Jessica Joseph

Background: The time of fetal neurodevelopment in utero is highly sensitive, and fetal neuroplasticity-related changes that are mediated through epigenetic related mechanisms have been shown to have lasting effects on brain development.^1-7  Elevated levels of maternal stress and anxiety lead to increased levels of glucocorticoids that are transmitted across the placenta to the fetus.⁷ Recent studies have shown that there appears to be an epigenetic mechanism that occurs as a result of elevated exposure to glucocorticoids at the transcriptional level of fetal NR3C1, a glucocorticoid receptor gene. Downregulation of NR3C1 levels leads to dysregulation of the fetal hypophyseal-pituitary-adrenal (HPA) axis and a subsequent increase in glucocorticoid production that has been shown to have pathogenic effects on the child’s stress reactivity.^3-4 Post-transcriptionally, microRNA molecule miR-124-3p has been shown to reduce the expression of glucocorticoid receptors expressed by NR3C1.⁸

Objective: In this literature review, we explored potential mechanisms underlying variable NR3C1 expression and the resultant effects on HPA axis functionality.

Search Methods: A search was conducted through the PubMed database from 2018 to 2024 utilizing the key words, “maternal stress”, “NR3C1”, and “fetal neurodevelopment”.

Results: A study involving 163 mother-infant dyads analyzed CpG island shore methylation levels present in leukocytes isolated from umbilical cord blood samples following delivery. Elevated maternal anxiety led to epigenetic alterations through increased methylation of CpG island shore site 1 in the promoter region of NR3C1 when compared to mothers who reported lower levels of prenatal stress.⁴ The increase in average methylation for infants exposed to elevated levels of prenatal anxiety was 2.54% compared to just 1.68% for infants experiencing exposure to prenatal trait anxiety, with the former level of methylation shown to be significant enough to sensitize the HPA axis.⁴ The subsequent downregulation of glucocorticoid receptor expression leads to a dampening of the negative feedback loop of the HPA axis which causes increased production of glucocorticoids in the fetus.⁴ A similar mechanism of genetic NR3C1 silencing is seen at the post-transcriptional level with regards to the role of miR-124-3p in Cushing’s Disease, a disease of excessive cortisol production.⁸ There are 2 highly conserved binding motifs in the 3’ UTR of NR3C1 transcripts for miR-124-3p, representing a high rate of expression variability for the proteins encoded by this gene.⁸ Rates of NR3C1 expression were analyzed amongst adenomas from individuals who experienced Cushing’s Disease (CD) and silent corticotroph adenomas (SCA).⁸ Adenomas causing CD exhibited lower rates of NR3C1 and higher levels of miR-124-3p compared to SCA patients, demonstrating a potential connection as to why those with CD express more symptoms than SCA patients.⁸

Conclusion: There are several points of regulation for the genetic expression of NR3C1, both transcriptionally and post-transcriptionally, providing hope for tangible potential targets to reverse the alterations to HPA axis functionality and subsequent behavioral disorders that are programmed in utero due to epigenetic influences.^4-5,8 More studies should be conducted to look into how postnatal epigenetic influences interact with prenatal epigenetic influences and how this interaction impacts long-term behavioral outcomes.⁶ Alleviating prenatal stress and anxiety should continue to be a major focus towards better outcomes for both mother and fetus.⁹

Works Cited

1.  Thomas JC, Letourneau N, Campbell TS, Giesbrecht GF. Social buffering of the maternal and infant HPA axes: Mediation and moderation in the intergenerational transmission of adverse childhood experiences. Development and Psychopathology. 2018;30(3):921-939. doi:10.1017/s0954579418000512
2. Wu Y, Espinosa KM, Barnett SD, et al. Association of elevated maternal psychological distress, altered fetal brain, and offspring cognitive and social-emotional outcomes at 18 months. JAMA Network Open. 2022;5(4). doi:10.1001/jamanetworkopen.2022.9244
3. Provençal N, Arloth J, Cattaneo A, et al. Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation. Proceedings of the National Academy of Sciences. 2019;117(38):23280-23285. doi:10.1073/pnas.1820842116
4. Dereix AE, Ledyard R, Redhunt AM, et al. Maternal anxiety and depression in pregnancy and DNA methylation of the NR3C1 glucocorticoid receptor gene. Epigenomics. 2021;13(21):1701-1709. doi:10.2217/epi-2020-0022
5. Jiang T, Hu S, Dai S, et al. Programming changes of hippocampal mir-134-5p/sox2 signal mediate the susceptibility to depression in prenatal dexamethasone-exposed female offspring. Cell Biology and Toxicology. 2021;38(1):69-86. doi:10.1007/s10565-021-09590-4
6. Dieckmann L, Czamara D. Epigenetics of prenatal stress in humans: The current Research Landscape. Clinical Epigenetics. 2024;16(1). doi:10.1186/s13148-024-01635-9
7. Berretta E, Guida E, Forni D, Provenzi L. Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental Exposures and Developmental Outcomes. Neuroscience & Biobehavioral Reviews. 2021;125:493-502.   doi:10.1016/j.neubiorev.2021.03.003
8. Mossakowska BJ, Kober P, Rusetska N, et al. Difference in MIRNA expression in functioning and silent corticotroph pituitary adenomas indicates the role of MIRNA in the regulation of corticosteroid receptors. International Journal of Molecular Sciences. 2022;23(5):2867. doi:10.3390/ijms23052867
9. Cao-Lei L, de Rooij SR, King S, et al. Prenatal stress and epigenetics. Neuroscience & Biobehavioral Reviews. 2020;117:198-210. doi:10.1016/j.neubiorev.2017.05.016.