Permeability Of Placental Barrier Research Articles

Monte Carlo Optimization Method Based QSAR Modeling of Placental Barrier Permeability.

In order to ensure that drug administration is safe during pregnancy, it is crucial to have the possibility to predict the placental permeability of drugs in humans. The experimental method which is most widely used for the said purpose is in vitro human placental perfusion, though the approach is highly expensive and time consuming. Quantitative structure-activity relationship (QSAR) modeling represents a powerful tool for the assessment of the drug placental transfer, and can be successfully employed to be an alternative in in vitro experiments. The conformation-independent QSAR models covered in the present study were developed through the use of the SMILES notation descriptors and local molecular graph invariants. What is more, the Monte Carlo optimization method, was used in the test sets and the training sets as the model developer with three independent molecular splits. A range of different statistical parameters was used to validate the developed QSAR model, including the standard error of estimation, mean absolute error, root-mean-square error (RMSE), correlation coefficient, cross-validated correlation coefficient, Fisher ratio, MAE-based metrics and the correlation ideality index. Once the mentioned statistical methods were employed, an excellent predictive potential and robustness of the developed QSAR model was demonstrated. In addition, the molecular fragments, which are derived from the SMILES notation descriptors accounting for the decrease or increase in the investigated activity, were revealed. The presented QSAR modeling can be an invaluable tool for the high-throughput screening of the placental permeability of drugs.

Modeling the Progression of Placental Transport from Early- to Late-Stage Pregnancy by Tuning Trophoblast Differentiation and Vascularization.

The early-stage placental barrier is characterized by a lack of fetal circulation and by a thick trophoblastic barrier, whereas the later-stage placenta consists of vascularized chorionic villi encased in a thin, differentiated trophoblast layer, ideal for nutrient transport. In this work, predictive models of early- and late-stage placental transport are created using blastocyst-derived placental stem cells (PSCs) by modulating PSC differentiation and model vascularization. PSC differentiation results in a thinner, fused trophoblast layer, as well as an increase in human chorionic gonadotropin secretion, barrier permeability, and secretion of certain inflammatory cytokines, which are consistent with in vivo findings. Further, gene expression confirms this shift toward a differentiated trophoblast subtype. Vascularization results in a molecule type- and size-dependent change in dextran and insulin permeability. These results demonstrate that trophoblast differentiation and vascularization have critical effects on placental barrier permeability and that this model can be used as a predictive measure to assess fetal toxicity of xenobiotic substances at different stages of pregnancy.

Cysteamine and N-Acetyl-cysteine Alleviate Placental Oxidative Stress and Barrier Function Damage Induced by Deoxynivalenol.

Sows are highly sensitive to deoxynivalenol (DON) and susceptible to reproductive toxicity caused by oxidative stress, but the potential mechanisms and effective interventions remain unclear. Here, we investigated the role of two antioxidants (cysteamine and N-acetyl-cysteine) in regulating the reproductive performance, redox status, and placental barrier function of sows and their potential mechanisms under DON exposure. Maternal dietary supply of antioxidants from day 85 of gestation to parturition reduced the incidence of stillbirths and low-birth-weight piglets under DON exposure. Moreover, the alleviation of DON-induced reproductive toxicity by dietary antioxidants was associated with the alleviation of placental oxidative stress, the enhancement of the placental barrier, and the vascular function of sows. Furthermore, in vivo and in vitro vascularized placental barrier modeling further demonstrated that antioxidants could reverse both DON transport across the placenta and DON-induced increase of placental barrier permeability. The molecular mechanism of antioxidant resistance to DON toxicity may be related to the signal transducer and activator of the transcription-3-occludin/zonula occludens-1 signaling pathway. Collectively, these results demonstrate the potential of antioxidants to protect the mother from DON-induced reproductive toxicity by alleviating placental oxidative stress and enhancing the placental barrier.

Ensemble learning for predicting ex vivo human placental barrier permeability

BackgroundThe placental barrier protects the fetus from exposure to some toxicants and is vital for drug development and risk assessment of environmental chemicals. However, in vivo experiments for assessing the placental barrier permeability of chemicals is not ethically acceptable. Although ex vivo placental perfusion methods provide good alternatives for the assessment of placental barrier permeability, the application to a large number of test chemicals could be time- and resource-consuming. Computational prediction models for ex vivo placental barrier permeability are therefore desirable.MethodsA total of 87 chemicals and corresponding 1444 physicochemical properties were divided into training and test datasets. Three types of algorithms including linear regression, random forest, and ensemble models were applied to develop prediction models for ex vivo placental barrier permeability.ResultsAmong the tested models, the ensemble model integrating the previous two methods performed best for predicting ex vivo human placental barrier permeability with correlation coefficients of 0.887 and 0.825 when considering the applicability domain. An additional test on seven newly curated chemicals from the literature showed a good correlation coefficient of 0.879 which was further improved to 0.921 by considering the variation of experiments.ConclusionIn this study, the first valid predicting model for ex vivo human placental barrier permeability was developed following the OECD guideline. The model is expected to be useful for assessing the human placental barrier permeability and can be integrated with developmental toxicity prediction models for investigating the toxic effects of chemicals on the fetus.

Placental barrier permeability to Ca, P, and Mg in the diagnosis of canine hip dysplasia

The experience carried out in two groups of female dogs of different gestational age on 35-th day (first period), 45-th day (second period), 55-th day (third period), and 65-th day (fourth period). The weight of animals ranged from 21-27 kg, and age from 2.4 to 4.5 years. We selected the animals of different breeds, in which the ultrasound detected at least five fetuses. Diet of control group consisted of natural foods (cereals, meat, vegetables), involved–with Bosch Production and vitamin-mineral complex Caniletten (tablets) or Canipulver (powder) according to the dosage recommended by the manufacturer. The experiments were conducted for five years in clinically healthy pregnant dogs, who had healthy puppies (control) and subclinical patients with the development in the postnatal period have they had fathered puppies of dysplasia or hip elbow (experience). At the same time the overall clinical status of all born pups up to 3 months of age determined. All pregnant animals were determined by morphological and biochemical composition of venous blood from pups of different age obtained at caesarean section, collected the umbilical cord, puncture of membranes – amniotic fluid and alantoine, after their autopsy, the liver, hip and elbow joints. Blood analysis and examination of fetuses and organs removed from them were carried out by conventional methods, mineral composition of blood, provisional organs and joint tissues by means of flame spectrophotometry. In the blood of pregnant female dogs we determined the content of Ca, P and Mg in the direction of a blood of mother – the fetal part of the placenta – the blood of the umbilical vein, the liver of fetal – tissue puppies – and alantoin amniotic fluid. There were no regular changes in the number of blood elements in the studied animals, but the number of red blood cells, the average volume, percentage, and absolute width of their distribution are lower in experimental animals compared to the control. The morphological analysis of differences in the cytological composition of blood and leucogramma did not revealed any variation, while the biochemical analysis found a significant increase in activity of AST and alkaline phosphatase for the experimental animals. We found that the fetal part of placenta accumulates Ca, P and Mg in concentrations much higher than in the mother blood. Main share of Ca from the mother blood in control group entered the fetal part of placenta during the second study period, share of P – during the first and third periods, and share of Mg gradually increased from the first to the fourth periods. The level of minerals in the blood of female dogs of the control group was critical during the second to third periods, from 45 to 55 days of pregnancy, and acted as a potential bioindicator of preventive diagnosis of canine joint dysplasia. During this period of pregnancy it is necessary to apply the adjustment rations by providing the animals with minerals. Key words: Intrauterine development; Fetus; Pregnancy; Provisional organs; Liver

Placental barrier permeability to Cadmium and Plumbum during cow pregnancy and at the foaling time of mares

The paper explores placental barrier permeability to Cadmium (Cd) and Plumbum (Pb) in cows in the dynamics of their pregnancy in the direction ‘maternal blood (MB) → maternal placental compartment (MPC) → fetal placental compartment (FPC) → the umbilical cord (UC) → fetal liver (FL) → amniotic (AMF) and allantoic (ALF) fluid’ and during parturition in relatively clean and contaminated with radioactive nuclides environments, with the injection of tissue medication fetoplacentat in the dry off time, and feeding with a mixture of saponite and sulphur supplementation in rations; in mares at the foaling time in the direction ‘maternal blood (MBm) → the fetal placental compartment of a mare (FPCm) → the umbilical cord of a foal (UCf ) → the foal’s liver (FLf) → amniotic (AMFf) and allantoic (ALFf) fluid → the allantoic membrane of a foal (ALMf)’. The age of the fetus during pregnancy was established by anatomical parameters, whereas Pb and Cd levels in blood and substrates were measured by the method of atomic absorption spectrophotometry (GOST 30170896). The MPC (caruncle) and FPC (cotyledon) were analyzed separately. Their barrier function in relation to Pb and Cd was performed at its full extent in 4–5 months of pregnancy and coincided with the highest concentration in the fetal liver. Wharton’s jelly absorbed Cd in 3–4 months of gestation. With the approach of calving, Pb and Cd levels decreased in the amniotic fluid and increased in the allantoic fluid. Under the influence of fetoplacentat in MPC and FPC Cd accumulated better in AMF and ALF, whereas its levels were lower in the cortical mucus of the cervix. Pb deposited in equal concentrations in MPC of all the cows (0.46 ± 0.18 μg/kg in the contaminated environment and 0.47 ± 0.17 μg/kg in the relatively clean environment). In the relatively clean environment its levels in ALF were lower in 8 times (0.62 ± 0.16 μg/kg and 0.08 ± 0.04 μg/kg) and 26 times lower in AMF (0.52 ± 0.07 μg/kg and 0.02 ± 0.002 μg/kg), whereas Pb concentration in the cortical mucus of the cervix was 17 times lower (0.06 ± 0.03μg/kg) than that in the contaminated environment, (1.01 ± 0.28 μg/kg). Pb transited from MPC (0.46 ± 0.18 μg/kg) to FPC (0.51 ± 0.19 μg/kg), deposited in the internal environment of the uterus wherefrom it was absorbed by the cortical mucus of the cervix (1.01 ± 0.28 μg/kg). While transiting through the fetal body Pb accumulated in amniotic (0.52 ± 0.07 μg/kg) and allantoic fluid (0.62 ± 0.16 μg/kg). Mineral supplement in rations led to a weakened barrier function of MPC (0.23 ± 0.14 μg/kg), a two-fold increase of Pb in FPC (0.47 ± 0.11 μg/kg), whereas in the allantoic (0.16 ± 0.05 μg/kg) and amniotic (0.38 ± 0.10 μg/kg) fluid Pb concentration was lower when compared to the control group (0.62 ± 0.16 μg/kg; Р < 0.05 і 0.52 ± 0.07 μg/kg; Р < 0.05, respectively). Pb deposited in the cortical mucus of the cervix (2.47 ± 0.26 μg/kg; Р < 0.001). With the injection of fetoplacentat the barrier function of MPC became weaker (0.06 ± 0.01 μg/kg) than that of the control group (0.46 ± 0.17 μg/kg – 0.57 ± 0.18 μg/kg), though the decrease was exhibited less than in the cortical mucus of the cervix (0.67 ± 0.06 μg/kg). At the first stage of foaling Pb levels in mares’ blood were twice as high as Cd; in UCf Pb was not identified, Cd didn’t deposit but penetrated into the fetal liver where its levels were 11 times higher than that of Pb. Presence of Cd in allantoic fluid indicated its ability to excrete through the kidneys. Рb concentration in ALMf were 26 times higher than in the chorion and 3.7 times higher in FPCm than in ALFf. Pb levels in amniotic fluid were 1.3 times lower than in allantoic fluid and almost 4.2 times lower than in the fetal liver. Pb levels in AMF and ALF exceeded its concentration in the umbilical cord by 24.5 and 31 times respectively.

Remodelling of collagen fibres in the placentas of women with venous insufficiency during pregnancy.

Haemodynamic changes produced during pregnancy lead to elevated venous pressure in the legs and an increased resting consumption of oxygen. These events can cause varicose veins, or venous insufficiency (VI), which by creating an environment of hypoxia could affect the structure and function of the placental barrier. This study assesses the remodelling state of the placental villi by examining differences in collagens with a known role in villus structure and in placental barrier permeability between patients with and without VI. Samples of 67 placentas from women with VI (n=24) and without VI (n=43) during their pregnancy were processed for gene and protein expression analysis of COL-I, COL-III, MMP-2 and MMP-9 by RT-qPCR and immunohistochemistry. While no differences in COL-I expression levels were detected in the samples from women with and without VI, significant differences did emerge in both gene and protein expression levels of COL-III. Importantly, COL-I/III ratios were reduced in the VI group compared to controls. MMP-2 activity was similar in the two groups while MMP-9 levels were significantly elevated in VI with greatest expression differences observed at the level of the decidual cells. Mothers who developed VI during pregnancy showed significantly higher COL-III and MMP-9 levels consistent with a state of remodelling of the placental villi.

Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies.

Our aim was to evaluate the effects of valproic acid (VPA) on the function of the placental barrier in vivo, in pregnant mice. Studies were conducted on gestational days 12.5 (mid-gestation) or 17.5 (late gestation), following intraperitoneal treatment with 200mg/kg VPA or the vehicle. Indocyanine green (ICG; 0.167mg, i.v.) was used as a marker for the placental barrier permeability. Transporter expression was evaluated by quantitative -PCR. VPA treatment was associated with a 40% increase (p<0.05) in accumulation of ICG in maternal liver in mid-pregnancy and a decrease by one fifth (p<0.05) in late pregnancy. Ex vivo, VPA treatment led to a 20% increase (p<0.05) in fetal ICG emission in mid-pregnancy. Also in mid-pregnancy, the placental expression of the L-type amino acid transporter, the organic anion-transporting polypeptide (Oatp)4a1 (thyroid hormone transporter), and the reduced folate carrier was lower in VPA-treated mice (p<0.05). In late pregnancy, hepatic Oatp4a1 levels were 40% less than in controls (p>0.05). The observed changes in placental transporter expression and function support further research into the potential role of the placenta in the adverse pregnancy outcomes of VPA. Near-infrared imaging provides a noninvasive, nonradioactive tool for future studies on the effects of epilepsy and antiepileptic drugs on tissue transport functions.

Prediction of placental barrier permeability: a model based on partial least squares variable selection procedure.

Assessing the human placental barrier permeability of drugs is very important to guarantee drug safety during pregnancy. Quantitative structure–activity relationship (QSAR) method was used as an effective assessing tool for the placental transfer study of drugs, while in vitro human placental perfusion is the most widely used method. In this study, the partial least squares (PLS) variable selection and modeling procedure was used to pick out optimal descriptors from a pool of 620 descriptors of 65 compounds and to simultaneously develop a QSAR model between the descriptors and the placental barrier permeability expressed by the clearance indices (CI). The model was subjected to internal validation by cross-validation and y-randomization and to external validation by predicting CI values of 19 compounds. It was shown that the model developed is robust and has a good predictive potential (r2 = 0.9064, RMSE = 0.09, q2 = 0.7323, rp2 = 0.7656, RMSP = 0.14). The mechanistic interpretation of the final model was given by the high variable importance in projection values of descriptors. Using PLS procedure, we can rapidly and effectively select optimal descriptors and thus construct a model with good stability and predictability. This analysis can provide an effective tool for the high-throughput screening of the placental barrier permeability of drugs.

Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study

Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function. The invitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The exvivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n= 8) or without (n= 8) cannabidoil. (1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 ± 0.1 vs 0.8 ± 0.1 at 120 minutes of perfusion, P < .001). (1) Placental breast cancer resistance protein function is inhibited following even a short-term exposure to cannabidoil; (2) the exvivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women.

HIV-1 Nef Breaches Placental Barrier in Rat Model

The vertical transmission of HIV-1 from the mother to fetus is known, but the molecular mechanism regulating this transmission is not fully characterized. The fetus is highly protected by the placenta, which does not permit microbial pathogens to cross the placental barrier. In the present study, a rat model was established to observe the effect of HIV-1 protein Nef on placental barrier. Evans blue dye was used to assay permeability of placental barrier and fourteen day pregnant Sprague Dawley rats were injected intravenously with 2% Evans blue dye along with various concentrations of recombinant Nef. After an hour, animals were sacrificed and dye migration was observed through the assimilation of peripheral blood into fetus. Interestingly, traces of recombinant Nef protein were detected in the embryo as well as amniotic fluid and amniotic membrane along with placenta and uterus. Our study indicates that recombinant HIV-1-Nef protein breaches the placental barrier and allows the migration of Evans blue dye to the growing fetus. Further the concentration of Nef protein in blood is directly proportional to the intensity of dye migration and to the amount of Nef protein detected in uterus, placenta, amniotic membrane, amniotic fluid and embryo. Based on this study, it can be concluded that the HIV-1 Nef protein has a direct effect on breaching of the placental barrier in the model we have established in this study. Our observations will be helpful to understand the molecular mechanisms related to this breach of placental barrier by Nef in humans and may be helpful to identify specific Nef inhibitors.

Effects of Diagnostic Contrast-Enhanced Ultrasound on Permeability of Placental Barrier: A Primary Study

Objective To evaluate the effects of contrast-enhanced ultrasound (CEU) on the permeability of placental barrier primarily. Methods A total of 60 pregnant Sprague Dawley (SD) rats were divided into 10 groups, including six groups of microbubbles-enhanced ultrasound (varied mechanical index (MI) of 0.13, 1.0 and 1.4 with continuous and intermittent insonation respectively) (US + MB), two groups of ultrasound insonation only (continuous and intermittent insonation respectively) (US), the group of microbubbles only (MB) and the control group. Evans blue (EB), as the tracer, was intravenously injected before treatment. The EB in placenta and fetus was observed under fluorescence microscope and analyzed quantitatively. The EB amount was compared between groups and between placenta and fetus. Lanthanum nitrate-tracing transmission electron microscope examination was performed to observe the distribution of lanthanum in the placenta and fetus. Results Observed by naked eye, the plancenta was dyed into deep blue while there was no sign of dyeing to the fetus in all groups. Under fluorescence microscope, the red fluorescence radiated by EB was observed in placenta but not in fetus. The EB amount in placenta, insonated by microbubbles-enhanced ultrasound of varied MI, was higher significantly than that in MB, US and control group (all P < 0.01) while there was no difference between the latter three groups. And in each group, EB amount was much higher in placenta than that in fetus ( P < 0.01). The lanthanum particles deposited in the intercellular space in the syntrophoblast while there was no lanthanum presented in the cytotrophoblast in all groups. Conclusion Our findings suggest that diagnostic CEU with SonoVue will not increase the permeability of placenta to the macromolecules larger than albumin, although it may affect placenta.

Experimental analysis of the placental barrier permeability in toxoplasmosis under conditions of normal and pathological pregnancy

The work was an attempt to elucidate the problem of placental barrier permeability in toxoplasmosis. Five series of experiments were set up on pregnant rabbits. The chief conclusion drawn was that during latent toxoplasmosis created by infection of pregnant rabbits which have been immunized before being mated, the placental barrier is impermeable to toxoplasma under conditions of normal pregnancy. In those cases with latent toxoplasmosis where the normal course of pregnancy was disturbed by stress (experimental neurosis, hypoxia), the placental barrier became permeable to toxoplasma.