Maternal-fetal Barrier Research Articles

Taprenepag restores maternal–fetal interface homeostasis for the treatment of neurodevelopmental disorders

Background and purposeNeurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development.Experimental ApproachThe maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons.Key resultsIn VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations.ConclusionTaprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development.

Acute response to pathogens in the early human placenta at single-cell resolution

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T.gondii. Finally, we revealed how P.falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.

Treatment of Equine Tarsus Long Medial Collateral Ligament Desmitis with Allogenic Synovial Membrane Mesenchymal Stem/Stromal Cells Enhanced by Umbilical Cord Mesenchymal Stem/Stromal Cell-Derived Conditioned Medium: Proof of Concept

Horses are high-performance athletes prone to sportive injuries such as tendonitis and desmitis. The formation of fibrous tissue in tendon repair remains a challenge to overcome. This impels regenerative medicine to develop innovative therapies that enhance regeneration, retrieving original tissue properties. Multipotent Mesenchymal Stem/Stromal Cells (MSCs) have been successfully used to develop therapeutic products, as they secrete a variety of bioactive molecules that play a pivotal role in tissue regeneration. These factors are released in culture media for producing a conditioned medium (CM). The aforementioned assumptions led to the formulation of equine synovial membrane MSCs (eSM-MSCs)—the cellular pool that naturally regenerates joint tissue—combined with a medium enriched in immunomodulatory factors (among other bioactive factors) produced by umbilical cord stroma-derived MSCs (eUC-MSCs) that naturally contribute to suppressing the immune rejection in the maternal–fetal barrier. A description of an equine sport horse diagnosed with acute tarsocrural desmitis and treated with this formulation is presented. Ultrasonographic ligament recovery occurred in a reduced time frame, reducing stoppage time and allowing for the horse’s return to unrestricted competition after the completion of a physical rehabilitation program. This study focused on the description of the therapeutic formulation and potential in an equine desmitis treatment using the cells themselves and their secretomes.

The influence of SARS-CoV-2 on the immune system elements and on the placental structure. Clinical, histological and immunohistochemical study.

The effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy remain relatively unknown. We present this original paper where we analyzed 60 parturients, at term, 30 without associated infection (C-) and 30 with associated infection (C+), present at birth. We analyzed the blood count and placental microscopic structure through classical and immunohistochemical staining and observed the placental areas affected by the presence of SARS-CoV-2. SARS-CoV-2 infection was accompanied by a decrease in the number of lymphocytes, the number of platelets and the presence of placental structural changes, identifying extensive areas of amyloid deposits, placental infarcts, vascular thrombosis, syncytial knots, with a decrease in placental vascular density and the presence of infection in the cells located at decidual level, at syncytiotrophoblast level and at the level of the cells of the chorionic plate, still without overcoming this barrier and without causing any fetal infection in the analyzed cases. This study shows that the invasion of SARS-CoV-2 in the placenta can produce significant structural changes, with a decrease in placental vascular density that can have significant implications on proper fetal perfusion. Also, the presence of immunoreactivity at the level of decidua, the placental villi, as well as the chorionic plate proves that the virus can overcome the maternal-fetal barrier. However, in the analyzed cases there were no fetal infections at birth, which may show that local placental factors can be a protective filter for the fetus.

Prevalence of preconception TORCH infections and its influential factors: evidence from over 2 million women with fertility desire in southern China

BackgroundTORCH (Toxoplasma gondii [TOX], Cytomegalovirus [CMV], Rubella virus [RV], and Herpes simplex virus [HSV]) represents pathogens known to traverse the maternal-fetal barrier and cause severe neonatal anomalies. We aimed to assess the prevalence of preconception TOX, CMV, and RV infections among women with fertility desire in southern China, and identify related risk factors.MethodsData were obtained from a population-based cross-sectional study conducted as part of the National Free Preconception Health Examination Project. Women planning to conceive within the next 6 months in Guangdong Province were enrolled between 2014 and 2019. Information on sociodemographic, gynecological, and obstetric characteristics was collected. Sera were analyzed for TOX IgG, CMV IgG, and RV IgG antibodies using an enzyme-linked immunosorbent assay. Descriptive, univariate, and multivariate logistic regression analyses were performed to assess the association between TORCH infections and related factors.ResultsAmong 2,409,137 participants, the prevalence of IgG antibodies for TOX, CMV, and RV was 3.20% (95% CI: 3.18–3.22%), 77.67% (95% CI: 77.62–77.71%) and 76.03% (95% CI: 75.98–76.07%), respectively. Of all participants, 141,047 women (5.85%, 95% CI:5.83–5.88%) reported a history of immunization for RV. Women living in the Pearl River Delta, a more developed region, have significantly lower vaccination rates than those living in other regions. The seropositivity of TOX IgG was highest among women aged 35 years and above, with primary or lower education levels, and rural registration. Factors such as being older, having a higher educational level, and being of other ethnicities were associated with a higher prevalence of naturally acquired CMV and RV infections. Women living in the Pearl River Delta showed a higher risk of TOX, CMV, and RV infections, with aORs of 2.21, 4.45, and 1.76, respectively. A history of pregnancy, gynecological diseases, and sexually transmitted infections were potentially associated with TORCH infections, but this association varied across pathogens.ConclusionThe findings of this study update the baseline of preconception TORCH infections among women with fertility desire in southern China, helping to estimate the risk of congenital infection and guide the development and implementation of effective prevention measures for preconception TORCH infections.

Cardiac Arrest Pregnancy and Amniotic Fluid Embolism

Amniotic fluid embolism remains one of the most devastating conditions in obstetric practice with an incidence of approximately 1 in 40,000 deliveries and a reported mortality rate ranging from 20% to 60%. The pathophysiology involves an abnormal maternal response to fetal tissue exposure associated with breaches of the maternal-fetal physiologic barrier during parturition. This abnormal response triggers a cascade of events similar to the systemic inflammatory response syndrome, involving the activation of proinflammatory mediators. Maternal treatment in cases of cardiopulmonary arrest is mainly supportive, focusing on resuscitation efforts and stabilizing the mother’s condition. However, it is crucial to prioritize prompt delivery in order to improve the newborn’s outcome.

In Vitro Nephrotoxicity and Permeation of Vancomycin Hydrochloride Loaded Liposomes.

Drugs can be toxic to the fetus depending on the amount that permeates across the maternal–fetal barrier. One way to limit the amount which penetrates this barrier is to increase the molecular size of the drug. In this study, we have achieved this by encapsulating our model antibiotic (vancomycin hydrochloride, a known nephrotoxic agent) in liposomes. PEGylated and non-PEGylated liposomes encapsulating vancomycin hydrochloride were prepared using two different methods: thin-film hydration followed by the freeze–thaw method and the reverse-phase evaporation method. These liposomes were characterized by their hydrodynamic size and zeta potential measurements, CryoTEM microscopy, loading and encapsulation efficiency studies, in vitro release measurements and in vitro cytotoxicity assays using NRK-52 E rat kidney cells. We also determined the in vitro permeability of these liposomes across the human placental cell and dog kidney cell barriers. Vancomycin hydrochloride-loaded PEGylated liposomes (VHCL-lipo) of a size less than 200 nm were prepared. The VHCL-lipo were found to have the faster release of vancomycin hydrochloride and resulted in greater viability of NRK-52E cells. In vitro, the VHCL-lipo permeated the human placental cell and dog kidney cell barriers to a lesser extent than the free vancomycin hydrochloride. The data suggest a reduction in nephrotoxicity and permeability of vancomycin hydrochloride after encapsulation in PEGylated liposomes.

Inducible knockout of syncytin-a leads to poor placental glucose transport in mice

IntroductionCell-cell fusion of cytotrophoblasts into the syncytiotrophoblast layer is a key process in placental development. Syncytin, an endogenous retroviral envelope protein, is expressed in placental trophoblasts and specifically mediates syncytiotrophoblast layer formation. Syncytin deficiency has been observed in fetal growth-restricted placentas. Abnormal fetal growth, especially fetal growth restriction, is associated with the decreased expression of glucose transporters. Here, we aimed to determine the role of syncytin in fetal growth restriction in placental glucose transport capacity. MethodsTo better explore the function of syncytin in fetal growth-restricted placenta, we generated an inducible knockout mouse model of syncytin-a gene. The expression levels of glucose transporters in BeWo cells were measured before and after HERV-W knockdown. ResultsSyncytin-A disruption was associated with significant abnormalities in placental and fetal development in mice. Syncytin-A destruction causes extensive abnormalities in the maternal-fetal exchange structures in the labyrinth, including an extremely reduced number and dramatically irregular distribution of fetal vessels. Moreover, glucose transporter 1, glucose transporters 3, and connexin 26 expression levels decreased after E14.5. Consistently, low glucose transporter 1, glucose transporter 3, and connexin 26 levels were observed in HERV-W-silenced BeWo cells. DiscussionSyncytin-A is crucial for both syncytiotrophoblast layer development and morphogenesis, suggesting that syncytin-A disruption leads to fetal growth restriction associated with abnormalities in the maternal-fetal exchange barrier and decreased glucose transport.

IFN-B DISRUPTS INVASIVE EXTRAVILLOUS TROPHOBLASTS FUNCTION ON IMPLANTATION-ON-A-CHIP MODEL

Chronic inflammatory conditions, such as systemic lupus erythematosus, have been linked to implantation and early pregnancy failures. Studies suggest this may be linked to changes in interferon signaling during implantation. Supporting animal data demonstrates that excessive stimulation of the interferon-β (IFN-β) pathway during gestation, via infectious or non-infectious etiologies, causes breakdown of the maternal-fetal barrier and poor pregnancy outcomes (i.e. IUGR, fetal demise). In this study, we aim to examine the role of IFN-β in regulating human extravillous trophoblast (EVT) invasion and spiral artery remodeling using a microfluidic organ-on-a-chip platform, Implantation-On-A-Chip (IOC).

22732 Impact of Type-I Interferon Manipulation During Embryo Implantation and Placentation

ABSTRACT IMPACT: This research will promote understanding the role of the Type-I Interferon signaling pathway during embryo implantation, potentially leading to a new diagnostic or treatment target in early pregnancy failure. OBJECTIVES/GOALS: Studies suggest interferon signaling regulation is tightly balanced between physiologic and pathophysiologic growth in early pregnancy. We propose to determine the impact of interferon-mediated inflammation on embryo implantation and early pregnancy failure in normal conditions and chronic inflammatory diseases in a novel mixed-mouse model. METHODS/STUDY POPULATION: To probe the role of type-I interferons (IFNs) in implantation, we will utilize a mouse model and non-surgically transfer both Ifnar1-/- and Ifnar1-/+ embryos into an immune-competent pseudopregnant wild-type female recipient. This will allow analysis of a litter with distinct genotypes within the same, immune-competent, uterine environment. Type-I IFN stimulation will be systemically induced with Poly-(I:C) at various time points around implantation. A similar approach will be used in mouse models of chronic inflammatory disease states associated with early pregnancy loss (e.g. systemic lupous erythematous). With this model, we will be able to control for deficiencies in maternal immune response to specifically determine the embryonic response to inflammation during implantation and development. RESULTS/ANTICIPATED RESULTS: We anticipate the Ifnar1-/+ embryos - those able to respond to Type-I IFN - and their surrounding implantation sites will exhibit more maternal-fetal barrier dysfunction in the form of impaired trophoblast fusion, improper formation of the microvascular architecture, and increased permeability of the maternal-fetal barrier, compared to embryos unable to respond to IFN. We will also conduct similar analyses in mouse models of chronic inflammatory diseases. We hypothesize these mice to have baseline endometrial inflammation that stimulated the IFN-pathway in IFN-capable embryos, producing breakdown of the maternal-fetal barrier. In these mice, we predict Ifnar1-/- embryos will show improved molecular outcomes when compared to Ifnar1-/+ embryos, and thus improved associated pregnancy outcomes. DISCUSSION/SIGNIFICANCE OF FINDINGS: This work can insight into the immunological mechanisms that govern embryo implantation and early placentation. This could provide more pointed means for management and intervention of early pregnancy failure and/or disease states that are commonly associated with poor reproductive outcomes.

1008 Autophagy and ZIKV viral replication co-occur in human and primate placentae

Evidence suggests that ZIKV induces autophagy via LC3-dependent mechanisms in trophoblasts, and inhibition of autophagy restricts placental infection in mice and cytotrophoblasts in vitro. Thus, anti-autophagal drugs (i.e, hydroxychloroquine) could inhibit vertical transmission. To generate preclinical data, we assessed primary cell culture and placentae from human congenital infections, and an experimental non-human primate (Callithrix jacchus) model for associated autophagal activity. Primary trophoblast cells were isolated from placenta (n=10) and infected in vitro with ZIKV. Autophagy-associated gene expression (ULK-1, BECN1, ATG5, ATG7, ATG12, ATG16L1, MAP1LC3A, MAP1LC3B, p62) was determined by TaqMan qPCR for changes with ZIKV. In in vivo validation experiments, autophagy genes LC3B and p62 were probed using in situ hybridization (ISH) in the placentae of Congenital Zika Syndrome (n=3) and ZIKV-infected primate placenta and fetal tissue (n=1). Infected and uninfected villi were compared for mean density and colocalization of autophagal markers. Studies of primary human trophoblasts revealed key autophagy genes ATG5 and p62 were decreased ∼2 fold in ZIKV-infected trophoblasts (p=0.04 and p=0.03). Histologic examination by ISH confirmed ZIKV replication in primate congenital infection cases (Fig 1A). Immunohistological identification of autophagal proteins LC3B and p62 demonstrates co-localization (Fig 1B-C). Protein expression was assessed via densitometry and revealed ∼0.8 fold decrease in p62 in villi with active ZIKV replication (p=0.007), confirming autophagal flux (Fig 2). We demonstrate for the first time that the association of autophagy at the maternal fetal barrier is observed following ZIKV in vivo using three methodologies. Downregulation of key autophagy genes is consistent with findings in Dengue virus, where autophagy is initially induced then downregulated in late stage infection. These findings collectively suggest antiautophagal drugs may be effective in mediating vertical transmission of ZIKV and potentially other novel RNA viruses.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts

Maternal decidual NK (dNK) cells promote placentation, but how they protect against placental infection while maintaining fetal tolerance is unclear. Here we show that human dNK cells highly express the antimicrobial peptide granulysin (GNLY) and selectively transfer it via nanotubes to extravillous trophoblasts to kill intracellular Listeria monocytogenes (Lm) without killing the trophoblast. Transfer of GNLY, but not other cell death-inducing cytotoxic granule proteins, strongly inhibits Lm in human placental cultures and in mouse and human trophoblast cell lines. Placental and fetal Lm loads are lower and pregnancy success is greatly improved in pregnant Lm-infected GNLY-transgenic mice than in wild-type mice that lack GNLY. This immune defense is not restricted to pregnancy; peripheral NK (pNK) cells also transfer GNLY to kill bacteria in macrophages and dendritic cells without killing the host cell. Nanotube transfer of GNLY allows dNK to protect against infection while leaving the maternal-fetal barrier intact.

MSphere of Influence: Innate Immunity at the Maternal-Fetal Barrier.

Kellie Ann Jurado works in the field of emerging infectious diseases. In this mSphere of Influence article, she reflects on how the papers "Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection" (https://doi.org/10.1016/j.chom.2016.03.008) and "A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance" (https://doi.org/10.1126/sciadv.1501462) by Carolyn Coyne's group have made an impact on her, inspiring her to explore immunity in the placenta by indicating the unique innate immune control elicited at the maternal-fetal barrier as well as by providing physiologically relevant model systems for study.

Oral Microbiome and Preterm Birth: Correlation or Coincidence? A Narrative Review

BACKGROUND: Physiological changes that occur during pregnancy involve, as a natural consequence, also modifications of oral microbiome. However, the addition with microbial imbalance due to pre-existing periodontal infection might impair a pathological alteration in the phylogenetic community structure and composition in the oral cavity, exacerbating an inflammatory status, and becoming a potential risk factor for preterm birth. From the empirical findings about the relationship between periodontal pathogens and systemic diseases, a clear interest focused on the potential impact of some periodontal pathogens on the preterm birth risk has emerged.
 AIM: Exploration of the potential interdependence existing between dysbiosis of oral microbiome and changes in maternal-fetal barrier in premature rupture of membranes.
 MATERIALS AND METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a Medline search was performed for studies focusing on oral microbioma and its association with pre-term birth, and completed by additional hand searching. Two reviewers independently selected studies and extracted data. The search was restricted to only reports written in English.
 RESULTS: The electronic search produced 66 items. Six duplicates were found. Among the collected studies, 56 were discarded because they met the exclusion criteria. The articles and reports in our review showed a connection between preterm birth and altered oral microbiome, suggesting a potential key role of Fusobacterium nucleatum, a notable periodontal pathogen involved in several pathological periodontal conditions, in increasing the risk of premature birth.
 CONCLUSIONS: Since F. nucleatum is frequently associated with preterm birth, it is coherent to hypothesize a potential role for the oral microbiota for preterm birth risk. Further studies should be carried out to determine the changes of the oral microflora in pregnancy and to provide comprehensive knowledge of the diversity of oral bacteria involved in preterm birth.

Yellow Fever Vaccination in a Mouse Model Is Associated With Uninterrupted Pregnancies and Viable Neonates Except When Administered at Implantation Period.

The potential risk of yellow fever (YF) infection in unvaccinated pregnant women has aroused serious concerns. In this study, we evaluated the effect of the YF vaccine during gestation using a mouse model, analyzing placental structure, immunolocalization of the virus antigen, and viral activity at the maternal-fetal barrier and in the maternal liver and fetus. The YF vaccine (17DD) was administered subcutaneously at a dose of 2.0 log10 PFU to CD-1 mice on gestational days (gd) 0.5, 5.5, and 11.5 (n = 5–10/group). The control group received sterile saline (n = 5–10/group). Maternal liver, implantation sites with fetus, and placentas were collected on gd18.5. The numbers of implantation sites, reabsorbed embryos, and stillborn fetuses were counted, and placentas and live fetuses were weighed. Tissues (placenta, fetuses, and liver) of vaccinated pregnant mice on gd5.5 (n = 15) were paraffin-embedded in 10% buffered-formalin and collected in TRIzol for immunolocalization of YF vaccine virus and PCR, respectively. PCR products were also subjected to automated sequence analysis. Fetal growth restriction (p < 0.0001) and a significant decrease in fetal viability (p < 0.0001) occurred only when the vaccine was administered on gd5.5. In stillbirths, the viral antigen was consistently immunolocalized at the maternal-fetal barrier and in fetal organs, suggesting a transplacental transfer. In stillbirths, RNA of the vaccine virus was also detected by reverse transcriptase-PCR indicating viral activity in the maternal liver and fetal tissues. In conclusion, the findings of this study in the mouse suggest that vaccination did not cause adverse outcomes with respect to fetal development except when administered during the early gestational stage, indicating the implantation period as a susceptible period in which the YF vaccine virus might interfere with pregnancy.

In vivo imaging of Zika virus reveals dynamics of viral invasion in immune-sheltered tissues and vertical propagation during pregnancy

Rationale: Zika virus (ZIKV) is a pathogenic virus known to cause a wide range of congenital abnormalities, including microcephaly, Guillain-Barre syndrome, meningoencephalitis, and other neurological complications, in humans. This study investigated the noninvasive detection of ZIKV infection in vivo, which is necessary for elucidating the virus's mechanisms of viral replication and pathogenesis, as well as to accelerate the development of anti-ZIKV therapeutic strategies.Methods: In this study, a recombinant ZIKV harbouring Nluc gene (ZIKV-Nluc) was designed, recovered, and purified. The levels of bioluminescence were directly correlated with viral loads in vitro and in vivo. The dynamics of ZIKV infection in A129 (interferon (IFN)-α/β receptor deficient), AG6 (IFN-α/β and IFN-γ receptor deficient), and C57BL/6 mice were characterized. Pregnant dams were infected with ZIKV-Nluc at E10 via intra footpad injection. Then, the pooled immune sera (anti-ZIKV neutralizing antibodies) #22-1 in ZIKV-Nluc virus-infected mice were visualized.Results: ZIKV-Nluc showed a high genetic stability and replicated well in cells with similar properties to the wild-type ZIKV (ZIKVwt). Striking bioluminescence signals were consistently observed in animal organs, including spleen, intestine, testis, uterus/ovary, and kidney. The ileocecal junction was found to be the crucial visceral target. Infection of pregnant dams with ZIKV-Nluc showed that ZIKV was capable of crossing the maternal-fetal barrier to infect the fetuses via vertical transmission. Furthermore, it was visualized that treatment with the pooled immune sera was found to greatly restrict the spread of the ZIKV-Nluc virus in mice.Conclusions: This study is the first to report the real-time noninvasive tracking of the progression of ZIKV invading immune-sheltered tissues and propagating vertically during pregnancy. The results demonstrate that ZIKV-Nluc represents a powerful tool for the study of the replication, dissemination, pathogenesis, and treatment of ZIKV in vitro and in vivo.

Scaling in vitro activity of CYP3A7 suggests human fetal livers do not clear retinoic acid entering from maternal circulation

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is a critical signaling molecule during embryonic and fetal development and is necessary for maternal health. Fetal exposure to endogenous atRA is tightly regulated during gestation in a tissue specific manner and maternal exposure to exogenous retinoids during pregnancy is teratogenic. The clearance of atRA is primarily mediated by the cytochrome P450 (CYP) 26 enzymes, which play an essential role in controlling retinoid gradients during organogenesis. We hypothesized that CYP26 enzymes in the human fetal liver also function as a protective barrier to prevent maternal atRA reaching fetal circulation. Using human fetal liver tissue, we found that the mRNA of CYP26A1 and CYP26B1 enzymes is expressed in the human fetal liver. However, based on inhibition studies, metabolite profiles and correlation of atRA metabolism with testosterone hydroxylation, clearance of atRA in the fetal livers was mediated by CYP3A7. Based on in vitro-to-in vivo scaling, atRA clearance in the fetal liver was quantitatively minimal, thus providing an insufficient maternal-fetal barrier for atRA exposure.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances affects leukocyte telomere length in female newborns.

Evidence has shown that leukocyte telomere length (LTL) at birth is related to the susceptibility to various diseases in later life and the setting of newborn LTL is influenced by the intrauterine environment. Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as a kind of persistent organic pollutants, are commonly used in commercial and domestic applications and are capable of crossing the maternal-fetal barrier during pregnancy. We hypothesized that intrauterine exposure to PFASs may affect fetal LTL by increasing oxidative stress. To verify this hypothesis, LTL, concentrations of PFASs and reactive oxygen species (ROS) were measured in umbilical cord blood of 581 newborns from a prospective cohort. Our results showed that there were interactions between PFOS/PFDA and sex on LTL and ROS. The LTL was significantly shorter (0.926 ± 0.053 vs 0.945 ± 0.054, P = .023 for PFOS; 0.919 ± 0.063 vs 0.940 ± 0.059, P = .011 for PFDA) and the ROS levels were extremely higher (252.9 ± 60.5 [M] vs 233.5 ± 53.6 [M], P = .031 for PFOS; 255.2 ± 62.9 [M] vs 232.9 ± 58.3 [M], P = .011 for PFDA) in the female newborns whose PFOS or PFDA concentrations fell in the upmost quartile compared with those in the lowest quartile after adjusting for potential confounders. ROS levels were inversely associated with LTL in female newborns (β = -1.42 × 10-4, P = .022). 13% of the effect of PFOS on female LTL was mediated through ROS approximately by the mediation analyses. However, in male newborns, no relationships among PFASs, ROS and LTL were observed. Our findings suggest a "programming" role of PFASs on fetal telomere biology system in females in intrauterine stage.

Type I interferons instigate fetal demise after Zika virus infection.

Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/β receptor (IFNAR)-deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1-/-) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1-/- dams mated with Ifnar1+/- sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/-) or do not express IFNAR (Ifnar1-/-) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1-/- than within the Ifnar1+/- concepti. Yet, rather unexpectedly, we found that only Ifnar1+/- fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1-/- littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.

Hofbauer Cells: Placental Macrophages of Fetal Origin.

Pregnancy complications such as preterm birth, miscarriage, maternal and/or neonatal morbidities, and mortality can be manifestations of underlying placental pathology. Hofbauer cells refer to a heterogeneous population of fetal macrophages that reside within the functional unit of the placenta known as the chorionic villus. Hofbauer cells can be detected within the connective tissue matrix of the placenta as early as 4 weeks post-conception and are present throughout pregnancy. These cells are implicated in a wide array of functions important for a successful pregnancy including placental morphogenesis, immune regulation, control of stromal water content, and the transfer of ions and serum proteins across the maternal-fetal barrier. Derangements in Hofbauer cell homeostasis are associated with placental pathologies involving infection, inflammation, and inadequate placental development. Despite a growing body of evidence that these cells are important, our knowledge about Hofbauer cell function in both normal and dysfunctional pregnancy is rudimentary. The goal of this chapter is to provide an overview of what is known about Hofbauer cell origins and their potential roles in normal and complicated pregnancy. We also review established and emerging methodologies available for the study of Hofbauer cells during in vitro and in vivo conditions.