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Updated: Apr 27, 2026
Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants
Published on: June 13, 2021
Maternal smoking during pregnancy and infant stress response: test of a prenatal programming hypothesis
Laura R Stroud1, George D Papandonatos2, Daniel Rodriguez3
1Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, United States; Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI 02906, United States.
Insights
Maternal smoking during pregnancy alters infant stress response by affecting the HPA axis. This may be due to epigenetic changes in the placental glucocorticoid receptor gene, impacting neurodevelopment.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Biology
Background:
- Maternal smoking during pregnancy (MSDP) is linked to neurobehavioral deficits in offspring.
- The underlying mechanisms for these deficits remain largely unknown.
- This study investigates the role of the hypothalamic-pituitary-adrenocortical (HPA) axis and epigenetic modifications in mediating these effects.
Purpose of the Study:
- To test the hypothesis that MSDP programs the offspring's HPA axis.
- To examine the association between MSDP and infant cortisol stress response.
- To explore if epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1) mediates alterations in cortisol response.
Main Methods:
- Prospective study of 100 mother-infant pairs (53% exposed to MSDP).
- MSDP assessed via timeline followback and cotinine verification.
- Infant cortisol response measured seven times in the first postnatal month.
- Placental NR3C1 promoter methylation analyzed using bisulfite pyrosequencing in a subsample.
Main Results:
- MSDP-exposed infants exhibited attenuated basal and reactive cortisol levels compared to unexposed infants.
- MSDP was associated with altered methylation of the placental NR3C1 promoter.
- Placental NR3C1 methylation mediated the effects of MSDP on infant basal cortisol levels.
Conclusions:
- Findings support the hypothesis that MSDP programs offspring HPA axis (dys)regulation.
- Epigenetic regulation of the placental glucocorticoid receptor (GR) may be a key mechanism.
- These results offer insights into pathways leading to adverse outcomes associated with MSDP.
Background:
Maternal smoking during pregnancy (MSDP) is associated with early and long-term neurobehavioral deficits; however mechanisms remain unknown. We tested the hypothesis that MSDP programs the hypothalamic pituitary adrenocortical (HPA) axis of the offspring leading to adverse outcomes. In an intensive, prospective study, we investigated associations between MSDP and infant cortisol stress response and explored whether alterations in cortisol response were mediated by epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1).
Methods:
Participants were 100 healthy mother-infant pairs (53% MSDP-exposed; 42% female) from a low income, racially/ethnically diverse sample (55% minorities). MSDP was assessed by timeline followback interview verified by saliva and meconium cotinine. Infant cortisol responses to a neurobehavioral exam were assessed seven times over the first postnatal month. Methylation of placental NR3C1 promoter exon 1F was assessed using bisulfite pyrosequencing in a subsample (n=45).
Results:
MSDP-exposed infants showed significantly and persistently attenuated basal and reactive cortisol levels over the first postnatal month vs. unexposed infants. Exploratory analyses revealed that MSDP was associated with altered methylation of the placental NR3C1 promoter; degree of methylation of the placental NR3C1 was associated with infant basal and reactive cortisol over the first postnatal month and mediated effects of MSDP on infant basal cortisol.
Conclusions:
Results provide initial support for our hypothesis that MSDP programs offspring HPA (dys)regulation. Epigenetic regulation of placental GR may serve as a novel underlying mechanism. Results may have implications for delineating pathways to adverse outcomes from MSDP.
