Early-life exposure to per- and polyfluoroalkyl substances: Analysis of levels, health risk and binding abilities to transport proteins.

Per- and polyfluoroalkyl substances (PFAS) can pass through the placenta and adversely affect fetal development. However, there is a lack of comparison of legacy and emerging PFAS levels among different biosamples in pregnant women and their offspring. This study, based on the Shanghai Maternal-Child Pairs Cohort, analyzed the concentrations of 16 PFAS in the maternal serum, cord serum, and breast milk samples from 1,076 mother-child pairs. The placental and breastfeeding transfer efficiencies of PFAS were determined in maternal-cord and maternal-milk pairs, respectively. The binding affinities of PFAS to five transporters were simulated using molecular docking. The results suggested that PFAS were frequently detected in different biosamples. The median concentration of perfluorooctane sulfonate (PFOS) was the highest at 8.85 ng/mL, followed by perfluorooctanoic acid (PFOA) at 7.13 ng/mL and 6:2 chlorinated polyfluorinated ether sulfonate at 5.59 ng/mL in maternal serum. The median concentrations of PFOA were highest in cord serum (4.23 ng/mL) and breast milk (1.08 ng/mL). PFAS demonstrated higher placental than breastfeeding transfer efficiencies. The transfer efficiencies and the binding affinities of most PFAS to proteins exhibited alkyl chain length-dependent patterns. Furthermore, we comprehensively assessed the estimated daily intakes (EDIs) of PFAS in breastfeeding infants of different age groups and used the hazard quotient (HQ) to characterize the potential health risk. EDIs decreased with infant age, and PFOS had higher HQs than PFOA. These findings highlight the significance of considering PFAS exposure, transfer mechanism, and health risks resulting from breast milk intake in early life.

Impact of xylene exposure during organogenesis on foeto-placental efficiency and foetal viability: Exploring its association with oxidative stress-induced inflammation and apoptosis in utero.

The potential maternal and foetal toxicity resulting from exposure to xylene at or below the allowable limit of 100 ppm during gestation is not thoroughly studied. The aim of this study was to investigate maternal and foetal outcomes following prenatal exposure to xylene during organogenesis. Pregnant Sprague Dawley (SD) rats were administered intraperitoneal (IP) corn oil (vehicle), 100, 500, and 1000 parts per million (ppm) of xylene from gestational day (GD) 6 until GD17. Clinical signs, maternal weight gain, and food consumption were recorded daily. A caesarean hysterectomy was performed on GD21 to assess the reproductive and foetal outcomes. Exposure to 1000 ppm of xylene caused a significant decrease in the maternal body weight and food consumption, and an increase in intrauterine foetal deaths. Foetal assessment revealed a significant decrease in foetal weight in both male and female foetuses of female rats treated with 500 and 1000 ppm. Male placental weight was significantly decreased in all xylene-treated groups, while 1000 ppm xylene significantly decreased female placental weight. Histologically, marked uterine inflammatory lesions, fibrosis of the liver and renal tissues, as well as increased placental glycogen content were observed. Immunohistochemistry revealed a significant increase in lipid peroxidation and apoptotic markers. Thus, the foeto-maternal toxicities of xylene have been shown to be mediated by a systemic inflammatory response that exacerbates intrauterine oxidative stress and impairs foeto-placental transfer, leading to an increase in foetal mortality.

Transplacental transfer of perfluorinated and poly-fluorinated substances in maternal-cord serum and association with birth weight: A birth cohort study, China.

Although the effects of traditional perfluorinated and polyfluorinated substances (PFASs) exposure have been extensively explored, research on novel PFASs remains limited, and there is a lack of data regarding their placental transfer and fetal impact. Herein, we aimed to examine maternal and fetal PFASs exposure levels, placental transfer efficiency (TTE), and the consequences of prenatal exposure on birth weight. The study included 214 mother-child pairs recruited in Wuxi birth cohort from 2019 to 2021. Twenty-three PFASs were quantified in maternal serum during the second trimester and umbilical serum during delivery. Median concentrations of ∑23PFASs in maternal and cord sera were 9.34 and 6.88 ng/mL, respectively. The novel alternatives exhibited elevated levels of maternal and fetal exposure, such as perfluorovaleric acid (PFPeA, 2.00 ng/mL and 1.66 ng/mL, respectively) and perfluorohexane sulfonate (PFHxS, 1.77 and 1.14 ng/mL, respectively). With increasing carbon chain length, the TTE of perfluorocarbonic acid (PFCAs) displayed a pattern of initially decreasing before subsequently increasing, with novel alternatives exhibiting a relatively high TTE. Multiple linear regression showed that exposure to perfluorobutane sulfonate (PFBS) and PFPeA in cord serum positively correlated with the birth weight of female infants (ß = 231.04 g, 95% confidence interval [CI]: 21.73-440.36; ß = 121.26 g, 95% CI: 29.51-213.00). No nonlinear relationship was observed between cord serum PFASs and birth weight. The weighted quantile sum (WQS) regression analysis has reaffirmed that PFPeA and PFBS were predominant contributors to the positive correlation observed between the mixture of PFASs and birth weight. Our findings suggest that novel PFASs may exhibit a heightened susceptibility for transplacental transfer and that exposure to PFBS and PFPeA during pregnancy could be linked to increased birth weight.

Influence of Maternal and Neonatal Factors on Transplacental Passive Immunity after Vaccination against COVID-19.

In the present study, we evaluated the influence of maternal and neonatal factors on the efficiency of the placental transfer of neutralizing antibodies against SARS-CoV-2. Vaccination during pregnancy provides fetal and neonatal protection through the passive transplacental transfer of maternal neutralizing antibodies. To date, little information is available regarding the factors that affect the transfer of antibodies against SARS-CoV-2. A retrospective, cross-sectional, observational, and analytical study was carried out. It was found that several biological factors could be altering transplacental passive immunity after vaccination against COVID-19. In our study population, type 2 diabetes mellitus and chronic hypertension tended to decrease efficiency, while data from women with pre-eclampsia showed better indices compared to those from women with healthy pregnancies. Neonates born prematurely showed lower transfer rates when compared to healthy neonates. The premature rupture of membranes significantly decreased antibody transfer. Taken together, the data suggest that vaccination against COVID-19 during pregnancy is effective even under certain unfavorable clinical conditions for the mother, fetus, and neonate. It is important to create and disseminate immunization strategies in vulnerable populations to reduce maternal and perinatal morbidity and mortality associated with infections preventable by vaccination.

Seroprevalence and placental transfer of SARS-CoV-2 antibodies in unvaccinated pregnant women.

PURPOSE: Pregnant women are at risk of severe SARS-CoV-2 infection, potentially leading to obstetric and neonatal complications. Placental transfer of antibodies directed to SARS-CoV-2 may be protective against neonatal COVID-19, but this remains to be studied. We aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a population of unvaccinated pregnant women and to determine the placental transfer of these antibodies. METHODOLOGY: A total of 1197 unvaccinated women with mostly unknown pre-study SARS-CoV-2 infection status, were tested at delivery for SARS-CoV-2 spike protein IgG antibodies during the first year of the pandemic. Umbilical cord samples were collected and assessed for seropositivity if the mother was seropositive. Maternal characteristics, pregnancy and neonatal outcomes and data on SARS-CoV-2 infection were extracted from medical records. RESULTS: Specific IgG were detected in 258 women (21.6%). A significant placental transfer to the newborn was observed in 81.3% of cases. The earlier in the 2nd and 3rd trimesters that the mother had contracted the disease and the more symptomatic she was, the greater the likelihood of transplacental transfer of IgG to her newborn. CONCLUSION: Approximately one in five women had detectable anti-SARS-CoV-2 spike protein IgG antibodies at delivery during the first year of the pandemic, and these antibodies were significantly transferred to their fetuses. This research provides further evidence to better understand the dynamics of the placental transfer of SARS-CoV-2 IgG antibodies from mothers to their newborns, which is necessary to improve vaccination strategies.

Efficient transplacental transfer of SARS-CoV-2 antibodies between naturally exposed mothers and infants in Accra, Ghana.

We aimed to determine SARS-CoV-2 antibody seropositivity among pregnant women and the transplacental transfer efficiency of SARS-CoV-2-specific antibodies relative to malaria antibodies among SARS-CoV-2 seropositive mother-cord pairs. This cross-sectional study was conducted in Accra, Ghana, from March to May 2022. Antigen- specific IgG antibodies against SARS-CoV-2 (nucleoprotein and spike-receptor binding domain) and malarial antigens (circumsporozoite protein and merozoite surface protein 3) in maternal and cord plasma were measured by ELISA. Plasma from both vaccinated and unvaccinated pregnant women were tested for neutralizing antibodies using commercial kit. Of the unvaccinated pregnant women tested, 58.12% at antenatal clinics and 55.56% at the delivery wards were seropositive for both SARS-CoV-2 nucleoprotein and RBD antibodies. Anti-SARS-CoV-2 antibodies in cord samples correlated with maternal antibody levels (N antigen rs = 0.7155, p < 0.001; RBD rs = 0.8693, p < 0.001). Transplacental transfer of SARS-CoV-2 nucleoprotein antibodies was comparable to circumsporozoite protein antibodies (p = 0.9999) but both were higher than transfer rates of merozoite surface protein 3 antibodies (p < 0.001). SARS-CoV-2 IgG seropositivity among pregnant women in Accra is high with a boost of SARS-CoV-2 RBD-specific IgG in vaccinated women. Transplacental transfer of anti-SARS-CoV-2 and malarial antibodies was efficient, supporting vaccination of mothers as a strategy to protect infants against SARS-CoV-2.

Gestational diabetes mellitus enhances cobalt placental transfer efficiency between mother and infant.

Background: The fetal stage is pivotal for growth and development, making it susceptible to the adverse effects of prenatal metal(loid)s exposure. This study evaluated the influence of gestational diabetes mellitus (GDM) on the placental transfer efficiency (PTE) of metal(loid)s and thus assessed the associated risks of prenatal metal(loid)s exposure.Materials and method: Designed as a case-control study, it incorporated 114 pregnant participants: 65 without complications and 49 diagnosed with GDM. We utilized inductively coupled plasma mass spectrometry to quantify seven metal(loid)s - manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), gallium (Ga), arsenic (As), and cadmium (Cd) - in both maternal venous blood and umbilical cord blood.Result: We compared metal(loid)s concentrations and their PTE in the maternal and cord blood between the two groups. Notably, Cu, Ga, As, and Co levels in the umbilical cord blood of the GDM group (657.9 ± 167.2 µg/L, 1.23 ± 0.34 µg/L, 5.19 ± 2.58 µg/L, 1.09 ± 2.03 µg/L) surpassed those of the control group, with PTE of Co showing a marked increase in GDM group (568.8 ± 150.4 µg/L, 1.05 ± 0.31 µg/L, 4.09 ± 2.54 µg/L, 0.47 ± 0.91 µg/L), with PTE of Co showing a marked increase in GDM group (p < 0.05). The PTE of Ni exhibited a reduction in the GDM group relative to the control group, yet this decrease did not reach statistical significance.Conclusion: This study indicates that GDM can influence the placental transfer efficiency of certain metal(loid)s, leading to higher concentrations of Co, Cu, Ga, and As in the umbilical cord blood of the GDM group. The marked increase in the PTE of Co suggests a potential link to placental abnormal angiogenesis due to GDM.

Transplacental transfer of maternal antibodies following immunization with recombinant pertussis vaccines during pregnancy: Real-world evidence.

AIM/OBJECTIVE: This study investigates placental antibody transfer following recombinant pertussis vaccination in pregnancy in a real-world setting. METHODS: This postmarketing observational study recruited pregnant women vaccinated with monovalent recombinant acellular pertussis (aP) vaccine (aPgen; n = 199) or combined to tetanus-diphtheria (TdaPgen; n = 200), or Td-vaccine only (n = 54). Pregnancy, delivery, and neonatal outcomes were assessed. Cord blood was collected postdelivery and pertussis toxin (PT)-IgG, filamentous hemagglutinin (FHA)-IgG, and PT-neutralizing antibodies (PT-Nab) were assessed. RESULTS: No adverse pregnancy, delivery, or neonatal outcomes attributed to aPgen, TdaPgen, or Td vaccination were reported. High anti-PT antibody levels were detected in cord samples from women vaccinated with aPgen (geometric mean concentration [GMC] PT-IgG 206.1 IU/ml, 95% confidence intervals [CI]: 164.3-258.6; geometric mean titer [GMT] PT-Nab 105.3 IU/ml, 95% CI: 81.7-135.8) or TdaPgen (GMC PT-IgG 153.1 IU/ml, 95% CI: 129.1-181.5; GMT PT-Nab 81.5 IU/ml, 95% CI: 66.4-100.0). In the Td-only group, anti-PT antibodies were low (GMC PT-IgG 6.5 IU/ml, 95% CI: 4.9-8.8; GMT PT-Nab 3.8 IU/ml, 95% CI: 2.8-5.1). The same was found for FHA-IgG. Recombinant pertussis vaccination at <27 or 27-36 weeks gestation induced similar cord pertussis antibody levels. CONCLUSION: This first real-world study confirms that recombinant pertussis vaccination in the second or third trimester of pregnancy results in high levels of passive immunity in infants. Thai Clinical Trial Registry: TCTR20200528006.

Placental MFSD2A expression in fetal growth restriction and maternal and fetal DHA status.

INTRODUCTION: Fetal growth restriction (FGR) may affect placental transfer of key nutrients to the fetus, such as the fatty acid docosahexaenoic acid (DHA). Major facilitator superfamily domain containing 2A (MFSD2A) has been described as a specific DHA carrier in placenta, but its expression has not been studied in FGR. The aim of this study was to evaluate for the first time the placental MFSD2A levels in late-FGR pregnancies and the maternal and cord plasma DHA. METHODS: 87 pregnant women from a tertial reference center were classified into late-FGR (N = 18) or control (N = 69). Fatty acid profile was determined in maternal and cord venous plasma, as well as placental levels of MFSD2A and of insulin mediators like phospho-protein kinase B (phospho-AKT) and phospho-extracellular regulated kinase (phospho-ERK). RESULTS: Maternal fatty acid profile did not differ between groups. Nevertheless, late-FGR cord vein presented higher content of saturated fatty acids than control, producing a concomitant decrease in the percentage of some unsaturated fatty acids. In the late-FGR group, a lower DHA fetal/maternal ratio was observed when using percentages, but not with concentrations. No alterations were found in the expression of MFSD2A in late-FGR placentas, nor in phospho-AKT or phospho-ERK. DISCUSSION: MFSD2A protein expression was not altered in late-FGR placentas, in line with no differences in cord DHA concentration between groups. The increase in the saturated fatty acid content of late-FGR cord might be a compensatory mechanism to ensure fetal energy supply, decreasing other fatty acids percentage. Future studies are warranted to elucidate if altered saturated fatty acid profile in late-FGR fetuses might predispose them to postnatal catch-up and to long-term health consequences.

A chirality-sensitive approach to predict chemical transfer across the human placental barrier.

The placenta is a membrane that separates the fetus from the maternal circulation, and in addition to protecting the fetus, plays a key role in fetal growth and development. With increasing drug use in pregnancy, it is imperative that reliable models of estimating placental permeability and safety be established. In vitro methods and animal models such as rodent placenta are limited in application since the species-specific nature of the placenta prevents meaningful extrapolations to humans. In this regard, in silico approaches such as quantitative structure-property relationships (QSPRs) are useful alternatives. However, despite evidence that drug transport across the placenta is stereoselective (i.e., governed by the spatial arrangement of the atoms in a molecule), many QSPR models for placental transfer have been built using 2D descriptors that do not account for chirality and stereochemistry. In this study, we apply a chirality-sensitive and proven QSPR methodology titled "EigenValue ANalySis" (EVANS) to build QSPR models for placental transfer. We deploy EVANS along with robust machine learning algorithms to build (i) regression models on a dataset of environmental chemicals (dataset PD I) followed by (ii) classification models on a set of drug-like compounds (dataset PD II). The best models were found to achieve state-of-the-art performance, with the support vector machine algorithm returning rtrain2=0.85,rtest2=0.75 for PD I, and the logistic regression algorithm giving accuracy 0.88 and F1 score 0.93 for PD II. The best models were interpreted with the Shapley Additive Explanations paradigm, and it was found that autocorrelation descriptors are crucial for modelling placental permeability. In conclusion, we demonstrate the need of a chirality-sensitive approach for modelling placental transfer of chemicals, and present two predictive QSPR models that may reliably be used for prediction of placental transfer.

Exposure to MEHP during Pregnancy and Lactation Impairs Offspring Growth and Development by Disrupting Thyroid Hormone Homeostasis.

Mono(2-ethylhexyl) phthalate (MEHP), as a highly toxic and biologically active phthalate metabolite, poses considerable risks to the environment and humans. Despite the existence of in vitro studies, there is a lack of in vivo experiments assessing its toxicity, particularly thyroid toxicity. Herein, we investigated the thyroid-disrupting effects of MEHP and the effects on growth and development of maternal exposure to MEHP during pregnancy and lactation on the offspring modeled by SD rats. We found that thyroid hormone (TH) homeostasis was disrupted in the offspring, showing a decrease in total TH levels, combined with an increase in free TH levels. Nonhomeostasis ultimately leads to weight loss in female offspring, longer anogenital distance in male offspring, prolonged eye-opening times, and fewer offspring. Our findings indicate that maternal exposure to MEHP during pregnancy and lactation indirectly influences the synthesis, transport, transformation, and metabolism of THs in the offspring. Meanwhile, MEHP disrupted the morphology and ultrastructure of the thyroid gland, leading to TH disruption. This hormonal disruption might ultimately affect the growth and development of the offspring. This study provides a novel perspective on the thyroid toxicity mechanisms of phthalate metabolites, emphasizing the health risks to newborns indirectly exposed to phthalates and their metabolites.

Placental Transfer Efficiency of Neutralizing Antibodies on SARS-CoV-2 Vaccination before and after Pregnancy in Mexican Women.

The protection of the neonate against pathogens depends largely on the antibodies transferred placentally from the mother; for this reason, maternal vaccination against emerging viruses, such as SARS-CoV-2, is of vital importance. Knowing some of the immunogenic factors that could alter the placental transfer of antibodies could aid in understanding the immune response and neonatal protection after maternal vaccination. In this study, we analyzed the efficiency of the placental transfer of binding and neutralizing antibodies, as well as some factors that could alter the passive immune response, such as the trimester of gestation at the time of immunization, the number of doses received by the mother and the type of vaccine. Binding IgG antibodies were detected by ELISA, and the detection of neutralizing antibodies was carried out using flow cytometry. Our results show efficient transfer rates (>1), which are higher when maternal vaccination occurs during the third trimester of gestation. Antibodies are detectable in mothers and their neonates after 12 months of maternal immunization, suggesting than the vaccination against COVID-19 before and during pregnancy in the Mexican population induces a lasting neutralizing response in mothers and their newborns.

Passive antibody transfer from pregnant women to their fetus are maximized after SARS-CoV-2 vaccination irrespective of prior infection.

Background: Pregnancy is associated with a higher risk of adverse symptoms and outcomes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for both mother and neonate. Antibodies can provide protection against SARS-CoV-2 infection and are induced in pregnant women after vaccination or infection. Passive transfer of these antibodies from mother to fetus in utero may provide protection to the neonate against infection. However, it is unclear whether the magnitude or quality and kinetics of maternally derived fetal antibodies differs in the context of maternal infection or vaccination. Objective: We aimed to determine whether antibodies transferred from maternal to fetus differed in quality or quantity between infection- or vaccination-induced humoral immune responses. Methods: We evaluated 93 paired maternal and neonatal umbilical cord blood plasma samples collected between October 2020 and February 2022 from a birth cohort of pregnant women from New Orleans, Louisiana, with histories of SARS-CoV-2 infection and/or vaccination. Plasma was profiled for the levels of spike-specific antibodies and induction of antiviral humoral immune functions, including neutralization and Fc-mediated innate immune effector functions. Responses were compared between 4 groups according to maternal infection and vaccination. Results: We found that SARS-CoV-2 vaccination or infection during pregnancy increased the levels of antiviral antibodies compared to naive subjects. Vaccinated mothers and cord samples had the highest anti-spike antibody levels and antiviral function independent of the time of vaccination during pregnancy. Conclusions: These results show that the most effective passive transfer of functional antibodies against SARS-CoV-2 in utero is achieved through vaccination, highlighting the importance of vaccination in pregnant women.

Transplacental migration of maternal natural killer and T cells assessed by ex vivo human placenta perfusion.

INTRODUCTION: The transplacental passage of cells between a mother and her fetus, known as microchimerism, is a less studied process during pregnancy. The frequency of maternal microchimeric cells in fetal tissues in physiological pregnancies and mechanisms responsible for transplacental cell trafficking are poorly understood. This study aimed to evaluate the placental trafficking of maternal peripheral blood mononuclear cells (PBMC) using human ex vivo placenta perfusion. METHODS: Ten placentas and maternal PBMC were obtained after healthy pregnancies. Flow cytometry was used to characterize PBMC subtypes. They showed a higher percentage of CD3+ T cells compared to CD56+ NK cells. The isolated PBMC were stained with a fluorescent dye and perfused through the maternal circuit of the placenta in an ex vivo perfusion system. Subsequent immunofluorescence staining for CD3+ T cells and CD56+ NK cells was performed on placental tissue sections, and the number of detectable PBMC in different tissue areas was counted using fluorescence microscopy. RESULTS: The applied method allowed discrimination of perfused autologous maternal cells from cells resident in the placenta before perfusion. Further, it allows additional immunohistochemical labelling and distinction of immune cell subsets. Perfused PBMC were detected in all analyzed placentas, mostly in contact to the syncytiotrophoblast. CD3+ T cells were identified more frequently than CD56+ NK cells and some CD3+ T cells were found inside fetoplacental tissues and vasculature. The results indicate that also other PBMCs than T or NK cells adhere to or enter villous tissue, but they have not been specified in this analysis. DISCUSSION: Previous studies have detected maternal cells in the fetal circulation which we could mimick in our ex vivo placenta perfusion experiments with fluorescence labelled autologous maternal PBMC. The applied experimental settings did not allow comparison of transmigration abilities of PBMC subsets, but slight modifications of the model will permit further studies of cell transfer processes and microchimerism in pregnancy.

The Association of Prenatal Vitamin D Status With Pregnancy and Neonatal Outcomes.

Context: Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. Objective: This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. Method: We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography-tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Results: Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P < .001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P = .032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Conclusion: Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies.

Immunomodulation of Antibody Glycosylation through the Placental Transfer.

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.

Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways.

The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of pregnant women, the placental transfer and developmental toxicity of 6PPD and 6PPDQ are unknown. Here, we treated C57Bl/6 mice with 4 mg/kg 6PPD or 6PPDQ to investigate their urine excretion and placental transfer. Female and male mice exhibited sex difference in excretion profiles of 6PPD and 6PPDQ. Urine concentrations of 6PPDQ were one order of magnitude lower than those of 6PPD, suggesting lower excretion and higher bioaccumulation of 6PPDQ. In pregnant mice treated with 6PPD or 6PPDQ from embryonic day 11.5 to 15.5, 6PPDQ showed ∼1.5-8 times higher concentrations than 6PPD in placenta, embryo body, and embryo brain, suggesting higher placental transfer of 6PPDQ. Using in vitro dual-luciferase reporter assays, we revealed that 6PPDQ activated the human retinoic acid receptor α (RARα) and retinoid X receptor α (RXRα) at concentrations as low as 0.3 µM, which was ∼10-fold higher than the concentrations detected in human urines. 6PPD activated the RXRα at concentrations as low as 1.2 µM. These results demonstrate the exposure risks of 6PPD and 6PPDQ during pregnancy and emphasize the need for further toxicological and epidemiological investigations.

Development of a physiologically based toxicokinetic model for lead in pregnant women: The role of bone tissue in the maternal and fetal internal exposure.

Epidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6 and 283 L.day-1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment.

Occurrence, placental transfer, and health risks of emerging endocrine-disrupting chemicals in pregnant women.

Previous studies demonstrated that many environmental chemicals can cross the human placental barrier. However, the risk regarding gestational exposure of emerging endocrine-disrupting chemicals (EDCs) is unclear. In this study, the occurrence of 24 EDCs, such as bisphenol A analogs, parabens, triclocarban, and triclosan, was investigated in serum and urine samples from Chinese pregnant women. Some metabolites were determined in matched serum-urine pairs (n = 75) to perform a comprehensive assessment of exposure. The placental transfer efficiency (PTE) of the detected chemicals was determined in matched maternal-cord serum pairs (n = 110). The mean PTEs of the chemicals showed a large variation from 43.1% to 171.0%. The potential effects of physicochemical properties, molecular structures, and biological factors on PTE were investigated using multiple linear regression models and molecular docking. We found that the PTE of methyl paraben, ethyl paraben, and propyl paraben was associated with their increasing alkyl chain lengths. Furthermore, a comprehensive exposure assessment of EDCs showed that 62.7% of pregnant women had a health index > 1, which indicted potential health risks during pregnancy. However, toxicity and the underlying mechanisms of these EDCs remain to be further studied.

A Review on Per- and Polyfluoroalkyl Substances in Pregnant Women: Maternal Exposure, Placental Transfer, and Relevant Model Simulation.

Per- and polyfluoroalkyl substances (PFASs) are important and ubiquitous environmental contaminants worldwide. These novel contaminants can enter human bodies via various pathways, subsequently posing risks to the ecosystem and human health. The exposure of pregnant women to PFASs might pose risks to the health of mothers and the growth and development of fetuses. However, little information is available about the placental transfer of PFASs from mothers to fetuses and the related mechanisms through model simulation. In the present study, based upon a review of previously published literature, we initially summarized the exposure pathways of PFASs in pregnant women, factors affecting the efficiency of placental transfer, and mechanisms associated with placental transfer; outlined simulation analysis approaches using molecular docking and machine learning to reveal the mechanisms of placental transfer; and finally highlighted future research emphases that need to be focused on. Consequently, it was notable that the binding of PFASs to proteins during placental transfer could be simulated by molecular docking and that the placental transfer efficiency of PFASs could also be predicted by machine learning. Therefore, future research on the maternal-fetal transfer mechanisms of PFASs with the benefit of simulation analysis approaches is warranted to provide a scientific basis for the health effects of PFASs on newborns.