Abstract
Metabolites reflect the biochemical dynamics for the maintenance of pregnancy and parturition. UPLC-Q/TOF-MS and LC-MS/MS metabolomics were performed to identify and validate the plasma metabolomic signatures of preterm birth (PTB). We recruited pregnant women between 16 and 40 weeks 5 days gestational age at Ewha Womans Mokdong Hospital for a nested case-control study. In untargeted UPLC-Q/TOF-MS, score plots of partial least-squares discriminant analysis clearly separated the PTB group from the term birth (TB, n = 10; PTB, n = 11). Fifteen metabolites were significantly different between the two groups, as indicated by a variable importance in projection >1 and p < 0.05. Metabolic pathways involving retinol, linoleic acid, d-arginine, and d-ornithine were associated with PTB. Verification by LC-MS/MS focused on retinol metabolism (TB, n = 39; PTB, n = 20). Retinol levels were significantly reduced in PTB compared to TB, while retinal palmitate, all-trans-retinal, and 13-cis-retinoic acid (13cis-RA) significantly increased (p < 0.05). Retinol-binding protein levels were also elevated in PTB. Additionally, all-trans-retinal (AUC 0.808, 95% CI: 0.683–0.933) and 13cis-RA (AUC 0.826, 95% CI: 0.723–0.930) showed improved predictions for PTB-related retinol metabolites. This study suggests that retinoid metabolism improves the accuracy of PTB predictions and plays an important role in maintaining pregnancy and inducing early parturition.
Highlights
Preterm birth (PTB) is defined as giving birth before 37 weeks of gestation and is a major cause of death in children below 5 years worldwide [1]
We collected peripheral blood from pregnant women, at 16 to 40 weeks and 5 days gestational age to identify the metabolomic signatures of PTB and to validate the targeted metabolites (TB, n = 39; PTB, n = 20) (Figure 1)
We focused on the metabolites involved in retinoid metabolism to investigate the pathological mechanisms underlying PTB and to identify indicators for predicting PreTtBin.oTihdemreettianbooidlitmeseitnabtholeitpelsaisnmthaeopf lparsemgnaaonftpwreogmnaentwweorme aenawlyezreedanuasilnyzgeLdCu-sMinSg/LMCSM(TSB/,MnS=(3T9B;,PnT=B,3n9;=P2T0B),. nW=h2e0n).thWehgeensttahteiogneasltagtieonwaalsaagdejwusatseda,drjeumsteadrk, arbemleadrikffaebrleendceifswfereernecfeosuwnderien ftohuenadmionutnhteoafmvoaruinotusofrevtainrioolums eretatibnoollitmesebtaebtwoleiteens PbTetBwaenedn TPBTB(FaignudreTB4T. aWblheiSle4)r.eWtinhoillelreevteinlsowl levreelssigwneirfiecsaingtnlyifilcoawntelry, lroewtinera,lrpeatilnmailtpaatelm, ailtlatera, anlsl t(rAatn)-sr(eAtint)a-rl,eatinndal1, 3a-ncdis1-r3e-tciinso-ricetainciodic(1a3cciids-(R13Aci)s-lRevAe)lslewverlse wsiegrneifisicgannitfliycahnigtlhyehriignhPerTiBntPhTanB tihnaTnBin(pT
Summary
Preterm birth (PTB) is defined as giving birth before 37 weeks of gestation and is a major cause of death in children below 5 years worldwide [1]. Spontaneous PTB results from preterm labor and preterm premature rupture of membrane (pPROM) induced by various pathological processes in approximately 70% of cases [12,13] It is not well known how the process of PTB is initiated, but the main pathways are fetal and maternal tissue activation by cervical insufficiency, stress, inflammation, hemorrhage, uterine distension, and immune dysregulation. Membrane rupture is related to biochemical changes in collagen structure and formation, as well as increased oxidative stress [15,16], involving an imbalance between synthesis and matrix metalloproteinase-induced collagen degradation within the extracellular matrix of the chorioamniotic membrane [17] Using these pathophysiological pathways, many researchers have sought to identify biomarkers of inflammation related to ascending intrauterine infection to predict PTB [18]. We report the results of validation focused on retinoid metabolism to improve the prediction of PTB and understand its broader mechanism
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