Type 1 Diabetes Mellitus and the First Trimester Placenta: Hyperglycemia-Induced Effects on Trophoblast Proliferation, Cell Cycle Regulators, and Invasion

Majali‐Martinez, Alejandro; Weiss-Fuchs, Ursula; Miedl, Heidi; Forstner, Désirée; Bandres-Meriz, Julia; Hoch, Denise; Djelmiš, Josip; Ivanišević, Marina; Hiden, Ursula; Gauster, Martin; Desoyé, Gernot

doi:10.3390/ijms222010989

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…The early pregnancy period, in particular the first trimester, is understudied. At the molecular and cellular level the placenta responds to maternal diabetes and obesity already at this early stage in pregnancy [ 77 , 78 ]. One can predict changes in DNAm associated with these conditions and, hence, there is an urgent need for these studies.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

et al. 2022

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SUMMARY Maternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the foetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analysed our findings with the focus of identifying overlaps, contradictions, and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycaemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Foetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

et al. 2022

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“…Importantly, the proliferation of ACH-3P cells [ 56 ] as well as of several other trophoblast cell lines [ 57 ] was shown to be affected by hyperosmolarity. Our results show similar effects of hyperglycemia when compared to either osmotic control ( Figure 1 ) or normoglycemic control ( Figure A1 ), suggesting that the expression of SERT , TPH1 and MAOA was directly affected by high glucose, and not elevated osmotic pressure.…”

Section: Discussionmentioning

confidence: 99%

Glucose, Insulin and Oxygen Modulate Expression of Serotonin-Regulating Genes in Human First-Trimester Trophoblast Cell Line ACH-3P

et al. 2023

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Serotonin signaling plays an important role in regulating development and functions of the placenta. We hypothesized that metabolic disturbances associated with maternal obesity and/or gestational diabetes mellitus (GDM) affect placental serotonin homeostasis. Therefore, we examined the effects of high glucose (25 mM) and insulin (10 nM)—two hallmarks of maternal obesity and GDM—on mRNA expression of key regulators of serotonin homeostasis, including serotonin transporter (SERT), tryptophan hydroxylase 1 (TPH1), and monoamine oxidase A (MAOA), in the first-trimester trophoblast cell line ACH-3P, focusing on oxygen levels characteristic of early human placental development. Glucose downregulated expression of SERT and MAOA independently of oxygen level and upregulated expression of TPH1 at 6.5% oxygen but not at 2.5% oxygen. Compared to 6.5% oxygen, 2.5% oxygen upregulated SERT and downregulated TPH1 expression, with no effect on MAOA expression. Insulin upregulated SERT only at 2.5% oxygen but had no effect on TPH1 and MAOA expression. These results suggest that maternal metabolic alterations in early pregnancy may be a driving force for changes in placental serotonin homeostasis.

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“…Upregulated Ki67 was observed in the term placenta of patients with GDM ( 38 ). However, Ki67 was downregulated in first-trimester human placental tissue with T1DM ( 39 ). In rat, the proliferative capacity of trophoblasts was weakened and the number of Ki67 positive cells decreased as the gestational day increases.…”

Section: Hg Affects the Biological Functions Of Trophoblasts In Uteri...mentioning

confidence: 99%

Hyperglycemia disturbs trophoblast functions and subsequently leads to failure of uterine spiral artery remodeling

Zhu

Liu

et al. 2023

Front. Endocrinol.

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Uterine spiral artery remodeling is necessary for fetal growth and development as well as pregnancy outcomes. During remodeling, trophoblasts invade the arteries, replace the endothelium and disrupt the vascular smooth muscle, and are strictly regulated by the local microenvironment. Elevated glucose levels at the fetal-maternal interface are associated with disorganized placental villi and poor placental blood flow. Hyperglycemia disturbs trophoblast proliferation and invasion via inhibiting the epithelial-mesenchymal transition, altering the protein expression of related proteases (MMP9, MMP2, and uPA) and angiogenic factors (VEGF, PIGF). Besides, hyperglycemia influences the cellular crosstalk between immune cells, trophoblast, and vascular cells, leading to the failure of spiral artery remodeling. This review provides insight into molecular mechanisms and signaling pathways of hyperglycemia that influence trophoblast functions and uterine spiral artery remodeling.

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Type 1 Diabetes Mellitus and the First Trimester Placenta: Hyperglycemia-Induced Effects on Trophoblast Proliferation, Cell Cycle Regulators, and Invasion

Cited by 8 publications

References 42 publications

Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

Glucose, Insulin and Oxygen Modulate Expression of Serotonin-Regulating Genes in Human First-Trimester Trophoblast Cell Line ACH-3P

Hyperglycemia disturbs trophoblast functions and subsequently leads to failure of uterine spiral artery remodeling

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