meaney MJ (2000) Variations in maternal care in infancy regulate the development of stress reactivity. Biol Psychiatry 48:1164–1174CrossRefGoogle Scholar
  12. Cole SW, Conti G, Arevalo JMG, Ruggiero AM, Heckman JJ, Suomi SJ (2012) Transcriptional modulation of the developing immune system by early life social adversity. Proc Natl Acad Sci U S A 109:20578–20583CrossRefGoogle Scholar
  13. Curley JP, Jensen CL, Mashoodh R, Champagne FA (2011) Social influences on neurobiology and behavior: epigenetic effects during development. Psychoneuroendocrinology 36:352–371CrossRefGoogle Scholar
  14. Del Giudice M (2014) Early stress and human behavioral development: emerging evolutionary perspectives. J Dev Orig Health Dis 5:270–280CrossRefGoogle Scholar
  15. Dogini DB, Pascoal VDB, Avansini SH, Vieira AS, Pereira TC, Lopes-Cendes I (2014) The new world of RNAs. Genet Mol Biol 37:285–293CrossRefGoogle Scholar
  16. Doherty TS, Forster A, Roth TL (2016) Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. Behav Brain Res 298:55–61CrossRefGoogle Scholar
  17. Drury SS, Mabile E, Brett ZH, Esteves K, Jones E, Shirtcliff EA, Theall KP (2014) The association of telomere length with family violence and disruption. Pediatrics 134:E128–E137CrossRefGoogle Scholar
  18. Entringer S (2013) Impact of stress and stress physiology during pregnancy on child metabolic function and obesity risk. Curr Opin Clin Nutr Metab Care 16:320–327CrossRefGoogle Scholar
  19. Entringer S, Kumsta R, Nelson EL, Hellhammer DH, Wadhwa PD, Wust S (2008a) Influence of prenatal psychosocial stress on cytokine production in adult women. Dev Psychobiol 50:579–587CrossRefGoogle Scholar
  20. Entringer S, Wust S, Kumsta R, Layes IM, Nelson EL, Hellhammer DH, Wadhwa PD (2008b) Prenatal psychosocial stress exposure is associated with insulin resistance in young adults. Am J Obstet Gynecol 199:498.e1CrossRefGoogle Scholar
  21. Fagiolini M, Jensen CL, Champagne FA (2009) Epigenetic influences on brain development and plasticity. Curr Opin Neurobiol 19:207–212CrossRefGoogle Scholar
  22. Fox SE, Levitt P, Nelson CA 3rd (2010) How the timing and quality of early experiences influence the development of brain architecture. Child Dev 81:28–40CrossRefGoogle Scholar
  23. Gluckman PD, Hanson MA (2006) The developmental origins of health and disease: the breadth and importance of the concept. Adv Exp Med Biol 573:1–7CrossRefGoogle Scholar
  24. Hackman DA, Farah MJ, Meaney MJ (2010) Socioeconomic status and the brain: mechanistic insights from human and animal research. Nat Rev Neurosci 11:651–659CrossRefGoogle Scholar
  25. Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R, Hornstein E, Chen A (2011) microRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J Neurosci 31:14191–14203CrossRefGoogle Scholar
  26. Harris A, Seckl J (2011) Glucocorticoids, prenatal stress and the programming of disease. Horm Behav 59:279–289CrossRefGoogle Scholar
  27. Houtepen LC, Vinkers CH, Carrillo-Roa T, Hiemstra M, van Lier PA, Meeus W, Branje S, Heim CM, Nemeroff CB, Mill J, Schalkwyk LC, Creyghton MP, Kahn RS, Joels M, Binder EB, Boks MP (2016) Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun 7:10967CrossRefGoogle Scholar
  28. Hudson WH, Pickard MR, de Vera IM, Kuiper EG, Mourtada-Maarabouni M, Conn GL, Kojetin DJ, Williams GT, Ortlund EA (2014) Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nat Commun 5:5395CrossRefGoogle Scholar
  29. Johansson A, Enroth S, Gyllensten U (2013) Continuous aging of the human DNA methylome throughout the human lifespan. PLoS One 8:e67378CrossRefGoogle Scholar
  30. Jung SH, Wang YF, Kim T, Tarr A, Reader B, Powell N, Sheridan JF (2015) Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: role of microRNA. Brain Behav Immun 44:195–206CrossRefGoogle Scholar
  31. Kanherkar RR, Bhatia-Dey N, Csoka AB (2014) Epigenetics across the human lifespan. Front Cell Dev Biol 2:49PubMedPubMedCentralGoogle Scholar
  32. Kertes DA, Kamin H, Hughes DA, Rodney N, Bhatt SS, Mulligan CJ (2015) Maternal stress predicts methylation of genes regulating the HPA axis in mothers and newborns in the Democratic Republic of Congo. Psychoneuroendocrinology 61:5CrossRefGoogle Scholar
  33. Khulan B, Manning JR, Dunbar DR, Seckl JR, Raikkonen K, Eriksson JG, Drake AJ (2014) Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state. Transl Psychiatry 4:e448CrossRefGoogle Scholar
  34. King S, Laplante DP (2005) The effects of prenatal maternal stress on children’s cognitive development: project ice storm. Stress 8:35–45CrossRefGoogle Scholar
  35. Kinnally EL, Feinberg C, Kim D, Ferguson K, Leibel R, Coplan JD, Mann JJ (2011) DNA methylation as a risk factor in the effects of early life stress. Brain Behav Immun 25:1548–1553CrossRefGoogle Scholar
  36. Klengel T, Binder EB (2013) Gene-environment interactions in major depressive disorder. Can J Psychiatry 58:76–83CrossRefGoogle Scholar
  37. Labonte B, Suderman M, Maussion G, Yerko V, Mechawar N, Szyf M, Meaney MJ, Turecki G (2012) Genome-wide epigenetic reprogramming in the brain of suicide completers. Biol Psychiatry 71:45sGoogle Scholar
  38. 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 109:17253–17260CrossRefGoogle Scholar
  39. Lee BE, Ha M, Park H, Hong YC, Kim Y, Kim YJ, Ha EH (2011) Psychosocial work stress during pregnancy and birthweight. Paediatr Perinat Epidemiol 25:246–254CrossRefGoogle Scholar
  40. Li J, Vestergaard M, Obel C, Christensen J, Precht DH, Lu M, Olsen J (2009) A nationwide study on the risk of autism after prenatal stress exposure to maternal bereavement. Pediatrics 123:1102–1107CrossRefGoogle Scholar
  41. Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445CrossRefGoogle Scholar
  42. Mars B, Collishaw S, Hammerton G, Rice F, Harold GT, Smith D, Jones RB, Sellers R, Potter R, Craddock N, Thapar AK, Heron J, Thapar A (2015) Longitudinal symptom course in adults with recurrent depression: impact on impairment and risk of psychopathology in offspring. J Affect Disord 182:32–38CrossRefGoogle Scholar
  43. McEwen BS, Wingfield JC (2010) What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav 57:105–111CrossRefGoogle Scholar
  44. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348CrossRefGoogle Scholar
  45. Meerson A, Cacheaux L, Goosens KA, Sapolsky RM, Soreq H, Kaufer D (2010) Changes in brain MicroRNAs contribute to cholinergic stress reactions. J Mol Neurosci 40:47–55CrossRefGoogle Scholar
  46. Mehta D, Klengel T, Conneely KN, Smith AK, Altmann A, Pace TW, Rex-Haffner M, Loeschner A, Gonik M, Mercer KB, Bradley B, Muller-Myhsok B, Ressler KJ, Binder EB (2013) Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A 110:8302–8307CrossRefGoogle Scholar
  47. Mueller BR, Bale TL (2008) Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 28:9055–9065CrossRefGoogle Scholar
  48. 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 7:853–857CrossRefGoogle Scholar
  49. Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmuhl Y, Fischer D, Holsboer F, Wotjak CT, Almeida OFX, Spengler D (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12:1559–U1108CrossRefGoogle Scholar
  50. Nasca C, Bigio B, Zelli D, Mathe A, McEwen B (2015) Epigenetic mechanisms of hippocampal plasticity: P300-driven mGlu2 Up-regulation mediates resilience and antidepressant responses. Neuropsychopharmacology 40:S502–S503CrossRefGoogle Scholar
  51. Nishi M, Horii-Hayashi N, Sasagawa T (2013) Effects of early life stress on brain activity: implications from maternal separation model in rodents. J Physiol Sci 63:S47–S47CrossRefGoogle Scholar
  52. Non AL, Hollister BM, Humphreys KL, Childebayeva A, Esteves K, Zeanah CH, Fox NA, Nelson CA, Drury SS (2016) DNA methylation at stress-related genes is associated with exposure to early life institutionalization. Am J Phys Anthropol 161:84–93CrossRefGoogle Scholar
  53. 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 3:97–106CrossRefGoogle Scholar
  54. Palma-Gudiel H, Cordova-Palomera A, Eixarch E, Deuschle M, Fananas L (2015) Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis. Epigenetics 10:893–902CrossRefGoogle Scholar
  55. Pearson RM, Evans J, Kounali D, Lewis G, Heron J, Ramchandani PG, O’Connor TG, Stein A (2013) Maternal depression during pregnancy and the postnatal period risks and possible mechanisms for offspring depression at age 18 years. JAMA Psychiat 70:1312–1319CrossRefGoogle Scholar
  56. Plongthongkum N, Diep DH, Zhang K (2014) Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat Rev Genet 15:647–661CrossRefGoogle Scholar
  57. 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:e21CrossRefGoogle Scholar
  58. Reynolds RM, Jacobsen GH, Drake AJ (2013) What is the evidence in humans that DNA methylation changes link events in utero and later life disease? Clin Endocrinol (Oxf) 78:814–822CrossRefGoogle Scholar
  59. Rubin LP (2016) Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics. Pediatr Res 79:127–135CrossRefGoogle Scholar
  60. Schouten M, Aschrafi A, Bielefeld P, Doxakis E, Fitzsimons CP (2013) Micrornas and the regulation of neuronal plasticity under stress conditions. Neuroscience 241:188–205CrossRefGoogle Scholar
  61. Segerstrom SC, Miller GE (2004) Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 130:601–630CrossRefGoogle Scholar
  62. Smalheiser NR, Lugli G, Rizavi HS, Torvik VI, Turecki G, Dwivedi Y (2012) MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One 7:e33201CrossRefGoogle Scholar
  63. Solis CB, Kelly-Irving M, Fantin R, Darnaudery M, Torrisani J, Lang T, Delpierre C (2015) Adverse childhood experiences and physiological wear- and-tear in midlife: findings from the 1958 British birth cohort. Proc Natl Acad Sci U S A 112:E738–E746CrossRefGoogle Scholar
  64. Suderman M, McGowan PO, Sasaki A, Huang TCT, Hallett MT, Meaney MJ, Turecki G, Szyf M (2012) Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci USA 109:17266–17272CrossRefGoogle Scholar
  65. Suderman M, Borghol N, Pappas JJ, Pereira SMP, Pembrey M, Hertzman C, Power C, Szyf M (2014) Childhood abuse is associated with methylation of multiple loci in adult DNA. BMC Med Genomics 7:1CrossRefGoogle Scholar
  66. Tamashiro KLK (2011) Metabolic syndrome: links to social stress and socioeconomic status. Ann N Y Acad Sci 1231:46–55CrossRefGoogle Scholar
  67. Teh AL, Pan H, Chen L, Ong ML, Dogra S, Wong J, MacIsaac JL, Mah SM, McEwen LM, Saw SM, Godfrey KM, Chong YS, Kwek K, Kwoh CK, Soh SE, Chong MFF, Barton S, Karnani N, Cheong CY, Buschdorf JP, Stunkel W, Kobor MS, Meaney MJ, Gluckman PD, Holbrook JD (2014) The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res 24:1064–1074CrossRefGoogle Scholar
  68. Turecki G, Meaney MJ (2016) Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry 79:87–96CrossRefGoogle Scholar
  69. Tyrka AR, Parade SH, Eslinger NM, Marsit CJ, Lesseur C, Armstrong DA, Philip NS, Josefson B, Seifer R (2015) Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children. Dev Psychopathol 27:577–585CrossRefGoogle Scholar
  70. Varese F, Smeets F, Drukker M, Lieverse R, Lataster T, Viechtbauer W, Read J, van Os J, Bentall RP (2012) Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 38:661–671CrossRefGoogle Scholar
  71. Vreugdenhil E, Verissimo CS, Mariman R, Kamphorst JT, Barbosa JS, Zweers T, Champagne DL, Schouten T, Meijer OC, de Kloet ER, Fitzsimons CP (2009) MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 150:2220–2228CrossRefGoogle Scholar
  72. Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854CrossRefGoogle Scholar
  73. Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086CrossRefGoogle Scholar
  74. Witzmann SR, Turner JD, Meriaux SB, Meijer OC, Muller CP (2012) Epigenetic regulation of the glucocorticoid receptor promoter 1(7) in adult rats. Epigenetics 7:1290–1301CrossRefGoogle Scholar
  75. Yang BZ, Zhang HP, Ge WJ, Weder N, Douglas-Palumberi H, Perepletchikova F, Gelernter J, Kaufman J (2013) Child abuse and epigenetic mechanisms of disease risk. Am J Prev Med 44:101–107CrossRefGoogle Scholar
  76. Zaidi SK, Young DW, Montecino M, Lian JB, Stein JL, van Wijnen AJ, Stein GS (2010) Architectural epigenetics: mitotic retention of mammalian transcriptional regulatory information. Mol Cell Biol 30:4758–66CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Paul L. Foster School of MedicineTexas Tech University Health Sciences Center El PasoEl PasoUSA
  2. 2.Departments of Pediatrics and Biomedical Sciences, Paul L. Foster School of MedicineTexas Tech University Health Sciences Center El PasoEl PasoUSA

Personalised recommendations