title: Metabolomics reveals metabolic alterations by intrauterine growth restriction in the fetal rabbit brain.
abstract: BACKGROUND
  Intrauterine Growth Restriction (IUGR) due to placental insufficiency occurs in 5-10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development.
  
  
  RESULTS
  At gestation day 25, IUGR was induced in two New Zealand rabbits by 40-50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR.
  
  
  CONCLUSIONS
  IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty acid profiles and oxidative stress mechanisms. Overall findings identified aspargine, ornithine, N-acetylaspartylglutamic acid, N-acetylaspartate and palmitoleic acid as potential metabolite candidates to develop clinical biomarkers for the perinatal diagnosis of IUGR related abnormal neurodevelopment.
authors.affiliation: Department of Maternal-Fetal Medicine, Institut Clinic de Ginecologia, Obstetricia i Neonatologia-ICGON, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Vliet
authors.forename: Elisenda
authors.initials: E
authors.lastname: Eixarch
authors.forename: Miriam
authors.initials: M
authors.lastname: Illa
authors.forename: Ariadna
authors.initials: A
authors.lastname: Arbat-Plana
authors.forename: Anna
authors.initials: A
authors.lastname: González-Tendero
authors.forename: Helena T
authors.initials: HT
authors.lastname: Hogberg
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Eduard
authors.initials: E
authors.lastname: Gratacos
mesh_terms: D000818:Animals; D001724:Birth Weight; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D007477:Ions / Q000378:metabolism; D055432:Metabolomics; D009929:Organ Size; D011247:Pregnancy; D025341:Principal Component Analysis; D011817:Rabbits
chemical_list: D007477:Ions