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The Placenta as a Target of Epigenetic Alterations in Women with Gestational Diabetes Mellitus and Potential Implications for the Offspring.

ABSTRACT: Gestational diabetes mellitus (GDM) is a pregnancy complication first detected in the second or third trimester in women that did not show evident glucose intolerance or diabetes before gestation. In 2019, the International Diabetes Federation reported that 15.8% of live births were affected by hyperglycemia during pregnancy, of which 83.6% were due to gestational diabetes mellitus, 8.5% were due to diabetes first detected in pregnancy, and 7.9% were due to diabetes detected before pregnancy. GDM increases the susceptibility to developing chronic diseases for both the mother and the baby later in life. Under GDM conditions, the intrauterine environment becomes hyperglycemic, while also showing high concentrations of fatty acids and proinflammatory cytokines, producing morphological, structural, and molecular modifications in the placenta, affecting its function; these alterations may predispose the baby to disease in adult life. Molecular alterations include epigenetic mechanisms such as DNA and RNA methylation, chromatin remodeling, histone modifications, and expression of noncoding RNAs (ncRNAs). The placenta is a unique organ that originates only in pregnancy, and its main function is communication between the mother and the fetus, ensuring healthy development. Thus, this review provides up-to-date information regarding two of the best-documented (epigenetic) mechanisms (DNA methylation and miRNA expression) altered in the human placenta under GDM conditions, as well as potential implications for the offspring.

SUBMITTER: Lizarraga D

PROVIDER: S-EPMC8594713 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThe offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model.MethodsBy creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation-quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells.ResultsWe found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia.ConclusionOur results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.

Project description:BackgroundGestational diabetes mellitus (GDM) produces numerous problems for maternal and fetal outcomes. However, the precise molecular mechanisms of GDM are not clear.MethodsIn our study, we randomly assigned 22 pregnant women with fasting glucose concentrations, 1 hour oral glucose tolerance test (1H-OGTT) and 2 hour oral glucose tolerance test (2H-OGTT), different than 28 normal pregnant women from a sample of 107 pregnant women at the First Affiliated Hospital of Jinan University in China. Lipopolysaccharide (LPS), interleukin 1 alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) were measured from blood plasma of pregnant women and umbilical arteries using ultraviolet spectrophotometry. Hematoxylin & Eosin (H&E), Periodic acid-Schiff (PAS) or Masson staining were performed to examine whether diabetes mellitus altered the morphology of placenta. Quantitative PCR (Q-PCR), western blotting and immunofluorescent staining were performed to examine whether diabetes mellitus and autophagy altered the gene expressions of the placental tissue.ResultsWe found that women with GDM exhibited increased placental weight and risk of neonatal infection. The concentrations of IL-6 protein and IL-8 protein in GDM were increased in both maternal and umbilical arterial blood. H&E, Masson and PAS staining results showed an increased number of placental villi and glycogen deposition in patients with GDM, but no placental sclerosis was found. Q-PCR results suggested that the expression levels of HIF-1α and the toll like receptor 4 (TLR4)/ myeloid differential protein-88 (MyD88)/ nuclear factor kappa-B (NF-κB) pathway were increased in the GDM placenta. Through Western Blotting, we found that the expression of NF-kappa-B inhibitor alpha (IKBα) and Nuclear factor-κB p65 (NF-κB p65) in GDM placenta was significantly enhanced. We also showed that the key autophagy-related genes, autophagy-related 7 (ATG7) and microtubule-associated protein 1A/1B-light chain 3 (LC3), were increased in GDM compared with normal pregnant women.ConclusionsOur results suggest that women with GDM exhibit an increased risk of neonatal infection via inflammation and autophagy in the placenta.

Project description:BackgroundGestational diabetes mellitus (GDM) is a common pregnancy-specific disease and is growing at an alarming rate worldwide, which can negatively affect the health of pregnant women and fetuses. However, most studies are limited to one tissue, placenta or umbilical cord blood, usually with one omics assay. It is thus difficult to systematically reveal the molecular mechanism of GDM and the key influencing factors on pregnant women and offspring.ResultsWe recruited a group of 21 pregnant women with GDM and 20 controls without GDM. For each pregnant woman, reduced representation bisulfite sequencing and RNA-seq were performed using the placenta and paired neonatal umbilical cord blood specimens. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were identified with body mass index as a covariate. Through the comparison of GDM and control samples, 2779 and 141 DMRs, 1442 and 488 DEGs were identified from placenta and umbilical cord blood, respectively. Functional enrichment analysis showed that the placenta methylation and expression profiles of GDM women mirrored the molecular characteristics of "type II diabetes" and "insulin resistance." Methylation-altered genes in umbilical cord blood were associated with pathways "type II diabetes" and "cholesterol metabolism." Remarkably, both DMRs and DEGs illustrated significant overlaps among placenta and umbilical cord blood samples. The overlapping DMRs were associated with "cholesterol metabolism." The top-ranking pathways enriched in the shared DEGs include "growth hormone synthesis, secretion and action" and "type II diabetes mellitus."ConclusionsOur research demonstrated the epigenetic and transcriptomic alternations of GDM women and offspring. Our findings emphasized the importance of epigenetic modifications in the communication between pregnant women with GDM and offspring, and provided a reference for the prevention, control, treatment, and intervention of perinatal deleterious events of GDM and neonatal complications.

Project description:BackgroundThe micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity.MethodsWe assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine.ResultsHigher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = - 4.8%; 95%CI - 8.9 to - 0.6%; p = 0.026).ConclusionsHigher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

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The Placenta as a Target of Epigenetic Alterations in Women with Gestational Diabetes Mellitus and Potential Implications for the Offspring.

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