ABSTRACT Prenatal hypoxia (PH) is a common pregnancy complication that can lead to cognitive impairment in the offspring, but the underlying mechanisms remain unclear. In this study, we established a model of PH by exposing C57 mice to hypoxia (10.5% oxygen) environment from gestational day (GD) 12.5–17.5. We found that PH resulted in cognitive impairment and reduced hippocampal neurogenesis in male offspring compared to control offspring. Mechanistically, PH is a form of prenatal stress that promotes placental transfer of maternal glucocorticoids (GC), which induces hyperactivity of the fetal hypothalamic–pituitary–adrenal (HPA) axis, leading to downregulation of the hippocampal glucocorticoid receptor (GR) in the offspring. In addition, PH promotes increased nuclear translocation of the GR and histone deacetylase 3 (HDAC3) complex, which represses the expression of immediate‐early gene Npas4. By acting as a GR receptor antagonist, Mifepristone (MIF) mitigates ameliorated neurogenesis and cognitive impairment in the hippocampus of PH male offspring through the GR/HDAC3‐Npas4 pathway. Thus, our study reveals that the GR/HDAC3‐Npas4 signaling pathway is implicated in reduced hippocampal neurogenesis and cognitive impairment in PH male offspring. This research provides support for the pathogenesis of fetal cognitive impairment caused by PH.
Zhao et al. (Mon,) studied this question.