Search Results (16)

Somatic cell nuclear transfer (SCNT) or cloning technology is widely used in agriculture and biomedicine. However, the application of this technology is limited by the low developmental competence of cloned embryos or fetuses, which frequently exhibit abnormal development of trophoblast cells or placentas. The purpose of this study was to investigate the possible causes of the erroneous placental development of SCNT-derived pig fetuses. The placental transcriptomic and lipidomic profiles were compared between 30-day-old SCNT- and artificial insemination (AI)-produced pig fetuses. Differentially expressed lipid metabolites between two groups of placentas were selected to test their effects on porcine trophoblast cell activity. The results showed that SCNT placentas exhibit impaired lipid metabolism and function. The level of a metabolite, lysophosphatidylcholine (LPC), in the glycerophospholipid metabolism pathway was substantially increased in SCNT placentas, compared with AI placentas. The elevation in LPC content may lead to impaired placental development in cloned pig fetuses, as LPC inhibited the proliferation and migration of porcine trophoblast cells. This study discovers a main cause of erroneous development of cloned pig fetuses, which will be beneficial for understanding the regulation of SCNT embryo development, as well as developing new methods to improve the efficiency of pig cloning. Full article

Placenta accreta spectrum (PAS) disorders remain a major cause of maternal morbidity and adverse perinatal outcomes due to abnormal placental adherence and invasion. Early and accurate prenatal diagnosis is essential to optimize surgical planning and reduce complications. Although ultrasound is well established as the cornerstone for PAS detection, the potential role of serial ultrasonography in refining risk assessment and predicting outcomes is increasingly being explored. Monitoring with serial ultrasonographic imaging may offer valuable insights into the progression of sonographic features, such as placental lacunae, myometrial thinning, placental bulge, and bladder wall disruption, which can predict surgical complexity and perinatal risk and influence decision-making and management. However, there is still limited evidence about the prognostic value of serial scans, and the variability in interpreting ultrasound markers continues, presenting challenges. While scoring systems incorporating ultrasound features show promise for risk stratification, further validation in larger studies is needed. Future research should focus on standardizing ultrasound protocols, validating predictive models, and exploring technological innovations, including artificial intelligence, to enhance diagnostic precision. Incorporating serial ultrasound assessments thoughtfully into clinical practice may improve individualized care and outcomes for women affected by PAS, but more studies are required. Full article

One of the functions of placenta is to protect the fetus against harmful xenobiotics. Protective mechanisms of placenta are based on enzymes, e.g., antioxidant enzymes from the glutathione S-transferases group (GST) or human N-acetyltransferase 2 (NAT2). Many organic sunscreens are known to cross biological barriers—they are detected in mother’s milk, semen, umbilical cord blood or placental tissues. Some organic sunscreens are able to cross the placenta and to interfere with fetal development; they are known or suspected endocrine disruptors or neurotoxins. In this study, 16 organic sunscreens were investigated in the context of their placenta permeability and interactions with gluthatione S-transferase and human N-acetyltransferase 2 enzymes present in the human placenta. Binary permeability models based on discriminant analysis and artificial neural networks proved that the majority of studied compounds are likely to cross the placenta by passive diffusion. Molecular docking analysis suggested that some sunscreens show stronger affinity for glutathione S-transferase and human N-acetyltransferase 2 that native ligands (glutathione and Coenzyme A for GST and NAT2, respectively)—it is therefore possible that they are able to reduce the enzyme’s protective activity. It was established that sunscreens bind to the studied enzymes mainly by alkyl, hydrogen bonds, van der Waals, π-π, π-alkyl and π-sulfur interactions. To conclude, sunscreens may become stressors affecting humans by different mechanisms and at different stages of development. Full article

Fetal growth restriction, or intrauterine growth restriction, is a common gestational condition characterized by reduced intrauterine growth. However, severe periviable fetal growth restriction is still associated with elevated perinatal mortality and morbidity. The current literature advises delivery once it is deemed that fetal compromise is evident. As uteroplacental insufficiency is the most common etiology of this condition, we hypothesize that the use of artificial ex utero systems to provide adequate nutrition and recreate the uterine environment may be a viable treatment option in this situation, even with the possibility of treating severe fetal growth restriction and prevent sequelae. There are promising experimental studies in sheep models investigating the artificial ex utero system for potential prenatal conditions, but future additional investigation is needed before translating to clinical trials in humans. Full article

The relationship between the intake of artificial sweetener (AS) and adverse pregnancy outcomes is under-researched, and existing studies yield inconsistent conclusions. A Mendelian randomization (MR) approach was employed to investigate the causal relationship between the intake of AS and adverse pregnancy outcomes. Instrumental variables related to the exposure phenotype were selected for analysis. The analysis was conducted using genome-wide association study summary data from public datasets. The inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode methods were used to evaluate the causal relationship between exposure and outcomes. Sensitivity analysis and multivariable Mendelian randomization enrolling body mass index, type 2 diabetes mellitus, and fasting glucose were employed to further validate the consistency and robustness of the results. In univariable MR, the intake of AS added to tea was associated with an increased risk of ectopic pregnancy [OR = 1.821 (1.118–2.967), p = 0.016]. In multivariable MR adjusting for body mass index and type 2 diabetes mellitus, the intake of AS added to cereal was linked to a reduced risk of ectopic pregnancy [OR = 0.361 (0.145–0.895), p = 0.028] and premature rupture of membranes [OR = 0.116 (0.019–0.704), p = 0.019], while the intake of artificial sweetener added to coffee was associated with an increased risk of placenta previa [OR = 1.617 (1.042–2.510), p = 0.032]. No causal relationship was identified between the intake of artificial sweetener and other adverse pregnancy outcomes. The consumption of artificial sweetener during pregnancy warrants careful consideration. Full article

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood–brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut–liver–kidney axis, gut–brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug–drug interactions and drug–metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs. Full article

The prevalence of obesity is increasing, and the origins of obesity and metabolic dysfunction may be traced back to fetal life. Currently, overweight pregnant women are advised to substitute sugar-sweetened beverages with diet drinks containing artificial sweeteners. Recent evidence suggests that the consumption of artificial sweeteners during pregnancy increases the risk of obesity in the child, but the mechanism is unknown. We hypothesized the transportation of artificial sweeteners across the placenta into the fetal circulation and the amniotic fluid. We included 19 pregnant women who were given an oral dose of acesulfame, cyclamate, saccharin, and sucralose immediately before a planned caesarean section. Nine women were included as controls, and they refrained from an intake of artificial sweeteners. The maternal and fetal blood and amniotic fluid were collected during the caesarean section, and concentrations of artificial sweeteners were measured using mass spectrometry. We found a linear relationship between the fetal plasma concentrations of artificial sweeteners and the maternal plasma concentrations, with adjusted coefficients of 0.49 (95% CI: 0.28–0.70) for acesulfame, 0.72 (95% CI: 0.48–0.95) for cyclamate, 0.51 (95% CI: 0.38–0.67) for saccharin, and 0.44 (95% CI: 0.33–0.55) for sucralose. We found no linear relationship between amniotic fluid and fetal plasma concentrations, but there were positive ratios for all four sweeteners. In conclusion, the four sweeteners investigated all crossed the placenta and were present in the fetal circulation and amniotic fluid. Full article

Exposure to environmental stressors during pregnancy plays an important role in influencing subsequent susceptibility to certain chronic diseases through the modulation of epigenetic mechanisms, including DNA methylation. Our aim was to explore the connections between environmental exposures during gestation with DNA methylation of placental cells, maternal and neonatal buccal cells by applying artificial neural networks (ANNs). A total of 28 mother–infant pairs were enrolled. Data on gestational exposure to adverse environmental factors and on mother health status were collected through the administration of a questionnaire. DNA methylation analyses at both gene-specific and global level were analyzed in placentas, maternal and neonatal buccal cells. In the placenta, the concentrations of various metals and dioxins were also analyzed. Analysis of ANNs revealed that suboptimal birth weight is associated with placental H19 methylation, maternal stress during pregnancy with methylation levels of NR3C1 and BDNF in placentas and mother’s buccal DNA, respectively, and exposure to air pollutants with maternal MGMT methylation. Associations were also observed between placental concentrations of lead, chromium, cadmium and mercury with methylation levels of OXTR in placentas, HSD11B2 in maternal buccal cells and placentas, MECP2 in neonatal buccal cells, and MTHFR in maternal buccal cells. Furthermore, dioxin concentrations were associated with placental RELN, neonatal HSD11B2 and maternal H19 gene methylation levels. Current results suggest that exposure of pregnant women to environmental stressors during pregnancy could induce aberrant methylation levels in genes linked to several pathways important for embryogenesis in both the placenta, potentially affecting foetal development, and in the peripheral tissues of mothers and infants, potentially providing peripheral biomarkers of environmental exposure. Full article

Objective: To describe the development of an artificial placenta (AP) system in sheep with learning curve and main bottlenecks to allow survival up to one week. Methods: A total of 28 fetal sheep were transferred to an AP system at 110–115 days of gestation. The survival goal in the AP system was increased progressively in three consecutive study groups: 1–3 h (n = 8), 4–24 h (n = 10) and 48–168 h (n = 10). Duration of cannulation procedure, technical complications, pH, lactate, extracorporeal circulation (EC) circuit flows, fetal heart rate, and outcomes across experiments were compared. Results: There was a progressive reduction in cannulation complications (75%, 50% and 0%, p = 0.004), improvement in initial pH (7.20 ± 0.06, 7.31 ± 0.04 and 7.33 ± 0.02, p = 0.161), and increment in the rate of experiments reaching survival goal (25%, 70% and 80%, p = 0.045). In the first two groups, cannulation accidents, air bubbles in the extracorporeal circuit, and thrombotic complications were the most common cause of AP system failure. Conclusions: Achieving a reproducible experimental setting for an AP system is extremely challenging, time- and effort-consuming, and requires a highly multidisciplinary team. As a result of the learning curve, we achieved reproducible transition and survival up to 7 days. Extended survival requires improving instrumentation with custom-designed devices. Full article

In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases. Full article

A fetal ultrasound (US) is a technique to examine a baby’s maturity and development. US examinations have varying purposes throughout pregnancy. Consequently, in the second and third trimester, US tests are performed for the assessment of Amniotic Fluid Volume (AFV), a key indicator of fetal health. Disorders resulting from abnormal AFV levels, commonly referred to as oligohydramnios or polyhydramnios, may pose a serious threat to a mother’s or child’s health. This paper attempts to accumulate and compare the most recent advancements in Artificial Intelligence (AI)-based techniques for the diagnosis and classification of AFV levels. Additionally, we provide a thorough and highly inclusive breakdown of other relevant factors that may cause abnormal AFV levels, including, but not limited to, abnormalities in the placenta, kidneys, or central nervous system, as well as other contributors, such as preterm birth or twin-to-twin transfusion syndrome. Furthermore, we bring forth a concise overview of all the Machine Learning (ML) and Deep Learning (DL) techniques, along with the datasets supplied by various researchers. This study also provides a brief rundown of the challenges and opportunities encountered in this field, along with prospective research directions and promising angles to further explore. Full article

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum. Full article

The preconception period has been recognized as one of the earliest sensitive windows for human development. Maternal dietary intake during this period may influence the oocyte quality, as well as placenta and early embryonic development during the first trimester of pregnancy. Previous studies have found associations between macronutrient intake during preconception and pregnancy outcomes. However, as food products consist of multiple macro- and micronutrients, it is difficult to relate this to dietary intake behavior. Therefore, the aim of this study was to investigate the association between intake of specific food groups during the preconception period with birth weight, using data from the Perined-Lifelines linked birth cohort. The Perined-Lifelines birth cohort consists of women who delivered a live-born infant at term after being enrolled in a large population-based cohort study (The Lifelines Cohort). Information on birth outcome was obtained by linkage to the Dutch perinatal registry (Perined). In total, we included 1698 women with data available on birth weight of the offspring and reliable detailed information on dietary intake using a semi-quantitative food frequency questionnaire obtained before pregnancy. Based on the 2015 Dutch Dietary Guidelines and recent literature 22 food groups were formulated. Birth weight was converted into gestational age-adjusted z-scores. Multivariable linear regression was performed, adjusted for intake of other food groups and covariates (maternal BMI, maternal age, smoking, alcohol, education level, urbanization level, parity, sex of newborn, ethnicity). Linear regression analysis, adjusted for covariates and intake of energy (in kcal) (adjusted z score [95% CI], P) showed that intake of food groups “artificially sweetened products” and “vegetables” was associated with increased birth weight (resp. (β = 0.001 [95% CI 0.000 to 0.001, p = 0.002]), (β = 0.002 [95% CI 0.000 to 0.003, p = 0.03])). Intake of food group “eggs” was associated with decreased birth weight (β = −0.093 [95% CI −0.174 to −0.013, p = 0.02]). Intake in food groups was expressed in 10 g per 1000 kcal to be able to draw conclusions on clinical relevance given the bigger portion size of the food groups. In particular, preconception intake of “artificially sweetened products” was shown to be associated with increased birth weight. Artificial sweeteners were introduced into our diets with the intention to reduce caloric intake and normalize blood glucose levels, without compromising on the preference for sweet food products. Our findings highlight the need to better understand how artificial sweeteners may affect the metabolism of the mother and her offspring already from preconception onwards. Full article

Pig embryo transfer (ET) is burdened by high embryo mortality, with cytokines playing a significant role in recruitment of immune cells during embryo attachment and placentation. We hereby tested if their levels in endometrium and placenta from sows carrying hemi-allogeneic (artificially inseminated sows; C+ positive control) or allogeneic embryos (sows subjected to ET; ET) during peri-implantation (D18) or post-implantation (D24) are suitable mirrors of embryo rejection or tolerance after ET. Non-pregnant sows (C−) were used as negative controls. A set of cytokines was assayed in the tissues through multiplexed microsphere-based flow cytometry (Luminex xMAP, Millipore. USA). Fewer (58.7%. p < 0.003) conceptuses were recovered at D24 after ET compared to C+ (80.9%); with more than 20% of the ET conceptuses being developmentally delayed. Cytokine levels shifted during implantation. Anti-inflammatory IL-10 levels were significantly (p < 0.05) lower in ET sows compared to C+ at D24 of pregnancy. The C+ controls (carrying hemi-allogeneic embryos) consistently showed higher levels of pro-inflammatory TNF-α, IFN-γ, and IL-2 cytokines at D18 and IL-1α at D24, compared to the ET group. This clear dysregulation of pro- and anti-inflammatory cytokine levels in sows subjected to ET could be associated with an impaired maternal immune tolerance, explaining the high embryonic mortality of ET programs. Full article

The molecular mechanisms of pre-eclampsia are being increasingly clarified in animals and humans. With the uncovering of these mechanisms, preventive therapy strategies using chronic infusion of adrenomedullin, vascular endothelial growth factor-121 (VEGF-121), losartan, and sildenafil have been proposed to block narrow spiral artery formation in the placenta by suppressing related possible factors for pre-eclampsia. However, although such preventive treatments have been partly successful, they have failed in ameliorating fetal growth restriction and carry the risk of possible side-effects of drugs on pregnant mothers. In this study, we attempted to develop a new symptomatic treatment for pre-eclampsia by directly rescuing placental ischemia with artificial oxygen carriers (hemoglobin vesicles: HbV) since previous data indicate that placental ischemia/hypoxia may alone be sufficient to lead to pre-eclampsia through up-regulation of sFlt-1, one of the main candidate molecules for the cause of pre-eclampsia. Using a rat model, the present study demonstrated that a simple treatment using hemoglobin vesicles for placental ischemia rescues placental and fetal hypoxia, leading to appropriate fetal growth. The present study is the first to demonstrate hemoglobin vesicles successfully decreasing maternal plasma levels of sFlt-1 and ameliorating fetal growth restriction in the pre-eclampsia rat model (p < 0.05, one-way ANOVA). In future, chronic infusion of hemoglobin vesicles could be a potential effective and noninvasive therapy for delaying or even alleviating the need for Caesarean sections in pre-eclampsia. Full article