Placental Levels Research Articles

Factors that affect placental retinol transfer in preterm infants and mothers with retinol deficiency.

The retinol level and retinol delivery to the placenta may vary depending on various factors involving the mother and newborn. The present study evaluates the factors affecting retinol levels in newborns and the transplacental retinol passage in preterm newborns. In this prospective cohort study, the retinol and retinol binding protein (RBP) in the umbilical cord blood of 44 preterm infants with a gestation age of <30 weeks were studied. Serum retinol and RBP levels were determined using an enzyme-linked immunosorbent assay, and the rate of transplacental retinol passage was calculated. The demographic data of mothers and newborns, the use of vitamins by the mother, the application of antenatal corticosteroids, and any diseases diagnosed during pregnancy were recorded. An evaluation was made of the retinol, RBP, and other factors of the mother and newborn affecting transplacental retinol passage. A retinol deficiency was identified in 68.2% of the study population. Retinol and RBP levels in umbilical cord blood (273.7 ± 150.03 ng/mL, 7.88 ± 5.6 ng/mL, respectively) were significantly higher than the corresponding levels in the mother (206.4 ± 86.26 ng/ mL, 1.04 ± 0.97 ng/mL, respectively). Umbilical cord blood retinol deficiency was more common in the male participants, while the transplacental retinol passage rate was higher in females. The umbilical cord blood RBP was found to be lower in those administered antenatal corticosteroids than in those who did not receive antenatal corticosteroids, and median maternal RBP levels were lower in patients with anemia and pregnancy-induced hypertension than in those with no disease. Placental adaptation and contributing factors may vary in populations with severe retinol deficiency. The finding of significantly increased cord blood retinol levels when compared to maternal retinol levels in the present study suggests that some compensatory mechanisms, such as increased placental RBP levels, support the presentation of retinol to the fetus, even if the mother has a retinol deficiency.

Cyclosporin A alleviates trophoblast apoptosis and senescence by promoting autophagy in preeclampsia.

Abnormal extravillous trophoblast (EVT) function is closely related to preeclampsia (PE) and may be caused by inadequate autophagy, apoptosis, and senescence. Cyclosporin A (CsA) is an effective immunosuppressant that has been reported to stimulate autophagy and exert benign biological effects on EVTs. Therefore, we hypothesized that CsA may display therapeutic efficacy against PE by activating autophagy. We established the nitro-l-arginine methyl ester (l-NAME)-induced preeclamptic mice model and a hypoxia-reoxygenation (H/R) model in vitro. The effects of CsA on autophagy were evaluated by western blotting (WB). The effects of CsA on apoptosis were analyzed by Hematoxylin-eosin (H&E) staining, cell apoptosis assay and WB. Senescence-associated β-galactosidase (SA-β-gal) staining, RT-qPCR and WB were used to examine the senescence level. RT-qPCR were used to detect the senescence-associated secretory phenotype (SASP) level. DCFH-DA fluorescent probe, dihydroethidium (DHE) staining and mitochondrial membrane potential (ΔΨm) were used to detect senescence-associated mitochondrial dysfunction (SAMD). CsA alleviated PE-like symptoms and reduced placental necrosis and senescence in mice injected with l-NAME. CsA ameliorated placental SASP and SAMD level induced by l-NAME. CsA also upregulated the expression of autophagic proteins in mouse placentas disrupted using l-NAME. In vitro, we found that CsA reversed H/R-induced apoptosis and senescence, as well as decreasing SASP and SAMD levels and upregulating autophagic proteins levels. Notably, 3-methyladenine (3-MA), an early phase inhibitor of autophagosome formation, abolished the protective effects of CsA against H/R. CsA may display some therapeutic effects against PE by activating autophagy in vivo and in vitro.

Effects of maternal iron deficiency anemia on placenta and cord blood iron status with specific reference to the iron transport protein ferroportin 1

Introduction: Iron deficiency anemia is the most prevalent nutritional deficiency disorder in pregnant women. During pregnancy, nutrients, including iron, are transferred from the mother to the fetus through the placenta, in which the placental transport protein Ferroportin1 (FPN1) plays a crucial role. It has been frequently observed that developing fetus is immune to anemia despite the presence of anemia in the mother, the mechanisms underlying which have not been identified. We, therefore, planned the present study to explore the effect of maternal iron deficiency anemia on the expression of FPN1 in the placenta. Material and Methods: Two hundred pregnant women recruited were divided into anemic and nonanemic groups based on their predelivery hemoglobin levels (<11 g/dl and ≥11 g/dl, respectively). After delivery, placental expression of FPN1 was studied by immunohistochemistry and mRNA analysis, and neonatal anthropometry was performed. Results: Of the 200 women, 59% were anemic. FPN1 protein immunohistochemical staining in placenta showed a statistically significant increase with increasing severity of anemia. Similarly, placental mRNA expression levels of the FPN1 gene were observed to be higher in anemic mothers when compared with nonanemic mothers. Discussion and Conclusion: Thus, our study for the first time shows that maternal iron deficiency increases placental FPN1 protein and mRNA expression, thereby probably facilitating increased transport of iron from the mother to the fetus.

PREGNANCY OUTCOMES IN WOMEN WITH EXTREMELY HIGH SFLT-1/PIGF RATIO: CASE SERIES

Preeclampsia (PE) is a multisystem disorder, usually defined as the development of hypertension and proteinuria after 20 weeks of pregnancy. The sFlt-1/PlGF ratio has been widely studied as a diagnostic and prognostic marker of preeclampsia and other manifestations of placental dysfunction. A sFlt-1/PlGF ratio greater than 85 for early PE, &lt;34 weeks of gestation suggests a high risk of PE requiring close clinical monitoring. Our main aim was to evaluate the maternal and perinatal outcomes of pregnancies with an extremely high sFlt-1/PlGF ratio. The analysis included data on placental growth factor and soluble fms-like tyrosine kinase serum levels, measured during 2017–2020 in 128 pregnant women. Here we present 8 cases of women with a numerical ratio greater than 850. In all 100% of cases, the signs of obstetric angiogenic catastrophe requiring imminent delivery developed soon. We observed a trend for worsening perinatal outcomes in women with an extremely high sFlt-1/PlGF of ≥850.

Placental epigenetic changes associated with polycyclic aromatic hydrocarbon exposures

PAHs are toxic byproducts of the incomplete combustion of fossil fuel, and classified under EPA as prevalent hazardous pollutants. We and others have established that exposure to certain environmental chemicals (such as PAHs) during pregnancy is significantly associated with PTB, SGA, and other adverse pregnancy outcomes. Specifically, we have previously reported that increased placental levels of the ubiquitous PAH benzo[a]pyrene (BaP) is significantly associated with PTB. However, no studies to-date have provided a mechanistic link between elevated PAHs and molecular changes (such as epigenomic modifications) which would give rise to preterm delivery.

Placental traits, and plasma concentration and placental mRNA expression of IGF-I in Bafra sheep breed with different birth type

Insulin-like growth factors (IGF) promote follicle development, ovulation, and embryonic development and affect placental and fetal growth and development in many mammalian species. Therefore, this study aimed to determine the relationship between birth type, plasma concentration, and placental mRNA expression of IGF-I in Bafra ewes. A total of 30 ewes, which have single (n=15) or twin (n=15) gestation and at least gave birth to 2, have been used as experimental animals. Before mating, blood samples were collected from the jugular vena of all ewes. Following lambing, birth type, live weight, and sex of lambs and placental traits have been recorded. Plasma IGF-I concentration was determined using a commercial ELISA kit. IGF-I gene expression level has been determined by real-time quantitative polymerase chain reaction. No difference was found between single and twin-bearing sheep in terms of placental weight and various cotyledon characteristics in the study. In contrast, total cotyledon weights were lower in singleton gestation than those in twin (P<0.05). Similarly, the total and medium cotyledon number and cotyledon efficiency of Bafra ewes with single deliveries were lower than Bafra sheep with twin births (P<0.05). Although the birth type did not affect both placental gene expression level and plasma concentration of IGF-I, sheep that gave birth to twins exhibited 0.908 times more gene expression than that to single births. The study results showed that birth type did not affect plasma IGF-I concentration and placental IGF-I gene expression level in Bafra sheep breed but changed placental characteristics.

Assessment of the value of measuring soluble fms-like tyrosine kinase-1 and placental growth factor levels following administration of tadalafil to treat fetal growth restriction

Purpose The aim of this study was to measure the blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) before and after tadalafil treatment in patients with fetal growth restriction. Materials and methods Maternal blood was collected from 13 women before and 2 weeks after tadalafil administration in the TADAFER II trial. The tadalafil treatment was conducted in addition to the conventional FGR treatment. As a control, maternal blood was also collected from 11 women before and 2 weeks after conventional treatment for fetal growth restriction. Blood sFlt-1 and PlGF were measured and the sFlt-1/PlGF ratio was calculated. Student’s t-test was used to statistically analyze differences in the sFlt-1 and PlGF levels, and in the sFlt-1/PlGF ratios. Results In both treatment groups, the levels of sFlt-1 and PlGF before and after treatment were not significantly different from each other. The sFlt-1/PlGF ratio was 2.0 ± 1.0 before and 17.6 ± 11.3 after treatment in the control group (p=.04). The sFlt-1/PlGF ratio was 2.2 ± 1.1 before and 22.2 ± 10.6 after tadalafil treatment in the tadalafil group (p=.06). The sFlt-1/PlGF ratios before and after tadalafil treatment were significantly increased in the control group. In both treatment groups, the sFlt-1/PlGF ratios before and after treatment were less than 38. Conclusions We conclude that the levels of sFlt-1 and PlGF were not significantly different as a result of tadalafil treatment. Further studies are needed to understand the mechanism of action of tadalafil in the treatment of fetal growth restriction.

Impaired Compensatory Vasodilatory Effect Mediated by Wolfram Syndrome 1 and Corticotropin-Releasing Hormone Family Peptides in 17α-Ethynylestradiol-Induced Intrahepatic Cholestasis Pregnant Rats When Under Additional Acute Hypoxia Stress

Abstract Objective: To investigate the possible regulatory mechanism of corticotropin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) in 17α-ethynylestradiol (EE)-induced intrahepatic cholestasis pregnant rats and its ischemia reperfusion (IR) model. Methods: Pregnant rats (n = 60) were randomly divided into four experimental groups by random number table (Control, EE, IR, and EE-IR groups), and were studied on the 17th, 19th, and 21st gestational days (GD) (n = 5 in each group at the indicated time). Growth and development indicators of fetal rats among these four groups were recorded. Enzyme-linked immunosorbent assay was employed to detect CRH, UCN, and WFS1 levels in maternal sera. Western blotting and real-time polymerase chain reaction were used to quantify placental protein and placental mRNA levels of CRH, UCN, and WFS1. Multivariate analysis of variance and least significant difference test were used to establish the group and individual comparisons. Results: A significant difference was found in placenta weight (F = 8.10, P &lt; 0.05), fetal rat weight (F = 40.86, P &lt; 0.05), fetal rat length (F = 61.61, P &lt; 0.05), and fetal rat tail length (F = 55.63, P &lt; 0.05) among four groups on the 17th ,19th , and 21st GD.What's more, the overall differences of maternal serum UCN levels among Control, EE, IR, and EE-IR groups were significant (F = 2.48, P &lt; 0.05). Expression of WFS1 mRNA in the EE-IR group was significantly increased and higher than Control (0.46 ± 0.15 vs. 0.24 ± 0.09, P &lt; 0.05), EE (0.46 ± 0.15 vs. 0.17 ± 0.04, P &gt; 0.05), and IR (0.46 ± 0.15 vs. 0.22 ± 0.15, P &gt; 0.05) groups at 19th GD, indicating that endoplasmic reticulum stress may be activated. However, the expression of CRH (0.42 ± 0.05 vs. 0.58 ± 0.12, P &lt; 0.05), UCN (0.43 ± 0.01 vs. 0.47 ± 0.16, P &gt; 0.05), and WFS1 (0.57 ± 0.07 vs. 0.74 ± 0.12, P &gt; 0.05) protein in the EE-IR group was subsided compared to the IR group at 17th GD. Conclusion: Fetal rat growth restriction was found in the EE-induced intrahepatic cholestasis model. This study revealed that significant changes in the maternal sera level of UCN , placental level of WFS1 mRNA and placental levels of CRH, UCN, and WFS1 protein in chronic versus acute stress in a rat model of pregnancy. This suggests an impaired compensatory vasodilatory effect mediated by these factors at gene transcription and protein translation levels, following acute hypoxia stress in EE-induced intrahepatic cholestasis in pregnant rats.

Placental mRNA and Protein Expression of VDR, CYP27B1 and CYP2R1 Genes Related to Vitamin D Metabolism in Preeclamptic Women

(1) Background: Considerable evidence indicates that the occurrence of preeclampsia (PE) is associated with a reduced vitamin D (VD) level. Several studies have found that VD deficiency is correlated with disturbed trophoblast invasion, reduced angiogenesis and increased vasoconstriction. Because the vitamin D receptor (VDR) and CYP27B1 and CYP2R1 hydrolases are strongly involved in VD metabolism, the goal of the present study was to evaluate their genes and proteins expression in the placentas from preeclamptic women. (2) Methods: Samples and clinical data were obtained from 100 Polish women (41 women with preeclampsia and 59 healthy pregnant controls). The whole PE group was divided into subgroups according to gestation week of pregnancy ending before and after 34 gestational weeks (early/late-onset preeclampsia (EOPE/LOPE)). However, finally, to reduce confounding by differences in gestational age, the EOPE group was excluded from the analysis of mRNA and protein placental expression, and we focus on the comparison between LOPE and control groups. The placental VDR, CYP27B1 and CYP2R1 mRNA expression was analyzed using RT-PCR, and placental protein levels were determined by ELISA assay. (3) Results. (3.1) Placental gene expression: Expression levels of both genes, CYP27B1 (1.17 vs. 1.05 in controls, p = 0.006) and CYP2R1 (2.01 vs. 1.89 in controls, p = 0.039), were significantly higher in preeclamptic placentas than in the control group. Interestingly, VDR expression was significantly lower in placentas from the PE group (1.15 vs. 1.20 in controls, p = 0.030). After dividing all preeclamptic women into subgroups only for the CYP27B1 gene, a significantly higher placental expression in the LOPE subgroup than the healthy controls was observed (padj = 0.038). (3.2) Placental protein expression: The results revealed that protein expression levels of CYP27B1 in the preeclamptic group were similar (5.32 vs. 5.23 in controls, p = 0.530). There was a significant difference in median VDR and CYP2R1 protein levels between studied groups (VDR: 2.56 vs. 3.32 in controls, p &lt; 0.001; CYP2R1: 1.32 vs. 1.43 in controls, p = 0.019). After stratification of preeclamptic women into subgroups, a significant difference was observed only in the VDR protein level. The medians in the LOPE subgroups were significantly lower compared to the healthy control group. In the whole study group, the placental VDR protein level was inversely correlated with systolic and diastolic blood pressure (all p &lt; 0.001), and positively correlated with gestational age (p &lt; 0.001) and infant birth weight (p = 0.014). (4) Conclusions: Lower mRNA and protein expression of VDR in preeclamptic placentas, and also VDR protein expression, could play a pivotal role in preeclampsia development. Additionally, the higher mRNA expression of both CYP27B1 and CYP2R1 hydrolase genes in placentas from preeclamptic women could indicate the compensatory role of these enzymes in preeclampsia etiology. Our results also indicate that placental VDR protein level could be one of the factors modulating blood pressure in pregnant women, as well as influencing gestational age and infant birth weight. Considering the importance of these findings, future studies are warranted.

In utero exposure to parabens and early childhood BMI z-scores - Associations between placental ethyl paraben, longitudinal BMI trajectories and cord blood metabolic biomarkers.

Parabens are used as antimicrobial preservatives in personal care products. Few studies have dealt with adverse health outcomes, transplacental transfer, and obesogenic effects of prenatal exposure to parabens. We examined the association between placental paraben levels and cord blood metabolic biomarkers, considering modulating effects of maternal pre-pregnancy BMI and underlying epigenetic mechanisms, and investigated longitudinal effects of in utero paraben exposure on early childhood trajectories of BMI z-scores. Placental concentrations of four parabens [methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 229 placentas of the ENVIRONAGE birth cohort. The association with cord blood metabolic biomarkers [glucose, insulin, γ-glutamyltransferase (GGT), high-density and low-density lipoprotein (HDL and LDL)] was analyzed in multiple regression models with two different sets of, a priori selected potential confounders, additionally stratified for different maternal BMI groups and assessed by causal mediation analysis. The association between placental paraben concentration and differential DNA methylation of CpGs annotated to GGT and longitudinal measurements of BMI z-scores were investigated with adjusted linear mixed models. The geometric means of placental MeP, EtP, PrP, and BuP levels above the limit of detection (LOD) were 4.42, 1.32, 1.51, and 0.35ng/g respectively, with only EtP showing sufficient (88%) measurements above LOD for further analyses. An interquartile ratio (IQR) increase in placental EtP was associated with an increase of 12.61 % (95% CI: 1.80 24.57) in the geometric mean of cord GGT activity, and with a decrease of -3.64 % (95% CI: -6.80 to -0.39) in the geometric mean of cord glucose. Placental EtP levels were significantly associated with hypermethylation of cg08612779 annotated to GGT7 after correcting for multiple testing (ß = 0.0017, p=0.049). An interquartile ratio (IQR) increment in placental EtP was associated with a decrease in longitudinal BMI z-score of 0.27 points (95% CI: -0.46 to -0.088). Prenatal EtP exposure may affect early childhood BMI. The association of placental EtP with cord blood GGT and glucose levels provides a starting point for further research on mechanisms of paraben-related metabolic processes in utero.

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

Effects of Melatonin Supplementation during Pregnancy on Reproductive Performance, Maternal-Placental-Fetal Redox Status, and Placental Mitochondrial Function in a Sow Model.

Melatonin (MT) is a bio-antioxidant that has been widely used to prevent pregnancy complications, such as pre-eclampsia and IUGR during gestation. This experiment evaluated the impacts of dietary MT supplementation during pregnancy on reproductive performance, maternal–placental–fetal redox status, placental inflammatory response, and mitochondrial function, and sought a possible underlying mechanism in the placenta. Sixteen fifth parity sows were divided into two groups and fed each day of the gestation period either a control diet or a diet that was the same but for 36 mg of MT. The results showed that dietary supplementation with MT increased placental weight, while the percentage of piglets born with weight < 900 g decreased. Meanwhile, serum and placental MT levels, maternal–placental–fetal redox status, and placental inflammatory response were increased by MT. In addition, dietary MT markedly increased the mRNA levels of nutrient transporters and antioxidant-related genes involved in the Nrf2/ARE pathway in the placenta. Furthermore, dietary MT significantly increased ATP and NAD+ levels, relative mtDNA content, and the protein expression of Sirt1 in the placenta. These results suggested that MT supplementation during gestation could improve maternal–placental–fetal redox status and reproductive performance by ameliorating placental antioxidant status, inflammatory response, and mitochondrial dysfunction.

Relationships Between Placental Lipid Activated/Transport-Related Factors and Macrosomia in Healthy Pregnancy.

To assess associations between infants with macrosomia and placental expression levels of lipid activated/transport-related factors and umbilical cord blood lipid concentrations in healthy pregnancy. We conducted a case-control study of 38 macrosomic neonates (MS group) and 39 normal-birth-weight newborns (NC group) in a healthy pregnancy. Cord blood lipid levels were measured by automatic biochemical analyzer, mRNA and protein expression levels of placental lipid activated/transport-related factors were determined by real-time polymerase chain reaction and western blot, respectively. Compared with NC group, cord blood total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and non-esterified fatty acid (NEFA) concentrations were decreased in the MS group. The mRNA and protein expression levels of placental peroxisome proliferator-activated receptors (PPARα, PPARγ), plasma membrane fatty acid-binding protein (FABPpm), and fatty acid translocase (FAT/CD36) were significantly higher in the MS group than the NC group. And there was a weak positive correlation between the expression of PPARγ, FABP4, and FABP3 mRNA in the placenta and the HDLC (rs = 0.439; P = 0.005), NEFA (rs = 0.342; P = 0.041), and TG (rs = 0.349; P = 0.034) levels in the cord blood in the MS group, respectively. After multivariate adjustment, the logistic regression analysis showed that high placental PPARα (adjusted odds ratio [AOR] = 3.022; 95% confidence interval [CI] 1.032-8.853) and FAT/CD36 (AOR=2.989; 95%CI 1.029-8.679) and low LDLC concentration in the cord blood (AOR=0.246; 95%CI 0.080-0.759) increased the risk of macrosomia. The increased PPARα and FAT/CD36 expression levels may influence the occurrence of fetal macrosomia through regulating placental lipid transport.

Maternal vitamin D deficiency reduces docosahexaenoic acid, placental growth factor and peroxisome proliferator activated receptor gamma levels in the pup brain in a rat model of preeclampsia

Background: Preeclampsia is a pregnancy disorder characterized with abnormal placental angiogenesis. Vitamin D and long chain polyunsaturated fatty acids (LCPUFA) play a crucial role in pregnancy and are required for normal placental and fetal growth and development. This study reports the effect of maternal vitamin D on LCPUFA levels in the mother and offspring brain fatty acid levels and angiogenic markers in a rat model of preeclampsia.Methods: Female rats were divided into four groups from pre-pregnancy to pregnancy, viz Control; Preeclampsia (PE); Vitamin D deficient with PE (VDD-PE) and Vitamin D supplemented with PE (VDS-PE). Preeclampsia was induced by administering l-nitroarginine methyl ester (L-NAME) at the dose of 50 mg/kg body weight/day from day 14 to day 19 of gestation. Dams were sacrificed at d20 of gestation to collect dam blood, placenta and pup brain. LCPUFA levels from dam plasma, erythrocytes and placenta and its transcription factor peroxisome proliferator activated receptor gamma (PPAR-g) from placenta were estimated. Pup brain LCPUFA levels, angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and transcription factor hypoxia inducible factor (Hif-1α) and PPAR-g were also estimated.Results: Maternal vitamin D status influences fatty acid levels. Placental PPAR-g levels were lower in the VDD-PE group as compared to the VDS-PE groups (p < 0.01). In the offspring brain, both PE and VDD-PE group showed lower levels of DHA (p < 0.05 for both) while saturated fatty acids (SFA) levels in the VDD-PE group were higher as compared to the control group (p < 0.05). VDD-PE group also showed lower levels of PlGF and PPAR-g (p < 0.01 and p < 0.05, respectively) in the pup brain while vitamin D supplementation demonstrated levels similar to control.Conclusion: This study for the first time demonstrates that maternal vitamin D status influences LCPUFA metabolism and angiogenesis in the offspring brain.

Comparison of Maternal Serum Levels and Placental mRNA Levels of Dickkopf-1 in Preeclamptic and Normal Pregnant Women at Delivery.

Background Preeclampsia remains a major cause of perinatal and maternal mortality and morbidity worldwide. Wnt/β-catenin signaling is known to be critically involved in placenta development processes. Dickkopf-1 (DKK1) is a key regulator of this transduction pathway. The aim of this study is to compare maternal serum DKK1 levels and placental mRNA levels of DKK1 and β-catenin in preeclamptic and normal pregnant women at delivery. Methods The present study included 30 women with preeclampsia and 30 women with normal pregnancy. Maternal serum DKK1 levels were measured by ELISA. Placental mRNA levels of DKK1 and β-catenin were detected using RT-PCR. Results Decreased maternal serum DKK1 levels were associated with worse maternal and fetal complications including HELLP syndrome, determination of one or more pathological symptom and IUGR diagnosis. No significant difference in maternal serum DKK1 levels was reported between preeclamptic women and women with normal pregnancy. Placental mRNA DKK1 levels were lower in preeclamptic women compared with normal pregnant women. Placental mRNA β-catenin levels showed no significant difference between two groups. Conclusions Our findings reported the aberrant placental mRNA DKK1 levels in patients with preeclampsia. In addition, worse preeclampsia features were associated with decreased maternal serum DKK1 levels. Hence, aberrant Wnt/β-catenin signaling might present a plausible mechanism in preeclampsia pathogenicity. Dysregulated expression of DKK1 at gene level in the placenta but not at protein level in the maternal serum might confirm the notion that preeclampsia is a type of placenta-derived disease.

Placental cadmium, placental genetic variations, and birth size

Background Maternal cadmium (Cd) burden has been associated with offspring birth size measures, yet associations of placental Cd with birth size are less clear. Further, the role of genetics in these associations has not been examined. We investigated associations of placental Cd with birth size and placental genotypes. We also examined the potential role of placental genotypes as modifiers of placental Cd and birth size associations. Methods Participants were 490 mother-child pairs from the Omega and Placenta Microarray studies based in Seattle, WA. Placental Cd was measured using Agilent 7500 ICP-MS. The birth size was characterized using birth weight (BW), ponderal index (PI), and head circumference (HC). Eleven placental single nucleotide polymorphisms (SNPs) related to metal transport, growth regulation, endocrine response, and cell signaling were genotyped. Adjusted multivariable linear regression models were used to examine overall and sex-specific associations of placental Cd with birth size (BW, PI and HC), as well as associations of placental genotypes with placental Cd. Effect modification of placenta Cd and birth size associations by placental SNPs was examined using interaction terms and stratified analyses. Results Mean maternal age was 33.6 years (SD = 4.4). Mean and median placental Cd levels were 4.0 ng/g tissue (SD = 2.7 ng/g tissue) and 3.6 ng/g (IQR 2.5 − 5.2 ng/g), respectively. Overall, compared with infants in the lowest quartile for placental Cd, infants in the second (ß = −102.8 g, 95% CI: −220.7, 15.1), third (ß = –83.2 g, 95% CI: −199.3, 32.9) and fourth (ß = −109.2 g, 95% CI: −225.4, 7.1) quartiles had lower BW, though associations were not statistically significant (all p-values > .05, trend p-value = .11). Among male infants, infants in the second (ß = −203.3 g, 95% CI: −379.7, −27.0) and fourth quartiles (ß = −198.3 g, 95% CI: −364.2, −32.5) had lower BW compared with those in the first quartiles (p-values < .05, trend p-value = .08). Similar relationships were not observed among female infants, though infant sex-placental Cd interaction terms were not significant. Similarly, male, but not female, infants had marginally significant positive associations between placental Cd and ponderal index (trend p-value = .06). The minor rs3811647 allele of the placental transferrin gene (NCBI Gene ID: 7018) was associated with an increase in Cd among all infants (p-value = .04). We did not find differences in associations of placental Cd with birth size markers among infants stratified by rs3811647 genotype. Conclusions Placental Cd was inversely associated with BW among male infants. The rs3811647 SNP of the transferrin gene was associated with placental Cd.

Placental levels of miR-1-3p and miR-133a-3p are decreased in pregnancies complicated gestational diabetes with large-for-gestational-age birth outcomes and may be influencing vascular smooth muscle differentiation

Placental levels of miR-1-3p and miR-133a-3p are decreased in pregnancies complicated gestational diabetes with large-for-gestational-age birth outcomes and may be influencing vascular smooth muscle differentiation

EGF stimulates human trophoblast cell invasion by downregulating ID3-mediated KISS1 expression

BackgroundDuring pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown.ResultsIn the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients.ConclusionsThis study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE.3yX-DcuH29NawtDrdPoN74Video

Placental Expression of Bile Acid Transporters in Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-related condition characterized by increased maternal circulating bile acids (BAs) having adverse fetal effects. We investigated whether the human placenta expresses specific regulation patterns to prevent fetal exposition to harmful amounts of BAs during ICP. Using real-time quantitative PCR, we screened placentae from healthy pregnancies (n = 12) and corresponding trophoblast cells (n = 3) for the expression of 21 solute carriers and ATP-binding cassette transporter proteins, all acknowledged as BA- and/or cholestasis-related genes. The placental gene expression pattern was compared between healthy women and ICP patients (n = 12 each). Placental SLCO3A1 (OATP3A1) gene expression was significantly altered in ICP compared with controls. The other 20 genes, including SLC10A2 (ASBT) and EPHX1 (EPOX, mEH) reported for the first time in trophoblasts, were comparably abundant in healthy and ICP placentae. ABCG5 was undetectable in all placentae. Placental SLC10A2 (ASBT), SLCO4A1 (OATP4A1), and ABCC2 mRNA levels were positively correlated with BA concentrations in ICP. Placental SLC10A2 (ASBT) mRNA was also correlated with maternal body mass index. We conclude that at the transcriptional level only a limited response of BA transport systems is found under ICP conditions. However, the extent of the transcriptional response may also depend on the severity of the ICP condition and the magnitude by which the maternal BA levels are increased.

Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?

To determine whether the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) differs at birth between fresh or frozen embryo transfers and natural conceptions. Prospective study. University hospital. A total of 202 singleton births were divided into three groups: 84 natural pregnancies (controls), 66 invitro fertilization/intracytoplasmic sperm injection with fresh embryo transfers, and 52 vitro fertilization/intracytoplasmic sperm injection with frozen embryo transfers. None. Pyrosequencing was used to assess the DNA methylation profiles of three IGs (H19/IGF2:IG-DMR [two sequences], KCNQ1OT1:TSS-DMR, and SNURF:TSS-DMR) and two TEs (LINE-1 and HERV-FRD) in cord blood and placenta. The quantitative reverse transcriptase polymerase chain reaction was used to study the transcription of three IGs (H19, KCNQ1, and SNRPN) and two TEs (LINE-1 and ORF2). After adjustment, the placental DNA methylation levels of H19/IGF2 were lower in the fresh embryo transfer group than in the control (H19/IGF2-seq1) and frozen embryo transfer (H19/IGF2-seq2) groups. The DNA methylation rate for LINE-1 was lower in placentas from the fresh embryo transfer group than in placentas from the control and frozen embryo transfer groups and for HERV-FRD compared with controls. In cord blood, DNA methylation levels were not significantly associated with the mode of conception. The relative expression of LINE-1 and ORF2 was decreased in both cord blood and placental tissues from fresh embryo transfer conceptions compared with natural conceptions and frozen embryo transfer conceptions. Compared with natural conceptions and frozen embryo transfers, fresh embryo transfers were associated with methylation and/or transcription changes in some TEs and IGs, mostly in placental samples, which could indicate altered placental epigenetic regulation resulting from ovarian stimulation protocols.