Environmental co-option of chromatin potential links prenatal hypoxia to persistent cortical circuit dysfunction

Transient prenatal hypoxia is associated with long-term neurodevelopmental impairment without overt structural brain injury, suggesting early regulatory disruptions precede detectable pathology. Whether these disruptions represent transient stress responses or redirect developmental programs remains unknown. Here, we combined single-nucleus RNA sequencing and chromatin accessibility profiling in the late-gestation mouse cortex immediately after transient hypoxia, capturing responses across more than 140,000 nuclei. Hypoxia induced a largely conserved transcriptional stress response across cell types, whereas chromatin accessibility showed more extensive, cell type–specific disruption. Developing glutamatergic neurons showed the strongest disruption of chromatin–transcription coupling, with hypoxia-responsive distal regulatory regions associated with genes governing synaptic organization and neuronal excitability. Consistent with these chromatin-associated programs, juvenile offspring displayed reduced dendritic spine density and increased intrinsic excitability in cortical neurons. These results support a model in which transient hypoxia co-opts the developing epigenome’s capacity to encode future transcriptional states before persistent circuit dysfunction emerges.