Placental Research Articles

Abnormal placental development induced by repeated cesarean sections: Investigating an animal model of placenta accreta spectrum disorders.

Placenta accreta spectrum (PAS) is a serious condition associated with severe postpartum hemorrhage, leading to emergency hysterectomy. Research has predominantly focused on clinical diagnosis and the prevention of adverse maternal outcomes, but the underlying pathological mechanisms remain poorly understood, partly due to the limitations of animal models. In this study, we conducted up to three cesarean sections (CS) on full-term pregnant mice, since a history of multiple CS is an independent risk factor for PAS. We evaluated pregnancy outcomes, placental development, morphology, trophoblast invasion, and angiogenesis at the maternal-fetal interface to assess the impact of repeated CS. Following repeated CS, the model mice displayed adverse pregnancy outcomes, including placental dysplasia, incomplete remodeling of spiral arteries, deep trophoblast invasion at the maternal-fetal interface, and reduced placental perfusion. Additionally, the mice exhibited abnormal fetal development, imbalances in angiogenic and anti-angiogenic both within the placenta and in peripheral blood. The pathological phenotypes of placenta and adverse pregnancy outcomes observed in mice with a history of three CSs closely resemble the clinical features of PAS. This model offers a valuable tool for studying the pathogenesis of PAS and could serve as a foundation for the development of early prevention strategies.

Lead exposure at the feto-maternal interface: A cause for concern for fetal membrane trophoblasts.

The integrity of fetal membranes enables biological functions that protect the fetus and maintain the pregnancy. Any compromise in fetal membrane function can predispose a pregnant woman to prelabor rupture of the membranes (pPROM) and subsequently to preterm birth (PTB). Epidemiologic data suggest that lead exposure during pregnancy is one of several risk factors associated with PTB and pPROM. This heavy metal can cross placental and fetal membrane barriers, disrupting homeostasis in these tissues. Autophagy contributes to the maintenance of fetal membrane homeostasis during gestation, and dysfunctional autophagy is associated with pPROM. In this study, we determined the mechanistic impact of lead-induced cellular changes, autophagy, senescence, and inflammation in chorion trophoblast cells (CTCs) and amnion epithelial cells (AECs) of the fetal membranes. Lead exposure in CTCs induced autophagy disfunction (increase in LC3B-II), augmented senescence (increased SA-β-galactosidase activity) and increased the release of inflammation. In AECs, lead exposure did effect autophagy, senescence, nor inflammation. The differential changes observed in CTCs and AECs after exposure to high lead concentrations may promote the weakening of fetal membranes and contribute to preterm rupture.

A Review of Emerging Viral Pathogens and Current Concerns for Vertical Transmission of Infection.

Vertical transmission, or mother-to-child transmission, of bacterial, viral, or parasitic infection is rare due to the success of the barrier functions of the placental maternal-fetal interface, which provides physical, molecular, and immunological mechanisms to protect the developing fetus. Infections in pregnancy that can cross the placenta and reach the fetus can cause fetal loss, stillbirth, or prematurity or can lead to congenital infection, malformation of organs, and neonatal disease at birth. The acronym TORCH stands for Toxoplasma gondii, other, rubella, cytomegalovirus, and herpes simplex virus (HSV). Within the TORCH category of 'other,' there are increasing emerging viral pathogens that can pass from mother to fetus, including Ebola virus, Zika virus, and emerging arbovirus infections, including West Nile virus and Rift Valley fever virus. Although SARS-CoV-2 has rarely been reported to show transplacental spread, the recent COVID-19 pandemic has highlighted the importance of surveillance of new human pathogens with rapidly evolving transmission patterns. This article reviews the protective roles of the placental maternal-fetal interface, the concept of TORCH infections, and the emergence of viral pathogens currently causing concerns for vertical transmission from mother to fetus.

Understanding the heterogeneity of natural killer cells at the maternal-fetal interface: implications for pregnancy health and disease.

Natural killer (NK) cells are the most abundant leukocytes located at the maternal-fetal interface; they respond to the pregnancy-related hormones and playing a pivotal role in maintaining homeostatic micro-environment during pregnancy. However, due to the high heterogeneity of NK cell subsets, their categorization has been controversial. Here, we systematically review previous studies on uterine NK (uNK) cell subsets, including the classic categorization based on surface markers, functional molecules and developmental stages, as well as single-cell RNA sequencing (scRNA-seq)-based clustering approaches. In addition, we summarize the potential pathways by which endometrial NK (eNK) cells differentiate into decidual NK (dNK) cells, as well as the differentiation pathways of various dNK subsets. Finally, we compared the alterations in the NK cell subsets in various pregnancy-associated diseases, emphasizing the possible contribution of specific subsets to the development of the disease.

Sniffing out morphological convergence in the turbinal complex of myrmecophagous placentals.

The length of the snout in mammals has important evolutionary consequences for the functional systems housed within the rostrum. However, whether increased snout lengths lead to expanded olfactory performance has rarely been examined. Here, we investigate inner rostral function among 10 species of myrmecophagous (ant- and/or termite-eating) placental mammals and 10 closely related species. We use nondestructive computed tomography scanning methods to characterize inner rostral function based on the underlying morphology of the turbinal bones in the nasal cavity. Three approaches were chosen to address this question, including the quantification of functional turbinal surface area, the quantification of functional turbinal three-dimensional complexity, and geometric morphometrics. By including non-model species from several different mammalian orders, we were able to extend the discussion surrounding turbinal homologies to comparisons across mammals. Our results show no increased olfactory function in all myrmecophagous species relative to their sister taxa, which suggests that there is no trade-off for increased olfactory capabilities in myrmecophagous species with elongated snouts. We found no evidence of convergence in turbinal morphology among all five myrmecophagous lineages. However, we found evidence of morphological convergence in the turbinals between the giant armadillo and the aardvark, suggesting a more complex interplay between the evolution of turbinal morphology and ecological correlates. While myrmecophagy alone may not be a strong enough ecological signal to overcome phylogenetic and developmental constraints, we suggest that this might be the case at the intersection of this dietary specialization with a primarily underground lifestyle where odorants may be difficult to detect.

Spatial multiomic landscape of the human placenta at molecular resolution.

Successful pregnancy relies directly on the placenta's complex, dynamic, gene-regulatory networks. Disruption of this vast collection of intercellular and intracellular programs leads to pregnancy complications and developmental defects. In the present study, we generated a comprehensive, spatially resolved, multimodal cell census elucidating the molecular architecture of the first trimester human placenta. We utilized paired single-nucleus (sn)ATAC (assay for transposase accessible chromatin) sequencing and RNA sequencing (RNA-seq), spatial snATAC-seq and RNA-seq, and in situ sequencing and hybridization mapping of transcriptomes at molecular resolution to spatially reconstruct the joint epigenomic and transcriptomic regulatory landscape. Paired analyses unraveled intricate tumor-like gene expression and transcription factor motif programs potentially sustaining the placenta in a hostile uterine environment; further investigation of gene-linked cis-regulatory elements revealed heightened regulatory complexity that may govern trophoblast differentiation and placental disease risk. Complementary spatial mapping techniques decoded these programs within the placental villous core and extravillous trophoblast cell column architecture while simultaneously revealing niche-establishing transcriptional elements and cell-cell communication. Finally, we computationally imputed genome-wide, multiomic single-cell profiles and spatially characterized the placental chromatin accessibility landscape. This spatially resolved, single-cell multiomic framework of the first trimester human placenta serves as a blueprint for future studies on early placental development and pregnancy.

High-resolution spatial multiomic census of the human placenta.

High-resolution spatial multiomic census of the human placenta.

Prenatal Triptan Use for Migraine and Child Neurodevelopment: A Systematic Review

Objective: Triptans are a class of drugs commonly used as an abortive medication for migraine. They can cross the placental barrier in pregnancy and bind to 5-HT receptors in the fetal brain, possibly affecting brain development. The objective of this systematic review was to summarize and evaluate published literature examining the association between prenatal triptan use for migraine and child neurodevelopment. Methods: Search terms for “pregnancy” and “triptans” were used to search MEDLINE, Embase, and CINAHL for relevant studies published from database inception to August 2023. Original research studies published in English examining the relationship between triptan use for maternal migraine during pregnancy and child neurodevelopment were included. An adapted version of the Systematic Assessment of Quality in Observational Research (SAQOR) protocol was used for the quality assessment of included studies. We also performed a narrative synthesis of eligible studies by describing their methods and main findings. Results: Our search strategy retrieved 1093 articles, of which 5 met the inclusion criteria. All 5 studies used data from the Norwegian Mother and Child Cohort Study (MoBa). Studies selected for review all used parental self-report to measure triptan use and were all rated as moderate quality (n = 5, 100%). Outcome variables varied across studies and included externalizing and internalizing behaviour problems, communication, psychomotor function, temperament, and Attention-Deficit/Hyperactivity Disorder (ADHD). Two studies reported an association between prenatal triptan use and externalizing behaviours in children up to 3 years old, but no associations with other neurodevelopmental outcomes or in older children were reported in the literature. All studies accounted for confounding by indication for migraine, but residual confounding by migraine severity was possible. Discussion: Prenatal triptan exposure may be associated with an increased risk of externalizing behaviours in children aged 1.5-3 years old. Future studies outside of the MoBa cohort are required to test the external validity of findings reported in the current literature. Additionally, future studies can expand the state of knowledge by considering different triptans as separate exposures and by utilizing more robust measures of triptan use in pregnancy that are less subject to recall bias than participant self-report.

Prenatal exposure to antibiotics and the risk of orofacial clefts: a protocol for a systematic review and meta-analysis

IntroductionOrofacial clefts (OFCs), including cleft lip, cleft palate and combined cleft lip and palate, are among the most common craniofacial malformations in newborns and present significant healthcare challenges. Emerging evidence...

Organic Sunscreens and Their Products of Degradation in Biotic and Abiotic Conditions-In Silico Studies of Drug-Likeness and Human Placental Transport.

A total of 16 organic sunscreens and over 160 products of their degradation in biotic and abiotic conditions were investigated in the context of their safety during pregnancy. Drug-likeness and the ability of the studied compounds to be absorbed from the gastrointestinal tract and cross the human placenta were predicted in silico using the SwissADME software (for drug-likeness and oral absorption) and multiple linear regression and "ARKA" models (for placenta permeability expressed as fetus-to-mother blood concentration in the state of equilibrium), with the latter outperforming the MLR models. It was established that most of the studied compounds can be absorbed from the gastrointestinal tract. The drug-likeness of the studied compounds (expressed as a binary descriptor, Lipinski) is closely related to their ability to cross the placenta (most likely by a passive diffusion mechanism). The organic sunscreens and their degradation products are likely to cross the placenta, except for very bulky and highly lipophilic 1,3,5-triazine derivatives; an avobenzone degradation product, 1,2-bis(4-tert-butylphenyl)ethane-1,2-dione; diethylamino hydroxybenzoyl hexyl benzoate; and dimerization products of sunscreens from the 4-methoxycinnamate group.

The Influence of Environmental Exposure to Xenoestrogens on the Risk of Cancer Development.

Xenoestrogens (XEs) are a group of exogenous substances that may interfere with the functioning of the endocrine system. They may mimic the function of estrogens, and their sources are plants, water or dust, plastic, chemical agents, and some drugs. Thus, people are highly exposed to their actions. Together with the development of industry, the number of XEs in our environment increases. They interact directly with estrogen receptors, disrupting the transmission of cellular signals. It is proven that XEs exhibit clinical application in e.g., menopause hormone therapy, but some studies observed that intense exposure to XEs leads to the progression of various cancers. Moreover, these substances exhibit the ability to cross the placental barrier, therefore, prenatal exposure may disturb fetus development. Due to the wide range of effects resulting from the biological activity of these substances, there is a need for this knowledge to be systematized. This review aims to comprehensively assess the environmental sources of XEs and their role in increasing cancer risk, focusing on current evidence of their biological and pathological impacts.

Intensive 2-days training on perfused human placenta for microvascular anastomoses

Background and PurposeWe report on an intensive two-day training program on microanastomoses performed on perfused human placenta models. A specific scoring system was elaborated to evaluate the participants’ microsurgical skills and report the participants’ results.Materials and MethodsTrainees who attended the Zurich Microsurgery Courses in 2023 were included in the study. Before performing the microanastomoses, each participant received a visual didactic training. Training was made on perfused human placenta models. To perform the microvascular anastomoses, vessels of different diameters were chosen, and 9–0 and 10–0 microsutures were used. The course was structured in two days. On day one, participants practiced microvascular dissection, microsuturing and end-to-end anastomoses, while the second day was dedicated to end-to-side and to repeat the most useful microanastomosis depending on the specialty. A score system for the evaluation of a successful microanastomosis was developed and applied to assess the participants’ anastomoses. User satisfaction was measured by means of a survey-based questionnaire.ResultsFifty-two participants from different institutions, specializations and levels of experience were included. A significant improvement in the overall microsurgical skills of the included cohort was documented (p < 0.005). The initial average score per anastomosis of 3.56 points (SD 0.71) increased to an average of 3.8 points (SD 0.87) at the end of the course. The steepest learning curve was observed in the placement of knots (Δ 0.48 points, p = 0.003) and microvascular dissection (Δ 0.44 points, p = 0.002). Most participants rated the fidelity and importance of the placental microsuturing course as extremely high.ConclusionThe two-day training program is efficient to teach microvascular dissection and microanastomosis techniques. A significant improvement of participants’ microsurgical skills was reported. The human placenta model proved to be a high-fidelity simulator with great user satisfaction.

Fangchinoline Inhibits Zika Virus by Disrupting Virus Internalization.

The Zika virus (ZIKV) has garnered significant public attention, particularly following the outbreak in Brazil, due to its potential to cause severe damage to the central nervous system and its ability to cross the placental barrier, resulting in microcephaly in infants. Despite the urgency, there remains a lack of targeted therapies or vaccines for the prevention or treatment of ZIKV infection and its related diseases. Fangchinoline (FAN), an alkaloid derived from traditional Chinese medicinal herbs, has a range of biological activities. In this study, we employed both in vitro and in vivo infection models to demonstrate the efficacy of FAN in inhibiting ZIKV. Our findings indicate that FAN effectively suppresses the replication of ZIKV viral RNA and protein, thereby validating its anti-ZIKV capabilities in living organisms. Further analysis through dosing time assays and infectious inhibition assays revealed that FAN exerts its antiviral effects by impeding the early stages of infection, specifically by inhibiting the internalization of ZIKV. These results underscore the potential of FAN as a candidate for anti-ZIKV drug development and offer novel insights into drug design strategies that target the virus's internalization process.

Reproductive and Metabolic Health Following Exposure to Environmental Chemicals: Mechanistic Insights from Mammalian Models.

The decline in human reproductive and metabolic health over the past 50years is associated with exposure to complex mixtures of anthropogenic environmental chemicals (ECs). Real-life EC exposure has varied over time and differs across geographical locations. Health-related issues include declining sperm quality, advanced puberty onset, premature ovarian insufficiency, cancer, obesity, and metabolic syndrome. Prospective animal studies with individual and limited EC mixtures support these observations and provide a means to investigate underlying physiological and molecular mechanisms. The greatest impacts of EC exposure are through programming of the developing embryo and/or fetus, with additional placental effects reported in eutherian mammals. Single-chemical effects and mechanistic studies, including transgenerational epigenetic inheritance, have been undertaken in rodents. Important translational models of human exposure are provided by companion animals, due to a shared environment, and sheep exposed to anthropogenic chemical mixtures present in pastures treated with sewage sludge (biosolids). Future animal research should prioritize EC mixtures that extend beyond a single developmental stage and/or generation. This would provide a more representative platform to investigate genetic and underlying mechanisms that explain sexually dimorphic and individual effects that could facilitate mitigation strategies.

Ruminating on Bovine Implantation: Its Importance in Fertility, Food Production, Conservation, and Health.

Implantation in cattle is a key developmental checkpoint for pregnancy success. It involves careful spatiotemporal changes to the transcriptional landscape of the endometrium, with the heterogeneous nature of the endometrium increasing the complexity of understanding of the mechanism involved. Implantation is impacted by the developmental competency of the embryo, use of assisted reproductive technologies, and the environment in which this process occurs. We identify the factors that most impact the implantation process in cattle and highlight how it differs with that in other placental mammals. We propose the major areas that lack evidence are the mechanism(s) by which implantation itself occurs and how different stressors alter this process. Our understanding is hindered by a lack of appropriate in vitro models; however, development of novel 3D tools and available data sets will further elucidate the implantation process. Perhaps more importantly, this will develop methods to mitigate against these stressors to improve implantation success and offspring health.

Noncanonical altPIDD1 protein: unveiling the true major translational output of the PIDD1 gene.

Proteogenomics has enabled the detection of novel proteins encoded in noncanonical or alternative open reading frames (altORFs) in genes already coding a reference protein. Reanalysis of proteomic and ribo-seq data revealed that the p53-induced death domain-containing protein (or PIDD1) gene encodes a second 171 amino acid protein, altPIDD1, in addition to the known 910-amino acid-long PIDD1 protein. The two ORFs overlap almost completely, and the translation initiation site of altPIDD1 is located upstream of PIDD1. AltPIDD1 has more translational and protein level evidence than PIDD1 across various cell lines and tissues. In HEK293 cells, the altPIDD1 to PIDD1 ratio is 40 to 1, as measured with isotope-labeled (heavy) peptides and targeted proteomics. AltPIDD1 localizes to cytoskeletal structures labeled with phalloidin and interacts with cytoskeletal proteins. Unlike most noncanonical proteins, altPIDD1 is not evolutionarily young but emerged in placental mammals. Overall, we identify PIDD1 as a dual-coding gene, with altPIDD1, not the annotated protein, being the primary product of translation.

Transcriptomic profiling with vascular tension analyses reveals molecular targets and phenotypes in preeclamptic placental vasculature.

The placental vascular system plays an important role in the development of pregnancy hypertension in preeclampsia. The gene profiles of whole placental tissue (containing blood vessels and many other structural components) and pure vascular tissue should be very different. All previous reports using RNA-seq analysis in the placenta have tested its whole tissue or the villous part, and thus the gene profiles in the pure placental blood vessels are unknown. This study was the first to address this point with RNA-seq in human placenta at the transcript level. Isolated placental micro-vessels from normal and preeclamptic pregnancies were used for RNA-seq analysis, real-time quantitative polymerase chain reaction (RT-qPCR) verification, and vascular function tests. Furthermore, a vascular function-centric core network was constructed to show the gene-gene interactions and gene-function associations in the placental vessel system. Differential expression analysis identified a total of 486 significantly changed transcripts. Bioinformatics analysis further confirmed that multiple genes were highly related to blood vessel and placental phenotypes. Several hub genes, including ELMO1, YWHAE, and IL6ST, were significantly reduced in the placental vessels in preeclampsia. Vascular tension experiments showed that angiotensin II-mediated vasoconstriction and exogenous NO donor sodium nitroprusside-induced vasodilation were decreased, while phenylephrine-mediated vascular responses were unchanged in placental micro-vessels in preeclampsia. The results provide important insights into the pathological process in the placental vasculature in preeclampsia and offer great potential for further investigation of these molecular targets in the human placental vascular system.

Are Δ9-Tetrahydrocannabinol and Its Major Metabolites Substrates or Inhibitors of Placental or Human Hepatic Drug Solute-Carrier Transporters?

Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis which is being increasingly consumed by pregnant people. In humans, THC is sequentially metabolized in the liver to its circulating metabolites 11-hydroxy-THC (11-OH-THC, psychoactive) and 11-nor-9-carboxy-THC (THC-COOH, non-psychoactive). Human and macaque data show that fetal exposure to THC is considerably lower than the corresponding maternal exposure. Through perfused human placenta studies, we showed that this is due to the active efflux of THC (fetal-to-maternal) by a placental transporter(s) other than P-glycoprotein or breast cancer resistance protein. The identity of this placental transporter(s) as well as whether THC or its metabolites are substrates or inhibitors of hepatic solute carrier transporters is unknown. Therefore, we investigated whether 5 μM THC, 0.3 μM 11-OH-THC, and 2.5 μM THC-COOH are substrates and/or inhibitors of placental or hepatic solute carrier transporters at their pharmacologically relevant concentrations. Using HEK cells overexpressing human OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, OAT4, or NTCP, and prototypic substrates/inhibitors of these transporters, we found that THC and THC-COOH were substrates but not inhibitors of OCT1. THC-COOH was a weak substrate of OCT3 and a weak inhibitor of OAT4. THC, 11-OH-THC, and THC-COOH were found not to be substrates/inhibitors of the remaining transporters investigated.

Anatomical study of brachial plexuses of a koala, a Tasmanian devil, and a common ringtail possum.

Marsupials have a narrower range of forelimb morphological features than placental mammals. It is hypothesized that this is due to a constraint in the reproductive biology of marsupials. The constraint is that newborn marsupials must crawl into their mother's pouch. However, anatomical knowledge of the brachial plexus in marsupials is scarce and has not been discussed. In the present study, the purpose is to examine the anatomy of the brachial plexuses of a koala, a Tasmanian devil, and a common ringtail possum and to discuss the brachial plexus of marsupials with reference to the previous reports. One adult koala (Phascolarctos cinereus) specimen, one adult Tasmanian devil (Sarcophilus harrisii), and one adult common ringtail possum (Pseudocheirus peregrinus) were used in this study. The ventral rami of C5, C6, C7, C8, and T1 formed the brachial plexus in all 3 marsupials. Each nerve branch differed by one segment among the 3 marsupials. Therefore, the brachial plexus was considered in the form of a few differences among marsupials. Because of a quite difficulty of getting an opportunity for anatomical examination on marsupials, an accumulation of cases like the present study is needed for future quantitative and qualitative analyses of the brachial plexus pattern of the marsupials.

Epigenetic dynamics of partially methylated domains in human placenta and trophoblast stem cells

BackgroundThe placenta is essential for nutrient exchange and hormone production between the mother and the developing fetus and serves as an invaluable model for epigenetic research. Most epigenetic studies of the human placenta have used whole placentas from term pregnancies and have identified the presence of partially methylated domains (PMDs). However, the origin of these domains, which are typically absent in most somatic cells, remains unclear in the placental context.ResultsUsing whole-genome bisulfite sequencing and analysis of histone H3 modifications, we generated epigenetic profiles of human cytotrophoblasts during the first trimester and at term, as well as human trophoblast stem cells. Our study focused specifically on PMDs. We found that genomic regions likely to form PMDs are resistant to global DNA demethylation during trophectoderm reprogramming, and that PMDs arise through a slow methylation process within condensed chromatin near the nuclear lamina. In addition, we found significant differences in histone H3 modifications between PMDs in cytotrophoblasts and trophoblast stem cells.ConclusionsOur findings suggest that spatiotemporal genomic features shape megabase-scale DNA methylation patterns, including PMDs, in the human placenta and highlight distinct differences in PMDs between human cytotrophoblasts and trophoblast stem cells. These findings advance our understanding of placental biology and provide a basis for further research into human development and related diseases.