PLACENTAL UNTARGETED LIPIDOMICS UNVEILS SPHINGOLIPID AND CARNITNE CHANGES IMPLICATED IN ER AND MITOCHONDRIAL DYSFUNCTION IN EARLY-ONSET PREECLAMPSIA

Preeclampsia (PE) is a one of the most severe obstetrical complications characterized by the presence of hypertension in a previously normotensive woman, along with a variety of damages to specific organs in addition to the hypertension. While documented for a long time, PE represents one of the leading causes of maternal and perinatal morbidity and mortality and its aetiology and pathogenesis are still unclear. This needs to be addressed due to the serious and lifelong consequences that can affect the mother and her baby. In the past decades, metabolomics has proved to be particularly useful in understanding the biochemical mechanisms involved in the pathophysiology of PE and in the identification of biomarkers for its diagnosis. In this work, the polar and the lipid metabolite profile of 22 placental tissues of patients affected by PE compared with those of normotensive patients has been studied by high resolution liquid chromatography coupled with several technological platforms based on mass spectrometry including a triple quadrupole, a quadrupole time of flight mass spectrometer and ion mobility mass spectrometry prior to multivariate statistical data analysis. The results highlight differences in the levels of numerous compounds related to the metabolism of lipids, nucleotides and amino acids and these metabolites discriminate PE samples from samples from normotensive women. Decreased levels of several sphingolipid species belonging to the classes of ceramides and sphingomyelins as well as different glycerophospholipids such as lysoPC and PC in PE samples reflect the structural alteration of the placenta and the dysregulation of different cellular compartments. Impaired mitochondrial function with reduced fatty acid oxidation in PE was demonstrated by decreased levels of long-chain acylcarnitines while increased levels of those with short and middle chain suggest peroxisome fatty acid impairment. Decreased levels of several amino acids and nucleotides support the hypothesis of the activation of unfolded protein response of endoplasmic reticulum resulting in the inhibition of the synthesis of proteins, RNA and DNA. However, despite the significant reduction of the levels of several metabolites, the placenta might activate an adaptive response under stress conditions to modulate the cellular activity and ensure the essential functions for foetal growth including the oxidation of long-chain fatty acids and the creatine-phosphocreatine system. In conclusion, the application of metabolomics to placental samples represent a useful approach to understand possible pathological mechanisms and a valuable tool for the investigation of the molecular aspects of PE pathogenesis.