title: Insulin-like growth factor axis in pregnancies affected by fetal growth disorders.
abstract: BACKGROUND
  Insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This silences gene expression, potentially altering the expression of IGFs and their binding proteins. This study investigates the relationship between DNA methylation of components of the IGF axis in the placenta and disorders in fetal growth. Placental samples were obtained from cord insertions immediately after delivery from appropriate, small (defined as birthweight <10th percentile for the gestation [SGA]) and macrosomic (defined as birthweight > the 90th percentile for the gestation [LGA]) neonates. Placental DNA methylation, mRNA expression and protein levels of components of the IGF axis were determined by pyrosequencing, rtPCR and Western blotting.
  
  
  RESULTS
  In the placenta from small for gestational age (SGA) neonates (n = 16), mRNA and protein levels of IGF1 were lower and of IGFBPs (1, 2, 3, 4 and 7) were higher (p < 0.05) compared to appropriately grown neonates (n = 37). In contrast, in the placenta from large for gestational age (LGA) neonates (n = 20), mRNA and protein levels of IGF1 was not different and those of IGFBPs (1, 2, 3 and 4) were lower (p < 0.05) compared to appropriately grown neonates. Compared to appropriately grown neonates, CpG methylation of the promoter regions of IGF1 was higher in SGA neonates. The CpG methylation of the promoter regions of IGFBP1, IGFBP2, IGFBP3, IGFBP4 and IGFBP7 was lower in the placenta from SGA neonates as compared to appropriately grown neonates, but was unchanged in the placenta from LGA neonates.
  
  
  CONCLUSIONS
  Our results suggest that changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis in fetal growth disorders. Differential methylation of the IGF1 gene and its binding proteins is likely to play a role in the pathogenesis of SGA neonates.
authors.affiliation: Imperial College London, London, UK ; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.
authors.forename: Aamod R
authors.initials: AR
authors.lastname: Nawathe
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Christian
authors.affiliation: Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.
authors.forename: Sung Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Imperial College London, London, UK ; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Imperial College London, London, UK ; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.
authors.forename: Makrina D
authors.initials: MD
authors.lastname: Savvidou
authors.affiliation: Imperial College London, London, UK ; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.
authors.forename: Vasso
authors.identifier: 0000-0002-7579-4947
authors.initials: V
authors.lastname: Terzidou
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000502:physiology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000502:physiology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000502:physiology; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000502:physiology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000502:physiology; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: C032231:IGFBP1 protein, human; C577903:IGFBP2 protein, human; C515497:IGFBP3 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
keywords: DNA methylation; Insulin growth factor; Large fetus; Placental expression; Small fetus
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