Transcriptional imprints of prenatal stress: sex- and time-specific signatures in early neurodevelopment

Prenatal stress (PNS) is a well-established animal model of foetal exposure to maternal stress and related psychiatric disorders. While its biological and behavioural effects on the offspring have been widely studied in adolescence and adulthood, early-life signatures remain largely unexplored. Here, we assessed whole-genome transcriptomic changes by RNA-sequencing, followed by pathway analyses, in hippocampi collected at postnatal day (PND)2 and PND14 from male and female rats exposed to PNS by physical maternal restraint, compared with non-stressed counterparts (n = 6 per group). We first analysed differences between PNS animals and controls at each timepoint. At PND2, both male and female PNS animals exhibited increased synaptic activity and decreased antioxidant processes, suggesting potential accelerated neurodevelopment, excitotoxicity, and oxidative stress, which may reflect early mitochondrial dysfunction. At PND14, PNS males showed increased oxidative phosphorylation, while females displayed reduced NAD+ signalling and increased immune-related processes, collectively indicating disruptions in mitochondrial energy metabolism and redox homeostasis during the juvenile period. Subsequently, we investigated the alterations between PND14 and PND2, focusing on those unique to PNS condition. Longitudinally, PNS animals of both sexes exhibited increased glucose and lactate metabolism, further supporting substantial alterations in mitochondrial function and energetic balance over time. Additionally, PNS males showed downregulation of cell cycle-related pathways, potentially indicating reduced neurogenesis, whereas PNS females displayed upregulated pregnenolone biosynthesis, suggesting increased steroidogenesis. The collected findings suggest a sex- and time-dependent different modulation of multiple biological processes, with mitochondrial dysfunction emerging as a central mechanism underlying developmental programming that may predispose to future behavioural impairments.