Wilsterman, K. | Search bioRxiv

bioRxiv2026

Reduced baseline male fertility and increased sensitivity to hypoxic stress in high-elevation deer mice

Extreme environments like high elevation impose chronic challenges to endothermic animals who must sustain metabolic demand despite reduced oxygen availability. Male reproduction is a tightly regulated physiological system, and hypoxia exposure has negative but transient effects on male reproductive output in diverse mammal species not adapted to high-elevation. Little is known about whether high elevation populations adapt to the detrimental effects of hypoxia on male reproductive physiology. Here, we use high- and low-elevation populations of deer mice (Peromyscus maniculatus) and a lowland congener, P. leucopus, to test how male reproductive phenotypes have diverged across populations and in response to hypoxia exposure across acute, intermediate, and chronic timescales. We complement these phenotypic assays with bulk RNA sequencing of testes to assess the testis-specific response to hypoxia. Contrary to expectations, hypoxia exposure had a negligible effect on low-elevation strains, while highland mice had both lower baseline fertility and heightened sensitivity to hypoxic stress including complete absence of mature sperm. Gene expression patterns indicate that hypoxia exposure dramatically reorganizes testes architecture in highland mice, consistent with testicular regression similar to that observed in seasonally breeding mammals. We hypothesize that this increased sensitivity of male reproductive physiology in highlanders reflects a life history trade-off, allowing energy reallocation between reproduction, survival, and thermogenesis in response to stress in extreme environments.

evolutionary biology↗

bioRxiv2022

Adaptive structural and functional evolution of the placenta protects fetal growth in high elevation deer mice

Environmental hypoxia challenges female reproductive physiology in placental mammals, increasing rates of gestational complications. Adaptation to high elevation has limited many of these effects in humans and other mammals, offering potential insight into the developmental processes that lead to and protect against hypoxia-related gestational complications. However, our understanding of these adaptations has been hampered by a lack of experimental work linking the functional, regulatory, and genetic underpinnings of gestational development in locally-adapted populations. Here, we dissect high-elevation adaptation in the reproductive physiology of deer mice, (Peromyscus maniculatus), a rodent species with an exceptionally broad elevational distribution that has emerged as a model for hypoxia adaptation. Using experimental acclimations, we show that lowland mice experience pronounced fetal growth restriction when challenged with gestational hypoxia, while highland mice maintain normal growth by expanding the compartment of the placenta that facilitates nutrient and gas exchange between dam and fetus. We then use compartmentspecific transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression within this same compartment. Genes associated with fetal growth in deer mice significantly overlap with genes involved in human placental development, pointing to conserved or convergent pathways underlying these processes. Finally, we overlay our results with genetic data from natural populations to identify can-didate genes and genomic features that contribute to these placental adaptations. Collectively, these experiments advance our understanding of adaptation to hypoxic environments by revealing physiological and genetic mechanisms that shape fetal growth trajectories under maternal hypoxia. Significance StatementResidence at high elevations is associated with higher risk pregnancies and low birth weight, yet the causal mechanisms remain poorly understood. Using a high elevation-adapted rodent model, we investigated the physiological traits that explain fetal growth trajectories in low oxygen environments, and how evolutionary adaptation has modified these traits. We showed that high- and low-elevation populations of deer mice differ in their susceptibility to fetal growth restriction during gestational hypoxia and that these population-level differences are associated with structural and transcriptomic changes in the placenta. We further link placental gene expression to genomic features under selection at high elevation. Our findings identify adaptations that are likely relevant to offsetting the effects of hypoxia on fetal and placental development across mammals.

evolutionary biology↗