Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation

Objectives: Gamete and embryo-foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. Methods: N omega-Nitro-L-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. Results: PE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. Conclusion: These findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.