INTRODUCTION:Gestational diabetes mellitus (GDM) is a major public health challenge characterized by placental immunometabolic dysregulation. This study aimed to identify molecular signatures associated with GDM-related placental pathology and evaluate their diagnostic and therapeutic implications. METHODS:Two bulk placental transcriptomic datasets (GSE70493 and GSE263483) and one single-cell dataset (GSE173193) were analyzed. Differential expression analysis, WGCNA, and machine-learning feature selection (LASSO and SVM-RFE) were used to identify candidate gene signatures. A two-gene logistic regression model was constructed and externally validated. Immune-cell correlation rewiring and single-cell in silicoperturbation analysis explored immune-network alterations and regulatory roles of identified genes. A drug-prioritization framework was used for therapeutic screening. RESULTS:Intersecting WGCNA modules with differentially expressed genes identified 29 candidates enriched in antigen presentation and mononuclear phagocyte functions. Dual-algorithm selection converged on HLA-DQA2 and FGL2. The two-gene model achieved an AUC of 0.786 in the discovery cohort and 0.813 in the external validation cohort. Immune rewiring analysis indicated a shift toward M1 macrophage polarization. Single-cell perturbation analysis supported regulatory roles of HLA-DQA2 and FGL2 within the macrophage lineage. Drug analysis reaffirmed insulin, metformin, and glyburide as stable therapeutic anchors. DISCUSSION:The HLA-DQA2/FGL2 signature captures key aspects of placental immunometabolic dysregulation in GDM, including altered antigen presentation and macrophage-associated immune rewiring. This integrated framework provides candidate biomarkers for GDM risk stratification and generates computational hypotheses for future mechanistic and therapeutic studies.
OBJECTIVES:Prenatal diagnosis of the placenta accreta spectrum (PAS) relies on subjective anatomical MRI interpretation and lacks objective quantitative biomarkers. This study aimed to validate diffusion MRI myometrial tractography for PAS detection and compare its performance with conventional visual MRI diagnosis. MATERIALS AND METHODS:This prospective study enrolled 154 pregnant women with suspected PAS. All subjects underwent routine MRI and DTI. Tractography-derived FA, fiber density and ADC were measured. Diagnosis was confirmed by 2023 FIGO criteria; participants were stratified into a 70% training set and independent 30% test set. Statistical analyses included group comparisons, ROC analyses with DeLong's test, and ICC for interobserver reliability. RESULTS:PAS patients exhibited lower FA (p < 0.001), reduced fiber density (p < 0.001) and higher ADC (p = 0.044). The clinically adjusted FA + fiber density model reached an AUC of 0.86 in the training set (conventional MRI AUC = 0.81) and maintained an AUC of 0.82 in the test set, comparable to conventional MRI. Combined parameters yielded an AUC of 0.82 for differentiating PAS grade 1 and grade 2. ICCs (0.788-0.948) indicated excellent interobserver agreement. CONCLUSION:Quantitative diffusion MRI tractography provides objective biomarkers for prenatal PAS evaluation. The combined FA and fiber density model yields stable diagnostic performance and delivers complementary quantitative information to mitigate subjectivity in conventional anatomical-MRI assessment. This proof-of-concept work requires further external multicenter validation before clinical adoption.
Introduction Gestational diabetes mellitus (GDM) occurs in pregnant women of advanced maternal age and is characterized by dysregulated elevation of blood glucose levels. Ginkgolide B (GB) is extracted from Ginkgo biloba leaves and possesses anti-inflammatory as well as antioxidant effects. This study aimed to assess the function of GB in gestational diabetes mellitus (GDM) and explore the underlying mechanisms. Methods Pregnant C57BL/KsJ-db/+ mice were assigned to the untreated GDM group or treated orally with GB at 100 or 200 mg/kg. Glucose tolerance, insulin sensitivity, fasting blood glucose, plasma insulin levels, and pregnancy outcomes were evaluated. Placental inflammation, oxidative stress, ferroptosis-related proteins, NLRP3 inflammasome components, and proteins involved in the Nrf2/HO-1 signaling pathway were assessed using ELISA, histological staining, immunofluorescence, biochemical assays, and Western blotting. Results Compared with the Control mice, GDM mice exhibited impaired glucose tolerance and insulin sensitivity, elevated fasting blood glucose and plasma insulin levels, increased placental inflammation and oxidative stress, enhanced ferroptosis, and reduced litter size. GB treatment significantly improved these metabolic and pregnancy-related abnormalities, attenuated inflammatory cytokine production and placental injury, reduced reactive oxygen species accumulation and lipid peroxidation, and restored GPX4 and SLC7A11 expressions. In addition, GB inhibited NLRP3 inflammasome activation, while restoring the expression of Nrf2, HO-1, and NQO1 in placental tissues. Discussion This study showed the beneficial effects of GB in GDM, suggesting potential therapeutic approaches for preventing the progression of GDM management.
BACKGROUND:Maternal high-fat diet (HFD) contributes to developmental programming through placental adaptations; however, the effects of exposure timing before and during pregnancy remain unclear. OBJECTIVE:To investigate the distinct effects of pre-pregnancy and gestational HFD on maternal metabolism, pregnancy outcomes, placental oxidative stress, placental gene-expression adaptations, and gut microbiota in rats. METHODS:Female Sprague-Dawley rats were fed a control diet (V) or HFD (H) before and/or during pregnancy, generating four groups (V/V, V/H, H/V, H/H). Maternal metabolic parameters, placental gene expression, oxidative stress, and gut microbiota composition were analyzed at gestational day 21. RESULTS:Pre-pregnancy high-fat diet increased maternal body and liver weights and elevated placental oxidative stress, whereas gestational high-fat diet increased adiposity and impaired glucose tolerance and insulin sensitivity without affecting pregnancy outcomes. Placental nutrient transporters, including glucose transporter 1 (Glut1) and solute carrier family 38 (Slc38) members, were mainly regulated by pre-pregnancy diet. Insulin-like growth factor 2 (Igf2) was influenced by gestational diet and its interaction with pre-pregnancy diet, while insulin-like growth factor 2 receptor (Igf2R) and insulin 2 (Ins2) expression were primarily influenced by pre-pregnancy diet. Forkhead box O1 (FoxO1) and Forkhead box O3 (FoxO3) exhibited differential responses to maternal dietary exposure. Gestational HFD also altered gut microbiota composition without affecting microbial diversity. CONCLUSION:Pre-pregnancy and gestational HFD exert distinct but complementary effects on maternal metabolism and placental adaptations. These findings highlight the stage-specific impact of maternal nutritional status on developmental programming and placental function.
INTRODUCTION:Insulin resistance (IR) occurs when insulin is ineffective in activating the IRS-PI3K-AKT pathway. Folic acid is used to prevent neural tube defects during pregnancy but the effects of folic acid supplementation on IR in maternal diabetes remain unclear. This study aimed to evaluate the effects of folic acid on an in vitro IR model. Therefore, we investigated the impact of folic acid on the IRS-PI3K-AKT pathway in relation to IR. METHODS:In vitro low and high dose IR models were carried out in human umbilical vein endothelial cells (HUVECs). Folic acid was applied at three different doses. Cell viability was measured using WST-1 analysis. Phospho-IRS-1, phospho-PI3K, and phospho-AKT levels were assessed via both immunocytochemistry and ELISA. RESULTS:Twenty-four hours after folic acid treatment, cell viability in the high dose-IR was higher than in the control group (p < 0.05). Forty-eight hours after folic acid treatment, cell viability was significantly lower in all three dose groups compared to the control group (p < 0.05). In both IR groups, the activity of the phospho-PI3K and phospho-AKT proteins was lower than in the control group. Following folic acid treatment, the activity of these proteins was higher than in both IR groups (p < 0.05). However, the reduced activity of the phospho-IRS-1 protein remained unchanged. CONCLUSIONS:The present study suggest that folic acid may protect HUVECs under IR conditions relevant to maternal diabetes, possibly via the IRS-PI3K-AKT pathway. Our results may provide new approaches regarding the possible protective effect of folic acid in diabetic vasculopathy.
Background: Placental dysfunction is associated with adverse pregnancy outcomes, yet normal placental growth and vascular adaptation remain incompletely understood. Most available data pertain to term placentas, limiting insight into earlier stages of development.This study develops a mathematical framework that conceptualizes potential feto-placental vascular growth between 24 and 40 weeks of gestation in backward fashion. By working backwards from a term placenta, the model provides a systematic approach to simulating placental development and vascular remodeling, enabling hypotheses generation. Methods: A volume-filling algorithm was applied to generate three term placentas: two with central cord insertion (based on ex-vivo and in-vivo geometrical data) and one with marginal cord insertion (based on in-vivo geometrical data).A growth algorithm, incorporating literature-based scaling functions, was applied in reverse to downscale the term vasculature to 24 weeks. Growth was simulated using a reverse sigmoid function for lateral expansion and a linear scale factor for vertical growth, initiated at the cord insertion. Results: The model replicated vascular growth trends observed in literature, including a linear increase in umbilical artery diameter and linear vascular volume expansion. Placental topology was influenced by cord insertion, with central insertions producing symmetric growth, while marginal insertions exhibited uneven lateral expansion. Discussion: A mathematical framework that conceptualizes feto-placental vascular growth between 24 and 40 weeks of gestation is developed. The framework aligns with existing but scarce data in the literature. Based on these findings, further research directions in vascular versus tissue growth are proposed to deepen our understanding of placental growth, ultimately enhancing the provided model.
Introduction The human placental trophoblast layer is a crucial barrier to the transfer of xenobiotics from maternal to fetal fluids. Intercellular spaces between adjacent trophoblast cells are sealed by bicellular and tricellular tight junctions (TJs), which respectively include claudins and angulins. However, which TJ components are involved in the barrier function of placental trophoblast cells remains unclear. Methods In this study, we used proteins that bind to the extracellular domain of claudins or angulins (hereafter referred to as binders) to investigate the contributions of various TJ components to barrier function in JEG-3 cells, a human trophoblast model. Results In this system, claudin binders enhanced the permeation of paracellular passage markers (dextrans with molecular mass of ≤150 kDa) and thus more effectively attenuated TJ integrity than did angulin binders. Gene expression analysis revealed that claudin-4 and angulin-1 are key components in bicellular and tricellular TJs, respectively. Conclusions This study is the first to characterize the barrier function of TJ components in JEG-3 cell monolayers, a human trophoblast model.
INTRODUCTION:Globally, more than two million babies are stillborn every year. The primary cause of stillbirth is placental dysfunction, which impairs oxygen and nutrient delivery to the fetus. From a physical perspective, the efficiency of this exchange depends on placental blood flow and microvascular villous structure. Doppler ultrasound (US) imaging is used clinically to assess abnormal placental blood flow, but evaluation of placental structure remains largely observational. Texture analysis of B-mode US images offers a quantitative approach to indirectly characterize placental structure through analysis of US image pixels. Therefore, the objective of this study was to investigate whether integrated quantitative biomarkers derived from placental texture, Doppler ultrasound, and standard clinical variables improve the assessment of pregnancies associated with adverse fetal outcomes. METHODS:Patients (N = 129) were recruited, and B-mode US images and Doppler measurements were acquired at visit 1 (28-32 weeks of gestation) and visit 2 (34-38 weeks of gestation). Clinical outcome data were used to define patients as High-Risk based on previously established markers of significant stillbirth risk (e.g., preeclampsia with severe features, severe FGR, perinatal hypoxia). Logistic regression and random forest models were used to evaluate the predictive value of each modality with clinical variables and in combination. RESULTS:Quantitative placental texture features demonstrated predictive performance comparable to Doppler ultrasound measurements, supporting their associations with adverse fetal outcomes. Integrating clinical, Doppler, and texture features further improved model performance compared with models developed from clinical variables alone or paired with either imaging modality individually. These findings demonstrate that quantifying placental US texture provides complementary information to Doppler and clinical variables. While further validation in larger external cohorts is required, this work supports the potential of quantitative multimodal ultrasound biomarkers for assessing pregnancies with adverse fetal outcomes.
The pulsation of blood in the umbilical artery and the feto-placental circulation has been a focus for computational modelling because of the important association between the patterns of pulsation and placental pathology. This review examines different approaches that have been used to study this relationship and the insights that can be drawn from these computational models. Wave reflection in the umbilical artery is presented both to aid in the interpretation of these patterns and as an example of how modelling approaches can be used to unify disparate hemodynamic measurements. The linkage between modelling and measurement methodologies is examined along with the considerations for model selection when approaching a new research question.
INTRODUCTION:The small GTPase RAC1 is crucial for blastocyst attachment to the endometrium during embryo implantation. RAC1 is regulated by RHOH, whose role in pregnancy establishment we investigated. METHODS:We analyzed uterine RHOH expression by immunoblotting during the endometrial receptivity window for embryo attachment and miscarriage (LPS-, and IFN-γ-induced), and abortion (RU-486-, and ormeloxifene-induced), using a mouse model, human-origin placenta and decidua-placenta, and human endometrial epithelial cells. Additionally, we determined the cellular localization of RHOH by immunohistochemistry. RESULTS:RHOH levels were elevated in placentas from human miscarriage cases (n = 7) and in decidua-placenta tissues (n = 13) from these cases. In the mouse model, RHOH expression was downregulated at the implantation site during both receptive and post-receptive stages. Conversely, during pseudopregnancy, uterine RHOH expression was higher in the pre-receptive stage. RHOH was primarily localized in stromal and epithelial cells at all stages examined. In the decidualized uterus, RHOH expression was reduced and predominantly detected in stromal cells. Additionally, upregulation of RHOH was observed in the uterus from miscarriage/abortion cases and inter-implantation sites in non-miscarriage/abortion mouse models. Furthermore, the downstream effector RAC1 was also increased in the miscarriage/abortion mouse models. DISCUSSION:RHOH was upregulated in the placenta and decidua-placenta tissues of human miscarriage cases. Similarly, in mouse models, RHOH expression increased in the endometrium during miscarriage/abortion. In contrast, RHOH expression decreased at implantation sites and in the decidualized endometrium. These findings suggest that RHOH functions as a regulator of endometrial receptivity, potentially involving RAC1, and that their upregulation is associated with miscarriage/abortion.
INTRODUCTION:Placenta is an essential organ for a healthy pregnancy, thus maternal vascular hypoperfusion has been associated with adverse outcomes. Syndecan-1 and VEGF-A are involved in the placentation process. However, whether these proteins could serve as early markers of placental damage or fetal vascular damage is still unknown. METHODS:A clinical study was carried out in 66 healthy pregnant women in the second trimester of pregnancy, with follow-up until delivery. The maternal age, height, and weight were collected. Ultrasound examination was performed to obtain fetal growth measures and fetal abdominal aorta characteristics. At birth, a histopathological study of the placenta was performed, and the newborn's weight and height were recorded. Maternal serum Syndecan-1 and VEGF-A levels were measured by ELISA in the second trimester and in cord blood serum at delivery. Analysis was performed with Student's t-test, and correlation tests. RESULTS:Placental histopathological analysis revealed a prevalence of 76% multiple infarcts, 64% increased syncytial knots, 27% distal villous hypoplasia, and 12% acute atherosis. Maternal Syndecan-1 levels were significantly lower in the presence of placental multiple infarcts (p < 0.001), acute atherosis (p = 0.018), distal villous hypoplasia (p < 0.001), and increased syncytial knots (p < 0.001). Maternal VEGF-A levels were not different in the presence of placental lesions. Maternal and umbilical cord blood Syndecan-1 levels correlated with fetal abdominal aorta Intima-media thickness (r = -0.57, p < 0.001, and r = 0.74, p < 0.001, respectively). Umbilical cord blood VEGF-A also correlated with fetal abdominal aorta Intima-media thickness (r = 0.43, p < 0.001). CONCLUSION:Maternal and cord blood Syndecan-1 could be an early marker of placental damage and fetal aortic intima media thickness.
INTRODUCTION:Early onset preeclampsia (EOPE), a complex complication of pregnancy, is a major contributor to maternal and fetal morbidity and mortality. The only symptom consistently observed in EOPE is new maternal hypertension. Other symptoms vary among patients, posing challenges for early detection. There are currently no clinically accepted molecular markers other than FLT1, which is highly upregulated and displays a small change in its splicing ratio in EOPE placentas. However, an exhaustive search for changes in transcript use in EOPE has not been performed. METHODS:Differential transcript usage (DTU) analysis was conducted between placental samples of women with and without EOPE for four public RNA sequencing datasets. To identify changes due to placental age, DTU events were compared to preterm placentas. Selected DTUs were experimentally validated in an independent cohort. RESULTS:We identified 43 DTU events between term-birth and EOPE placentas in more than one dataset, and attributed 3 of the 43 to placental age. The genes that carry those DTUs were enriched for cell junction and cell membrane-associated pathways, which were previously suggested to be altered in preeclampsia at the gene expression level, although the alteration was mediated by other genes. DISCUSSION:Alterations in transcript usage are part of the EOPE molecular mechanism. The validated DTUs in FLT4, ADGRG6, MXI1, and LCP1 may contribute to the development of EOPE. Surprisingly, the splicing change in FLT4 takes place in the intracellular domain, whereas the preeclampsia-associated changes in its paralog FLT1 are in the extracellular domain.
BACKGROUND:Preterm premature rupture of membranes (PPROM) before full term can lead to adverse pregnancy outcomes. Chorioamnionitis is the main cause of premature birth. This investigation aims to evaluate the clinical value of miR-338-3p in PPROM with histological chorioamnionitis (HCA), and its mechanism in human amniotic epithelial cells (hAECs). METHODS:215 patients with PPROM were included (PPROM-HCA group (n = 105), PPROM group (n = 110)). MiR-338-3p and PTN expression in the tissues were measured via real time quantitative polymerase chain reaction. The diagnostic value of miR-338-3p for PPROM with HCA was evaluated using receiver operating characteristic analysis. Cell proliferation, apoptosis and inflammatory factor levels were quantified via cell counting kit-8, flow cytometry and enzyme-linked immunosorbent assay. RESULTS:Compared with PPROM group, miR-338-3p was upregulated in the tissues of PPROM-HCA patients, while PTN was downregulated. MiR-338-3p had a good diagnostic value for PPROM-HCA patients. MiR-338-3p overexpression suppressed hAECs proliferation, promoted apoptosis, and increased interleukin-6 and tumor necrosis factor-α levels; inhibition of miR-338-3p showed the reverse phenotypes. PTN was the target gene of miR-338-3p. PTN overexpression partially reversed the cell proliferation inhibition, increased apoptosis and release of inflammatory factors induced by the upregulation of miR-338-3p. CONCLUSION:MiR-338-3p is upregulated in PPROM-HCA patients, and it has a good diagnostic value. MiR-338-3p modulates the proliferation, apoptosis and inflammatory response of hAECs via targeting PTN. These findings offer novel insights into the pathological research of PPROM-HCA.
BACKGROUND:Maternal obesity is a well-established risk factor for preeclampsia; however, whether increased maternal BMI is associated with biologically distinct subtypes of this disorder remains unknown. OBJECTIVE:To investigate whether maternal BMI is associated with differences in placental gene expression patterns observed in preeclampsia and to identify transcriptomic signatures with potential relevance for future biomarker research. STUDY DESIGN:This exploratory analysis used placental transcriptomic data obtained from the Gene Expression Omnibus. Differential expression within prespecified contrasts encoding preeclampsia status and maternal BMI was analyzed using a multivariable linear modeling framework with adjustment for relevant confounders. In a secondary analysis, maternal BMI was modeled continuously with an interaction term between BMI and preeclampsia status. RESULTS:Placental transcriptomic data from 132 placentas representing a range of maternal hypertensive and normotensive states were analyzed. Genes commonly associated with preeclampsia, including FLT1, LEP, HTRA4, and FSTL3, were differentially expressed across all BMI categories. SERPINA3 demonstrated the strongest differential expression in the obese contrast, with an estimated eight-fold increase (95% CI: 3.9-16.6) in preeclamptic pregnancies complicated by obesity, whereas expression differences were smaller and not statistically significant in healthy-weight and overweight contrasts. Gene set enrichment analysis suggested heterogeneity in the underlying biology of preeclampsia across BMI strata. CONCLUSION:Placental transcriptional patterns associated with preeclampsia differed across maternal BMI strata. These findings are consistent with previously proposed molecular subtypes of preeclampsia and highlight SERPINA3 as a candidate transcriptomic marker warranting further investigation, specifically in pregnancies complicated by obesity.
OBJECTIVES:The primary objective was to elucidate whether placental histopathology representative of intrauterine insults during pulmonary vascular development are associated with a diagnosis of persistent pulmonary hypertension of the newborn (PPHN). The secondary objective was to compare placental histopathologic lesions across PPHN etiologies. STUDY DESIGN:We conducted a case-control study of mother-infant dyads ≥35 weeks gestation who delivered at a tertiary care center between 2020 and 2025. Cases were infants diagnosed with PPHN and treated with inhaled nitric oxide; unaffected controls were infants without congenital anomalies. Placentas underwent blinded histopathologic review using standardized criteria. Multivariate logistic regression modeling was used to control for confounding maternal and infant factors. RESULTS:106 placentas were analyzed (53 PPHN, 53 controls). Placental lesions were significantly more common in PPHN placentas, including fetal vascular malperfusion (30.2% vs 9.4%, p < 0.01), placental inflammation (66.0% vs 37.7%, p < 0.01), chronic presence of meconium (43.4% vs 15.2%, p < 0.01), and chorangiosis (7.6% vs 0%, p = 0.04). In adjusted analyses compared to controls, among 41 placentas with fetal development etiologies (e.g. congenital anomalies) of PPHN, fetal vascular malperfusion, placental inflammation and fetal inflammatory response were more common. Among 12 placentas with typical causes of PPHN (e.g. meconium aspiration syndrome), placental inflammation, maternal and fetal inflammatory responses, and meconium were more common. CONCLUSIONS:PPHN placentas demonstrate lesions of malperfusion, inflammation, and chronic meconium, suggesting a complex interplay between intrauterine hypoxia and inflammation as a potential mechanism for the abnormal pulmonary vascular development and function seen in PPHN.
INTRODUCTION:The haemodynamics of maternal blood flow in the intervillous space (IVS) impacts placental exchange efficiency. The resulting shear stress can also affect syncytiotrophoblast function, and in turn placental development. Here, we use anatomically-informed multiscale modelling approaches to predict flow in the IVS and syncytiotrophoblast shear stress in fetal growth restriction (FGR). METHODS:Three-dimensional placentone models were established and parameterised to normal and FGR scenarios. Normal term and FGR placental tissue punches were microCT imaged, segmented, and used in tissue-level computational fluid dynamics simulations to predict syncytiotrophoblast shear stress. Tissue and placentone-level models were combined to predict syncytiotrophoblast shear stress ranges. Mechanosensing protein expression was determined by immunohistochemistry. RESULTS:Placentone-level models demonstrate variation in IVS flow velocity across the placental depth, with higher velocity regions at spiral artery mouths that extended further in FGR. Tissue-level models predicted higher levels of syncytiotrophoblast shear stress in FGR. Combined models predicted a greater proportion of tissue is exposed to higher shear stresses in FGR, with ∼2-fold increase in peak shear stress proximal to spiral artery openings. Including septal veins increased penetration of maternal blood and the proportion of tissue exposed to higher shear. In FGR, the syncytiotrophoblast had greater Dynein-1 and lower Kinesin-2 and TRVP6 expression, but no difference in IFT88, Polycystin-2 or Piezo-1 expression. CONCLUSIONS:In FGR, impaired remodelling of the spiral arteries and changes in villous tissue architecture combine to increase the proportion of placental tissue exposed to higher shear stress. Septal veins and central cavities act synergistically to ensure adequate placental perfusion.
INTRODUCTION:Most mammals are poorly developed at birth, with closed eyes and little hair. Others are well-developed with eyes open and a full coat of hair. The former are altricial and born in large litters after a brief gestation; the latter are precocial and from smaller litters, often singletons, born after a long gestation. METHODS:This paper reviews the work of Adolf Portmann and his successors on this dichotomy and considers whether evolutionary transitions from altricial to precocial, or the reverse, are reflected in placental morphology. RESULTS:Portmann emphasized that human babies underwent intrauterine development like precocial mammals yet differ from them in being fully dependent on parental care. Recently it was proposed that the ancestral type of placentation (discoid, labyrinthine and haemochorial) is well suited to the altricial strategy, whereas transition to the precocial type triggered a placental crisis that drives placental evolution. These ideas are further explored. DISCUSSION:Transitions from altricial to precocial are seen in hystricognath rodents and strepsirrhine primates and from precocial to altricial in carnivores. In each instance the transition is accompanied by marked innovations in placental morphology.
INTRODUCTION:Maternal depressive symptoms during pregnancy are associated with a range of adverse neurodevelopmental outcomes in offspring. DNA methylation, influenced by both genetic and environmental factors, has been identified as a potential mechanism mediating these associations. Because the placenta serves as an interface between mother and fetus, epigenetic marks in this tissue may provide insights into how the intrauterine environment influences child outcomes. The present study aimed to determine whether maternal Edinburgh Postnatal Depression Scale (EPDS) scores in mid-pregnancy (20 + 6 to 30 + 0 gestational weeks) are associated with placental DNA methylation marks and whether these marks differ from those associated with EPDS scores in early pregnancy. METHODS:In this descriptive analysis, the DNA methylomes of placental samples collected at birth from 91 women in the FinnBrain cohort were analyzed using reduced representation bisulfite sequencing. The association of EPDS with DNA methylation of each CpG site was examined using the PQLseq. RESULTS:A total of 1345 CpG sites in 381 genes were identified with FDR ≤0.05, suggesting a potential association with mid-pregnancy EPDS scores. The most significant methylation marks were found in the following genes: PTPRO, RPTOR, TBX1, SLC7A4, FBRSL1, and ADAMTS17. When accounting for early pregnancy EPDS scores, 272 methylation marks remained significant. The genes were functionally enriched in biological pathways such as cell adhesion, nervous system development, and anatomical structure development. Compared with methylation marks associated with early pregnancy EPDS scores, similar methylation marks were found in 29 distinct genic regions. Further studies are needed to determine whether these methylation marks mediate the effects of maternal depressive symptoms on the fetus.
INTRODUCTION:The monoterpenoid eucalyptol (EUC; 1,8-cineole) has a vasodilatory effect on rat arteries; however, its effects on the human fetoplacental vasculature had not yet been described. Thus, the objective of this study is to evaluate the endothelium-independent vasorelaxant effect of EUC on human umbilical veins from normoglycemic parturients (HUV-NG) and parturients with gestational diabetes mellitus (HUV-GDM). METHOD:Denuded HUV rings were mounted in organ bath for isometric recordings under different experimental protocols in the presence of EUC (1-3000 μM). RESULTS:EUC (1-3000 μM) inhibited vasoconstriction induced by KCl (60 mM) and 5-HT (10 μM), exhibiting greater potency in HUV-GDM. EUC (3000 μM) prevented vasoconstriction induced by CaCl2 or BaCl2 (0.1-30 mM) in HUV-NG. However, its efficacy in preventing vasoconstriction induced by high concentrations of BaCl2 was attenuated in HUV-GDM. The presence of potassium channel blockers (TEA, 4-AP, GLI, and BaCl2) reduced the vasorelaxant efficacy and potency of EUC, differentially in HUV-NG and HUV-GDM. DISCUSSION:The results suggest that EUC acts by modulating ion channels to induce vasorelaxation in HUV, possibly through the inhibition of voltage-operated calcium channels and the activation of potassium channels in vascular smooth muscle. Furthermore, the pathophysiological changes induced by GDM in HUV appear to alter the pharmacodynamics of EUC; nevertheless, the vasorelaxant effect of EUC was more potent via electromechanical and pharmacomechanical pathways in HUV-GDM. Thus, the current study provides a basis for the development of new pharmacological vasodilator strategies.
