A Non-Targeted LC-MS Profiling Reveals Elevated Levels of Carnitine Precursors and Trimethylated Compounds in the Cord Plasma of Pre-Eclamptic Infants

Abstract

Preeclampsia (PE) is a complex pregnancy disorder. It is not extensively known how the metabolic alterations of PE women contribute to the metabolism of newborn. We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted metabolomics to determine whether the metabolic profile of plasma from umbilical cord differs between infants born to PE and non-PE pregnancies in the FINNPEC study. Cord plasma was available from 42 newborns born from PE and 53 from non-PE pregnancies. 133 molecular features differed between PE and non-PE newborns after correction for multiple testing. Decreased levels of 4-pyridoxic acid were observed in the cord plasma samples of PE newborns when compared to non-PE newborns. Compounds representing following areas of metabolism were increased in the cord plasma of PE newborns: urea and creatine metabolism; carnitine biosynthesis and acylcarnitines; putrescine metabolites; tryptophan metabolism and phosphatidylcholines. To our knowledge, this study is the first one to apply LC-MS based metabolomics in cord plasma of PE newborns. We demonstrate that this strategy provides a global picture of the widespread metabolic alterations associated with PE and particularly the elevated levels of carnitine precursors and trimethylated compounds appear to be associated with PE at birth.

The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester

“…In this study, we explored third trimester placental creatine metabolism in early-onset PE and gestation-matched normotensive pregnancies. Our findings confirm the recent metabolomic reports of altered creatine homeostasis with PE [9]; moreover, we identified significant changes in expression of genes associated with the synthesis and transport of creatine within the placenta. Our main finding was that total creatine content of the third trimester PE placentae was significantly higher than controls.…”

“…This could simply be the result of increased maternal circulating creatine levels with PE. While no studies have characterized changes in maternal creatine levels in PE cases, increased creatine in cord plasma has been reported [9]. The retrospective nature of the current study and lack of maternal blood sampling inhibited our ability to explore this hypothesis further.…”

“…A recent wide-spectrum metabolomic analysis identified increased creatine and creatinine in cord plasma in PE pregnancies [9] indicating that, among other metabolic changes, fetal and potentially placental creatine homeostasis is altered in PE. Creatine-N-(aminoiminomethyl)N-methyl glycine-is a nitrogenous amino acid derivative obtained from our diet and endogenously synthesized by some tissues, including the placenta [10].…”

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

“…While difficult to determine without further detailed confirmatory tests, the presence of 3M-4-TMAB and 4-TMAP in other diseases is suggested through publicly available data and the literature. A molecule of the exact m/z of 3M-4-TMAB and 4-TMAP (160.133) has been described in the literature as a biomarker in type 2 diabetes (T2D), significantly increased in cord plasma during preeclampsia, and predictive of diabetic nephropathy in T1D patients (28)(29)(30). These diseases all have associated mitochondrial dysfunction or incomplete FAO.…”

A double hit preeclampsia model results in sex-specific growth restriction patterns

“…This suggests that the symmetrical growth-restricted female fetuses in our double-hit pre-eclampsia model have dysbalanced fat and energy metabolism. Recently, a study reported differences in the cord blood metabolome from pre-eclamptic neonates in comparison to that from controls (Jääskeläinen et al, 2018). The most affected metabolites are similar to the ones we report and included acylcarnitines, PCs and metabolites of urea and tryptophan metabolism.…”