Abstract Adverse pregnancy outcomes, such as preeclampsia, gestational diabetes mellitus, fetal growth restriction, and recurrent miscarriage, occur frequently in pregnant women and might further induce morbidity and mortality for both mother and fetus. Increasing studies have shown that dysfunctions of human trophoblast are related to these adverse pregnancy outcomes. Recent studies also showed that environmental toxicants could induce trophoblast dysfunctions. Moreover, non-coding RNAs (ncRNAs) have been reported to play important regulatory roles in various cellular processes. However, the roles of ncRNAs in the regulation of trophoblast dysfunctions and the occurrence of adverse pregnancy outcomes still need to be further investigated, especially with exposure to environmental toxicants. In this review, we analyzed the regulatory mechanisms of ncRNAs and m6A methylation modification in the dysfunctions of trophoblast cells and the occurrence of adverse pregnancy outcomes and also summarized the harmful effects of environmental toxicants. In addition to DNA replication, mRNA transcription, and protein translation, ncRNAs and m6A modification might be considered as the fourth and fifth elements that regulate the genetic central dogma, respectively. Environmental toxicants might also affect these processes. In this review, we expect to provide a deeper scientific understanding of the occurrence of adverse pregnancy outcomes and to discover potential biomarkers for the diagnosis and treatment of these outcomes.

Regulatory roles of non-coding RNAs and m6A modification in trophoblast functions and the occurrence of its related adverse pregnancy outcomes

Abstract The etiology and pathogenesis of miscarriage, which is the most common pregnancy complication, have not been fully elucidated. There is a constant search for new screening biomarkers that would allow for the early diagnosis of disorders associated with pregnancy pathology. The profiling of microRNA expression is a promising research area, which can help establish the predictive factors for pregnancy diseases. Molecules of microRNAs are involved in several processes crucial for the development and functioning of the body. These processes include cell division and differentiation, programmed cell death, blood vessel formation or tumorigenesis, and the response to oxidative stress. The microRNAs affect the number of individual proteins in the body due to their ability to regulate gene expression at the post-transcriptional level, ensuring the normal course of many cellular processes. Based on the scientific facts available, this paper presents a compendium on the role of microRNA molecules in the miscarriage process. The expression of potential microRNA molecules as early minimally invasive diagnostic biomarkers may be evaluated as early as the first weeks of pregnancy and may constitute a monitoring factor in the individual clinical care of women in early pregnancy, especially after the first miscarriage. To summarize, the described scientific data set a new direction of research in the development of preventive care and prognostic monitoring of the course of pregnancy. Summary Sentence: The expression of potential miRNA molecules as early minimally invasive diagnostic biomarkers may be evaluated in the first weeks of pregnancy and may constitute a monitoring factor in the individual clinical care of women in early pregnancy. Graphical Abstract

/pdf/the-role-of-mirna-molecules-in-the-miscarriage-process-212yjr7o.pdf

The role of miRNA molecules in the miscarriage process

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is strongly associated with an increased risk of adverse perinatal outcomes. Total bile acid (TBA) levels in the late second or third trimester are a major factor in the diagnosis. Here, we sought to establish the miRNA expression profile of plasm exosomes of ICP and identify possible biomarkers for the diagnosis of ICP. Methods This case–control study involved 14 ICP patients as the experimental group and 14 healthy pregnant women as the control group. Electron microscopy was used to observe the presence of exosomes in plasma. Nanosight and Western blotting of CD63 was used to assess exosome quality. Among them, three ICP patients and three controls were used for isolation plasmic exosome and preliminary miRNA array analysis. The Agilent miRNA array was utilized to dynamically monitor the miRNA expression in plasmic exosomes of included patients in the first trimester(T1), second trimester (T2), third trimester (T3), and delivery (T4). Then, Quantitative real-time Polymerase chain reaction was used to identify and validate differentially expressed miRNAs in plasma-derived exosomes. Results The expression levels of hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p in plasma-derived exosomes of ICP patients were significantly higher than those of healthy pregnant women. Besides, these three miRNAs were also significantly up-regulated at the plasma, placental, and cellular levels ( P &lt; 0.05). The diagnostic accuracy of hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p was further evaluated by the ROC curve, the area under the curve (AUC) values for each were 0.7591, 0.7727, and 0.8955, respectively. Conclusions We identified three differentially expressed miRNAs in the plasma exosomes of ICP patients. Hence, hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p may be potential biomarkers for enhancing the diagnosis and prognosis of ICP. 

/pdf/unique-microrna-expression-profiles-in-plasmic-exosomes-from-2j6xahqo.pdf

Unique microRNA expression profiles in plasmic exosomes from intrahepatic cholestasis of pregnancy

Abstract Purpose The purpose of this study is to investigate the function of miR-150-5p in URSA. Method Twenty-six chorionic villous tissues were collected to examine the expression of miR-150-5p and VEGFA by using quantitative polymerase chain reaction (qPCR) and western blot assay, respectively. Transwell assay was conducted to assess the migration and invasion ability of trophoblast cells. The dual-luciferase reporter assay was applied to determine the relationship between miR-150-5p and VEGFA in vitro. Relevant signaling pathway protein expression level was measured via western blot assay. Signaling transduction inhibitor LY294002 was used to block PI3K/AKT/mTOR signaling pathway. Finally, in vivo the effect of miR-150-5p on embryonic absorption rate was evaluated in mice. Results Clinical samples revealed that miR-150-5p expression was significantly elevated in the villous tissues and serum of URSA patients. Moreover, the overexpressing of miR-150-5p could inhibit both HTR-8/SVneo cell and JAR cell migration, invasion, and restrained PI3K/AKT/mTOR signaling pathway by targeting VEGFA in vitro. This inhibitory effect of miR-150-5p could be reversed by overexpressing the gene of vascular epithelial growth factor A ( VEGFA ). In contrary, inhibition of miR-150-5p significantly enhanced migration, invasion ability of both HTR-8/SVneo and JAR cells, and also could stimulate PI3K/AKT/mTOR signaling pathway. This promoting effect of miR-150-5p could be ameliorated by LY294002 (PI3K inhibitor). Finally, after miR-150-5p overexpression in vivo, the embryo resorption rate in pregnant mice was increased significantly. Conclusions Overall, these findings imply that miR-150-5p is among the key factors that regulate the pathogenesis of URSA. 

MiR-150-5p contributes to unexplained recurrent spontaneous abortion by targeting VEGFA and downregulating the PI3K/AKT/mTOR signaling pathway

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be the result of sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing was used to identify miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n=113) and parturition (n=47). Sequencing and differential expression (DE) analysis identified 432 mature miRNAs expressed in the first trimester female, 425 in the first trimester male, 400 in the third trimester female, and 508 in the third trimester male placenta (baseMean >10). Of these, 11 sexually dimorphic (FDR 10) miRNAs were identified in the first and 4 miRNAs were identified in the third trimester, including miR-361-5p, significant in both trimesters, all upregulated in females. Across gestation, 207 miRNAs were DE across gestation, common to both females and males, miR-4483, the most DE across gestation. There were twice as many female-specific differences across gestation as male-specific (44 miRNAs vs 21 miRNAs), indicating that miRNA abundance across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex independent and sex specific placenta miRNA atlas across gestation which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences. Summary Sentence Sex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are twice as many female-specific gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.

https://biorxiv.org/content/10.1101/2021.05.13.444056v1.full.pdf

Sex differences in microRNA expression in first and third trimester human placenta

Objective Our study aims to explore whether microRNA-940 could participate in early abortion by inhibiting placenta implantation and its underlying mechanism. Patients and methods Expressions of microRNA-940 and ZNF672 in the placental villi of 6 early abortion pregnancies and 6 normal pregnancies were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Expressions of microRNA-940 and ZNF672 in trophoblast cells (BeWo, JEG3, Wish and HTR-8) were also detected. Cell counting kit-8 (CCK-8) assay was performed to detect the effect of microRNA-940 on the proliferation of trophoblast cells after being transfected with microRNA-940 inhibitor or mimics, respectively. Dual-Luciferase reporter gene assay and RNA binding protein immunoprecipitation (RIP) assay were conducted to demonstrate the binding condition of microRNA-940 to ZNF672. Results MicroRNA-940 was highly expressed in placental villi of early abortion pregnancies, whereas ZNF672 was lowly expressed. HTR-8 cells expressed the highest level and BeWo cells expressed the lowest level of microRNA-940. After transfection of microRNA-940 inhibitor in HTR-8 cells, the proliferative capacity was remarkably increased. On the contrary, the transfection of microRNA-940 mimic downregulated the proliferation of BeWo cells. Dual-Luciferase reporter gene assay demonstrated that microRNA-940 targets ZNF672. RIP results further indicated that microRNA-940 binds to ZNF672. Conclusions MicroRNA-940 is highly expressed in the placental villi of early abortion pregnancies and promotes the occurrence of early abortion by inhibiting the proliferation of trophoblast cells by targeting ZNF672.

Highly expressed microRNA-940 promotes early abortion by regulating placenta implantation by targeting ZNF672.

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Highly expressed microRNA-940 promotes early abortion by regulating placenta implantation by targeting ZNF672.