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1.
Int J Mol Sci ; 25(11)2024 Jun 02.
Article de Anglais | MEDLINE | ID: mdl-38892323

RÉSUMÉ

The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early identification of at-risk pregnancies could significantly improve the management, therapy and prognosis of these pregnancies, especially if these at-risk pregnancies are identified in the first trimester. The aim of this review was to summarize the possible biomarkers that can be used to diagnose early placental dysfunction and, consequently, at-risk pregnancies. We divided the biomarkers into proteins and non-proteins. Among the protein biomarkers, some are already used in clinical practice, such as the sFLT1/PLGF ratio or PAPP-A; others are not yet validated, such as HTRA1, Gal-3 and CD93. In the literature, many studies analyzed the role of several protein biomarkers, but their results are contrasting. On the other hand, some non-protein biomarkers, such as miR-125b, miR-518b and miR-628-3p, seem to be linked to an increased risk of complicated pregnancy. Thus, a first trimester heterogeneous biomarkers panel containing protein and non-protein biomarkers may be more appropriate to identify and discriminate several complications that can affect pregnancies.


Sujet(s)
Marqueurs biologiques , Placenta , Issue de la grossesse , Premier trimestre de grossesse , Humains , Grossesse , Femelle , Premier trimestre de grossesse/métabolisme , Placenta/métabolisme , Pré-éclampsie/diagnostic , Pré-éclampsie/métabolisme , microARN/génétique , Protéine A plasmatique associée à la grossesse/métabolisme , Diabète gestationnel/diagnostic , Diabète gestationnel/métabolisme
2.
Article de Anglais | MEDLINE | ID: mdl-38788346

RÉSUMÉ

A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization. Decidualization is interlinked with its inflammatory environment. Our study aimed to investigate the presence and role of pro-resolving lipid mediators in first trimester maternal tissue. We assessed the levels of LXA4 and RvD1, along with their metabolic LOX enzymes, in elective (control) and sporadic miscarriage samples. We investigated the effects of LXA4 and RvD1 on decidualization using primary endometrial stromal cells and the immortalized endometrial stromal St-T1b cell line. The upregulation of 12- and 15-LOX expression was observed in pregnancy tissue after sporadic miscarriage, suggesting an inflammatory imbalance. Furthermore, incubation with these lipid mediators led to a decrease in decidualization biomarkers PRL and IGFBP-1, accompanied by morphological changes indicative of aberrant differentiation. The expression of LOX enzymes in decidual natural killer cells suggests their involvement in regulating the inflammatory surroundings and the extent of decidualization.


Sujet(s)
Avortement spontané , Arachidonate 15-lipoxygenase , Caduques , Lipoxines , Premier trimestre de grossesse , Femelle , Humains , Grossesse , Premier trimestre de grossesse/métabolisme , Avortement spontané/métabolisme , Caduques/métabolisme , Adulte , Lipoxines/métabolisme , Arachidonate 15-lipoxygenase/métabolisme , Cellules stromales/métabolisme , Protéine-1 de liaison aux IGF/métabolisme , Prolactine/métabolisme , Cellules tueuses naturelles/métabolisme , Lignée cellulaire , Différenciation cellulaire , Endomètre/métabolisme , Endomètre/anatomopathologie , Acide docosahexaénoïque
3.
Placenta ; 151: 67-78, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38723477

RÉSUMÉ

INTRODUCTION: Interleukin-1 beta (IL-1ß) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1ß in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration. METHODS: First trimester placenta and decidua were collected to study the expression levels of IL-1ß and its receptors by immunohistochemical staining. Primary isolates of first trimester EVT or the HTR-8/SVneo trophoblast like cell line were used to assess migration and invasion. Matrix metalloproteinase levels were assessed by gelatin zymography and ELISA. The phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. Differentially expressed proteins in cells was detected and verified by Western Blot. RESULTS: IL-1ß, its receptors and antagonist are expressed in first trimester placenta and decidua, exogenous IL-1ß stimulates trophoblast cell outgrowth, migration and invasion through the ERK signaling pathway. IL-1ß was significantly increased in the placenta at 6-7 weeks gestation compared with 8-9 weeks gestation (P < 0.0001). Transwell and RTCA assays indicated that IL-1ß stimulates the invasion and migration of EVT. In addition, IL-1ß promoted the phosphorylation of ERK 1/2. It also promoted the expression of MMP2 and MMP9 in EVT as demonstrated by gelatin zymography assay and enzyme linked immunosorbent assay. DISCUSSION: This study demonstrated IL-1ß expression in placenta and decidua, and that it regulates EVT invasion and migration.


Sujet(s)
Mouvement cellulaire , Interleukine-1 bêta , Système de signalisation des MAP kinases , Premier trimestre de grossesse , Trophoblastes , Humains , Femelle , Grossesse , Trophoblastes/métabolisme , Mouvement cellulaire/physiologie , Premier trimestre de grossesse/métabolisme , Interleukine-1 bêta/métabolisme , Système de signalisation des MAP kinases/physiologie , Placenta/métabolisme , Caduques/métabolisme , Matrix metalloproteinase 9/métabolisme
4.
Sci Rep ; 14(1): 9355, 2024 04 23.
Article de Anglais | MEDLINE | ID: mdl-38654093

RÉSUMÉ

Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development.


Sujet(s)
Cortex cérébral , Transporteurs d'acides monocarboxyliques , Neurogenèse , Organoïdes , ARN messager , Symporteurs , Récepteurs alpha des hormones thyroïdiennes , Femelle , Humains , Grossesse , Cortex cérébral/embryologie , Cortex cérébral/métabolisme , Régulation de l'expression des gènes au cours du développement , Transporteurs d'acides monocarboxyliques/génétique , Transporteurs d'acides monocarboxyliques/métabolisme , Cellules souches neurales/métabolisme , Cellules souches neurales/cytologie , Neurogenèse/génétique , Neurones/métabolisme , Organoïdes/métabolisme , Premier trimestre de grossesse/métabolisme , ARN messager/génétique , ARN messager/métabolisme , Symporteurs/génétique , Symporteurs/métabolisme , Récepteurs alpha des hormones thyroïdiennes/génétique , Récepteurs alpha des hormones thyroïdiennes/métabolisme , Hormones thyroïdiennes/métabolisme , Hormones thyroïdiennes/génétique
5.
Placenta ; 150: 8-21, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38537412

RÉSUMÉ

INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.


Sujet(s)
Séquençage nucléotidique à haut débit , Placenta , Caractères sexuels , Humains , Femelle , Grossesse , Mâle , Placenta/métabolisme , ARN messager/métabolisme , ARN messager/génétique , Adulte , Transcriptome , Troisième trimestre de grossesse/génétique , Analyse de séquence d'ARN , Premier trimestre de grossesse/génétique , Premier trimestre de grossesse/métabolisme
6.
Histochem Cell Biol ; 160(6): 577-593, 2023 Dec.
Article de Anglais | MEDLINE | ID: mdl-37750996

RÉSUMÉ

Plasma concentrations of N-arachidonyletholamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) increase at term and can predict when a woman is likely to go into labour. We hypothesised that increased plasma AEA concentrations in women in preterm and term labour might also be increased and have a function in the placenta at the end of pregnancy. Here we examined the expression of the N-acylethanolamine-modulating enzymes fatty acid amide hydrolase (FAAH) and N-acyl-phosphatidylethanolamine-specific phospholipase-D (NAPE-PLD) and of the cannabinoid receptors (CB1 and CB2) in the placenta and their activation in an in vitro model of the third-trimester placenta to determine if those expressions change with labour and have functional significance. Expression of CB1, CB2, FAAH and NAPE-PLD was examined by immunohistochemistry (IHC) and RT-qPCR in placental samples obtained from four patient groups: preterm not in labour (PTNL), term not in labour (TNL), preterm in labour (PTL) and term in labour (TL). Additionally, the effects of AEA on a third-trimester human cell line (TCL-1) were evaluated. All ECS components were present in the third-trimester placenta, with NAPE-PLD and CB2 being the key modulated proteins in terms of expression. Functionally, AEA reduced TCL-1 cell numbers through the actions of the CB2 receptor whilst CB1 maintained placental integrity through the expression of the transcription regulators histone deacetylase 3, thyroid hormone receptor ß 1 and the modulation of 5α reductase type 1. The placenta in the third trimester and at term is different from the placenta in the first trimester with respect to the expression of CB1, CB2, FAAH and NAPE-PLD, and the expression of these proteins is affected by labour. These data suggest that early perturbation of some ECS components in the placenta may cause AEA-induced PTL and thus PTB.


Sujet(s)
Endocannabinoïdes , Placenta , Nouveau-né , Humains , Femelle , Grossesse , Endocannabinoïdes/métabolisme , Placenta/métabolisme , Récepteurs de cannabinoïdes/métabolisme , Premier trimestre de grossesse/métabolisme
7.
Mol Cell Endocrinol ; 576: 112038, 2023 10 01.
Article de Anglais | MEDLINE | ID: mdl-37544354

RÉSUMÉ

The invasion of human extravillous trophoblast (EVT) cells is a critical event required for a successful pregnancy. Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), has been shown to stimulate cell invasion in an immortalized human EVT cell line, HTR-8/SVneo. The with-no-lysine kinase 1 (WNK1) is involved in regulating cell invasion. It is known that WNK1 is expressed in the human placenta, but its role in human EVT cells remains unknown. In the present study, we show that AREG treatment phosphorylated WNK1 at Thr60 in both HTR-8/SVneo and primary human EVT cells. The stimulatory effect of AREG on WNK1 phosphorylation was mediated by the activation of PI3K/AKT, but not the ERK1/2 signaling pathway. AREG upregulated matrix metalloproteinase 9 (MMP9) but not MMP2. In addition, cell invasiveness was increased in response to the treatment of AREG. Using the siRNA-mediated knockdown approach, our results showed that the knockdown of WNK1 attenuated the AREG-induced upregulation of MMP9 expression and cell invasion. Moreover, the expression of WNK1 was downregulated in the placentas with preeclampsia, a disease resulting from insufficiency of EVT cell invasion during pregnancy. This study discovers the physiological function of WNK1 in human EVT cells and provides important insights into the regulation of MMP9 and cell invasion in human EVT cells.


Sujet(s)
Matrix metalloproteinase 9 , Trophoblastes , Protéine kinase déficiente en lysine WNK-1 , Femelle , Humains , Grossesse , Amphiréguline/génétique , Amphiréguline/métabolisme , Mouvement cellulaire , Matrix metalloproteinase 9/génétique , Matrix metalloproteinase 9/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Premier trimestre de grossesse/métabolisme , Trophoblastes/métabolisme , Protéine kinase déficiente en lysine WNK-1/génétique , Protéine kinase déficiente en lysine WNK-1/métabolisme
8.
Nature ; 619(7970): 595-605, 2023 Jul.
Article de Anglais | MEDLINE | ID: mdl-37468587

RÉSUMÉ

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.


Sujet(s)
Échange foetomaternel , Trophoblastes , Utérus , Femelle , Humains , Grossesse , Artères/physiologie , Caduques/vascularisation , Caduques/cytologie , Caduques/immunologie , Caduques/physiologie , Premier trimestre de grossesse/génétique , Premier trimestre de grossesse/métabolisme , Premier trimestre de grossesse/physiologie , Trophoblastes/cytologie , Trophoblastes/immunologie , Trophoblastes/physiologie , Utérus/vascularisation , Utérus/cytologie , Utérus/immunologie , Utérus/physiologie , Échange foetomaternel/génétique , Échange foetomaternel/immunologie , Échange foetomaternel/physiologie , Facteurs temps , Protéomique , Analyse de profil d'expression de gènes , Jeux de données comme sujet , Âge gestationnel
9.
Mol Reprod Dev ; 89(9): 431-440, 2022 09.
Article de Anglais | MEDLINE | ID: mdl-35842832

RÉSUMÉ

Glucose is critical during early pregnancy. The uterus can store glucose as glycogen but uterine glycogen metabolism is poorly understood. This study analyzed glycogen storage and localization of glycogen metabolizing enzymes from proestrus until implantation in the murine uterus. Quantification of diastase-labile periodic acid-Schiff (PAS) staining showed glycogen in the glandular epithelium decreased 71.4% at 1.5 days postcoitum (DPC) and 62.13% at DPC 3.5 compared to proestrus. In the luminal epithelium, glycogen was the highest at proestrus, decreased 46.2% at DPC 1.5 and 63.2% at DPC 3.5. Immunostaining showed that before implantation, glycogen metabolizing enzymes were primarily localized to the glandular and luminal epithelium. Stromal glycogen was low from proestrus to DPC 3.5. However, at the DPC 5.5 implantation sites, stromal glycogen levels increased sevenfold. Similarly, artificial decidualization resulted in a fivefold increase in glycogen levels. In both models, decidualization increased expression of glycogen synthase as determine by immunohistochemistry and western blot. In conclusion, glycogen levels decreased in the uterine epithelium before implantation, indicating that it could be used to support preimplantation embryos. Decidualization resulted in a dramatic increase in stromal glycogen levels, suggesting it may have an important, but yet undefined, role in pregnancy.


Sujet(s)
Endomètre , Glycogène , Premier trimestre de grossesse , Amylases/composition chimique , Animaux , Endomètre/composition chimique , Endomètre/métabolisme , Femelle , Glucose/métabolisme , Glycogène/analyse , Glycogène/métabolisme , Glycogen synthase/métabolisme , Souris , Réaction à l'acide periodique de Schiff , Grossesse , Premier trimestre de grossesse/métabolisme
10.
BMC Pregnancy Childbirth ; 22(1): 174, 2022 Mar 02.
Article de Anglais | MEDLINE | ID: mdl-35236326

RÉSUMÉ

BACKGROUND: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35-40 years at early and late gestation. METHODS: Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS). RESULTS: One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester. CONCLUSION: This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35-40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age.


Sujet(s)
Diabète gestationnel/sang , Diabète gestationnel/métabolisme , Diabète gestationnel/urine , Âge maternel , Métabolome , Adulte , Études cas-témoins , Chine/épidémiologie , Femelle , Humains , Métabolomique/méthodes , Plasma sanguin/métabolisme , Grossesse , Premier trimestre de grossesse/métabolisme , Troisième trimestre de grossesse/métabolisme , Études prospectives , Courbe ROC
11.
Reprod Biol Endocrinol ; 20(1): 36, 2022 Feb 21.
Article de Anglais | MEDLINE | ID: mdl-35189928

RÉSUMÉ

BACKGROUND: In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics. METHODS: Trophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC-MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student's t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities. RESULTS: A total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways. CONCLUSIONS: Overall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.


Sujet(s)
Caduques/métabolisme , Viabilité foetale/physiologie , Issue de la grossesse , Protéome/métabolisme , Trophoblastes/métabolisme , Avortement spontané/métabolisme , Avortement spontané/anatomopathologie , Adulte , Études cas-témoins , Caduques/anatomopathologie , Implantation embryonnaire/physiologie , Femelle , Âge gestationnel , Humains , Grossesse , Premier trimestre de grossesse/métabolisme , Grossesse extra-utérine/métabolisme , Grossesse extra-utérine/anatomopathologie , Protéome/analyse , Transduction du signal , Trophoblastes/anatomopathologie , Utérus/métabolisme , Utérus/anatomopathologie , Jeune adulte
12.
Reprod Biol ; 22(1): 100602, 2022 Mar.
Article de Anglais | MEDLINE | ID: mdl-35016050

RÉSUMÉ

Extravillous trophoblasts (EVTs) are the main participants in the process of placentation, an early process critical for placental growth and function involving an adequate invasion and complete remodelling of the maternal spiral arteries during early pregnancy. An increase in oxidative stress during pregnancy is associated with the onset and progression of several pregnancy disorders, including preeclampsia and gestational diabetes mellitus and it also occurs due to exposure of pregnant women to some xenobiotics (eg. alcohol). This study aimed to investigate how oxidative stress affects EVTs, and the ability of several distinct antioxidant agents to prevent these changes. For this, we exposed HTR8/SVneo cells to tert-butylhydroperoxide (0.5 µM; 24 h), which was able to increase lipid peroxidation and protein carbonyl levels. Under these conditions, there was a decrease in proliferation rates, culture growth, migratory and angiogenic capacities and an increase in the apoptosis rates. The antiproliferative effect of TBH was supressed by simultaneous treatment of the cells with α-tocopherol, but other antioxidants (vitamin C, allopurinol, apocynin, N-acetylcysteine, quercetin and resveratrol) were ineffective. α-tocopherol was also able to abolish the effect of TBH on lipid peroxidation and protein carbonyl levels. Overall, our results show that oxidative stress interferes with EVT characteristics essential for the placentation process, which may contribute to the association between oxidative stress and pregnancy disorders. Our results also show that the nature of the in vitro model of oxidative stress-induction is an important determinant of the cellular consequences of oxidative stress and, therefore, of the efficacy of antioxidants.


Sujet(s)
Placenta , alpha-Tocophérol , Lignée cellulaire , Mouvement cellulaire , Femelle , Humains , Stress oxydatif , Placenta/métabolisme , Placentation , Grossesse , Premier trimestre de grossesse/métabolisme , Trophoblastes/métabolisme , alpha-Tocophérol/métabolisme , alpha-Tocophérol/pharmacologie
13.
Reprod Sci ; 29(1): 110-121, 2022 01.
Article de Anglais | MEDLINE | ID: mdl-34291416

RÉSUMÉ

Fragile X-related protein 1 (FXR1) is an RNA-binding protein that can regulate specific mRNA decay in cells. Our previous study showed that FXR1 expression was significantly decreased in trophoblasts from patients with unexplained recurrent spontaneous abortion (RSA); however, the role of FXR1 in trophoblast function during early placenta development has not been fully elucidated. In this study, we found that knockdown of FXR1 using siRNA effectively inhibited the migration of HTR-8 cells and extravillous trophoblast (EVT) outgrowth in an ex vivo extravillous explant culture model. Furthermore, through analysis of a panel of cytokines, we found that the GDF-15 protein was upregulated after knockdown of FXR1 in HTR-8/SVneo cells. This was further confirmed by western blotting and immunofluorescence in HTR-8/SVneo cells and an extravillous explant. Our data also showed that FXR1 expression was downregulated and GDF-15 was upregulated in chorionic villous tissues from RSA patients compared with those from healthy controls (HCs). Further, immunohistochemistry showed a strong expression of GDF-15 in chorionic villous tissue in the RSA group, which was mainly distributed in villous trophoblasts (CTBs) and syncytiotrophoblasts (STBs). Moreover, knockdown of GDF-15 enhanced the migration of HTR-8 cells, while overexpression of GDF-15 using plasmid or treatment with recombinant human GDF-15 protein inhibited trophoblast migration. Importantly, RNA-binding protein immunoprecipitation showed that FXR1 directly bound to the 3'-UTR of GDF-15 mRNA to promote GDF-15 mRNA decay. Together, our data provide new insight into the function of FXR1 in human placenta via regulation of GDF-15 expression in trophoblasts and suggest a possible pathological process involved in RSA.


Sujet(s)
Mouvement cellulaire/physiologie , Régulation négative , Facteur-15 de croissance et de différenciation/métabolisme , Protéines de liaison à l'ARN/métabolisme , Trophoblastes/métabolisme , Adulte , Lignée cellulaire , Femelle , Facteur-15 de croissance et de différenciation/génétique , Humains , Placenta/métabolisme , Grossesse , Premier trimestre de grossesse/métabolisme , Protéines de liaison à l'ARN/génétique
14.
J Clin Endocrinol Metab ; 107(2): e804-e814, 2022 01 18.
Article de Anglais | MEDLINE | ID: mdl-34453541

RÉSUMÉ

CONTEXT: While the associations between thyroid markers and gestational diabetes mellitus (GDM) have been extensively studied, the results are inconclusive and the mechanisms remain unclear. OBJECTIVE: We aimed to investigate the prospective associations of thyroid markers in early gestation with GDM risk, and examine the mediating effects through lipid species. METHODS: This study included 6068 pregnant women from the Tongji-Shuangliu Birth Cohort. Maternal serum thyroid markers (free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody) were measured before 15 weeks. Deiodinase activity was assessed by fT3/fT4 ratio. Plasma lipidome were quantified in a subset of 883 participants. RESULTS: Mean age of the participants was 26.6 ± 3.7 years, and mean gestational age was 10.3 ± 2.0 weeks. Higher levels of fT4 were associated with a decreased risk of GDM (OR = 0.73 comparing the extreme quartiles; 95% CI 0.54, 0.98, Ptrend = .043), while higher fT3/fT4 ratio was associated with an increased risk of GDM (OR = 1.43 comparing the extreme quartiles; 95% CI 1.06, 1.93, Ptrend = .010) after adjusting for potential confounders. Multiple linear regression suggested that fT3/fT4 ratio was positively associated with alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, sphingomyelin 34:1, and phosphatidylcholine 40:7 (false discovery rate [FDR] adjusted P < .05). Mediation analysis indicated 67.9% of the association between fT3/fT4 ratio and GDM might be mediated through the composite effect of these lipids. CONCLUSION: Lower concentration of serum fT4 or higher fT3/fT4 ratio in early pregnancy was associated with an increased risk of GDM. The association of fT3/fT4 ratio with GDM was largely mediated by specific lipid species.


Sujet(s)
Diabète gestationnel/épidémiologie , Lipides/sang , Premier trimestre de grossesse/sang , Hormones thyroïdiennes/sang , Adolescent , Adulte , Marqueurs biologiques/sang , Marqueurs biologiques/métabolisme , Études cas-témoins , Diabète gestationnel/métabolisme , Femelle , Humains , Incidence , Lipidomique , Grossesse , Premier trimestre de grossesse/métabolisme , Études prospectives , Appréciation des risques/méthodes , Tests de la fonction thyroïdienne , Hormones thyroïdiennes/métabolisme , Jeune adulte
15.
Cells ; 10(9)2021 08 27.
Article de Anglais | MEDLINE | ID: mdl-34571867

RÉSUMÉ

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (ß-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.


Sujet(s)
Inhibiteur p21 de kinase cycline-dépendante/métabolisme , Placenta/métabolisme , Pré-éclampsie/métabolisme , Trophoblastes/métabolisme , Adulte , Gonadotrophine chorionique/métabolisme , Inhibiteur p27 de kinase cycline-dépendante/métabolisme , Femelle , Expression des gènes/physiologie , Humains , Placentation/physiologie , Grossesse , Premier trimestre de grossesse/métabolisme
16.
Tissue Cell ; 73: 101616, 2021 Dec.
Article de Anglais | MEDLINE | ID: mdl-34481230

RÉSUMÉ

In early pregnancy, hypoxia is a typical extrinsic factor that regulates EVT functions including proliferation, migration and invasion which are essential for a successful pregnancy. Human differentiated embryonic chondrocyte-expressed gene 1 (DEC1), a hypoxia-regulated gene, has been reported to be overexpressed in several types of cancers. Given that the placenta and the cancer share several similarities with respect to their capacity to proliferate and invade adjacent tissues, we focused on the role of DEC1 on trophoblast function in a physiologically hypoxic environment, which may be associated with unexplained recurrent spontaneous abortion (URSA).In our study, we measured the expression of HIF-1α and DEC1 in first-trimester villi through real-time-PCR (RT-PCR) and immunohistochemical analysis. in vitro, DEC1 expression was downregulated in trophoblast cells via DEC1-specific shRNA plasmid transfection. The expression of DEC1 and HIF-1α was detected via western blotting and RT-PCR analysis. The proliferation and migration of HTR-8/SVneo cells were assayed using CCK-8 and Transwell migration assays, respectively.Our results indicated that the expression of DEC1 was significantly reduced in villi of URSA compared to that in normal pregnant women. in vitro, hypoxia induced the expression of HIF-1ɑ and DEC1 and upregulated proliferation and migration of the HTR-8/SVneo cells. Knockdown of DEC1 inhibited proliferation and migration of HTR-8/SVneo cells exposure to hypoxia. Furthermore, inhibition of HIF1α expression resulted in a significant decrease in DEC1. These findings illustrate that hypoxia-induced DEC1 expression promotes trophoblast cell proliferation and migration through the HIF1α signaling pathway, which plays an important role during placentation.


Sujet(s)
Mouvement cellulaire , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Trophoblastes/cytologie , Trophoblastes/métabolisme , Protéines suppresseurs de tumeurs/métabolisme , Adulte , Hypoxie cellulaire/génétique , Lignée cellulaire , Mouvement cellulaire/génétique , Prolifération cellulaire/génétique , Femelle , Humains , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Grossesse , Premier trimestre de grossesse/métabolisme , Protéines suppresseurs de tumeurs/génétique
17.
PLoS One ; 16(9): e0257391, 2021.
Article de Anglais | MEDLINE | ID: mdl-34516586

RÉSUMÉ

Gestational diabetes mellitus (GDM) is associated with adverse perinatal and maternal outcomes. Epidemiological studies have reported that non-alcoholic fatty liver disease (NAFLD) and a high hemoglobin (Hb) concentration are risk factors for GDM in the middle trimester. However, no consistent conclusions have been reached, especially in Chinese pregnant women. A case-control study was conducted to better understand the associations between NAFLD and Hb concentration in the first trimester and the risk of GDM and their interactive effects. Multivariable logistic regression analysis and a cross-product term of Hb and steatosis were used to evaluate the associations between first trimester Hb concentration, steatosis, and GDM and their interactive effects. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using two-sided statistical tests at an alpha level of 0.05. For the study, 1,017 normal pregnant women, and 343 pregnant women diagnosed with GDM (25.22%) were recruited from the First Hospital of Shanxi Medical University, Shanxi Province, China. NAFLD-associated steatosis was found to be independent risk factors for developing GDM compared with grade 0 steatosis, with ORs of 1.98 (95% CI: 1.35-2.89) and 2.27 (95% CI:1.29-3.96), respectively. Meanwhile, a high Hb concentration was found to be a risk factor for developing GDM compared with the normal Hb concentration (OR = 1.88; 95% CI:1.24-2.83). The risk of developing GDM was more pronounced among pregnant women who had both high-grade steatosis and higher Hb concentrations during their first trimester (OR = 6.24; 95% CI: 1.81-23.66). However, we found no significant interactions between Hb concentration and steatosis grade. In conclusion, our study confirmed that a high Hb concentration and NAFLD-associated steatosis during the first trimester play important roles in predicting the risk of GDM in Chinese women. Future studies are required to verify the interactive effects between NAFLD-associated steatosis and Hb concentration.


Sujet(s)
Diabète gestationnel/métabolisme , Diabète gestationnel/anatomopathologie , Stéatose hépatique non alcoolique/métabolisme , Stéatose hépatique non alcoolique/anatomopathologie , Premier trimestre de grossesse/métabolisme , Adulte , Glycémie/métabolisme , Études cas-témoins , Femelle , Humains , Odds ratio , Grossesse , Trimestres de grossesse , Facteurs de risque , Échographie
18.
Front Endocrinol (Lausanne) ; 12: 694885, 2021.
Article de Anglais | MEDLINE | ID: mdl-34394001

RÉSUMÉ

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells. Methods: The expression and localization of BDNF receptors-p75NTR and TrkB-in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot. Results: In first trimester human placentas, TrkB and p75NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 µM and 10 µM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged. Conclusions: BDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment.


Sujet(s)
Facteur neurotrophique dérivé du cerveau/métabolisme , Fluorocarbones/toxicité , Trophoblastes/effets des médicaments et des substances chimiques , Femelle , Humains , Exposition maternelle/effets indésirables , Glycoprotéines membranaires/métabolisme , Phosphorylation , Placenta/effets des médicaments et des substances chimiques , Placenta/métabolisme , Placentation/effets des médicaments et des substances chimiques , Grossesse , Premier trimestre de grossesse/effets des médicaments et des substances chimiques , Premier trimestre de grossesse/métabolisme , Récepteur trkB/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Trophoblastes/métabolisme , Cellules cancéreuses en culture
19.
Prenat Diagn ; 41(10): 1277-1286, 2021 Sep.
Article de Anglais | MEDLINE | ID: mdl-34297415

RÉSUMÉ

OBJECTIVE: Reasons for first trimester noninvasive prenatal screening (NIPS) test failure in obese women remain elusive. As dilution from maternal sources may be explanatory, we determined the relationship between obesity, fetal fraction (FF), and total cell-free DNA (cfDNA) using our NIPS platform. METHODS: We assessed differences in first trimester (≤14 weeks) FF, indeterminate rate, and total cfDNA between obese (n = 518) and normal-weight women (n = 237) after exclusion of confounders (anticoagulation, autoimmunity, aneuploidy) and controlling for covariates. RESULTS: Fetal fraction was lower, and the indeterminate rate higher, in obese compared to controls (9.2% ± 4.4 vs. 12.5% ± 4.5, p < 0.001 and 8.4 vs. 1.7%, p < 0.001, respectively), but total cfDNA was not different (92.0 vs. 82.1 pg/µl, p = 0.10). For each week, the FF remained lower in obese women (all p < 0.01) but did not increase across the first trimester for either group. Obesity increased the likelihood of indeterminate result (OR 6.1, 95% CI 2.5, 14.8; p < 0.001) and maternal body mass index correlated with FF (ß -0.27, 95% CI -0.3, -0.22; p < 0.001), but not with total cfDNA (ß 0.49, 95% CI -0.55, 1.53; p = 0.3). CONCLUSIONS: First trimester obese women have persistently low FF and higher indeterminate rates, without differences in total cfDNA, suggesting placental-specific mechanisms versus dilution from maternal sources as a potential etiology.


Sujet(s)
Acides nucléiques acellulaires/analyse , Obésité/génétique , Premier trimestre de grossesse/physiologie , Adulte , Acides nucléiques acellulaires/sang , Acides nucléiques acellulaires/génétique , Femelle , Humains , Obésité/complications , Grossesse , Premier trimestre de grossesse/métabolisme , Diagnostic prénatal/méthodes , Diagnostic prénatal/statistiques et données numériques
20.
PLoS One ; 16(4): e0249925, 2021.
Article de Anglais | MEDLINE | ID: mdl-33831087

RÉSUMÉ

During pregnancy, the vaginal microbiome plays an important role in both maternal and neonatal health outcomes. Throughout pregnancy, the vaginal microbial composition undergoes significant changes, including a decrease in overall diversity and enrichment with Lactobacillus spp. In turn, the modifications in the microbial profiles are associated with shifts in the composition of vaginal metabolites. In this study, we characterized the vaginal metabolic profiles throughout pregnancy at two different gestational ages, correlating them with a microscopic evaluation of the vaginal bacterial composition. A total of 67 Caucasian pregnant women presenting to the Family Advisory Health Centres of Ravenna (Italy) were enrolled and a vaginal swab was collected at gestational ages 9-13 weeks (first trimester) and 20-24 weeks (second trimester). The composition of the vaginal microbiome was assessed by Nugent score and women were divided in 'H' (normal lactobacilli-dominated microbiota), 'I' (intermediate microbiota), and 'BV' (bacterial vaginosis) groups. Starting from the cell-free supernatants of the vaginal swabs, a metabolomic analysis was performed by means of a 1H-NMR spectroscopy. From the first to the second trimester, a greater number of women showed a normal lactobacilli-dominated microbiota, with a reduction of cases of dysbiosis. These microbial shifts were associated with profound changes in the vaginal metabolic profiles. Over the weeks, a significant reduction in the levels of BV-associated metabolites (e.g. acetate, propionate, tyramine, methylamine, putrescine) was observed. At the same time, the vaginal metabolome was characterized by higher concentrations of lactate and of several amino acids (e.g. tryptophan, threonine, isoleucine, leucine), typically found in healthy vaginal conditions. Over time, the vaginal metabolome became less diverse and more homogeneous: in the second trimester, women with BV showed metabolic profiles more similar to the healthy/intermediate groups, compared to the first trimester. Our data could help unravel the role of vaginal metabolites in the pathophysiology of pregnancy.


Sujet(s)
Bactéries/classification , Métabolomique/méthodes , Premier trimestre de grossesse/métabolisme , Deuxième trimestre de grossesse/métabolisme , Vagin/composition chimique , Adulte , Acides aminés/analyse , Bactéries/génétique , Bactéries/isolement et purification , ADN bactérien/génétique , Femelle , Humains , Italie , Acide lactique/analyse , Grossesse , Spectroscopie par résonance magnétique du proton , Vagin/microbiologie , Jeune adulte
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