Neurotoxic Window of Prenatal Dexamethasone Exposure on Offspring Hippocampal Development: A Dose-time-duration Dependency Study

OBJECTIVE To investigate the specific effects of key parameters of prenatal dexamethasone exposure(dose, time window, and treatment course) on offspring hippocampal development and function.

METHODS A subcutaneous dexamethasone injection model was established in pregnant Kunming mice to systematically simulate clinical exposure scenarios. Gradient doses(low: 0.2 mg·kg⁻¹; medium: 0.4 mg·kg⁻¹; high: 0.8 mg·kg⁻¹), administration windows(mid-to-late gestation, GD14–15; late gestation, GD16–17), and treatment courses(single course GD14–15 or GD16–17 and multiple courses GD14–17), with saline-treated mice serving as controls. On GD18, fetal hippocampi were analyzed by histological assessment, neuronal proliferation/apoptosis assays, immunodetection of glial markers(S100b, Gfap, Iba1, Trem2), and evaluation of key signaling molecules(Sox2, Notch1).

RESULTS Compared with the control group, late-gestation dexamethasone exposure significantly impaired hippocampal morphology, inhibited neuronal proliferation, promoted apoptosis, and markedly downregulated the astrocyte marker S100b, while microglial marker Iba1 remained unchanged. Furthermore, prenatal dexamethasone exposure suppressed the expression of the key signaling pathways Sox2 and Notch1, which regulate neural progenitor cell proliferation, in a dose, timing, and course dependent manner. The degree of impairment followed the pattern: late gestation > mid-to-late gestation, high dose > medium/low dose, and multiple courses > single course, with the most severe damage observed in the high-dose, multiple-course group during late gestation.

CONCLUSION Prenatal dexamethasone exposure, particularly high-dose, repeated administration during late pregnancy, can significantly impair fetal hippocampal development by disrupting the Sox2 and Notch signaling pathways. This study provides important experimental and theoretical evidence for optimizing the clinical use of dexamethasone during pregnancy and assessing its neurodevelopmental toxicity risks in the fetus.