Placental metabolomics in obese pregnancies

Irene Cetin, Chiara Novielli, and Chiara Mandò

Introduction

Obesity is one of the most challenging health burdens worldwide, with increasing prevalence in the last decade (1,2). Obesity during pregnancy has short- and long-term adverse consequences for the mother and the fetus, involving both genetic and epigenetic changes (3–5). Obesity increases the risk of obstetrical complications and pregnancy pathologies such as gestational diabetes mellitus (GDM) and preeclampsia (PE) (6–8) and raises the likelihood of excessive gestational weight gain, which further increases the chance of developing metabolic syndrome later in life (9). Obstetric morbidity and mortality are increased in the offspring of obese women (10). Long-term risks of obesity and metabolic dysfunction in the offspring have been reported suggesting epigenetic, metabolic, and endocrine alterations in the fetoplacental compartment (3,11–14). Of note, several placental changes have been reported in maternal obesity (3,12,14,15). Indeed, the metabolic and endocrine alterations of the pregnant obese mother and her intrauterine lipotoxic environment have been shown to specifically affect placental development and function, possibly causing alterations in nutrient-sensing pathways, fetal development, and thus fetal programming (3,12,14–16). Fetal sex-specific changes in placental function, biometry, and epigenetic signatures have also been recently reported related to maternal body mass index (BMI) (15,17–19). Therefore, the need of a wide and deeper characterization of placental metabolic signatures depending on maternal BMI and gestational weight gain has become mandatory for better understanding the mechanisms involved in long-term adverse consequences of maternal obesity.

In the last decade, the rapid emergence of high-throughput technologies has provided new insights in disease mechanisms, and their use has been very recently advocated also in pregnancy (5,20–25). Metabolomics is one of the most promising “omics” technologies. High-throughput platforms, namely, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy allow the identification of any molecule less than 1 kDa in mass that represents the final product of transcriptional/posttranscriptional regulation and of interactions among proteins in the complex biological cell pathways. This provides a snapshot of dynamic cellular processes, thus giving novel insights into disease onset and severity. The holistic approach of metabolomics can therefore represent an effective method to characterize the placental phenotypic fingerprinting in pregnancies with adverse outcomes (26) and specifically to improve knowledge of obesity pathophysiology.

To date, most metabolomics studies in pregnancy have been performed in biofluids, such as blood, urine, or amniotic fluid (24,26–29). Metabolome analysis has the potential to improve the prediction, screening, and diagnosis of pregnancy pathologies early in pregnancy by the identification of specific fluids biomarkers. Pregnancies of obese women with GDM have shown different blood metabolic profiles compared to non-GDM obese women, including exaggerated dyslipidemia, at least 10 weeks before GDM diagnosis by oral glucose tolerance test (28). Blood metabolic changes throughout gestation of obese women have also been recently reported, showing a larger increase in lipoproteins and triglycerides compared to a general pregnant population of unselected women (29).

Nevertheless, the study of placental metabolome represents an important tool to unravel etiopathogenetic mechanisms undergoing placental dysfunctions, leading to altered fetal programming and long-term consequences. To date, only a few recent studies evaluated the placental metabolome using MS or NMR spectroscopy (23,30–35). Among them, one investigated placental metabolome changes in a rat model of maternal obesity (31). Few recent works specifically focused on human pregnancies of obese women (32,36–37). Alterations in metabolic profiles following a maternal high-fat diet were reported in rat placenta (31) using gas and liquid chromatography (LC) combined with MS. Specifically, pathway analysis showed placental alterations in the biosynthesis of unsaturated fatty acids, and in the metabolism of the essential fatty acids linoleic acid and α-linolenic acid, which are both converted to long-chain polyunsaturated fatty acids (LC-PUFAs). The unbalance of these lipids can promote inflammatory processes and have negative effects on placental and fetal development (38–41), thus suggesting that disruption of pathways involving fatty acids in placentas could be part of altered mechanisms leading to adverse pregnancy outcomes in the presence of maternal obesity.

Changes in placental fatty acids profile have been recently reported also in human pregnancies of obese women (36). Fattuoni et al. performed untargeted metabolomics analysis using a gas chromatography-mass spectrometry (GC-MS) platform. Increased levels of palmitic acid and decreased levels of stearic acid and of the LC-PUFA derivatives DHA (docosahexaenoic acid) and arachidonic acid were found in placentas of obese versus normal weight women, delivered by elective cesarean section thus avoiding molecular alterations due to labor. These results confirmed previous observations indicating that in human pregnancies of obese women a disruption of the physiologic LC-PUFA placental biomagnification occurs (38–39). This leads to decreased availability of arachidonic acid and DHA to the fetus, with important consequences on fetal development and on the risk of adverse fetal outcomes and future diseases (42–43). This study also showed alterations in a broad range of metabolites belonging to the hydrophilic phase extracted from human placentas from obese relative to normal weight women. Namely, obese placentas presented higher levels of nucleobases (uracil, hypoxanthine), glucose-6-phosphate, 3-phoshoglycerate, glycerol, nicotinamide, and the amino acids tyrosine, isoleucine, phenylalanine, leucine, and serine. Lower levels of the amino acids lysine, taurine, aspartic acid, and glutamine, along with the nucleosides inosine and guanosine, an inositol isomer, and gluconic acid were also detected. Significant changes in several amino acids levels may be the result of a disrupted placental metabolism. Moreover, many of the altered hydrophilic metabolites in obese placentas are involved in metabolic pathways that support nucleotide production, antioxidant defenses, and lipid synthesis. Overall, these data suggest a generalized shift toward higher placental metabolism in obese pregnancies.

Another study recently described placental lipid droplets composition in obese pregnancies, using LC-MS/MS technology (37

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