Jessika Harris

Background:  Maternal stress has been linked to preterm births, low birth weights, and decreased gray matter volumes in the prefrontal cortex, temporal lobe, and cerebellum, which can be predictors of increased risk for cognitive, behavioral, and emotional problems in children.² Epigenetic pathways likely play a role in mediating the impact of maternal stress on fetal brain development. Maternal stress impacts DNA methylation of target stress related genes – specifically the glucocorticoid reception gene (NR3C1) and the serotonin transporter gene (SLC6A4). Understanding more about epigenetic changes due to maternal stress could lead to primary prevention or early detection and treatment.

Objective:  To explore epigenetic changes caused by maternal stress that could impact fetal neurodevelopment resulting in mental and behavioral conditions.

Search Methods:  PubMed searches were conducted for literature published between 2017-2023 using the following key words: “maternal stress and neurodevelopment”,  “epigenetics and neurodevelopment”, “maternal stress and glucocorticoid receptors,” “maternal stress and psychological disorders in children”, and “placental DNA methylation.”

Results:  Evolving evidence links maternal stress exposure to changes in placental DNA methylation of specific genes regulating placental function that may have implications for the programming of a host of chronic disorders. Brunst el al. (2018) used the Infinium HumanMethylation450 BeadChip (450K) to investigate epigenome-wide placental DNA methylation in relation to maternal experiences of stressors.

Results demonstrated three clusters that exhibited differential methylation in response to high maternal lifetime stress. Targeted enrichment analyses of the three largest clusters of probes, identified using the gap statistic, were enriched for genes associated with endocytosis, tight junctions, and metabolic pathways.¹ These findings reveal that altering placental permeability impacts the fetal environment and explains changes in fetal development. St. Pierre et al. (2018) evaluated the impact of prenatal stress on the placental glucocorticoid system and glucose transporters to determine if prenatal stress increased or decreased expression levels of genes associated with glucocorticoid effects and to evaluate if these responses were impacted by gestational age. Data show that the impact of maternal stress varies based on both fetal sex and gestational age at time of stress.^4,5,6 There are eight isoforms originating from the NR3C1-α mRNA ,and the difference in isoform expression was thought to mediate, in part, the sexually dimorphic placental response.⁶ Buccal swabs allow for assessment of DNA methylation of NR3C1 and SLC6A4 and could be used as a noninvasive diagnostic tool that might help identify infants at risk for future neurocognitive developmental issues.^4,5

Conclusions:  Epigenetic changes including DNA methylation of the glucocorticoid reception gene (NR3C1) and the serotonin transporter gene (SLC6A4), are impacted by maternal stress and related to fetal neurodevelopment. Maternal stress research has shown gender and gestational age differences.^4,6 There are potential diagnostic tools that could help identify children at an early age to allow for earlier identification of at-risk children and interventions to mitigate or minimize the long-term implications of neurological disorders.

Works Cited:   

1. Brunst KJ, Tignor N, Just A, et al. Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort. Epigenetics. 2018;13(6):665-681. doi:10.1080/15592294.2018.1497387
2. DeSocio JE. Epigenetics, maternal prenatal psychosocial stress, and infant mental health. Arch Psychiatr Nurs. Dec 2018;32(6):901-906. doi:10.1016/j.apnu.2018.09.001
3. Gray SAO, Jones CW, Theall KP, Glackin E, Drury SS. Thinking across generations: Unique contributions of maternal early life and prenatal stress to infant physiology. J Am Acad Child Adolesc Psychiatry. Nov 2017;56(11):922-929. doi:10.1016/j.jaac.2017.09.001
4. Nazzari S, Grumi S, Mambretti F, et al. Maternal and infant NR3C1 and SLC6A4 epigenetic signatures of the COVID-19 pandemic lockdown: when timing matters. Translational Psychiatry. 2022/09/16 2022;12(1):386. doi:10.1038/s41398-022-02160-0
5. Sharma R, Frasch MG, Zelgert C, et al. Maternal–fetal stress and DNA methylation signatures in neonatal saliva: an epigenome-wide association study. Clinical Epigenetics. 2022/07/14 2022;14(1):87. doi:10.1186/s13148-022-01310-x
6. St-Pierre J, Laplante DP, Elgbeili G, et al. Natural disaster-related prenatal maternal stress is associated with alterations in placental glucocorticoid system: The QF2011 Queensland Flood Study. Psychoneuroendocrinology. Aug 2018;94:38-48. doi:10.1016/j.psyneuen.2018.04.027