Gestational Diabetes Alters Offspring DNA Methylation Profiles in Human and Rat: Identification of Key Pathways Involved in Endocrine System Disorders, Insulin Signaling, Diabetes Signaling, and ILK Signaling

Abstract

Gestational diabetes is associated with risk for metabolic disease later in life. Using a cross-species approach in rat and humans, we examined the hypothesis that gestational diabetes during pregnancy triggers changes in the methylome of the offspring that might be mediating these risks. We show in a gestation diabetes rat model, the Cohen diabetic rat, that gestational diabetes triggers wide alterations in DNA methylation in the placenta in both candidate diabetes genes and genome-wide promoters, thus providing evidence for a causal relationship between diabetes during pregnancy and DNA methylation alterations. There is a significant overlap between differentially methylated genes in the placenta and the liver of the rat offspring. Several genes differentially methylated in rat placenta exposed to maternal diabetes are also differentially methylated in the human placenta of offspring exposed to gestational diabetes in utero. DNA methylation changes inversely correlate with changes in expression. The changes in DNA methylation affect known functional gene pathways involved in endocrine function, metabolism, and insulin responses. These data provide support to the hypothesis that early-life exposures and their effects on metabolic disease are mediated by DNA methylation changes. This has important diagnostic and therapeutic implications.

Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating

“…Whereas the mechanisms leading to sex differences in disease risk remain unidentified, defective placental insulin signaling is common to these pregnancy complications and has been implicated in adverse fetal outcomes, especially in male individuals (19–28). We hypothesized that impaired insulin signaling in the placenta, the critical and sex-specific maternal–fetal intermediary, is a mechanistic link between maternal metabolic dysfunction and male-biased neurodevelopmental reprogramming.…”

“…Impaired insulin action is common to these maternal metabolic conditions, where reduced insulin production is a hallmark of type 1 diabetes mellitus and impaired cellular responses to insulin are characteristic of type 2 diabetes, gestational diabetes, and obesity. Insulin dysfunction has been demonstrated in placental tissue from pregnancies complicated by diabetes, preeclampsia, intrauterine growth restriction, and inflammation (19–27). Critically, then, placental insulin signaling may serve as a novel mediator of neurodevelopmental programming by maternal adversity contributing to disease risk.…”

Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring

“…Growing evidence showed that DNA methylation disorder in some key genes is a linkage between maternal malnutrition and offspring metabolic disorder. Both in a rat model and humans, several genes in the insulin response pathway are differentially methylated in placenta exposed to gestational diabetes [38]. Maternal protein restricted diet reduced the methylation of glucocorticoid receptor (GR) promoter and enhanced GR expression in rat offspring liver.…”

Paternal obesity in a rodent model affects placental gene expression in a sex-specific manner

“…Placental hypermethylation has also been linked to other complications of pregnancy including preeclampsia and placental mesenchymal dysplasia, both of which are associated with increased rates of FGR and fetal death (Anton et al 2014, Chen et al 2014. Interestingly, a rodent model of gestational diabetes has shown overlap between differentially methylated genes in the placenta and fetal tissues, which affect metabolic pathways (Petropoulos et al 2015). The effect of paternal obesity on fetal methylation status also warrants attention.…”