Collaborative Research: Gestational metabolism and preservation of reproductive success at high elevations

About This Grant

Low oxygen, as is common at high altitudes, poses major challenges to the body. These effects are well-described with respect to activities like exercise; however, low oxygen also challenges reproduction. Across mammals, low oxygen found at high altitudes leads to greater risk for pregnancy complications, especially low birth weight. Even though understanding how this happens could help us predict and prevent these poor outcomes, the processes by which low oxygen influences pregnancy and fetal growth trajectories remains poorly understood. This research will test the hypothesis that maternal metabolism and its response to low oxygen are important factors that determine pregnancy outcomes and fetal growth at high altitudes. The research uses a rodent model, the North American deer mouse, for which some populations have resided at high altitude for many generations and no longer experience birth weight reductions at high altitude. The research aims will compare how low oxygen alters the maternal physiology of high-altitude deer mice (that don’t experience birth weight reductions) versus low altitude-resident deer (which do experience birth weight reductions). The proposed experiments will also use advanced genetic and genomic tools to determine how the expression of key genes in the placenta influence maternal metabolism. This work will advance our basic understanding of how reproductive biology contributes to mammalian adaptation while also providing new perspectives on some of the most common pregnancy complications that are linked to low oxygen, like pre-eclampsia. This research applies experimental approaches to determine how reproductive physiologies evolve and adapt to cope with challenging environments (specifically, low oxygen). The experiments aim to test two main hypotheses: (a) that adaptation to high elevations modifies or prevents hypoxia-dependent adjustments to maternal metabolism and glucose regulation, and (b) that these protective maternal metabolic changes are directed by adaptions in imprinted gene networks found in the placenta. To test these hypotheses, North American deer mice of high- and low-altitude ancestry will be experimentally acclimated to high elevation during pregnancy. The maternal and fetal contributions to the physiologies that shape gestational metabolism will be parsed by measuring maternal energy allocation, fuel use, and the metabolic gene networks that interact with genomic imprinting in the. The integrated, whole-organism approach will enable the identification of links between specific gene expression patterns in the placenta and the fetal and maternal metabolic traits that are associated with growth outcomes under environmental hypoxia. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.