BACKGROUND: The rapid increase in cannabis use during pregnancy-up by 170 % between 2009 and 2016-raises pressing concerns about its effects on fetal health, particularly on the delicate monoamine system within the fetoplacental unit, which is crucial for placental function and neurodevelopment. OBJECTIVE: This systematic review explores the impact of prenatal cannabinoid exposure on the monoamine system within the fetoplacental unit, with a focus on its implications for fetal development through the lens of the Developmental Origins of Health and Disease (DOHaD) framework. METHODS: A comprehensive search across multiple databases initially retrieved 18,252 papers. After rigorous screening, only 16 animal studies and 4 human studies met the inclusion criteria. Findings were synthesized to evaluate the effects of prenatal cannabis exposure on neurotransmitter regulation, receptor function, and gene expression. RESULTS: Although no studies directly addressed the monoamine system in the placenta, animal models revealed significant disruptions in neurotransmitter regulation and neurodevelopmental changes following prenatal cannabis exposure. Human studies suggested potential cognitive and behavioral risks for offspring exposed in utero. CONCLUSION: This review exposes a critical gap in the literature on cannabis' effects on the placental monoamine system. While evidence points to notable neurodevelopmental risks, the scarcity of focused research underscores the need for further investigation to fully understand the implications of prenatal cannabis exposure.

• Klíčová slova
• Animal models, Cannabinoid, Cannabis, Dopamine, Fetal health, Monoamine system, Neurodevelopment, Pregnancy, Prenatal exposure, Serotonin, Tetrahydrocannabinol,
• MeSH
• biogenní monoaminy metabolismus   MeSH
• kanabinoidy * metabolismus   MeSH
• lidé MeSH
• placenta * metabolismus   účinky léků   MeSH
• těhotenství MeSH
• vývoj plodu účinky léků   MeSH
• zpožděný efekt prenatální expozice * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• biogenní monoaminy MeSH
• kanabinoidy * MeSH

The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental "methylome" is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.

• Klíčová slova
• DNA methylation, DNMT3L, differentiation, epigenetics, histone modifications, human trophoblast stem cells, partially methylated domains, placenta, syncytiotrophoblast,
• MeSH
• DNA-(cytosin-5-)methyltransferasa * metabolismus   genetika   MeSH
• epigenom MeSH
• kmenové buňky metabolismus   cytologie   MeSH
• lidé MeSH
• metylace DNA * genetika   MeSH
• myši MeSH
• placenta * metabolismus   cytologie   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   cytologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-(cytosin-5-)methyltransferasa * MeSH

Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality.

• Klíčová slova
• Anti-β2GPI antibodies, Antiphospholipid syndrome, Cell proliferation, Endothelial cells, Mouse model, NK cells, Placenta, RNAseq, Trophoblasts,
• MeSH
• antifosfolipidový syndrom * imunologie   patologie   MeSH
• buňky NK * imunologie   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• placenta * metabolismus   patologie   MeSH
• proliferace buněk MeSH
• stanovení celkové genové exprese MeSH
• těhotenství MeSH
• transkriptom MeSH
• trofoblasty metabolismus   patologie   imunologie   MeSH
• uterus * patologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Syncytin-1, a human fusogenic protein of retroviral origin, is crucial for placental syncytiotrophoblast formation. To mediate cell-to-cell fusion, Syncytin-1 requires specific interaction with its cognate receptor. Two trimeric transmembrane proteins, Alanine, Serine, Cysteine Transporters 1 and 2 (ASCT1 and ASCT2), were suggested and widely accepted as Syncytin-1 cellular receptors. To quantitatively assess the individual contributions of human ASCT1 and ASCT2 to the fusogenic activity of Syncytin-1, we developed a model system where the ASCT1 and ASCT2 double knockout was rescued by ectopic expression of either ASCT1 or ASCT2. We demonstrated that ASCT2 was required for Syncytin-1 binding, cellular entry, and cell-to-cell fusion, while ASCT1 was not involved in this receptor interaction. We experimentally validated the ASCT1-ASCT2 heterotrimers as a possible explanation for the previous misidentification of ASCT1 as a receptor for Syncytin-1. This redefinition of receptor specificity is important for proper understanding of Syncytin-1 function in normal and pathological pregnancy.

• Klíčová slova
• Syncytin-1, cell-to-cell fusion, endogenous retrovirus, placenta, viral receptor,
• MeSH
• antigeny CD98 - těžký řetězec MeSH
• fúze buněk * MeSH
• genové produkty env * metabolismus   genetika   MeSH
• lidé MeSH
• placenta * metabolismus   MeSH
• těhotenské proteiny * metabolismus   genetika   MeSH
• těhotenství MeSH
• transportní systém ASC pro aminokyseliny * metabolismus   genetika   MeSH
• transportní systémy pro neutrální aminokyseliny metabolismus   genetika   MeSH
• trofoblasty metabolismus   cytologie   MeSH
• vedlejší histokompatibilní antigeny metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD98 - těžký řetězec MeSH
• genové produkty env * MeSH
• SLC1A5 protein, human MeSH Prohlížeč
• SLC3A2 protein, human MeSH Prohlížeč
• syncytin MeSH Prohlížeč
• těhotenské proteiny * MeSH
• transportní systém ASC pro aminokyseliny * MeSH
• transportní systémy pro neutrální aminokyseliny MeSH
• vedlejší histokompatibilní antigeny MeSH

The placenta plays a critical role in maternal-fetal nutrient transport and fetal protection against drugs. Creating physiological in vitro models to study these processes is crucial, but technically challenging. This study introduces an efficient cell model that mimics the human placental barrier using co-cultures of primary trophoblasts and primary human umbilical vein endothelial cells (HUVEC) on a Transwell®-based system. Monolayer formation was examined over 7 days by determining transepithelial electrical resistance (TEER), permeability of Lucifer yellow (LY) and inulin, localization of transport proteins at the trophoblast membrane (immunofluorescence), and syncytialization markers (RT-qPCR/ELISA). We analysed diffusion-based (caffeine/antipyrine) and transport-based (leucine/Rhodamine-123) processes to study the transfer of physiologically relevant compounds. The latter relies on the adequate localization and function of the amino-acid transporter LAT1 and the drug transporter P-glycoprotein (P-gp) which were studied by immunofluorescence microscopy and application of respective inhibitors (2-Amino-2-norbornanecarboxylic acid (BCH) for LAT1; cyclosporine-A for P-gp). The formation of functional monolayer(s) was confirmed by increasing TEER values, low LY transfer rates, minimal inulin leakage, and appropriate expression/release of syncytialization markers. These results were supported by microscopic monitoring of monolayer formation. LAT1 was identified on the apical and basal sides of the trophoblast monolayer, while P-gp was apically localized. Transport assays confirmed the inhibition of LAT1 by BCH, reducing both intracellular leucine levels and leucine transport to the basal compartment. Inhibiting P-gp with cyclosporine-A increased intracellular Rhodamine-123 concentrations. Our in vitro model mimics key aspects of the human placental barrier. It represents a powerful tool to study nutrient and drug transport mechanisms across the placenta, assisting in evaluating safer pregnancy therapies.

• Klíčová slova
• LAT1, P‐gp, co‐culture, endothelial cell, placental barrier, polarized monolayer, primary trophoblast, transport,
• MeSH
• biologické modely MeSH
• biologický transport MeSH
• endoteliální buňky pupečníkové žíly (lidské) * metabolismus   MeSH
• inulin metabolismus   MeSH
• isochinoliny MeSH
• kokultivační techniky MeSH
• leucin metabolismus   MeSH
• lidé MeSH
• maternofetální výměna látek * MeSH
• P-glykoprotein metabolismus   MeSH
• placenta * metabolismus   MeSH
• rhodamin 123 metabolismus   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inulin MeSH
• isochinoliny MeSH
• leucin MeSH
• lucifer yellow MeSH Prohlížeč
• P-glykoprotein MeSH
• rhodamin 123 MeSH

Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.

• Klíčová slova
• OCT3, gestational diabetes mellitus, metformin, placenta, pregnancy, serotonin,
• MeSH
• biologický transport účinky léků   MeSH
• hypoglykemika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• metformin * farmakologie   MeSH
• oktamerní transkripční faktor 3 metabolismus   MeSH
• placenta * metabolismus   účinky léků   MeSH
• potkani Wistar MeSH
• proteiny přenášející organické kationty MeSH
• serotonin * metabolismus   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hypoglykemika MeSH
• metformin * MeSH
• oktamerní transkripční faktor 3 MeSH
• proteiny přenášející organické kationty MeSH
• serotonin * MeSH
• solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč

INTRODUCTION: The aim of the study was to identify predictive values of the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively. METHODS: This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within 7 days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys® sFlt-1, PlGF, and IL-6 immunoassays. RESULTS: Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p < 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs. 8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p < 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL. CONCLUSION: Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within 7 days.

• Klíčová slova
• Amniocentesis, Amniotic fluid, Angiogenic factors, Biomarker, Inflammation, Interleukin-6, PlGF, Preeclampsia, Pregnancy, Preterm birth, Preterm labor with intact membrane, Rapid point-of-care test, Receptor, VEGF, sFlt-1,
• MeSH
• biologické markery krev   MeSH
• chorioamnionitida krev   diagnóza   MeSH
• dospělí MeSH
• fetální krev metabolismus   MeSH
• interleukin-6 * krev   MeSH
• lidé MeSH
• placenta metabolismus   MeSH
• placentární růstový faktor * krev   MeSH
• plodová voda metabolismus   MeSH
• předčasná porodní činnost * krev   MeSH
• prediktivní hodnota testů * MeSH
• receptor 1 pro vaskulární endoteliální růstový faktor * krev   MeSH
• retrospektivní studie MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• FLT1 protein, human MeSH Prohlížeč
• IL6 protein, human MeSH Prohlížeč
• interleukin-6 * MeSH
• PGF protein, human MeSH Prohlížeč
• placentární růstový faktor * MeSH
• receptor 1 pro vaskulární endoteliální růstový faktor * MeSH

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways.

• Klíčová slova
• Cannabidiol, Kynurenine, Pregnancy, Serotonin, Tryptophan,
• MeSH
• kanabidiol * farmakologie   MeSH
• kynurenin metabolismus   MeSH
• lidé MeSH
• placenta * metabolismus   účinky léků   MeSH
• serotonin * metabolismus   MeSH
• těhotenství MeSH
• tryptofan * metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kanabidiol * MeSH
• kynurenin MeSH
• serotonin * MeSH
• tryptofan * MeSH

OBJECTIVES: This study aimed to determine the occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta, marked by elevated levels of interferon gamma-induced protein 10 (IP-10) (≥2200 pg/mL) in the amniotic fluid of women with preterm prelabor rupture of membranes (PPROM). Specifically, the study investigated whether these intra-amniotic inflammatory changes were more common in women with microbial invasion of amniotic cavity (MIAC) and intra-amniotic inflammation (IAI), as indicated by increased amniotic fluid interleukin (IL)-6 concentration (≥3000 pg/mL). STUDY DESIGN: A cohort of 114 women with singleton pregnancies complicated by PPROM between 24+0 and 36+6 weeks of gestation were included. Amniotic fluid samples were obtained via amniocentesis upon admission. MIAC diagnosis involved aerobic and anaerobic cultures, as well as polymerase chain reaction (PCR) analysis of the amniotic fluid. Immunoassay tests and enzyme-linked immunosorbent assay (ELISA) were used to determine IL-6 and IP-10 concentrations, respectively. RESULTS: Among the participants, 19.3 % and 15.8 % had MIAC and IAI, respectively. The occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was similar between women with and without MIAC (25 % vs. 40.9 %, p = 0.136, adjusted p = 0.213). The rate of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was significantly higher in women with IAI compared to those without, after adjusting for gestational age at sampling (55.6 % vs. 22.9 %, p = 0.005, adjusted p = 0.011). CONCLUSION: This study revealed comparable rates of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with and without MIAC, but a higher prevalence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with IAI. These findings suggest involvement of chronic inflammation even in women with PPROM with acute intra-amniotic inflammation.

• Klíčová slova
• IAI, IP-10, Interferon gamma-induced protein 10, Intra-amniotic inflammation, MIAC, Microbial invasion of the amniotic cavity, PPROM,
• MeSH
• chemokin CXCL10 metabolismus   MeSH
• chorioamnionitida * diagnóza   MeSH
• gestační stáří MeSH
• interferon gama MeSH
• lidé MeSH
• novorozenec MeSH
• placenta metabolismus   MeSH
• plodová voda metabolismus   MeSH
• předčasný odtok plodové vody * diagnóza   MeSH
• těhotenství MeSH
• zánět komplikace   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemokin CXCL10 MeSH
• interferon gama MeSH

Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development.

• Klíčová slova
• fetal brain development, intrauterine infections, placenta, programming, tryptophan metabolism,
• MeSH
• indolamin-2,3,-dioxygenasa metabolismus   MeSH
• kynurenin * metabolismus   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• placenta * metabolismus   MeSH
• poly I metabolismus   MeSH
• serotonin metabolismus   MeSH
• těhotenství MeSH
• tryptofan metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• indolamin-2,3,-dioxygenasa MeSH
• kynurenin * MeSH
• lipopolysacharidy MeSH
• poly I MeSH
• serotonin MeSH
• tryptofan MeSH