The chromosomal characteristics of spontaneous abortion and its potential associated copy number variants and genes.

PURPOSE: This study aimed to investigate the correlation between chromosomal abnormalities in spontaneous abortion with clinical features and seek copy number variations (CNVs) and genes that might be connected to spontaneous abortion. METHODS: Over 7 years, we used CNV-seq and STR analysis to study POCs, comparing chromosomal abnormalities with clinical features and identifying critical CNVs and genes associated with spontaneous abortion. RESULTS: Total chromosomal variants in the POCs were identified in 66.8% (2169/3247) of all cases, which included 45.2% (1467/3247) numerical abnormalities and 21.6% (702/3247) copy number variants (CNVs). Chromosome number abnormalities, especially aneuploidy abnormalities, were more pronounced in the group of mothers aged ≥ 35 years, the early miscarriage group, and the chorionic villi group. We further analyzed 212 pathogenic and likely pathogenic CNVs in 146 POCs as well as identified 8 statistically significant SORs through comparison with both a healthy population and a group of non-spontaneously aborted fetuses. Our analysis suggests that these CNVs may play a crucial role in spontaneous abortion. Furthermore, by utilizing the RVIS score and MGI database, we identified 86 genes associated with spontaneous abortion, with particular emphasis on PARP6, ISLR, ULK3, FGFRL1, TBC1D14, SCRIB, and PLEC. CONCLUSION: We found variability in chromosomal abnormalities across clinical features, identifying eight crucial copy number variations (CNVs) and multiple key genes that may be linked to spontaneous abortion. This research enhances the comprehension of genetic factors contributing to spontaneous abortion.

Bisphenol A induces placental ferroptosis and fetal growth restriction via the YAP/TAZ-ferritinophagy axis.

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis.

Bisphenol A induces placental ferroptosis and fetal growth restriction via the YAP/TAZ-ferritinophagy axis.

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis.

Extracellular vesicles derived from hypoxic HTR-8/SVneo trophoblast inhibit endothelial cell functions through the miR-150-3p /CHPF pathway.

INTRODUCTION: Endothelial dysfunction is one of the basic pathological changes in pre-eclampsia. Extracellular vesicles (EVs) can transport miRNAs expressed by placental trophoblast cells into endothelial cells. The aim of this study was to explore the differential effects of EVs induced by hypoxic trophoblasts (1%HTR-8-EV) and those derived from normoxic trophoblasts (20%HTR-8-EV) on the regulation of endothelial cell functions. METHODS: Normoxia and hypoxia were preconditioned to induce trophoblast cells-derived EVs. The effect of EVs, miRNA, target gene, and their interactions on endothelial cell proliferation, migration, and angiogenesis were determined. Quantitative analysis of miR-150-3p and CHPF were verified by qRT-PCR and western blotting. The binding relationship among EVs pathway was demonstrated by luciferase reporter assay. RESULTS: Compared with 20%HTR-8-EV, 1%HTR-8-EV had a suppressive effect on proliferation, migration, and angiogenesis of endothelial cells. The results of miRNA sequencing showed the vital role of miR-150-3p in trophoblast-to-endothelium communication. 1%HTR-8-EV carrying miR-150-3p could move into endothelial cells and target chondroitin polymerizing factor (CHPF) gene. MiR-150-3p inhibited endothelial cell functions by regulating CHPF. In patient-derived placental vascular tissues, there was a similar negative correlating between miR-150-3p and CHPF. DISCUSSION: Our findings indicate that extracellular vesicles miR-150-3p derived from hypoxic trophoblasts inhibits endothelial cells proliferation, migration, and angiogenesis by modulating CHPF, illuminating a novel mechanism of hypoxic trophoblasts regulation of endothelial cells and their potential role in PE pathogenesis.

Pregnancy-related venous thromboembolism in Wuhan, China 2010-2022: A case-control study.

OBJECTIVE: To explore the time trends and risk factors for pregnancy-related venous thromboembolism (VTE) in the Chinese population. METHODS: A case-control study was conducted with 120 652 pregnancies between Jan 2010 and June 2022 in Wuhan, China. Medical records from pregnant patients with VTE and patients without VTE were reviewed and analyzed. RESULTS: There were 197 cases of VTE diagnosed during pregnancy or postpartum, with an overall incidence of 1.63 per 1000 pregnancies, and the incidence rate trend of VTE was increasing year by year and then declining. The incidence of deep venous thrombosis (DVT) was 1.24 per 1000 pregnancies (76.1%). Consistent with previous studies, most VTE occurred in the puerperium (1.05 per 1000 pregnancies, 64.5%). Significant risk factors included immobility, previous VTE, systemic infection, BMI over 30, and hypertensive disorders of pregnancy. CONCLUSION: Pregnancy-related VTE is not uncommon in China which is consistent with current foreign reports, and the change in incidence trend may be related to greater physicians' understanding of VTE and effective preventive measures after the publication of Chinese guidelines.

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance.

Immune imbalance of Treg/Th17 cells may contribute to recurrent implantation failure (RIF) during in vitro fertilization and embryo transfer (IVF-ET). In this study, we sought to determine the effect of intrauterine administration of mouse PBMCs prior to embryo implantation on endometrial receptivity and embryo implantation, and examine the underlying mechanism of Treg/Th17 cell balance following intrauterine administration of PBMCs. Pregnant mice were randomly divided into three groups: control group, embryo implantation dysfunction (EID) group, and EID with PBMCs group, and the number of embryo implantation sites was recorded during early pregnancy (Pd7.5). The balance of Treg/Th17 cells in the peripheral blood, spleen, and local implantation sites was detected during the peri-implantation period (Pd4.0) and early pregnancy (Pd7.5). The EID group demonstrated a significant decrease in the number of embryo implantation sites, while the EID with PBMCs group demonstrated higher number of embryo implantation sites compared to the EID group. The balance of Treg/Th17 cells in the peripheral blood and spleen tissues was not significantly different between the aforementioned groups. However, the local uterine ratio of the Treg/Th17 cells increased in the EID with PBMCs group compared to that in the EID group. Collectively, we found that intrauterine administration of PBMCs prior to embryo implantation effectively promotes embryo implantation rates. This may be attributed to the improvement in the local immune balance of Treg and Th17 cells compared with the overall immune balance.

Identification of potential crucial genes associated with early-onset preeclampsia via bioinformatic analysis.

INTRODUCTION: Early-onset preeclampsia is a pregnancy complication associated with high maternal and perinatal morbidity, mortality. Intense efforts have been made to elucidate the pathogenesis, but the molecular mechanism is still elusive. This study aimed to identify potential key genes related to early-onset preeclampsia, and to obtain a better understanding of the molecular mechanisms of this disease. METHODS: We performed a multi-step integrative bioinformatics analysis of microarray dataset GSE74341 downloaded from Gene Expression Omnibus (GEO) database including 7 early-onset preeclampsia and 5 gestational age matched normotensive controls. The differentially expressed genes (DEGs) were identified using the "limma" package, and their potential functions were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Furthermore, the protein-protein interaction network (PPI) was obtained from the STRING database and the PPI network was visualized by Cytoscape software. Then, hub modules and hub genes were screened out from the PPI network, and enrichment analysis was performed for them. Also, validation of hub genes expression in early-onset PE was down by using microarray dataset GSE44711. RESULTS: A total of 628 DEGs (256 down- and 372 up-regulated) were identified in early-onset PE compared to controls. A total of 4 significant hub modules and 26 significant hub genes were identified. CONCLUSION: In conclusion, the DEGs related to cell-cell or cell-extracellular matrix interaction (ITGA5, SPP1, LUM, VCAN, APP), placenta metabolic or oxidative stress (CCR7, NT5E, CYBB) were predicted to be newly potential crucial genes that may play significant roles in the pathogenesis of early-onset PE.

Integrated analysis of multiple microarray studies to identify novel gene signatures in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is one of the major causes of maternal and fetal morbidity and mortality in pregnancy worldwide. However, the intrinsic molecular mechanisms underlying the pathogenesis of PE have not yet been fully elucidated. METHODS: Robust rank aggregation (RRA), weighted correlation network analysis (WGCNA) and protein-protein interaction (PPI) methods were used to identify robust differentially expressed genes (DEGs) and hub genes in preeclampsia and subgroups based on 10 Gene Expression Omnibus (GEO) datasets. Subsequently, enrichment analysis and correlation analysis were performed to explore the potential function of the robust DEGs and hub genes. The diagnostic role of hub genes was further investigated by GSE12767. The miRNA regulators and the effect of hypoxia on hub genes were explored by using GSE84260 and GSE65271, respectively. RESULTS: Robust DEGs were identified in each subgroup including preeclampsia. Totally, 24 hub genes enriched in inflammatory response, renin-angiotensin system and JAK-STAT pathway, and 24 related miRNA regulators were identified. DISCUSSION: Our integrated analysis identified novel gene signatures in preeclampsia and subgroups and will contribute to the understanding of comprehensive molecular changes in preeclampsia.

Predictive role of neutrophil-to-lymphocyte ratio in preeclampsia: A meta-analysis including 3982 patients.

OBJECTIVE: The predictive role of neutrophil-to-lymphocyte ratio (NLR) for preeclampsia (PE) has been explored in several studies and current evidence seems to be conflicting. The aim of this study is to compare the NLR values of mild and severe preeclampsia with the normotensive pregnant women, in order to explore the predictive role of NLR for preeclampsia and whether the NLR value has significant difference between severe and mild preeclampsia. DESIGN AND METHODS: We systematically searched Pubmed, Embase, Web of Science and Cochrane database for relative literature up to May 2019. The statistical analysis was performed using Stata 12.0 software. RESULTS: Totally 15 eligible studies consisting of 3982 patients were enrolled in our meta-analysis. The NLR value is higher in preeclampsia when compared to healthy pregnant women (3270 women, MD: 1.44, 95% CI [1.04, 1.83]). Furthermore, NLR value is higher in severe preeclampsia than in mild preeclampsia (1287 women, MD: 1.12, 95% CI [0.69,1.56]). CONCLUSIONS: The findings of our meta-analysis suggest that NLR value is higher in preeclampsia patients especially in severe preeclampsia. The NLR might be a useful laboratory marker for clinical prediction and disease severity evaluation of preeclampsia. However, given that the available evidence is mainly drawn from case-control studies, future cohorts are needed in this field to accurately determine optimal timing and cut-off values that may be used in the clinical setting.