Alteration in Expression and Methylation of IGF2/H19 in Placenta and Umbilical Cord Blood Are Associated with Macrosomia Exposed to Intrauterine Hyperglycemia.

Chen Wang,Huixia Yang,Rina Su,Li Lin,Xinyue Liu,Hui Feng,Yumei Wei,Dongmei Li

doi:10.1371/journal.pone.0148399

Chen Wang, Huixia Yang + Show 6 more

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https://doi.org/10.1371/journal.pone.0148399

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Abstract

ObjectiveMacrosomia is one of the most common complications in gestational diabetes mellitus. Insulin-like growth factor 2 and H19 are two of the imprinted candidate genes that are involved in fetal growth and development. Change in methylation at differentially methylated region of the insulin-like growth factor 2 and H19 has been proved to be an early event related to the programming of metabolic profile, including macrosomia and small for gestational age in offspring. Here we hypothesize that alteration in methylation at differentially methylated region of the insulin-like growth factor 2 and H19 is associated with macrosomia induced by intrauterine hyperglycemia.ResultsThe expression of insulin-like growth factor 2 is significant higher in gestational diabetes mellitus group (GDM group) compared to normal glucose tolerance group (NGT group) both in umbilical cord blood and placenta, while the expression of H19 is significant lower in GDM group in umbilical cord blood. The expression of insulin-like growth factor 2 is significant higher in normal glucose tolerance with macrosomia group (NGT-M) compared to normal glucose tolerance with normal birthweight group (NGT-NBW group) both in placenta and umbilical cord blood. A model with interaction term of gene expression of IGF2 and H19 found that IGF2 and the joint action of IGF2 and H19 in placenta showed significantly relationship with GDM/NGT and GDM-NBW/NGT-NBW. A borderline significant association was seen among IGF2 and H19 in cord blood and GDM-M/NGT-M. The methylation level at different CpG sites of insulin-like growth factor 2 and H19 in umbilical cord blood was also significantly different among groups. Based on the multivariable linear regression analysis, the methylation of the insulin-like growth factor 2 / H19 is closely related to birth weight and intrauterine hyperglycemia.ConclusionsWe confirmed the existence of alteration in DNA methylation in umbilical cord blood exposed to intrauterine hyperglycemia and reported a functional role in regulating gene associated with insulin-like growth factor 2/H19. Both of these might be the underlying pathogenesis of macrosomia. We also provided the evidence of strong associations between methylation of insulin-like growth factor 2/H19 and macrosomia induced by intrauterine hyperglycemia.

Highlights

Gestational diabetes mellitus (GDM), which is defined as any degree of glucose intolerance with onset during pregnancy, affects 10~20% of all pregnancies [1, 2]
We confirmed the existence of alteration in DNA methylation in umbilical cord blood exposed to intrauterine hyperglycemia and reported a functional role in regulating gene associated with insulin-like growth factor 2/H19
We provided the evidence of strong associations between methylation of insulin-like growth factor 2/H19 and macrosomia induced by intrauterine hyperglycemia

Summary

Introduction

Gestational diabetes mellitus (GDM), which is defined as any degree of glucose intolerance with onset during pregnancy, affects 10~20% of all pregnancies [1, 2]. A growing body of research suggests that exposure to intrauterine hyperglycemia can increase the incidence of macrosomia, and these infants are prone to have obesity, abnormal glucose metabolism, hypertension and dyslipidemia in adulthood [3,4]. Many studies suggested that intrauterine hyperglycemia may increase maternal supply of carbohydrates leading to fetal hyperinsulinemia, and stimulation of the insulin sensitive tissue by hyperinsulinemia results in increased fetal growth [5,6], but the exact mechanism of macrosomia induced by intrauterine hyperglycemia environment of GDM is still not completely understood. Epigenetic abnormalities induced by GDM may be involved in metabolic diseases progression and fetal growth [8, 9]. We hypothesize that GDM increases the risk of macrosomia in offspring by altering epigenetic modification

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