An increasing body of evidence demonstrates that various chronic diseases in adulthood are linked to intrauterine programming triggered by adverse conditions during pregnancy. This study aimed to elucidate that prenatal exposure to dexamethasone (PDE) can result in diminished baseline activity of the hypothalamic-pituitary-adrenal axis (HPAA) in male rats and to explore the underlying mechanisms. Pregnant rats were administered subcutaneous injections of 0.2 mg/kg/day dexamethasone from gestational day 9 to day 20. Male fetuses at gestational day 20 and adult male offspring at postnatal day 85 were euthanized under anesthesia. Hypothalamic cells were harvested from fetal male rats between gestational day 20 and postnatal day 7, and subsequently treated with varying concentrations of dexamethasone and the glucocorticoid receptor (GR) antagonist mifepristone for five days. The results revealed that dexamethasone enhances the expression of hypothalamic L-glutamic acid decarboxylase (GAD) 67 via GR activation, thereby promoting the conversion of glutamate to gamma-aminobutyric acid (GABA). This process induces an imbalance between glutamatergic and GABAergic inputs within the hypothalamic paraventricular nucleus (PVN). Such imbalance persists postnatally, leading to the suppression of parvocellular neurons and contributing to the reduced baseline activity of the HPAA in PDE-exposed offspring, as indicated by lower levels of adrenocorticotropic hormone (ACTH) and corticosterone in the blood, along with decreased expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus. The development of an imbalance in glutamatergic and GABAergic inputs in the PVN may represent a critical mechanism underlying the attenuated baseline activity of the HPAA in male rats exposed to PDE.

Hypothalamic-Pituitary-Adrenal Axis, Dexamethasone, Programming, Glutamatergic and GABAergic Afferents, Reduced Basal Activity