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Gestational diabetes mellitus and EDCs
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Gestational diabetes mellitus (GDM) remains a significant clinical and public health issue due to its increasing prevalence and the possibility for numerous short- and long-term complications. The growing incidence of GDM seems to coincide with the widespread use of endocrine disrupting chemicals (EDCs). The extensive production and common use of these substances in everyday life has resulted in constant exposure to harmful substances from the environment. That may result in epigenetic changes, which may manifest themselves also after many years and be passed on to future generations. It is important to consider the possible link between environmental exposure to endocrine disrupting chemicals (EDCs) during pregnancy, epigenetic mechanisms and an increased risk for developing gestational diabetes mellitus (GDM).

EDCs gestational diabetes mellitus epigenetics

1. Introduction

Diabetes is one of the most common metabolic diseases globally. The prevalence of pregestational and gestational diabetes continues to increase and is now at the upper end of previous estimates in Europe [1]. Gestational diabetes is detected in approximately 15% of pregnancies [2]. Although GDM usually resolves after delivery, it may have numerous, long-lasting health consequences, such as increased risk for type II diabetes mellitus (T2DM) and cardiovascular disease in the mother, and future metabolic and cardiovascular complications such as increased adiposity or even obesity, impaired glucose metabolism, hypertension, hyperlipidemia, and nonalcoholic fatty liver disease in the offspring, as well as preterm puberty, but only in girls [3][4][5][6][7]. The increasing incidence of GDM seems to coincide with the growing use of endocrine disrupting chemicals (EDCs). EDCs are a group of chemical substances that, due to their structural similarities with steroid hormones, interact with receptors for estrogens, androgens, and progesterone, thereby increasing the risk of endocrinopathy and diseases of civilization [8]. Exposure of pregnant women to EDCs might be a cause of the growing incidence of gestational diabetes, and as a consequence, increased risk of epigenetic “diabetogenic” and “obesogenic” changes in the offspring DNA, thereby escalating the risk of developing civilization diseases in subsequent generations. There are many examples in the literature that provide proofs of concept that EDCs should be treated as possible risk factors for poor fetal and maternal outcomes [9]. On the basis of existing evidence concerning the widespread effects of EDCs as well as the potential diabetogenic actions of particular EDCs, it is important to consider the possible association between environmental exposure to EDCs during pregnancy and an increased risk for developing gestational diabetes mellitus (GDM). Exposure of the maternal-fetal unit to EDCs may also, and perhaps more likely, result in epigenetic changes, which may manifest themselves immediately or after many years and be passed on to future generations. This sets in motion a vicious intergenerational cycle of metabolic diseases that influence the health of the human population [10].

2. Patophysiological Aspects of Gestational Diabetes Mellitus

In early gestation, insulin sensitivity increases, promoting the uptake and storage of glucose to meet the energy demands of later pregnancy [11]. Increasing insulin resistance instead is one of the most important metabolic adaptations in the course of pregnancy, emerging at 14 weeks’ gestation and increasing up to two-fold by late pregnancy [12]. This process is caused by a rise in the concentration of pregnancy hormones—estrogen, progesterone, leptin, cortisol, placental lactogen, and placental growth hormone, which enable an adequate supply of glucose to the developing fetus. In most women, the increase in insulin requirements is compensated for by the growing insulin production. Evidence in animals suggests that this process results from hypertrophy and hyperplasia of pancreatic βcells, as well as increased glucose-stimulated insulin secretion [13]. Maternal insulin sensitivity returns to pre-pregnancy levels within a few days after delivery [14].Physiologic metabolic adaptations to pregnancy do not always function adequately during pregnancy, and both

-cell impairment (reduced β-cell mass, reduced β-cell number, β

-cell dysfunction, or a mix of all three), and tissue insulin resistance are critical components of the pathophysiology of GDM. Additional factors contributing to the development of gestational diabetes have also been identified: adipose expandability, low-grade chronic inflammation, and oxidative stress [15][16][17]. Increased gut permeability is also thought to facilitate the movement of inflammatory mediators from the gut into the circulation, promoting systemic insulin resistance [18].

GDM is defined as glucose intolerance that is first diagnosed in pregnancy. Maternal hyperglycemia increases transplacental glucose transfer to the fetal circulation, resulting in overstimulation of the fetal pancreas. Physiologically insulin does not pass the placenta and the fetus begins to produce its own insulin around 9 weeks of age. Fetal hyperinsulinemia intensifies the metabolism and growth of the fetus (an overgrowth of muscle tissue, including the heart muscle, adipose tissue, and liver), increasing the demand for oxygen, especially in the last stage of pregnancy. As a consequence, fetuses from pregnancies complicated by GDM are more likely to suffer from intrauterine hypoxia and perinatal injuries resulting from excessive birth weight. The offspring of mothers with GDM may also have an increased risk for long-term sequelae. GDM increases the risk of maternal and fetal complications during pregnancy and long-lasting health consequences, such as amplifying the risk of T2DM and cardiovascular disease in the mother, and future metabolic and cardiovascular complications such as increased adiposity or even obesity [3][4][5][19], impaired glucose metabolism [6], hypertension [7], hyperlipidemia, and nonalcoholic fatty liver disease in the offspring, as well as preterm puberty, but only in girls [20][21][22][23]. GDM is associated with an enlarged risk for pre-eclampsia, birth complications such as shoulder dystocia and neonatal hypoglycemia, and an extended rate of cesarean section [24][25]. Mentioned GDM complications may represent intergenerational epigenetic inheritance, but embryonic exposure to an altered intrauterine environment also might cause an epigenetic transgenerational effect. It seems more and more likely that epigenetic factors have an important role in the complex interplay between genes and the environment. These interactions may result in the activation or deactivation of genes by epigenetic mechanisms, facilitating adaptation to environmental changes [26].

Extensive primary and secondary prophylaxis allows for early diagnosis of the disease, but a better screening strategy could result in diagnosis and treatment at a much earlier stage of pregnancy. Thus, there is strong a need to identify currently overlooked root causes of GDM and new and more accurate GDM risk biomarkers [27].

3. Overview of Epigenetics

A change in gene activity without a change in the nucleotide sequence is known as an epigenetic modification. Epigenetic modifications can be transmitted through cell division (mitotic inheritance) and through subsequent generations (meiotic inheritance) [28]. These modifications can be induced by the occurrence of some environmental factors influencing biologic systems, making them important pathogenic mechanisms in the development of complex multifactorial diseases. Intergenerational epigenetic inheritance is considered when direct environmental influence cannot be ruled out, and transgenerational epigenetic inheritance is defined as germ line-mediated inheritance of epigenetic information between generations in the absence of a direct stressor that leads to phenotypic variation. Exposure during pregnancy has a direct influence on the mother, fetus (intergenerational), and developing primordial germ cells of the growing fetus (transgenerational inheritance) [29][30], as seen on Figure 1. DNA methylation, histone modifications, noncoding RNA regulation, and chromatin remodeling are the main processes of epigenetic reprogramming, whose basic role in the milieu of the genome is to react to external and internal factors by dynamic, reversible changes in chromatin structure and gene expression [31]. Disturbances to this complementary process are believed to be the cause of a growing incidence of several multifactorial diseases, including GDM [32].

Figure 1. Exposure during pregnancy means direct influence on mother and fetus (intergenerational) and developing primordial germ cells of growing fetus (transgenerational inheritance).

DNA methylation is the most frequently studied modification. Methylation turns off repressor elements and increases gene expression, while methylation at the promoter regions decreases gene expression. Moreover, increased expression or alternative splicing may be caused by methylation in the gene body [33]. It is mainly regulated through methylation of CpG islets. Histone modification is another type of epigenetic regulation that can influence chromatin packing and subsequently gene expression [34]. Yet another type of epigenetic regulation is micro RNA (miRNA), which is involved in the post-transcriptional regulation of gene expression. Micro RNA is a short non-coding RNA that can affect both the translation and stability of mRNA. Most often, miRNA binding to mRNA leads to translational inhibition or destabilization [35].

4. Epigenetic Regulations in Gestational Diabetes Mellitus

An aberrant intrauterine environment may induce changes in gene expression by epigenetic mechanisms, thereby affecting the development of the fetus and altering the offspring’s long-term risk for obesity and metabolic diseases such as diabetes in adulthood [36]. In utero, maternal glucose freely crosses the placenta, whereas maternal insulin does not, resulting in overstimulation of the fetal pancreas that is exposed to high glucose levels in GDM pregnancies. Increased need for insulin in the early stage of life is a likely trigger of epigenetic changes involving genes crucial for pancreatic development; β

-cell development, differentiation, and function; peripheral glucose uptake; and insulin sensitivity. The transgenerational persistence of the insulin-resistant phenotype suggests that the epigenotype can be transmitted to the next generation [37][38][39].

Epigenetic modifications, although they do not change the genome as a whole, can be mitotically stable over time, causing long-term changes in gene expression [40]. The importance of epigenetic marks emerging at a very early stage of human development as potential modulators and predictors of future health and diseases was recently mentioned [40][41][42]. Periconceptional and intrauterine periods are crucial for fetal programming [43]. Epigenetic changes seem to take part in the complex interplay between genes and the environment that is related to insulin resistance, T2DM, and GDM. In fact, a growing number of studies have identified specific gene variants for susceptibility to GDM [44][45][46][47], as well as epigenetic alterations [40][41][42][48]. One of the largest groups among genes being investigated for their connection to diabetes are those linked to β

-cell function and insulin secretion. The predisposition might be increased in the presence of transcription factor 7-like 2 (TCF7L2), hepatocyte nuclear factor 4 alpha (HNF4a) polymorphisms, and variants among glucokinase and glucokinase regulatory protein genes. However, the presented inherited genetic variants may be under the influence of the mentioned epigenetic mechanism. Some of the most significant studies investigating the epigenetic background of GDM focused on mechanisms concerning gene silencing or augmentation are presented below. The ATP-binding cassette transporter A1 is another gene whose demethylation reduces high-density lipoprotein concentrations and raises glucose levels in OGTT [49].

In the EPOCH study, Yang et al. [50] divided patients into two groups: offspring of GDM and non-GDM mothers. Samples of cord and peripheral blood were obtained to identify GDM-associated DNA methylation areas and assess their possible association with child metabolic outcomes. The researchers identified significant changes in 51 areas of the genome and demonstrated that the methylation of five genes is linked to GDM. They demonstrated that methylation at the differentially methylated position in SH3PXD2A was significantly positively correlated with adiposity-related outcomes: BMI; waist circumference; triceps, suprailiac, and subscapular skinfold thickness; subcutaneous adipose tissue quantity; and leptin levels. DNA methylation in E2F6 was also associated with fasting insulin and the homeostatic model assessment for insulin resistance (Homa-IR). According to the researchers, these findings suggest that DNA methylation is affected by GDM exposure in utero and epigenetic changes may represent a significant link between this exposure and childhood obesity. SH3PXD2A hypomethylation was associated with GDM exposure in cord blood at birth [51], and with T2DM in pancreatic islets [52]. Furthermore, a CpG site within its homologue SH3PXD2B is also hypomethylated in severe childhood obesity [53]. Although the biologic function of the SH3PXD2A involvement in diabetes and obesity remains unclear, these multiple studies strongly suggest that it plays a crucial role in the molecular basis of metabolic disorders. As reported by Weng et al., 37 methylated CpGs (representing 20 genes) between the GDM and healthy groups were identified and showed potential as clinical biomarkers for GDM, suggesting it has epigenetic effects on genes that are preferentially involved in the Type I diabetes mellitus pathway, immune MHC-related pathways and neuron development-related pathways. The analysis was performed on umbilical cord blood [54]. Ruchat et al. demonstrated that differentially methylated genes identified in the placenta and in cord blood were also correlated with newborn weight [48]. A recent study conducted by Chen et al. identified differentially methylated CpGs in 39 genomic regions influenced by in utero exposure to GDM in offspring’s peripheral blood [55]. Methylation at three sites was also nominally associated with insulin secretion, while a fourth site was associated with a future risk of T2DM. Complex interactions between genetic (probably polygenic) susceptibility, unfavorable fetal surroundings, and the environmental impact of chemicals such as EDCs may lead to activation or deactivation of genes by epigenetic mechanisms, enabling adaptation (to some extent) to miscellaneous environmental situations, but sometimes bringing about the development of various disorders.

Epigenetic modifications have become a probable link between the in utero exposure to a diabetic environment and poor outcomes of the offspring. The association of GDM and diabetes during pregnancy with the epigenetic changes detected in in utero-exposed children has been confirmed by many others [40][41][42][55][56][57].

Wu et al. found significant differences in methylation patterns among women who developed GDM compared with those who did not [58]. Moreover, another study conducted by Reichetzeder et al. revealed that patients who develop GDM had higher levels of DNA methylation in placental tissues [59]. According to Michalczyk et al., the histone H3K27 and H3K4 demethylation levels are correlated with GDM progression to T2DM. The percentage of H3K27 and H3K4 methylation was lower in women who develop T2DM later in life than in women who are unaffected by T2DM post-GDM [60]. Another study performed by Wander et al. showed that miR-155-5p and miR-21-3p plasma levels in early pregnancy are associated with a higher risk of GDM. The miRNAs miR-21-3p and miR-210-3p were also linked to GDM, but only in overweight women. Moreover, pregnant women with male fetuses had a higher risk of GDM because of interferences in the plasma levels of miR-29a-3p, miR-223-3p, miR146b-5p, and miR-517-5p [61]. According to Zhao et al., pregnant women with considerably decreased expression levels of miRNAs miR-29a, miR-132, and miR-222 later developed GDM. miR-29a is involved in glucose metabolism, but the roles of miR-222 and miR-132 have yet to be determined [62].

Wu et al. [58] reported DNA methylation modifications in the blood of gravid women even before GDM was detected. They recognized a set of diversely methylated genes shared by the blood, umbilical cord, and placenta: retinol dehydrogenase 12, hook microtubule tethering protein 2, phosphoinositide-3-kinase regulatory subunit 5, constitutive photomorphogenic homolog subunit 8, coiled-coil domain containing 124, 3- hydroxyanthranilate 3,4-dioxygenase, and chromosome 5 open-reading frame 34.

Cardenas et al. [63] carried out an epigenome-wide association study on samples of placenta and plasma glucose, matching them up with 2 h post-OGTT plasma glucose levels. They discovered that plasma glucose at 2 h OGTT positively correlates with reduced DNA methylation of four CpG sites within the phosphodiesterase 4b gene. Moreover, three other CpG sites in the TNFRSF1B, LDLR, and BLM genes were found to be differentially methylated in association with maternal glucose.

Martinez-Ibarra et al. [64] explored the connection between GDM, EDCs, and miRNA. They observed higher levels of miR-9-5p, miR-29a-3p, and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Moreover, according to Li et al., expression levels of miR-9-5p were significantly decreased in placental villous tissues and cytotrophoblast of GDM patients [65]. miR-9-5p directly targets hexokinase-2 (HK-2) and affects its expression. HK-2 was upregulated in both placental villous tissues and cytotrophoblasts from GDM patients compared with healthy women. Zhang et al. demonstrated that miR-9-5p significantly reduces the expression of glucose transporter 1 and glycolytic enzymes (HK-2, phosphofructokinase, and lactate dehydrogenase) [66]. Another study conducted by Kong et al. showed that overexpression of miR-9-5p in the serum of newly diagnosed T2DM patients was also found to reduce the expression of glucose transporter 1, hexokinase-2 (HK-2), phosphofructokinase, and lactate dehydrogenase, compared with a control group [67]. Sebastiani et al. also presented that miR-29a-3p modifies the expression of various genes involved in the insulin signaling pathway, such as HK2, and negatively regulates fatty acid oxidation through peroxisome proliferator-activated receptor γ

coactivator 1-α expression. The expression levels of miR-330-3p, which is related to the proliferation and differentiation of β

-cells and insulin secretion, are were high [68]. Table 1 summarizes some of the studies.

Table 1. Epigenetic studies on gestational diabetes mellitus.

Study Effect
Weng et al. [54] Thirty-seven methylated CpGs linked to GDM
Yang et al. [50] Significant changes in 51 areas of the genome and demonstration that the methylation of 5 genes is linked to GDM
Finer et al. [51] SH3PXD2A hypomethylation is associated with GDM exposure in cord blood at birth
Chen et al. [55] Differentially methylated CpGs in 39 genomic regions influenced by in utero exposure to GDM in offspring peripheral blood
Reichetzeder et al. [59] Higher levels of DNA methylation in placental tissues in patients with gestational diabetes mellitus
Michalczyk et al. [60] Histone H3K27 and H3K4 demethylation levels are correlated with GDM progression to T2DM.
Zhao et al. [62] Decreased expression levels of miRNAs miR-29a, miR-132, and miR-222 associated with later development of GDM
Wander et al. [61] miR-155-5p and miR-21-3p plasma levels in early pregnancy are associated with a higher risk for GDM
Wu et al. [58] Differentially methylated genes shared by the blood, umbilical cord, and placenta
Cardenas et al. [63] Three CpG sites in the TNFRSF1B, LDLR, and BLM genes are differentially methylated in association with maternal glucose
  Plasma glucose at 2 h OGTT positively correlates with reduced DNA methylation of 4 CpG sites within the phosphodiesterase 4b gene
Sebastiani et al. [68] Increased expression levels of miR-330-3p
Li et al. [65] miR-9-5p were significantly decreased in placental villous tissues and cytotrophoblast of GDM patients
Martinez-Ibarra et al. [64] Higher levels of miR-9-5p, miR-29a-3p, and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects

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