Fetal epigenetic programming of the IGF axis in pregnancies affected by growth disorders, gestational diabetes and obesity
Creators: name: Nawathe, Aamod
Publisher: name: Imperial College London
Year: 2015

description: Gestational diabetes and maternal obesity are associated with impaired maternal glycaemic control and increased risk of delivering a macrosomic fetus. Macrosomic as well as growth restricted neonates have an increased risk of metabolic syndrome and cardiovascular disease in adult life which may be mediated through an altered intra-uterine environment. The placenta acts as a mediator between the mother and the fetus and handles placental nutrient exchange and transfer. Insulin-like growth factors 1 and 2 (IGF1 and IGF2) are hormones similar to insulin and are known for their growth promoting function in the body. They are also present in the placenta and play an important role in regulating placental and fetal growth. Animal and human studies have shown that IGF1 and IGF2 deletions are associated with growth restriction. The IGFs are bound to their binding proteins called insulin-like growth factor binding proteins (IGFBPs) which modulate their bioavailability and can therefore modulate fetal growth. The IGFs and IGFBPs are associated with glucose regulation but their role in gestational diabetes is unclear. We hypothesized that the placental gene expression of IGF system related genes is altered in pregnancies complicated by fetal growth disorders (pregnancies with small or large fetuses) and in those women who had gestational diabetes mellitus (GDM) or increased body mass index (BMI&gt;30). Epigenetics is the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence. 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 can potentially alter the expression of IGFs and their binding proteins. We have also hypothesized that a relationship existed between DNA methylation and gene expression of components of the IGF axis in the placenta. The placental IGF1 expression was found to be reduced in women with small for gestational age (SGA) neonates. The expression of IGFBPs was upregulated in SGA neonates and downregulated in large for gestational age (LGA) neonates. The placental IGF1 gene promoter was found to be hypermethylated while the promoters of the binding proteins were hypomethylated in the placentas of SGA neonates. The umbilical cord levels of IGF1 and the binding proteins in SGA and LGA neonates showed a similar trend to the placental gene expression changes. We have also analysed the placental gene expression and umbilical levels of imprinted gene GRB10 which has been investigated in mice studies and is known to cause growth restriction. We found increased placental expression of GRB10 and hypomethylation of its promoter in SGA neonates. The placental expression of IGF1, IGFBP1 and IGFBP2 was found to be decreased in women with GDM on diet and on metformin but not in those on insulin. The IGF1, IGFBP1 and IGFBP2 promoters were noted to be hypermethylated but only in women on diet treatment and not on metformin on insulin. The umbilical levels of IGF1 and IGFBP1 but not IGFBP2, were increased in GDM thus showing an inverse trend to the placental gene expression changes. In conclusion our results suggest that in SGA neonates, changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis and GRB10 in fetal growth disorders. Differential methylation of the IGF1 gene, its binding proteins and GRB10 is likely to play a role in the pathogenesis of SGA neonates. Our results also suggest that GDM is associated with gene expression and epigenetic alterations in the IGF1, IGFBP1 and IGFBP2 genes, which could be part of the wider metabolic complexities associated with GDM.