Role of maternal prenatal stress in dysregulation of the fetal Hypothalamic-Pituitary-Adrenal Axis, predisposing offspring to neurobehavioral disorders and depression.

Hunter Graham

Introduction: An estimated 30% of mothers report that they were exposed to stress during pregnancy. This chronic prenatal stress is hypothesized to allow exposure of the fetus to increased maternal cortisol levels, resulting in hypermethylation of the fetal NR3C1 glucocorticoid receptor gene1. This downregulation of glucocorticoid receptor expression leads to reduced negative feedback of the offspring’s Hypothalamic-Pituitary-Adrenal (HPA) Axis—a primary regulator of cortisol release during episodes of stress2. As a result, overactivity of the HPA Axis causes increased cortisol production which may lead to the development of physiological disorders later in life. In this presentation, we observe the methylation patterns of NR3C1 associated with prenatal anxiety and depression and ask: how may maternal psychological states during pregnancy predispose offspring to development of neurobehavioral disorders?  Methods: Self-reported psychological questionnaires were used to assess maternal mental status in relation to salivary cortisol levels obtained from the mothers each trimester as well as to offspring NR3C1 epigenetic patterns, sequenced from mononuclear cell DNA obtained at birth and buccal infant cells obtained at 2 months of age3,4. Methylation patterns of NR3C1 and 11B-HSD2 DNA from placental samples were then compared to newborn behavioral trends assessed by the Network Neurobehavioral Scale5. Finally, DNA samples of individuals diagnosed with Major Depressive Disorder (MDD) were examined for epigenetic modifications of NR3C16. Results: Maternal cortisol levels were found to not differ significantly among pregnant women of various psychological states and did not predict NR3C1 methylation patterns3. However, self-reports of prenatal stress did result in increased methylation of NR3C1, particularly Exon 1F CpG 9, with pregnancy-related anxiety resulting in the greatest increase3. In addition, male offspring were shown to have greater increases in methylation following exposure to prenatal depression compared to females4. Hypermethylation of NR3C1 was then observed to contribute to neurobehavior abnormalities in offspring, exhibited by increased hypotonia and lethargy and decreased self-regulation of newborns5. Finally, MDD patients with suicide ideation were also found to obtain similar increases in methylation of NR3C16. Conclusions: These results confirm that offspring are epigenetically susceptible to prenatal anxiety and depression. These methylation patterns predict newborn neurobehavior abnormalities and predispose offspring to development of MDD. By better understanding the relationship between fetal environment, HPA Axis dysregulation, and neurobehavior, physicians can therapeutically target the HPA Axis in treatment of MDD patients as well as implement prevention strategies to protect offspring from development of neurobehavior disorders and MDD, even beginning in utero.

 

  1. Van den Bergh BRH, van den Heuvel MI, Lahti M, et al. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neuroscience & Biobehavioral Reviews. 2017.
  2. Kang H, Bae K, Kim S, et al. Longitudinal associations between glucocorticoid receptor methylation and late-life depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018;84:56-62.
  3. Hompes T, Izzi B, Gellens E, 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. Journal of Psychiatric Research. 2013;47:880-891.
  4. Braithwaite EC, Kundakovic M, Ramchandani PG, Murphy SE, Champagne FA. Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics. 2015;10:408-417.
  5. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ. The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics. 2013;8:1321-1329.
  6. Roy B, Shelton RC, Dwivedi Y. DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. Journal of Psychiatric Research. 2017;89:115-124.