McGuckin Molly M, Wang Dong, Ortiz Jasmine, Dobrinskikh Evgenia, Tong Wen, Botting-Lawford Kimberley J, Niu Youguo, Giussani Dino A, Wesolowski Stephanie R
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
J Physiol. 2025 May;603(10):3223-3243. doi: 10.1113/JP288724. Epub 2025 May 5.
Fetal chronic hypoxia is a common pregnancy complication associated with fetal growth restriction. Growth-restricted offspring have a higher risk for liver metabolic disease. Our objective was to better understand how chronic hypoxia impacts the developing fetal liver. We hypothesized that hypoxia promotes hepatocellular injury, shifts nutrient metabolism, and activates energetic and oxidative stress in the fetal liver. We used an ovine model of chronic hypoxia where pregnant ewes were housed under normoxic (CON) or hypoxic (HOX) conditions for 30 days in late gestation. Fetal liver was obtained, histologically analysed and profiled using bulk-RNA sequencing and metabolomics. Nutrient and oxidative stress signalling pathways were also measured. HOX fetuses had greater hepatic periportal collagen deposition. Metabolomics and transcriptomics predicted disruptions in central carbon metabolism, mitochondrial dysfunction and decreased oxidative phosphorylation. In support, we found potentiation of the gluconeogenic pathway and increased lactate production, pyruvate oxidation and AMPK activation. By contrast to the predicted effects, hypoxic livers maintained mitochondrial oxidation and antioxidant capacity. Interestingly, acylcarnitines were increased, yet hepatic triglyceride content was similar. Although there was little activation of oxidative stress markers, such as lipid peroxidation or oxidized glutathione, we uncovered a unique profile of liver stress-related metabolites in association with periportal collagen. Thus, hypoxic pregnancy increased fetal hepatic collagen deposition, indicating liver injury, in association with a unique profile of liver stress metabolites and adaptations in central carbon metabolism. These results provide new insight into how chronic fetal hypoxia may initiate fibrotic and metabolic liver disease risk in offspring of adverse pregnancy. KEY POINTS: Chronic exposure to hypoxic pregnancy increased fetal hepatic collagen deposition, indicating hepatocellular injury. Hypoxic fetal livers had a unique profile of stress metabolites and adaptations in central carbon metabolism. This provides new insight into how hypoxia, a common pregnancy complication associated with fetal growth restriction, may initiate fibrotic and metabolic liver disease risk.
胎儿慢性缺氧是一种与胎儿生长受限相关的常见妊娠并发症。生长受限的后代患肝脏代谢疾病的风险更高。我们的目标是更好地了解慢性缺氧如何影响发育中的胎儿肝脏。我们假设缺氧会促进肝细胞损伤、改变营养代谢，并激活胎儿肝脏中的能量和氧化应激。我们使用了慢性缺氧的绵羊模型，在妊娠晚期将怀孕的母羊置于常氧（CON）或缺氧（HOX）条件下30天。获取胎儿肝脏，进行组织学分析，并使用批量RNA测序和代谢组学进行分析。还测量了营养和氧化应激信号通路。HOX胎儿的肝门周胶原沉积更多。代谢组学和转录组学预测中心碳代谢、线粒体功能障碍和氧化磷酸化减少。作为支持，我们发现糖异生途径增强，乳酸生成、丙酮酸氧化和AMPK激活增加。与预测的效果相反，缺氧肝脏维持线粒体氧化和抗氧化能力。有趣的是，酰基肉碱增加，但肝脏甘油三酯含量相似。尽管氧化应激标志物如脂质过氧化或氧化型谷胱甘肽几乎没有激活，但我们发现了与门周胶原相关的独特肝脏应激相关代谢物谱。因此，缺氧妊娠增加了胎儿肝脏胶原沉积，表明肝脏损伤，同时伴有独特的肝脏应激代谢物谱和中心碳代谢的适应性变化。这些结果为慢性胎儿缺氧如何在不良妊娠后代中引发肝纤维化和代谢性肝病风险提供了新的见解。要点：慢性缺氧妊娠增加胎儿肝脏胶原沉积，表明肝细胞损伤。缺氧胎儿肝脏具有独特的应激代谢物谱和中心碳代谢的适应性变化。这为缺氧这种与胎儿生长受限相关的常见妊娠并发症如何引发肝纤维化和代谢性肝病风险提供了新的见解。
