Hypoxic Pregnancy Promotes Fibrosis and Increases Stress Metabolites in the Ovine Fetal Liver

Fetal hypoxemia is a common pregnancy complication associated with fetal growth restriction (FGR). Offspring born with FGR have a higher risk for postnatal liver metabolic disease and injury. Our objective was to better understand how hypoxemia impacts the developing fetal liver. We hypothesized hypoxemia promotes hepatocellular injury, shifts nutrient metabolism, and activates energetic and oxidative stress signaling pathways in the fetal liver. To test this, we used an established ovine model of hypoxia during late gestation. Pregnant ewes were housed in isobaric chambers under normoxia (CON) or hypoxic (HOX) conditions for 30 days, and fetal liver biopsies were analyzed. Compared to CON, HOX fetuses had asymmetrical growth restriction, higher hemoglobin concentration, and greater liver collagen deposition localized in periportal regions. HOX liver had unique metabolic profiles, including shifts to amino acid and central carbon metabolism and increased stress metabolites. The hepatic transcriptome of HOX fetuses included downregulation of genes involved in glutathione synthesis and redox balance and upregulation of mitochondrial dysfunction and downregulation of oxidative phosphorylation genes. Despite predicted oxidative stress, there was no difference in lipid peroxidation, oxidative phosphorylation complex abundance, or antioxidant response proteins NRF2, NQO1 or SOD2. In summary, hypoxic pregnancy increased fetal hepatic collagen deposition, an indicator of hepatic injury, with a unique profile of liver stress metabolites and metabolic adaptations in central carbon metabolism. These results provide new insight into how fetal hypoxia may initiate fibrotic and metabolic liver disease risk in exposed offspring. To investigate the effect of hypoxic pregnancy on fetal liver development and metabolism , we used a sheep model of hypoxia in late gestation. Ewes were subject to normoxia (CON) or hypoxic (HOX) conditions for 30 days and fetal livers were collected at ~day 130 of gestation. We performed gene expression analysis on bulk RNAseq data from 9 CON and 7 HOX fetal livers.