Early Metabolic Reprogramming in the Placenta Shapes Resilience to Gestational Hypoxia in High‐Elevation Deer Mice

ABSTRACT

Environmental hypoxia at high elevations is linked to increased rates of gestational complications. Evolutionary adaptation to high elevation environments mitigates these complications across mammals, in part through changes in placental function that shape foetal growth potential in late pregnancy. To investigate the developmental origins of placental adaptation to hypoxia, we acclimated pregnant deer mice ( Peromyscus maniculatus ) derived from low‐ and high‐elevation populations to normoxia or hypoxia (equivalent to 4300 m) and characterized the structure and transcriptome of foetal placentas. We show that gestational hypoxia induced remodelling of the placental transcriptome in susceptible, lowland‐derived mice, but not in highland‐derived mice. A subset of this transcriptional plasticity displayed genetic assimilation, in which highland placentas expressed the induced value observed in lowlanders. However, we also found evidence that highland‐derived mice reversed some of the ancestral lowland responses to hypoxia. Specifically, gestational hypoxia tended to suppress metabolic pathways in the placentas of lowland mice, whereas these responses were attenuated in highland mice. This divergence was centred on mitochondrial metabolic pathways. More broadly, we show that both constitutive population‐level differences and remodelling of ancestral plasticity in the placenta tune expression within a stable transcriptional network architecture. Our results point to the developing placenta's metabolic responses to hypoxia as an early and developmentally specific functional target that likely contributes to pathologies associated with gestational hypoxia in humans and other mammals.