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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 gestational parent and fetus. We then use compartment-specific 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 candidate 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.
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Fetal growth, high altitude, and evolutionary adaptation: a new perspective
Residence at high altitude is consistently associated with low birthweight among placental mammals. This reduction in birthweight influences long-term health trajectories for both the offspring and mother. However, the physiological processes that contribute to fetal growth restriction at altitude are still poorly understood, and thus our ability to safely intervene remains limited. One approach to identify the factors that mitigate altitude-dependent fetal growth restriction is to study populations that are protected from fetal growth restriction through evolutionary adaptations (e.g., high altitude-adapted populations). Here, we examine human gestational physiology at high altitude from a novel evolutionary perspective that focuses on patterns of physiological plasticity, allowing us to identify 1) the contribution of specific physiological systems to fetal growth restriction and 2) the mechanisms that confer protection in highland-adapted populations. Using this perspective, our review highlights two general findings: first, that the beneficial value of plasticity in maternal physiology is often dependent on factors more proximate to the fetus; and second, that our ability to understand the contributions of these proximate factors is currently limited by thin data from altitude-adapted populations. Expanding the comparative scope of studies on gestational physiology at high altitude and integrating studies of both maternal and fetal physiology are needed to clarify the mechanisms by which physiological responses to altitude contribute to fetal growth outcomes. The relevance of these questions to clinical, agricultural, and basic research combined with the breadth of the unknown highlight gestational physiology at high altitude as an exciting niche for continued work.
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- Award ID(s):
- 1907233
- PAR ID:
- 10296000
- Date Published:
- Journal Name:
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Volume:
- 321
- Issue:
- 3
- ISSN:
- 0363-6119
- Page Range / eLocation ID:
- R279 to R294
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1152/ajpregu.00067.2021
