High Altitude Hypoxia Impacts Omega‐3 Fatty Acid Metabolites in Plasma of Fetal and Newborn Sheep

Abstract

Perinatal hypoxia has profound effect on an infant's development, with physiological impairment of multiple organ systems. The present study explored the effect of hypoxia due to long term high altitude exposure during gestation and after birth on lipid mediators by measuring the metabolites that foreshadow oxidative stress and inflammation, which are primary drivers of dysfunction. We tested the hypothesis that long term hypoxia reduces the amount of oxylipin and endocannabinoid production, which are important mediators of oxidative stress and inflammation. To test this hypothesis pregnant sheep and newborn lambs were housed at a low altitude (700 m) or exposed to an altitude of 3,800 meters starting gestation day 30. UPLC‐MS/MS analysis was used to investigate the lipid mediator composition in plasma collected from veins of near‐term fetal and newborn animals. The results show that hypoxia causes an overwhelming effect on omega‐3 fatty acids and their derivatives, which are crucial in late‐stage fetal development. Several of the omega‐3 fatty acids reduced with hypoxia have well known effects on inflammation, vascular tone, and oxidative stress. Furthermore, we tracked the origin of the identified oxylipins and endocannabinoids by tracing their pathways. The cytochrome P450 (CYP) pathway enzymes and the subsequent activity of soluble epoxide hydrolase (sEH) are prominent synthesizers of the oxylipins such as epoxyeicosatrienoic acids (EETs) and epoxyoctadecenoic acids (EpOMEs). Previous studies have suggested the role of EETs and EpOMEs in vasodilation, a feature in inflammation. Based on these findings we demonstrated that a majority of the affected oxylipins were produced from CYP and sEH enzymes, which are important to vascular function. These findings provide novel insight into our understanding of lipid metabolites to hypoxia‐induced dysfunction in the developing fetus and newborn. In the long term this may help us develop novel therapies that target inflammatory pathways induced by pre and post‐natal hypoxia.Support or Funding InformationThis material is based upon work supported by NIH grants P01HD083132 and 1U24DK097154 through a pilot project grant to Sean Wilson. VL is a recipient of the American Physiological Society's Short‐Term Research Education Program to Increase Diversity in Health‐Related Research (STRIDE) Fellowship funded by the APS and a grant from the National Heart, Lung and Blood Institute R25HL115473.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.