Developmental timing of repeated dexamethasone exposure determines growth and modulates metabolic responsiveness in adulthood.

Dexamethasone (DEX), a synthetic glucocorticoid (GC) widely used for its anti-inflammatory and immunosuppressive properties, is associated with adverse metabolic and diabetogenic effects. Whether early-life exposure to DEX modifies metabolic disturbances induced by subsequent treatments remains unclear. We investigated this by subjecting male Wistar rats to up to three treatment cycles initiated on postnatal days 30, 60, and 90. Each cycle consisted of five consecutive daily intraperitoneal injections of DEX (1.0 mg/kg) or saline (1 mL/kg). Animals were assigned to five groups according to exposure history: Control, 90, 30 + 90, 60 + 90, and 30 + 60 + 90. After the final cycle, glucose tolerance tests were performed, followed by blood and tissue collection. DEX reduced body mass gain and food intake across all regimens, leading to lower adult body mass, particularly after three cycles. All DEX-treated groups developed glucose intolerance, although this effect was attenuated in the 30 + 60 + 90 group. Hyperinsulinemia and increased hepatic triacylglycerol and glycogen content were observed in all groups except the 30 + 60 + 90 group. DEX-induced β-cell mass expansion was absent in animals exposed on postnatal day 30. Hepatic genes involved in glucose metabolism were upregulated after one or two exposures, without corresponding changes in protein levels. In contrast, repeated exposure (30 + 60 + 90) enhanced GC-responsive gene expression, indicating that upstream GC receptor signaling was preserved despite limited metabolic remodeling. Increased hypothalamic Zbtb16 mRNA expression further supported the integrity of central GC responsiveness. In summary, early-life DEX exposure impairs growth but attenuates several metabolic disturbances induced by later treatments, highlighting long-term consequences of GC therapy.