Skip to main content
SpringerLink
Log in

Hypothalamus-Pituitary-Adrenal Axis Programming by Early-Life Stress: A Role Played by Inflammatory and Epigenetic Mechanisms

  • Chapter
  • First Online:
Book cover Perinatal Inflammation and Adult Psychopathology

Part of the book series: Progress in Inflammation Research ((PIR,volume 84))

Abstract

Early-life stress exposure, regardless whether pre-, peri-, or post-natal, has been shown to increase the risk for psychiatric disorders in vulnerable subjects. One of the hypothesis that explains this association suggests that early-life stress can induce a programming of the main physiological system responsible for the stress response, namely, the hypothalamus-pituitary-adrenal (HPA) axis. Indeed, several lines of evidence suggest that exposure to early trauma or stressful events can induce permanent alterations in the HPA axis, some of which are also seen in patients with psychiatric disorders. This chapter will discuss clinical and preclinical evidence of HPA programming by early-life stress and the molecular mechanisms suggested to underlie it, i.e., inflammation and epigenetic mechanisms. Future perspectives and clinical implications of the HPA programming and its biological basis are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Darnaudery M, Maccari S. Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev. 2008;57:571–85.

    Article  CAS  PubMed  Google Scholar 

  2. Agorastos A, Pervanidou P, Chrousos GP, Kolaitis G. Early life stress and trauma: developmental neuroendocrine aspects of prolonged stress system dysregulation. Hormones (Athens). 2018;17:507–20.

    Article  Google Scholar 

  3. Howland MA, Sandman CA, Glynn LM. Developmental origins of the human hypothalamic-pituitary-adrenal axis. Expert Rev Endocrinol Metab. 2017;12:321–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Egliston KA, McMahon C, Austin MP. Stress in pregnancy and infant HPA axis function: conceptual and methodological issues relating to the use of salivary cortisol as an outcome measure. Psychoneuroendocrinology. 2007;32:1–13.

    Article  CAS  PubMed  Google Scholar 

  5. Murgatroyd C, Spengler D. Epigenetic programming of the HPA axis: early life decides. Stress (Amsterdam, Netherlands). 2011;14:581–9.

    Article  CAS  Google Scholar 

  6. Maniam J, Antoniadis C, Morris MJ. Early-life stress, HPA Axis adaptation, and mechanisms contributing to later health outcomes. Front Endocrinol. 2014;5:73.

    Article  Google Scholar 

  7. Heim C, Nemeroff CB. Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry. 2002;7:147–59.

    Article  PubMed  Google Scholar 

  8. Heim C, Mletzko T, Purselle D, Musselman DL, Nemeroff CB. The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry. 2008;63:398–405.

    Article  CAS  PubMed  Google Scholar 

  9. Woythaler M. Neurodevelopmental outcomes of the late preterm infant. Semin Fetal Neonatal Med. 2019;24:54–9.

    Article  PubMed  Google Scholar 

  10. Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev. 2010;20:327–48.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brunton PJ, Russell JA. Neuroendocrine control of maternal stress responses and fetal programming by stress in pregnancy. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35:1178–91.

    Article  CAS  Google Scholar 

  12. McTernan CL, et al. Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab. 2001;86:4979–83.

    CAS  PubMed  Google Scholar 

  13. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term. Pediatr Res. 1973;7:509–19.

    Article  CAS  PubMed  Google Scholar 

  14. Niu X, et al. Maternal high fat diet programs hypothalamic-pituitary-adrenal function in adult rat offspring. Psychoneuroendocrinology. 2019;102:128–38.

    Article  CAS  PubMed  Google Scholar 

  15. Osborne S, et al. Antenatal depression programs cortisol stress reactivity in offspring through increased maternal inflammation and cortisol in pregnancy: the psychiatry research and motherhood – depression (PRAM-D) study. Psychoneuroendocrinology. 2018;98:211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Bruijn AT, van Bakel HJ, Wijnen H, Pop VJ, van Baar AL. Prenatal maternal emotional complaints are associated with cortisol responses in toddler and preschool aged girls. Dev Psychobiol. 2009;51:553–63.

    Article  PubMed  CAS  Google Scholar 

  17. O’Donnell KJ, Glover V, Jenkins J, Browne D, Ben-Shlomo Y, Golding J, O’Connor TG. Prenatal maternal mood is associated with altered diurnal cortisol in adolescence. Psychoneuroendocrinology. 2013;38:1630–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Van den Bergh BR, Van Calster B, Smits T, Van Huffel S, Lagae L. 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. 2008;33:536–45.

    Article  PubMed  Google Scholar 

  19. Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wust S. Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav. 2009;55:292–8.

    Article  CAS  PubMed  Google Scholar 

  20. Brummelte S, Chau CM, Cepeda IL, Degenhardt A, Weinberg J, Synnes AR, Grunau RE. Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress. Psychoneuroendocrinology. 2015;51:151–63.

    Article  CAS  PubMed  Google Scholar 

  21. Grunau RE, et al. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain. 2005;113:293–300.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Finken MJJ, van der Voorn B, Hollanders JJ, Ruys CA, de Waard M, van Goudoever JB, Rotteveel J. Programming of the hypothalamus-pituitary-adrenal axis by very preterm birth. Ann Nutr Metab. 2017;70:170–4.

    Article  CAS  PubMed  Google Scholar 

  23. Koe AS, Salzberg MR, Morris MJ, O’Brien TJ, Jones NC. Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming. Psychoneuroendocrinology. 2014;42:124–33.

    Article  CAS  PubMed  Google Scholar 

  24. Sakhai SA, Saxton K, Francis DD. The influence of early maternal care on perceptual attentional set shifting and stress reactivity in adult rats. Dev Psychobiol. 2016;58:39–51.

    Article  PubMed  Google Scholar 

  25. Kumsta R, et al. HPA axis dysregulation in adult adoptees twenty years after severe institutional deprivation in childhood. Psychoneuroendocrinology. 2017;86:196–202.

    Article  PubMed  Google Scholar 

  26. Koss KJ, Hostinar CE, Donzella B, Gunnar MR. Social deprivation and the HPA axis in early development. Psychoneuroendocrinology. 2014;50:1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rohleder N. Stress and inflammation – the need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology. 2019.

    Google Scholar 

  28. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun. 2002;16:622–53.

    Article  CAS  PubMed  Google Scholar 

  29. Fleshner M, Frank M, Maier SF. Danger signals and Inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology. 2017;42:36–45.

    Article  CAS  PubMed  Google Scholar 

  30. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? An N Y Acad Sci. 2019;1437:57–7.

    Google Scholar 

  31. Bethin KE, Vogt SK, Muglia LJ. Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation. Proc Natl Acad Sci U S A. 2000;97:9317–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vanbesien-Mailliot CC, et al. Prenatal stress has pro-inflammatory consequences on the immune system in adult rats. Psychoneuroendocrinology. 2007;32:114–24.

    Article  CAS  PubMed  Google Scholar 

  33. Laviola G, et al. Beneficial effects of enriched environment on adolescent rats from stressed pregnancies. Eur J Neurosci. 2004;20:1655–64.

    Article  PubMed  Google Scholar 

  34. Day JC, Koehl M, Deroche V, Le Moal M, Maccari S. Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats. J Neurosci Off J Soc Neurosci. 1998;18:1886–92.

    Google Scholar 

  35. Soualeh N, Dridi I, Eppe G, Nemos C, Soulimani R, Bouayed J. Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: gender selective effects. Brain Behav Immun. 2017;63:137–47.

    Article  PubMed  Google Scholar 

  36. Wang HL, et al. Prenatal maternal vaginal inflammation increases anxiety and alters HPA axis signalling in adult male mice. Int J Dev Neurosci. 2019;75:27–35.

    Article  CAS  PubMed  Google Scholar 

  37. Shen J, et al. Changes in DNA methylation and chromatin structure of pro-inflammatory cytokines stimulated by LPS in broiler peripheral blood mononuclear cells. Poult Sci. 2016;95:1636–45.

    Article  CAS  PubMed  Google Scholar 

  38. Verschoor CP, et al. The relation between DNA methylation patterns and serum cytokine levels in community-dwelling adults: a preliminary study. BMC Genet. 2017;18:57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Nicolia V, Cavallaro RA, Lopez-Gonzalez I, Maccarrone M, Scarpa S, Ferrer I, Fuso A. DNA methylation profiles of selected pro-inflammatory cytokines in Alzheimer disease. J Neuropathol Exp Neurol. 2017;76:27–31.

    CAS  PubMed  Google Scholar 

  40. Smith AK, et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Gen Part B Neuropsychiatr Gen. 2011;156b:700–8.

    Article  CAS  Google Scholar 

  41. McIlwrick S, Rechenberg A, Matthes M, Burgstaller J, Schwarzbauer T, Chen A, Touma C. Genetic predisposition for high stress reactivity amplifies effects of early-life adversity. Psychoneuroendocrinology. 2016;70:85–97.

    Article  PubMed  Google Scholar 

  42. Deans C, Maggert KA. What do you mean, “epigenetic”? Genetics. 2015;199:887–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reyes-Contreras M, Glauser G, Rennison DJ, Taborsky B. Early-life manipulation of cortisol and its receptor alters stress axis programming and social competence. Philos Trans R Soc Lond Ser B Biol Sci. 2019;374:20180119.

    Article  CAS  Google Scholar 

  44. Galigniana NM, Ballmer LT, Toneatto J, Erlejman AG, Lagadari M, Galigniana MD. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neurochem. 2012;122:4–18.

    Article  CAS  PubMed  Google Scholar 

  45. A D, T H. Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des. 2004;10:2807–16.

    Article  Google Scholar 

  46. Fries GR, Gassen NC, Rein T. The FKBP51 glucocorticoid receptor co-chaperone: regulation, function, and implications in health and disease. Int J Mol Sci. 2017;18.

    Google Scholar 

  47. Jaaskelainen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11:326–31.

    Article  PubMed  CAS  Google Scholar 

  48. Palma-Gudiel H, Cordova-Palomera A, Tornador C, Falcon C, Bargallo N, Deco G, Fananas L. Increased methylation at an unexplored glucocorticoid responsive element within exon 1D of NR3C1 gene is related to anxious-depressive disorders and decreased hippocampal connectivity. Eur Neuropsychopharmacol. 2018;28:579–88.

    Article  CAS  PubMed  Google Scholar 

  49. Klengel T, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33–41.

    Article  CAS  PubMed  Google Scholar 

  50. Criado-Marrero M, Rein T, Binder EB, Porter JT, Koren J, 3rd, Blair LJ. Hsp90 and FKBP51: complex regulators of psychiatric diseases. Philos Trans R Soc Lond Ser B Biol Sci. 2018;373.

    Google Scholar 

  51. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3:97–106.

    Article  PubMed  Google Scholar 

  52. Hompes T, et al. 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. 2013;47:880–91.

    Article  PubMed  Google Scholar 

  53. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ. The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics. 2013;8:1321–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tobi EW, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.

    Article  CAS  PubMed  Google Scholar 

  55. Tobi EW, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;18:4046–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Perroud N, et al. The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatr. 2014;15:334–45.

    Article  Google Scholar 

  57. Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, Elbert T. Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry. 2011;1:e21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jawahar MC, Murgatroyd C, Harrison EL, Baune BT. Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders. Clin Epigenetics. 2015;7:122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lutz PE, Turecki G. DNA methylation and childhood maltreatment: from animal models to human studies. Neuroscience. 2014;264:142–56.

    Article  CAS  PubMed  Google Scholar 

  60. Fish EW, Shahrokh D, Bagot R, Caldji C, Bredy T, Szyf M, Meaney MJ. Epigenetic programming of stress responses through variations in maternal care. Ann N Y Acad Sci. 2004;1036:167–80.

    Google Scholar 

  61. Weaver IC, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54.

    Article  CAS  PubMed  Google Scholar 

  62. Roth TL, Sweatt JD. Epigenetic marking of the BDNF gene by early-life adverse experiences. Horm Behav. 2011;59:315–20.

    Article  CAS  PubMed  Google Scholar 

  63. Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65:760–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Doherty TS, Forster A, Roth TL. Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment. Behav Brain Res. 2016;298:55–61.

    Article  CAS  PubMed  Google Scholar 

  65. Ramo-Fernandez L, et al. The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach. Sci Rep. 2019;9:983.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Nothling J, Malan-Muller S, Abrahams N, Joanna Hemmings SM, Seedat S. Epigenetic alterations associated with childhood trauma and adult mental health outcomes: a systematic review. World J Biolog Psychiatr. 2019:1–20.

    Google Scholar 

  67. Alexander N, et al. Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity. Psychoneuroendocrinology. 2018;90:68–75.

    Article  CAS  PubMed  Google Scholar 

  68. Houtepen LC, et al. Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun. 2016;7:10967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Szyf M, Weaver I, Meaney M. Maternal care, the epigenome and phenotypic differences in behavior. Reprod Toxicol (Elmsford, NY). 2007;24:9–19.

    Article  CAS  Google Scholar 

  70. Blaze J, Scheuing L, Roth TL. Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy. Dev Neurosci. 2013;35:306–16.

    Article  CAS  PubMed  Google Scholar 

  71. Houtepen LC, et al. Childhood adversity and DNA methylation in two population-based cohorts. Transl Psychiatry. 2018;8:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. O’Donnell KJ, et al. DNA methylome variation in a perinatal nurse-visitation program that reduces child maltreatment: a 27-year follow-up. Transl Psychiatry. 2018;8:15.

    Article  PubMed  PubMed Central  Google Scholar 

  73. van der Doelen RH, Arnoldussen IA, Ghareh H, van Och L, Homberg JR, Kozicz T. Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain. Dev Psychopathol. 2015;27:123–35.

    Article  PubMed  Google Scholar 

  74. Gedo JE. The enduring scientific contributions of Sigmund Freud. Perspect Biol Med. 2002;45:200–11.

    Article  PubMed  Google Scholar 

  75. Brennan LJ, Goulopoulou S, Bourque SL. Prenatal therapeutics and programming of cardiovascular function. Pharmacol Res. 2019;139:261–72.

    Article  CAS  PubMed  Google Scholar 

  76. Vaiserman AM. Epigenetic programming by early-life stress: evidence from human populations. Dev Dyn. 2015;244:254–65.

    Article  CAS  PubMed  Google Scholar 

  77. Tain YL, Hsu CN. Developmental programming of the metabolic syndrome: can we reprogram with resveratrol? Int J Mol Sci. 2018;19

    Google Scholar 

  78. Agorastos A, Pervanidou P, Chrousos GP, Baker DG. Developmental trajectories of early life stress and trauma: a narrative review on neurobiological aspects beyond stress system dysregulation. Front Psych. 2019;10:118.

    Article  Google Scholar 

  79. Kosten TA, Nielsen DA. Litter and sex effects on maternal behavior and DNA methylation of the Nr3c1 exon 17 promoter gene in hippocampus and cerebellum. Int J Dev Neurosci. 2014;36:5–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Candemir E, Post A, Dischinger US, Palme R, Slattery DA, O’Leary A, Reif A. Limited effects of early life manipulations on sex-specific gene expression and behavior in adulthood. Behaviour Brain Res. 2019;111927.

    Google Scholar 

  81. Schmidt KL, Kubli SP, MacDougall-Shackleton EA, MacDougall-Shackleton SA. Early-life stress has sex-specific effects on immune function in adult song sparrows. Physiolog Biochem Zool. 2015;88:183–94.

    Article  Google Scholar 

  82. Farrell MR, Holland FH, Shansky RM, Brenhouse HC. Sex-specific effects of early life stress on social interaction and prefrontal cortex dendritic morphology in young rats. Behav Brain Res. 2016;310:119–25.

    Article  CAS  PubMed  Google Scholar 

  83. Weber-Stadlbauer U, Richetto J, Labouesse MA, Bohacek J, Mansuy IM, Meyer U. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Mol Psychiatry. 2017;22:102–12.

    Article  CAS  PubMed  Google Scholar 

  84. Richetto J, Massart R, Weber-Stadlbauer U, Szyf M, Riva MA, Meyer U. Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders. Biol Psychiatry. 2017;81:265–76.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Gabriel R. Fries

Authors
  1. Gabriel R. Fries
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriel R. Fries .

Editor information

Editors and Affiliations

  1. Psychiatry and Behavioral Sciences, UT Health Houston, Houston, TX, USA

    Antonio L. Teixeira

  2. Physiology and Pharmacology, Universidade Federal do Ceara, Fortaleza, Brazil

    Danielle Macedo

  3. Psychiatry, University of Munster, Munster, Germany

    Bernhard T. Baune

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fries, G.R. (2020). Hypothalamus-Pituitary-Adrenal Axis Programming by Early-Life Stress: A Role Played by Inflammatory and Epigenetic Mechanisms. In: Teixeira, A.L., Macedo, D., Baune, B.T. (eds) Perinatal Inflammation and Adult Psychopathology. Progress in Inflammation Research, vol 84. Springer, Cham. https://doi.org/10.1007/978-3-030-39335-9_4

Download citation

Publish with us

Policies and ethics

Search

Navigation