Article pubs.acs.org/jpr
Maternal and Cord Blood LC-HRMS Metabolomics Reveal Alterations in Energy and Polyamine Metabolism, and Oxidative Stress in Verylow Birth Weight Infants Marie-Cécile Alexandre-Gouabau,*,† Frédérique Courant,‡ Thomas Moyon,† Alice Küster,†,§ Gwénael̈ le Le Gall,∥ Illa Tea,⊥ Jean-Philippe Antignac,‡ and Dominique Darmaun†,§ †
UMR Physiologie des Adaptations Nutritionnelles, INRA, IMAD, CRNH, Nantes, and University of Nantes, France LUNAM Université, Oniris, USC INRA 1329 Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA), Nantes, France ∥ Institute of Food Research, Norwich Research Park, Colney, Norwich, NR4 7UA, United Kingdom § Neonatology and INSERM, Centre d’Investigation Clinique (CIC), CHU, Nantes, France ⊥ Elucidation of Biosynthesis by Isotopic Spectrometry Group, Unit for Interdisciplinary Chemistry, Synthesis-Analysis-Modelling (CEISAM), University of Nantes−CNRS UMR 6230, Nantes, France ‡
S Supporting Information *
ABSTRACT: To assess the global effect of preterm birth on fetal metabolism and maternal−fetal nutrient transfer, we used a mass spectrometric-based chemical phenotyping approach on cord blood obtained at the time of birth. We sampled umbilical venous, umbilical arterial, and maternal blood from mothers delivering very-low birth weight (VLBW, with a median gestational age and weight of 29 weeks, and 1210 g, respectively) premature or full-term (FT) neonates. In VLBW group, we observed a significant elevation in the levels and maternal-fetal gradients of butyryl-, isovaleryl-, hexanoyl- and octanoyl-carnitines, suggesting enhanced short- and medium chain fatty acid β-oxidation in human preterm feto-placental unit. The significant decrease in glutamineglutamate in preterm arterial cord blood beside lower levels of amino acid precursors of Krebs cycle suggest increased glutamine utilization in the fast growing tissues of preterm fetus with a deregulation in placental glutamate-glutamine shuttling. Enhanced glutathione utilization is likely to account for the decrease in precursor amino acids (serine, betaine, glutamate and methionine) in arterial cord blood. An increase in both the circulating levels and maternal−fetal gradients of several polyamines in their acetylated form (diacetylspermine and acetylputrescine) suggests an enhanced polyamine metabolic cycling in extreme prematurity. Our metabolomics study allowed the identification of alterations in fetal energy, antioxidant defense, and polyamines and purines flux as a signature of premature birth. KEYWORDS: metabolomics, prematurity, neonatal, cord blood, nutrition
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INTRODUCTION Prematurity, defined as the delivery of a baby before 33 weeks of amenorrhea, occurs in 5−11% of all pregnancies in industrialized countries. Although major advances in ventilatory support and other techniques of perinatal care have dramatically improved the survival rate of very-low birth weight (VLBW) infants over the last 2 decades, premature birth remains a leading cause of perinatal morbidity and mortality.1 As more and more preterm infants are allowed to survive, improving the nutritional management of preterm infants has become a major challenge, as a large proportion of preterm infants still suffer extra-uterine growth failure during their stay in the neonatal intensive care unit.2 Improving our understanding of the metabolic adaptations of the mother and the feto-placental unit in case of prematurity may help improve the care of VLBW infants. Indeed, adequate fetal growth is © 2013 American Chemical Society
primarily determined by nutrient availability, which in turn depends on nutrient transport from the maternal to the fetal circulation across the placenta. Placenta acts as a nutrient sensor,3 and its capacity to supply nutrients is dependent on several factors, including uterine and umbilical blood flows, the gradient between maternal and fetal blood, placental metabolism, and the activity of specific placental transporters and enzymes.4 Metabolomics allows for the simultaneous assessment of the levels of a broad range of low molecular weight metabolites and has been shown to generate new insights when investigating physiological status, diagnosing diseases, identifying disrupted pathways due to disease or treatment and discovering new Received: February 7, 2013 Published: March 26, 2013 2764
dx.doi.org/10.1021/pr400122v | J. Proteome Res. 2013, 12, 2764−2778
Journal of Proteome Research
Article
to first the unpredictability of natural premature delivery, and second to the ethical requirement of not disturbing the mother at this stressful moment. The study population consisted of: (a) a group of 7 inborn VLBW neonates. Inclusion criteria were a gestational age (GA) net umbilical uptake [CV-CA] FT and a ratio
