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Molecular and Cellular Endocrinology Nov 2023and purpose: Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1). Ghrelin, and GHS-R1, may have a role in placental growth and...
BACKGROUND
and purpose: Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1). Ghrelin, and GHS-R1, may have a role in placental growth and function, and its unacylated form desacylghrelin (DAG) could be involved in fetal growth. Nevertheless, the effects of DAG on placental function, and the receptor involved in its actions, remain to be determined. We aimed to investigate the effect of DAG in placental BeWo cells viability, proliferation, differentiation, and GSH-R1 expression.
METHODS
BeWo cells, a human trophoblast cell line, was cultured with 3 nM DAG during 12, 24, 48, and 72 h. Cell viability, proliferation, differentiation (assessed by human Chorionic Gonadotropin quantification), and GSH-R1 expression were analyzed. To evaluate the mechanism of DAG effect on GSH-R1, 30 nM receptor antagonist ([D-Lys3]-GHRP-6) was added alone or in combination with 3 nM DAG during 12 h and 24 h.
RESULTS
DAG has no effect on cell proliferation or viability, but it has an inhibitory effect on cell differentiation. DAG had a stimulatory effect on GSH-R1 expression at 12 and 24 h (p = 0.029 and p = 0.025, respectively). On the contrary, culture with 48 h DAG inhibits GSH-R1 expression compared to the control (p = 0.005), while GSH-R1 antagonist inhibited the effect of DAG on GSH-R1 expression. DAG also reduces intracellular (p = 0.020) and secreted (p = 0.011) hCG concentration in BeWo cells.
CONCLUSION
DAG increases GHS-R1 expression, potentially mediated through GHS-R1 itself. DAG may also inhibit placental BeWo cell differentiation, suggesting a possible role of DAG in placental and fetal physiology.
Topics: Pregnancy; Female; Humans; Placenta; Ghrelin; Receptors, Ghrelin; Cell Differentiation
PubMed: 37506870
DOI: 10.1016/j.mce.2023.112035 -
BJOG : An International Journal of... May 2024To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human...
OBJECTIVE
To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs).
DESIGN
Prospective cohort study of nulliparous singleton pregnancy.
SETTING
Cambridge, UK.
POPULATION OR SAMPLE
4056 pregnancy outcome prediction study participants.
METHODS
The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross-validation.
MAIN OUTCOME MEASURES
Pre-eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre-viable loss and stillbirth, plus combinations of outcomes.
RESULTS
Lower values of PAPP-A, PlGF and sFlt-1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48-0.74], OR 0.56 [95% CI 0.44-0.70], OR 0.68 [95% CI 0.54-0.87] and OR 1.53 [95% CI 1.25-1.88]), severe SGA (OR 0.59 [95% CI 0.49-0.72], OR 0.71 [95% CI 0.57-0.87], OR 0.74 [95% CI 0.60-0.91] and OR 1.41 [95% CI 1.17-1.71]), sPTB (OR 0.61 [95% CI 0.50-0.73], OR 0.79 [95% CI 0.66-0.96], OR 0.57 [95% CI 0.47-0.70] and OR 1.41 [95% CI 1.18-1.67]) and iPTB (OR 0.72 [95% CI 0.57-0.91], OR 0.62 [95% CI 0.49-0.78], OR 0.71 [95% CI 0.56-0.90] and OR 1.44 [95% CI 1.16-1.78]), respectively. When combinations of biomarkers were assessed, PAPP-A and AFP were independently associated with severe SGA; PAPP-A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta-hCG, AFP and PAPP-A with the combination of PE and SGA; AFP and sFlt-1 with sPTB; and AFP and PlGF with iPTB.
CONCLUSIONS
Combinations of first-trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Pregnancy Outcome; Pregnancy Trimester, First; alpha-Fetoproteins; Pregnancy-Associated Plasma Protein-A; Prospective Studies; Premature Birth; Placenta; Placenta Growth Factor; Chorionic Gonadotropin, beta Subunit, Human; Biomarkers; Fetal Growth Retardation; Pre-Eclampsia; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37822261
DOI: 10.1111/1471-0528.17691 -
The Journal of Maternal-fetal &... Dec 2023Fetal death is a complication of pregnancy caused by multiple etiologies rather than being the end-result of a single disease process. Many soluble analytes in the...
OBJECTIVES
Fetal death is a complication of pregnancy caused by multiple etiologies rather than being the end-result of a single disease process. Many soluble analytes in the maternal circulation, such as hormones and cytokines, have been implicated in its pathophysiology. However, changes in the protein content of extracellular vesicles (EVs), which could provide additional insight into the disease pathways of this obstetrical syndrome, have not been examined. This study aimed to characterize the proteomic profile of EVs in the plasma of pregnant women who experienced fetal death and to evaluate whether such a profile reflected the pathophysiological mechanisms of this obstetrical complication. Moreover, the proteomic results were compared to and integrated with those obtained from the soluble fraction of maternal plasma.
METHODS
This retrospective case-control study included 47 women who experienced fetal death and 94 matched, healthy, pregnant controls. Proteomic analysis of 82 proteins in the EVs and the soluble fractions of maternal plasma samples was conducted by using a bead-based, multiplexed immunoassay platform. Quantile regression analysis and random forest models were implemented to assess differences in the concentration of proteins in the EV and soluble fractions and to evaluate their combined discriminatory power between clinical groups. Hierarchical cluster analysis was applied to identify subgroups of fetal death cases with similar proteomic profiles. A -value of <.05 was used to infer significance, unless multiple testing was involved, with the false discovery rate controlled at the 10% level ( < 0.1). All statistical analyses were performed by using the R statistical language and environment-and specialized packages.
RESULTS
Nineteen proteins (placental growth factor, macrophage migration inhibitory factor, endoglin, regulated upon activation normal T cell expressed and presumably secreted (RANTES), interleukin (IL)-6, macrophage inflammatory protein 1-alpha, urokinase plasminogen activator surface receptor, tissue factor pathway inhibitor, IL-8, E-Selectin, vascular endothelial growth factor receptor 2, pentraxin 3, IL-16, galectin-1, monocyte chemotactic protein 1, disintegrin and metalloproteinase domain-containing protein 12, insulin-like growth factor-binding protein 1, matrix metalloproteinase-1(MMP1), and CD163) were found to have different plasma concentrations (of an EV or a soluble fraction) in women with fetal death compared to controls. There was a similar pattern of change for the dysregulated proteins in the EV and soluble fractions and a positive correlation between the log-fold changes of proteins significant in either the EV or the soluble fraction ( = 0.89, < .001). The combination of EV and soluble fraction proteins resulted in a good discriminatory model (area under the ROC curve, 82%; sensitivity, 57.5% at a 10% false-positive rate). Unsupervised clustering based on the proteins differentially expressed in either the EV or the soluble fraction of patients with fetal death relative to controls revealed three major clusters of patients.
CONCLUSION
Pregnant women with fetal death have different concentrations of 19 proteins in the EV and soluble fractions compared to controls, and the direction of changes in concentration was similar between fractions. The combination of EV and soluble protein concentrations revealed three different clusters of fetal death cases with distinct clinical and placental histopathological characteristics.
Topics: Pregnancy; Female; Humans; Retrospective Studies; Case-Control Studies; Placenta Growth Factor; Placenta; Proteomics; Vascular Endothelial Growth Factor A; Fetal Death; Extracellular Vesicles; Biomarkers
PubMed: 36813269
DOI: 10.1080/14767058.2023.2177529 -
Psychoneuroendocrinology May 2024Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain...
Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (β=3.06, 95%CI: 0.40, 5.72), Internalizing (β=0.89, 95%CI: 0.03, 1.76), and Externalizing (β=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: β=-1.99, 95%CI: -3.89, -0.09; Internalizing: β=-0.82, 95%CI: -1.42, -0.23; Externalizing: β=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.
Topics: Humans; Pregnancy; Female; Male; Child, Preschool; Corticotropin-Releasing Hormone; Placenta; Problem Behavior; Fetal Development; Prenatal Care; Prenatal Exposure Delayed Effects
PubMed: 38387218
DOI: 10.1016/j.psyneuen.2024.106994 -
European Journal of Obstetrics &... Sep 2023A fetal pituitary hormone, oxytocin which causes uterine contractions, increases throughout gestation, and its increase reaches 10-fold from week 32 afterward. Oxytocin... (Review)
Review
A fetal pituitary hormone, oxytocin which causes uterine contractions, increases throughout gestation, and its increase reaches 10-fold from week 32 afterward. Oxytocin is, on the other hand, degraded by placental leucine aminopeptidase (P-LAP) which exists in both terminal villi and maternal blood. Maternal blood P-LAP increases with advancing gestation under the control of non-genomic effects of progesterone, which is also produced from the placenta. Progesterone is converted to estrogen by CYP17A1 localized in the fetal adrenal gland and placenta at term. The higher oxytocin concentrations in the fetus than in the mother demonstrate not only fetal oxytocin production but also its degradation and/or inhibition of leakage from fetus to mother by P-LAP. Until labor onset, the pregnant uterus is quiescent possibly due to the balance between increasing fetal oxytocin and P-LAP under control of progesterone. A close correlation exists between the feto-placental and maternal units in the placental circulation, although the blood in the two circulations does not necessarily mix. Fetal maturation results in progesterone withdrawal via the CYP17A1 activation accompanied with fetal oxytocin increase. Contribution of fetal oxytocin to labor onset has been acknowledged through the recognition that the effect of fetal oxytocin in the maternal blood is strictly regulated by its degradation by P-LAP under the control of non-genomic effects of progesterone. In all senses, the fetus necessarily takes the initiative in labor onset.
PubMed: 37753515
DOI: 10.1016/j.eurox.2023.100210 -
The Science of the Total Environment Jan 2024Intrauterine growth retardation (IUGR) is a major cause of perinatal morbidity and mortality. Previous studies showed that 1-nitropyrene (1-NP), an atmospheric...
FUNDC1-mediated mitophagy triggered by mitochondrial ROS is partially involved in 1-nitropyrene-evoked placental progesterone synthesis inhibition and intrauterine growth retardation in mice.
Intrauterine growth retardation (IUGR) is a major cause of perinatal morbidity and mortality. Previous studies showed that 1-nitropyrene (1-NP), an atmospheric pollutant, induces placental dysfunction and IUGR, but the exact mechanisms remain uncertain. In this research, we aimed to explore the role of mitophagy on 1-NP-evoked placental progesterone (P4) synthesis inhibition and IUGR in a mouse model. As expected, P4 levels were decreased in 1-NP-exposed mouse placentas and maternal sera. Progesterone synthases, CYP11A1 and 3βHSD1, were correspondingly declined in 1-NP-exposed mouse placentas and JEG-3 cells. Mitophagy, as determined by LC3B-II elevation and TOM20 reduction, was evoked in 1-NP-exposed JEG-3 cells. Mdivi-1, a specific mitophagy inhibitor, relieved 1-NP-evoked downregulation of progesterone synthases in JEG-3 cells. Additional experiments showed that ULK1/FUNDC1 signaling was activated in 1-NP-exposed JEG-3 cells. ULK1 inhibitor or FUNDC1-targeted siRNA blocked 1-NP-induced mitophagy and progesterone synthase downregulation in JEG-3 cells. Further analysis found that mitochondrial reactive oxygen species (ROS) were increased and GCN2 was activated in 1-NP-exposed JEG-3 cells. GCN2iB, a selective GCN2 inhibitor, and MitoQ, a mitochondria-targeted antioxidant, attenuated GCN2 activation, FUNDC1-mediated mitophagy, and downregulation of progesterone synthases in JEG-3 cells. In vivo, gestational MitoQ supplement alleviated 1-NP-evoked reduction of placental P4 synthesis and IUGR. These results suggest that FUNDC1-mediated mitophagy triggered by mitochondrial ROS may contribute partially to 1-NP-induced placental P4 synthesis inhibition and IUGR.
Topics: Humans; Mice; Female; Pregnancy; Animals; Placenta; Mitophagy; Progesterone; Reactive Oxygen Species; Cell Line, Tumor; Fetal Growth Retardation; Mitochondria; Membrane Proteins; Mitochondrial Proteins
PubMed: 37951264
DOI: 10.1016/j.scitotenv.2023.168383 -
Reproductive Biology and Endocrinology... Jul 2023To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes. (Meta-Analysis)
Meta-Analysis Review
RESEARCH QUESTION
To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes.
DESIGN
CENTRAL, CNKI, Cochrane Systematic Reviews, EMBASE, MEDLINE, PUBMED, and Web of Science up to May 13 2023 were searched for studies reporting associations between hCG-ovum pickup intervals and assisted reproductive technology outcomes. Intervention types included short (≤ 36 h) and long (> 36 h) hCG-ovum pickup intervals in assisted reproductive technology cycles. All outcomes were based upon only fresh embryo transfers. Primary outcome is defined as the clinical pregnancy rate. Data were pooled using random-effects models. Heterogeneity was assessed using the I 2 statistics.
RESULTS
Twelve studies were included in the meta-analysis, including five retrospective cohort studies, one prospective cohort study, and six randomized or quasi-randomized controlled trials. The short and long interval groups had similar oocyte maturation rates, fertilization rate and high-quality embryo rate (OR, 0.69; 95% CI, 0.45-1.06; I 2 = 91.1%, OR, 0.88; 95% CI, 0.77-1.0; I 2 = 44.4% and OR, 1.05; 95% CI, 0.95-1.17; I 2 = 8.6%, respectively). The clinical pregnancy rates in the long retrieval group were significantly higher than in the short retrieval group (OR, 0.66; 95% CI, 0.45-0.95; I 2 = 35.4%). The groups had similar miscarriage and live birth rates (OR, 1.92; 95% CI, 0.66-5.60; I 2 = 0.0% and OR, 0.50; 95% CI, 0.24-1.04; I 2 = 0.0%, respectively).
CONCLUSIONS
The clinical pregnancy rates can be increased by prolonging the hCG-ovum pickup interval, which would help us develop more reasonable time schedules for fertility centers and patients.
META-ANALYSIS REGISTRATION
PROSPERO CRD42022310006 (28 Apr 2022).
Topics: Pregnancy; Female; Humans; Oocyte Retrieval; Retrospective Studies; Prospective Studies; Pregnancy Rate; Chorionic Gonadotropin; Live Birth; Fertilization in Vitro
PubMed: 37400840
DOI: 10.1186/s12958-023-01110-9 -
FASEB Journal : Official Publication of... Oct 2023Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on...
Growth differentiation factor myostatin regulates epithelial-mesenchymal transition genes and enhances invasion by increasing serine protease inhibitors E1 and E2 in human trophoblast cells.
Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes have underlying poor placental trophoblast cell invasion into uterine tissues. Placental invasion is controlled by many hormones and growth factors. Myostatin (MSTN) is a transforming growth factor-β superfamily member recognized for its important role in muscle growth control. MSTN has also been shown to be secreted and functioning in the placenta, and its serum and/or placental levels were found to be upregulated in preeclampsia and intrauterine growth restriction. Considering that the mechanistic role of MSTN in placentation remains poorly understood, we hypothesized that MSTN uses ALK4/5-SMAD2/3/4 signaling to increase human trophoblast invasion through a group of epithelial-mesenchymal transition genes including SERPINE2, PAI-1, and SOX4. mRNA sequencing of control and MSTN-treated primary human trophoblast cells (n = 5) yielded a total of 610 differentially expressed genes (false discovery rate <0.05) of which 380 genes were upregulated and 230 were downregulated. These differentially expressed genes were highly enriched in epithelial-mesenchymal transition genes, and a subset including SERPINE2, PAI-1, and SOX4 was investigated for its role in MSTN-induced trophoblast cell invasion. We found that MSTN induced upregulation of SERPINE2 via ALK4/5-SMAD2/3/4 signaling; however, SMAD2 was not involved in MSTN-induced PAI-1 upregulation. SOX4 was involved in MSTN-induced upregulation of SERPINE2, but not PAI-1. Collectively, this study discovers novel molecular mechanisms of MSTN-induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.
Topics: Female; Humans; Pregnancy; Epithelial-Mesenchymal Transition; Fetal Growth Retardation; Intercellular Signaling Peptides and Proteins; Myostatin; Placenta; Placental Insufficiency; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Serine Proteinase Inhibitors; Serpin E2; SOXC Transcription Factors; Trophoblasts
PubMed: 37738042
DOI: 10.1096/fj.202300740R -
International Journal of Molecular... Jul 2023Metabolic changes in pregnant women begin in the first weeks after conception under the influence of placental hormones that affect the metabolism of all nutrients. An... (Review)
Review
Metabolic changes in pregnant women begin in the first weeks after conception under the influence of placental hormones that affect the metabolism of all nutrients. An increased concentration of total lipids accompanies pregnancy and an increased accumulation of triglycerides in low-density lipoproteins (LDL) particles. Lipids in small dense LDL particles are more susceptible to oxidative modification than normal-density LDL particles. Unlike LDL high-density lipoproteins (HDL), lipoprotein particles have an atheroprotective role in lipid metabolism. The very growth of the fetus depends on the nutrition of both parents, so obesity is not only in the mother but also in the father. Nutritional programming of the offspring occurs through changes in lipid metabolism and leads to an increased risk for cardiometabolic diseases. Pregnancy is accompanied by an increased need for oxygen in the mitochondria of the placenta and a tendency to develop oxidative stress. Oxidative stress represents a disturbance in the balance of oxidation-reduction processes in the body that occurs due to the excessive production of free oxygen radicals that cellular homeostatic mechanisms are unable to neutralize. When the balance with the antioxidant system is disturbed, which happens when free oxygen radicals are in high concentrations, serious damage to biological molecules occurs, resulting in a series of pathophysiological and pathological changes, including cell death. Therefore, oxidative stress plays a significant role in the pathogenesis of many complications that can occur during pregnancy. The oxidative status of pregnant women is also influenced by socioeconomic living conditions, lifestyle habits, diet, smoking, and exposure to environmental air pollution. During a healthy pregnancy, the altered lipid profile and oxidative stress create an increased risk for premature birth and pregnancy-related diseases, and a predisposition to adult diseases.
Topics: Adult; Humans; Female; Pregnancy; Reactive Oxygen Species; Placenta; Lipoproteins, LDL; Lipoproteins, HDL; Triglycerides; Oxidative Stress; Free Radicals; Pregnancy Complications
PubMed: 37569340
DOI: 10.3390/ijms241511964 -
Methods in Molecular Biology (Clifton,... 2024The human placenta is a transient organ that functions to support the needs of the fetus throughout gestation. Trophoblasts are the major epithelial cells found within...
The human placenta is a transient organ that functions to support the needs of the fetus throughout gestation. Trophoblasts are the major epithelial cells found within the placenta and comprise a variety of distinct cell types with specialized roles in fetal-maternal communication. Our understanding of human trophoblast development remains limited due to ethical and legal restrictions on accessing first-trimester placental tissues, as well as the inability of common animal models to replicate primate placental development. It is therefore important to advance in vitro models of human trophoblast development as a basis for studying pregnancy-associated complications and diseases. In this chapter, we describe a protocol for generating 3D trophoblast organoids from naïve human pluripotent stem cells (hPSCs). The resulting stem-cell-derived trophoblast organoids (SC-TOs) contain distinct cytotrophoblast (CTB), syncytiotrophoblast (STB), and extravillous trophoblast (EVT) cell types, which closely correspond to trophoblast identities in the human post-implantation embryo. We discuss methods for characterizing SC-TOs by immunofluorescence, flow cytometry, mRNA and microRNA expression profiling, and placental hormone secretion. Furthermore, SC-TOs can undergo differentiation into specialized 3D EVT organoids, which display robust invasion when co-cultured with human endometrial cells. Thus, the protocol described herein offers an accessible 3D model system of human placental development and trophoblast invasion.
Topics: Pregnancy; Humans; Female; Placenta; Trophoblasts; Pluripotent Stem Cells; Pregnancy Trimester, First; Cell Differentiation; Organoids
PubMed: 37402094
DOI: 10.1007/7651_2023_496