Glucocorticoid Receptor Signaling: Multilevel Organization, Roles in Fetal Development, and Postnatal Outcomes

Area of Science:

• Endocrinology and Neurobiology
• Developmental Biology
• Epigenetics

Background:

• The hypothalamic-pituitary-adrenal (HPA) axis regulates crucial physiological responses.
• Glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are key molecular effectors, with distinct roles in stress response and basal hormone sensing.
• Pregnancy involves placental mechanisms that modulate maternal glucocorticoid exposure to the fetus.

Purpose of the Study:

• To review the structure and function of GRs and MRs.
• To explore the mechanisms of GR regulation, including post-translational and epigenetic modifications.
• To elucidate the role of the placenta in mediating prenatal stress effects on fetal development.

Main Methods:

• Literature review integrating evidence on HPA axis regulation.
• Analysis of molecular mechanisms of GR/MR function and regulation.
• Examination of placental control layers and their impact on fetal exposure to glucocorticoids.

Main Results:

• Placental barrier function can be compromised by stress, inflammation, or hypoxia, increasing fetal glucocorticoid exposure.
• Prenatal overexposure to glucocorticoids can lead to epigenetic modifications (e.g., DNA methylation, histone remodeling) of the GR gene (nr3c1).
• These changes can result in long-term alterations in stress reactivity, cognitive function, and immune/metabolic risk.

Conclusions:

• Prenatal stress exposure epigenetically reprograms the HPA axis, influencing long-term health trajectories.
• The placenta plays a critical role in protecting the fetus from excessive maternal glucocorticoids.
• Identifying targets for early prevention of prenatal stress consequences is crucial for mitigating lifelong health risks.