Prenatal glucocorticoids and long-term brain vulnerability: GR signaling, epigenetic programming, and crosstalk with...

Glucocorticoids (GCs) are key regulators of stress responses and fetal maturation, and their physiological rise during pregnancy supports coordinated organ development. Clinically relevant GC exposure during sensitive windows of brain development occurs in several contexts, including antenatal treatment for risk of preterm birth to promote lung maturation, prolonged maternal therapy for chronic inflammatory or autoimmune conditions, and postnatal GC treatment in preterm infants, including regimens used to prevent or treat bronchopulmonary dysplasia. Although these contexts differ in timing, dose, and duration, they share the capacity to engage a glucocorticoid receptor (GR) signaling during critical windows of neurodevelopment, with possible long-term consequences for brain development and stress responsiveness. This review synthesizes clinical, experimental, and stem cell-based evidence to examine how GC signaling can shape brain structure and function across the lifespan. We discuss GR signaling in the central nervous system (CNS) and summarize evidence that sustained activation can be associated with paradoxical pro-inflammatory and neurotoxic phenotypes. We highlight epigenetic mechanisms through which GC signals may produce persistent changes in gene regulation, and we integrate data from prenatal exposure together with evidence on maternal metabolic and inflammatory context as modifiers of developmental risk. Finally, we propose an integrated view in which CNS outcomes attributed to GCs reflect a composite of direct neural actions and indirect effects shaped by peripheral tissues. We discuss adipose- and muscle-linked pathways as candidate mediators of systemic-to-central communication. This perspective links stress endocrinology, metabolism, and brain vulnerability, and highlights key mechanistic gaps and translational priorities for future research.