Intergenerational Conditioning via Intermittent Parental Hypoxia Confers Stroke Resilience in Offspring

BACKGROUND: Intergenerational disease transmission, where parental exposures or experiences influence disease susceptibility in offspring, may represent a crucial layer of stroke risk that extends beyond genetics alone. Environmental conditioning, such as intermittent sublethal hypoxia, can induce adaptive protective stress responses in the brain. However, whether such parental conditioning enhances offspring resilience to cerebral ischemia remains unclear. This study investigates whether intermittent hypoxia in parents acts as an intergenerational conditioning stimulus, conferring resilience to ischemic stroke in offspring, and explores associated molecular mechanisms. METHODS: , 2 hours every other day, 16 cycles) before mating. To confirm parental neuroprotection, F0 mice underwent transient middle cerebral artery occlusion. First filial (offspring) generation from hypoxia-exposed F0 were divided into biparental, paternal-only, maternal-only hypoxia, and normoxic groups. Adult first filial (offspring) generation (8-10 weeks old) offspring also underwent transient middle cerebral artery occlusion to model ischemic stroke. Infarct volume and brain swelling were assessed 48 hours post-ischemia. A subgroup of F0 and first filial (offspring) generation brains was analyzed by tandem mass tag proteomics to identify molecular pathways linked to neuroprotection. RESULTS: Parental intermittent hypoxia significantly reduced infarct size and swelling in F0 mice. These protective effects were inherited by the first filial (offspring) generation, with biparental exposure producing the greatest reduction in infarct volume, followed by maternal-only and paternal-only groups, and exhibiting sex-specific differences. Proteomic profiling revealed distinct treatment and lineage clusters. Key pathways implicated in offspring neuroprotection included metabolic regulation, immune signaling, cytoskeletal organization, and cell survival, notably involving PI3K-Akt (phosphoinositide 3-kinase-Akt signalling pathway) and EGFR (epidermal growth factor receptor) pathways. CONCLUSIONS: Intermittent hypoxia in parents acts as an intergenerational conditioning stimulus, conferring offspring resilience to stroke. This neuroprotective phenotype is supported by coordinated molecular adaptations in key pathways involved in survival and stress response. These findings highlight the potential for parental environmental conditioning to shape stroke outcomes in offspring, opening new avenues for therapeutic exploration.