Stage-, dose- and course-dependent disruption of mice fetal ovarian development following prenatal dexamethasone exposure.

Abstract

Background: Dexamethasone, a synthetic glucocorticoid, is widely used during pregnancy to prevent preterm infant respiratory distress syndrome. While our prior work established that multiple courses of prenatal dexamethasone exposure (PDE) impair offspring ovarian function with transgenerational effects, the specific impacts of exposure stages, doses, and courses remain poorly defined.

Materials and methods: Pregnant Kunming mice were treated with dexamethasone during mid-late gestation (GD14-15) or late gestation (GD16-17) with low/moderate/high doses, either as a single course or as two consecutive courses. Fetal ovaries were collected at GD18 to assess morphology, cell proliferation/apoptosis, steroidogenic markers, and oocyte-development genes; network toxicology was used to infer candidate pathways.

Results: PDE disrupted fetal ovarian morphogenesis, characterized by premature germ-cell nest breakdown, reduced proliferation and increased apoptosis. PDE at different stages, doses and courses can increase ovarian steroid synthesis (SF1\StAR\CYP11A1\Hsd3b\CYP19A1) while suppressing oocyte and folliculogenesis genes (NOBOX\Figlα\Sohlh2\Bmp15\Gdf9). These effects are stage-, dose- and course-dependent, with the most obvious toxicity resulting from exposure in the mid-late stages of pregnancy, at high doses and in a single course. Network toxicology and qPCR revealed the NR3C1-MAPK14-IL6 axis: IL6 was positively correlated with proliferation and oocyte development markers, while NR3C1/MAPK14 was associated with apoptosis and steroidogenesis.

Conclusions: This study provides experimental evidence for guiding clinical "precision medicine" and effectively assessing the risk of fetal ovarian developmental toxicity.