bims-placeb 2025-11-23 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–11–23
seventeen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss.
Inducible Trophoblast-Specific Knockdown of Mechanistic Target of Rapamycin Impairs Placental Folate Transport in Mice.
Towards early diagnosis of Preeclampsia: Emerging roles of circulating microRNAs.
E-cigarette exposure during pregnancy impairs uterine artery blood flow and feto-placental function.
Placental mitochondrial respiration is inhibited in mice with trophoblast specific AdipoR2 overexpression.
Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality.
Exploring eNOS-Caveolin-1 interaction in placentas of SARS-Cov-2 positive pregnancies.
In Vitro Evaluation of the Impact of Oxygen Concentrations on Thrombomodulin Expression in a First-Trimester Trophoblast Cell Line.
Influenza a(H1N1) virus infection impairs syncytiotrophoblast functions by promoting ferroptosis through the TNF-α/ISG15/EGR1 axis.
ZIKV infection causes placental inflammation through activating PANoptosis.
Adenosine promotes trophoblast proliferation without inducing differentiation or apoptosis.
The long-term impact of obesity in pregnancy on offspring hypothalamic feeding pathways.
5-Hydroxymethylcytosine Dynamics Reveals Coordinated Reprogramming of Parental Genomes and X Chromosome Dosage Balance in Mouse SCNT Embryos.
Polystyrene nanoparticles induced adverse pregnancy outcomes via the activation of placental ferroptosis and gut microbiota dysfunction.
Melatonin mitigates Autophagy: Unlocking Conditional Resilience in Sheep Trophoblast Cells Exposed to a Hypoxic Environment.
Placenta-derived extracellular vesicles in maternal plasma of Hb Bart's fetuses.
New models of implantation: towards a whole better than the sum of parts.

bioRxiv. 2025 Oct 02. pii: 2025.09.30.679604. [Epub ahead of print]

Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss.

Purbasa Dasgupta, Rajnish Kumar, Soma Ray, Namrata Roy, Asef Jawad Niloy, Mounika Vallakati, Courtney Marsh, Sebastian J Arnold, Soumen Paul.

1-2% of all human pregnancies suffer from idiopathic recurrent pregnancy loss (RPL) and underlying molecular causes are poorly understood. Here we show that defective Protein Arginine Methyltransferase 1 (PRMT1) function in trophoblast progenitors is a molecular cause for early pregnancy failure. PRMT1 is conserved in trophoblast progenitors and conditional deletion of PRMT1 in mouse trophoblast progenitors arrests placenta and embryonic development leading to lethality ∼E7.5. Remarkably, a subset of idiopathic RPL is associated with loss of PRMT1 in cytotrophoblast progenitors (CTBs). Experiments with human trophoblast stem cells (hTSCs), derived from these RPL-patients as well as PRMT1-depleted hTSCs revealed that PRMT1 is crucial for trophoblast progenitors self-renewal. Employing RNA-seq and CUT&RUN-sequencing in hTSCs, CTBs and primary mouse trophoblast progenitors we discover that PRMT1 promotes transcription of trophoblast stem-state regulators, like TEAD4 and MYBL2, by directly enriching histone H4 arginine 3 asymmetric di-methylation (H4R3Me2a) at their chromatin loci. PRMT1 is also essential for extravillous trophoblast (EVT) development during human placentation, while loss of PRMT1 in hTSCs spontaneously promotes syncytiotrophoblast (STB) differentiation. Our findings indicate that PRMT1 is an epigenetic governor that orchestrates mammalian trophoblast development and implicate the therapeutic potential of targeting the PRMT1-H4R3Me2a axis to mitigate early pregnancy loss.

DOI: https://doi.org/10.1101/2025.09.30.679604
J Nutr Biochem. 2025 Nov 17. pii: S0955-2863(25)00351-1. [Epub ahead of print] 110189

Inducible Trophoblast-Specific Knockdown of Mechanistic Target of Rapamycin Impairs Placental Folate Transport in Mice.

Hiroshi Shimada, Johann Urschitz, Theresa L Powell, Thomas Jansson, Fredrick J Rosario.

  Folate deficiency in pregnancy is strongly associated with fetal growth restriction (FGR). Fetal folate availability is determined by maternal folate intake and the capacity of the placenta to transport folate. However, the mechanisms regulating placental folate transport remain poorly understood. The mechanistic target of rapamycin (mTOR) regulates placental function and fetal growth, but it is unknown if mTOR regulates folate transport in vivo. We hypothesized that trophoblast-specific mTOR knockdown inhibits placental folate transport in mice. We generated transgenic mice with a doxycycline-inducible, trophoblast-specific Mtor knockdown using PiggyBac transposase-enhanced pronuclear injection. Doxycycline administration on embryonic day (E) 14.5 induced placental-specific Mtor knockdown, resulting in reduced fetal weight, placental weight, and fetal-to-placental weight ratio. Functionally, mTOR knockdown reduced folate uptake in isolated trophoblast plasma membranes (TPM), decreased the TPM protein expression of the three main placental folate transporters (FRα, RFC, and PCFT) without affecting protein expression of theses transporters in placental homogenates, and lowered fetal plasma folate concentration. In conclusion, mTOR signaling is a positive regulator of the three main placental folate transporters in vivo mediated by posttranslational mechanisms, likely involving effects of plasma membrane trafficking. Trophoblast mTOR signaling is essential for maintaining adequate fetal folate supply and we propose that the inhibition of placental mTOR signaling reported in FGR contributes to fetal folate deficiency and decreased fetal growth in this pregnancy complication. Our data supports the potential to target placental mTOR signaling as a novel intervention in pregnancies affected by abnormal fetal growth.

Keywords:  FRα; Maternal-Fetal Exchange; PCFT; Placenta; RFC; fetal growth restriction; folate transporters; mTOR

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110189
Eur J Obstet Gynecol Reprod Biol. 2025 Nov 11. pii: S0301-2115(25)01098-X. [Epub ahead of print]316 114822

Towards early diagnosis of Preeclampsia: Emerging roles of circulating microRNAs.

Guilherme Brasil Grezzana, Airton Tetelbom Stein, Melissa Medeiros Markoski.

  Preeclampsia (PE) is a pregnancy-specific hypertensive disorder and a major contributor to maternal and fetal morbidity and mortality worldwide. Its pathophysiology involves placental dysfunction, immune dysregulation, heightened inflammatory activation, imbalance between angiogenic and antiangiogenic factors, and metabolic alterations. Despite extensive research, early diagnosis of PE remains challenging, as current approaches rely on specialized professionals, costly biochemical tests, and advanced equipment, which are not always widely accessible. Emerging evidence indicates that microRNAs (miRNAs) secreted by placental trophoblasts play a central role in regulating placental function, and their altered expression is closely associated with both early- and late-onset PE. Circulating miRNAs in maternal blood therefore represent promising early biomarkers of this gestational complication. However, the heterogeneity of miRNA expression across populations, shaped by genetic, epigenetic, and ethnic factors, highlights the need for population-specific diagnostic strategies. We propose that systematic investigation of early pregnancy miRNA signatures in diverse populations could enable the development of accessible, accurate, and clinically relevant diagnostic tools for PE.

Keywords:  Biomarkers; Gestational hypertension; Placenta; Preeclampsia; Public health; microRNAs

DOI:  https://doi.org/10.1016/j.ejogrb.2025.114822
Toxicol Sci. 2025 Nov 17. pii: kfaf161. [Epub ahead of print]

E-cigarette exposure during pregnancy impairs uterine artery blood flow and feto-placental function.

Zianne A Olverson, Sierra J Saldaña, Roy A Miller, Matthew W Gorr.

  The popularity of electronic cigarettes (e-cigs) has risen in recent years, largely due to perceptions of reduced harm compared to traditional tobacco cigarettes. E-cig use has spread into vulnerable populations such as adolescents and individuals of reproductive age, yet their safety during pregnancy remains poorly understood. E-cigs differ from conventional cigarettes in composition, and their aerosolized components may uniquely affect the uterine environment and placental function. Proper placental development, maternal vascular remodeling and tone are essential for healthy pregnancy outcomes, but it remains unclear how e-cig aerosol components affect these processes. To address this gap, we investigated how in utero exposure to sub-ohm e-cig aerosols, with and without nicotine, affects maternal and fetal cardiovascular function, uterine vascular function, and placental morphology. Pregnant female FVB/J mice were exposed to filtered air (FA), vehicle (propylene glycol/vegetable glycerin; PG: VG or PV), or vehicle with nicotine (PV + Nicotine) from embryonic day (E) 0.5 to E17.5 (4 hours/day, 5 days/week). Maternal and fetal cardiovascular parameters were assessed at E16.5 via echocardiography and ultrasound. At E17.5, maternal, fetal and placental tissues were collected for histological and molecular analysis. E-cig exposure resulted in maternal diastolic dysfunction, reduced uterine artery (UtA) blood flow, fetal bradycardia, structural alterations in the placenta, and reduced placental sufficiency. These effects were observed in both e-cig exposure groups, with some differences between the PV and PV + Nicotine groups, suggesting that exposure to aerosolized e-cig vehicle components alone can also contribute to gestational impairments. Our findings demonstrate that e-cig exposure during pregnancy disrupts cardiovascular adaptation and fetal development, highlighting the need for reevaluation of e-cig safety during pregnancy and guiding future mechanistic studies of its effects on placental and vascular dysfunction.

Keywords:  Electronic cigarettes; maternal exposure; vaping in pregnancy

DOI:  https://doi.org/10.1093/toxsci/kfaf161
Free Radic Biol Med. 2025 Nov 18. pii: S0891-5849(25)01370-X. [Epub ahead of print]

Placental mitochondrial respiration is inhibited in mice with trophoblast specific AdipoR2 overexpression.

Hiroshi Shimada, Toshihide Sakuragi, Kenneth Barentsen, Kathryn Erickson, Johann Urschitz, Theresa L Powell, Thomas Jansson, Fredrick J Rosario.

  Maternal circulating levels of adiponectin are inversely correlated with fetal growth mediated by its effect on placental function. The cellular effects of adiponectin on trophoblast are mainly mediated by adiponectin receptor isoform 2 (AdipoR2,) resulting in the activation of PPARα and synthesis of ceramides, which inhibit insulin and mTOR signaling. We have recently demonstrated that trophoblast-specific overexpression of AdipoR2 in pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Trophoblast mTORC1 signaling is a positive regulator of mitochondrial respiration. However, it is unknown if placental adiponectin signaling is mechanistically linked to mitochondrial function. We hypothesized that trophoblast-specific overexpression of AdipoR2 in pregnant mice decreases placental oxidative phosphorylation. At Embryonic day (E) 3.5, blastocysts from super-ovulated, time-mated B6D2F1 female mice were collected and transduced with lentivirus constructs for AdipoR2-overexpression (AdipoR2-OX) or scramble (SCR) sequences. The blastocysts were surgically transferred to pseudo-pregnant CD-1 recipient dams. Following euthanasia at E18.5, we separated the labyrinth and the junctional zone. In the labyrinth, AdipoR2 overexpression significantly inhibited placental mitochondrial GMPP respiration as determined by high-resolution respirometry. Moreover, placental AdiopoR2-OX decreased GLUD1, TOM22 and PGC1α protein expression. In the junctional zone, we found no significant differences between control (SCR) and AdipoR2-OX groups. In conclusion, our data suggests that maternal adiponectin signaling in the trophoblast decreases placental mitochondrial respiration, specifically in the labyrinth zone. This effect is possibly mediated by inhibition of mTORC1 and decreased expression of PGC1α.

Keywords:  Adiponectin; cell respiration; fetal development; maternal-fetal exchange; pregnancy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.025
Cell Mol Life Sci. 2025 Nov 19. 82(1): 413

Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality.

Sarah E Conduit, Cindy X W Zhang, Wayne Pearce, Julie Guillermet-Guibert, Amanda N Sferruzzi-Perri, Bart Vanhaesebroeck.

  The placenta is essential for embryonic development, in part by mediating nutrient transfer from mother to embryo. Placental insufficiency is the most common cause of intrauterine growth restriction which has long-term health consequences lasting into adulthood. p110β is a class IA phosphoinositide 3-kinase (PI3K) catalytic subunit, a family of lipid kinases which are critical regulators of adult metabolism, immunity and embryonic and placental development. However, unlike the other class IA PI3K isoforms, the in vivo functions of p110β remain unclear. While homozygous p110β kinase-dead mice are mostly embryonically lethal, some survive into adulthood with no apparent phenotypes, other than reduced fertility. The mechanism(s) underlying this embryonic lethality remain unclear. Therefore, we performed an in-depth characterisation of p110β kinase-dead embryos, revealing a previously unrecognised role for p110β in controlling the expression of system A amino acid transporters. We show that homozygous p110β kinase-dead embryos are phenotypically normal, but growth-restricted and exhibit placental insufficiency. The placenta is small with a reduced nutrient storing junctional zone and downregulation of the system A amino acid transporters, required for maternal-to-embryo amino acid transfer. These data suggest defective amino acid transfer drives embryonic growth restriction and partial lethality of p110β kinase-dead embryos. This predominantly embryonic p110β phenotype is consistent with the notion that system A amino acid transporters are more critical during development than in adult physiology. The greater significance of p110β in development than in adult homeostasis may also help explain why p110β inhibitors, compared to inhibitors of other PI3K isoforms, are well-tolerated in adults.

Keywords:   PIK3CB ; Drug target; Inhibitor; Nutrient transporters; PI 3-kinase; Placenta

DOI:  https://doi.org/10.1007/s00018-025-05937-w
Hum Immunol. 2025 Nov 14. pii: S0198-8859(25)00386-6. [Epub ahead of print]86(6): 111615

Exploring eNOS-Caveolin-1 interaction in placentas of SARS-Cov-2 positive pregnancies.

Canan Hurdag, T Önel, K Sandal, S Demircan.

   BACKGROUND: The placenta serves as a vital interface between mother and fetus, facilitating nutrient exchange and immune regulation. Although generally effective in preventing pathogen transmission, some viruses such as CMV and Zika can cross this barrier. The mechanism of vertical transmission of SARS-CoV-2 remains unclear.
OBJECTIVE: To investigate the expression and interaction of caveolin-1 (Cav-1) and endothelial nitric oxide synthase (eNOS) in placental tissues from SARS-CoV-2-positive pregnancies and their potential role in limiting vertical transmission.
MATERIALS AND METHODS: Placental samples were obtained from RT-PCR-confirmed COVID-19-positive and healthy pregnancies. Histological, immunohistochemical, and immunofluorescence techniques were used to evaluate tissue morphology and Cav-1/eNOS expression.
RESULTS: Control placentas exhibited intact villous structures, normal erythrocyte morphology, and strong Cav-1 and eNOS expression in endothelial cells. SARS-CoV-2-positive placentas showed villous damage, swollen erythrocytes, decreased collagen, and reduced endothelial expression of Cav-1 and eNOS. Cav-1 was absent in syncytiotrophoblasts in all samples.
CONCLUSION: Reduced expression of Cav-1 and eNOS in endothelial cells, combined with the absence of Cav-1 in syncytiotrophoblasts, may contribute to the placental resistance against SARS-CoV-2. These findings support the hypothesis that molecular features of the placenta, particularly involving Cav-1/eNOS pathways, play a protective role in preventing vertical transmission.

Keywords:  COVID-19; Caveolin-1; Placenta; SARS-CoV-2; Vertical transmission; eNOS

DOI:  https://doi.org/10.1016/j.humimm.2025.111615
Arch Med Res. 2025 Nov 15. pii: S0188-4409(25)00152-3. [Epub ahead of print]57(4): 103332

In Vitro Evaluation of the Impact of Oxygen Concentrations on Thrombomodulin Expression in a First-Trimester Trophoblast Cell Line.

Paula Cardona, Daniel Palacios, Anny Alvarez, Alicia E Damiano, Reggie García-Robles, Paola Ayala-Ramírez.

   INTRODUCTION: The placenta is a transient organ essential for fetal development. Abnormal placental development can lead to obstetric syndromes, such as preeclampsia (PE) and fetal growth restriction (FGR). Physiological hypoxia activates intracellular pathways via hypoxia-inducible transcription factors (HIFs), which are crucial for placentation. This study uses an in vitro model to investigate the role of oxygen concentration in the expression of thrombomodulin (THBD), a protein involved in placental hemostasis.
METHODS: Swan 71, a first-trimester trophoblast cell line, was cultured under normoxic (21 % O2) and physiological hypoxic (2 and 8 % O2) conditions. Hypoxia/reoxygenation assays were also performed. To assess potential modulation of THBD expression by HIF-1α, cobalt chloride (CoCl₂) was used to stabilize HIF-1α, while zinc chloride (ZnCl₂) inhibited its expression. RT-qPCR and Western blot analyses were performed to quantify THBD and KLF4 expression.
RESULTS: Significant increases in THBD mRNA and protein levels were observed under 2 % O2 conditions (p = 0.03). CoCl2 treatment further enhanced THBD and KLF4 expression (p < 0.01 in both experiments), while ZnCl2 inhibited these effects (p < 0.01). This suggests a key role for HIF-1α in THBD regulation. However, in silico analysis did not identify any direct hypoxia response elements within the human THBD gene, suggesting the presence of an indirect regulatory mechanism potentially involving KLF4.
DISCUSSION: These results suggest that physiological hypoxia positively regulates THBD expression through HIF-1α stabilization and KLF4-mediation. These findings provide insight into the molecular mechanisms of placental adaptation to hypoxia and are relevant for understanding pregnancy complications like PE and intrauterine growth restriction (IUGR).

Keywords:  Hypoxia; Hypoxia-inducible factor 1; Kruppel-like factor 4; Placenta; Pregnancy complications

DOI:  https://doi.org/10.1016/j.arcmed.2025.103332
Virol J. 2025 Nov 17. 22(1): 379

Influenza a(H1N1) virus infection impairs syncytiotrophoblast functions by promoting ferroptosis through the TNF-α/ISG15/EGR1 axis.

Yetian Zhao, Yanwen Wang, Kailun Huang, Feifei Wang, Yan Wang.

  Influenza A virus (IAV) is linked to adverse pregnancy outcomes like spontaneous abortion, preterm birth, and neonatal death. Inhibition of trophoblast cell fusion by IAV infection is a key factor contributing to these adverse pregnancy outcomes. Cytokine TNF-α modulates fusion defects in human trophoblast cells. Ferroptosis, a new form of programmed cell death, involves iron-dependent lipid peroxide buildup. It's unclear if the adverse outcomes of IAV infection on pregnant women are related to trophoblast cell ferroptosis. This study made a syncytiotrophoblast (STB) cell model by treating BeWo cells with forskolin (FSK) in vitro. We investigated the impact of H1N1 virus infection on trophoblast cell syncytialization. We found TNF-α expression rose significantly in H1N1-infected fused trophoblast cells, causing ferroptosis and disrupting syncytialization. ISG15 was identified as a downstream gene of TNF-α, and its knockdown reversed the effects of TNF-α. ISG15 overexpression enhanced ferroptosis-related gene transcription via EGR1, further disrupting syncytialization. EGR1 was found to promote TNF-α transcription, thereby forming a TNF-α, ISG15, EGR1 positive feedback loop. In vivo TNF-α inhibition reduced ferroptosis markers and improved trophoblast cell fusion. This investigation demonstrated that H1N1 infection initiates ferroptosis and compromises trophoblast cell fusion through the TNF-α/ISG15/EGR1 pathway. These findings imply a potential therapeutic approach for pregnancy complicated by influenza A virus infection.

Keywords:  EGR1; Ferroptosis; H1N1; ISG15; Syncytification; TNF-α

DOI:  https://doi.org/10.1186/s12985-025-02995-1
J Virol. 2025 Nov 20. e0175925

ZIKV infection causes placental inflammation through activating PANoptosis.

Shuqing Zhang, Delin Chen, Kexin Zhang, Minjie Liu, Hao Liang, Linyue Liang, Jingyao Liang, Minqi Liang, Shu An, Mingcui Lyu, Junying Zhu, Shangwei Li, Dingwen Hu, Xun Zhu, Jueheng Wu, Zhenjian He, Mengfeng Li.

  Infection by the Zika virus (ZIKV) during pregnancy can cause congenital Zika syndrome (CZS) or other central nervous system conditions in infants, underscoring the importance of understanding the role of ZIKV-induced placental damage in the development of CZS. Here, we established a ZIKV-infected pregnant mouse model and examined the pathological changes in the placenta following ZIKV infection. We found that ZIKV infection induces severe placental inflammation associated with trophoblast PANoptosis. Specifically, ZIKV activates RIG-I and recruits ASC, caspase-1, NLRP3, caspase-8, and RIPK1 to form a PANoptosome complex, leading to the activation of PANoptosis. Moreover, the combined use of Z-VAD-FMK with GSK872 or with the RIG-I inhibitor RIG012 robustly suppressed ZIKV-induced cell death, attenuated the inflammatory response in trophoblast cells and the placenta induced by ZIKV infection. Collectively, we elucidate a previously unrecognized mechanism by which ZIKV infection causes severe placental inflammation by activating PANoptosis and provide a foundation for the potential application of anti-PANoptotic therapy against ZIKV-associated diseases.IMPORTANCEZika virus (ZIKV), a mosquito-borne virus, has caused significant disease in humans during outbreaks over the last decade. Currently, there is no approved preventive vaccine or specific therapeutic drug against ZIKV. The World Health Organization declared a Public Health Emergency of International Concern regarding microcephaly and other neurological disorders caused by ZIKV during pregnancy in 2016, highlighting the importance of understanding the role of the maternal-fetal barrier in this viral disease. The mechanism by which ZIKV causes placental pathogenesis, however, remains unclear. In this study, our data elucidate a previously unrecognized mechanism underlying ZIKV infection that causes severe placental inflammation by activating PANoptosis. Furthermore, we propose a treatment that effectively inhibits ZIKV-induced PANoptosis and attenuates the inflammatory response in trophoblast cells in vitro and in vivo.

Keywords:  PANoptosis; ZIKV; placental inflammation; trophoblast cells

DOI:  https://doi.org/10.1128/jvi.01759-25
Placenta. 2025 Nov 07. pii: S0143-4004(25)00741-6. [Epub ahead of print]172 150-158

Adenosine promotes trophoblast proliferation without inducing differentiation or apoptosis.

Mohammed N H Ali, Mariia Adler, Magdalena Novotna, Viktor Gala, Cilia Abad, Frantisek Staud, Lukas Cerveny.

   OBJECTIVE: Adenosine and other nucleosides are essential regulators of cellular processes, but their specific roles in trophoblast growth and regulation remain incompletely defined. This study investigated the effects of purine and pyrimidine nucleosides on trophoblast proliferation, and further examined whether adenosine influences apoptosis, differentiation, or the expression of its receptors, transporters, and metabolizing enzymes.
METHODS: Nucleoside-induced proliferation was assessed by measuring metabolic activity, DNA synthesis, total DNA content, and MKI-67 expression in BeWo and JEG-3 cell lines, and by PCNA protein levels in placental explants. Adenosine was further evaluated for its effects on apoptosis, cytotrophoblast differentiation, and gene expression. Apoptosis was assessed via caspase-3 and -8 activity, differentiation by human chorionic gonadotropin (hCG) secretion and ERVW-1 expression, and gene regulation by qPCR analysis of adenosine receptors, nucleoside transporters, and metabolizing enzymes.
RESULTS: All nucleosides promoted proliferation in BeWo and JEG-3 cells, as indicated by increased metabolic activity, DNA synthesis, and total DNA content. For adenosine, MKI-67 expression analysis further confirmed its pro-proliferative effect. In placental explants, only adenosine significantly increased PCNA levels. Furthermore, adenosine did not affect caspase activity, hCG secretion, ERVW-1 expression, or the gene and protein expression of adenosine receptors, transporters, and metabolizing enzymes.
CONCLUSIONS: Nucleosides, particularly adenosine, promote trophoblast proliferation. Adenosine has no additional effects on differentiation, apoptosis, or transcriptional changes in genes regulating its signaling or metabolism. Given adenosine's diverse biological roles beyond proliferation, further research is warranted to explore its broader impact on placental function and adaptation, especially under pathological conditions.

Keywords:  Adenosine; Adenosine receptors; Apoptosis; Differentiation; Proliferation; Trophoblast

DOI:  https://doi.org/10.1016/j.placenta.2025.11.005
R Soc Open Sci. 2025 Nov;12(11): 250681

The long-term impact of obesity in pregnancy on offspring hypothalamic feeding pathways.

Pit Shan Chong, Laura Dearden.

  An accumulating body of evidence shows that offspring exposure to maternal obesity in the peri-natal period causes an increased risk to develop obesity later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is preceded by increased food intake, implicating altered brain control of food intake as a likely cause. The hypothalamus is crucial for regulating feeding behaviour and energy homeostasis. This article reviews findings from human and animal studies to provide an updated perspective on how maternal obesity alters fetal hypothalamic development, predisposing offspring to long-term metabolic dysfunction. We discuss how maternal obesity impacts on hypothalamic development and the key molecular mechanisms, including epigenetic modifications, hormonal disruption, neuroinflammation and gut-brain axis interactions, which may mediate these changes. We highlight the critical gaps that remain in understanding the specific molecular pathways driving neurodevelopmental alterations in offspring, as well as emerging areas of research, including the role of extracellular vesicles in maternal-fetal communication. An in depth understanding of the molecular mechanisms that mediate the link between maternal metabolic state and offspring hypothalamic control of feeding is crucial in informing public health policies and clinical interventions aimed at reducing the intergenerational transmission of obesity.

Keywords:  developmental programming; feeding; hypothalamus; obesity; pregnancy

DOI:  https://doi.org/10.1098/rsos.250681
Adv Sci (Weinh). 2025 Nov 18. e09682

5-Hydroxymethylcytosine Dynamics Reveals Coordinated Reprogramming of Parental Genomes and X Chromosome Dosage Balance in Mouse SCNT Embryos.

Zeming Xiang, Rui Yan, Jing Guo, Mengyao Wang, Xin Cheng, Fan Zhang, Tianzi Guo, Xin Long, Fan Guo, Dan Liang.

  Somatic cell nuclear transfer (SCNT) embryos exhibit widespread epigenetic defects, particularly aberrant DNA methylation. DNA 5-hydroxymethylcytosine (5hmC) is involved in methylation reprogramming during early embryonic development, yet its role in SCNT embryos remains largely unknown. Here, the genome-wide 5hmC landscapes in mouse SCNT embryos are systematically profiled with parental allele specificity. It is revealed that both maternal and paternal genomes of donor somatic cells acquire a transient, sperm-like but attenuated and allele symmetric distribution of 5hmC at the 2-cell stage, distinct from the parental asymmetric pattern observed in naturally fertilized eggs. This is characterized by insufficient DNA hydroxymethylation of the X chromosome in female SCNT embryos, as well as resistance to 5hmC-associated DNA demethylation at germline imprinting control regions (gICRs). While de novo 5hmC generation is closely associated with initial DNA demethylation during somatic-to-zygotic transition, it later becomes uncoupled from ongoing methylation changes. Importantly, global elevation of 5hmC via Tet3 overexpression leads to premature activation of developmental genes at the 2-cell stage and severely impairs SCNT embryo development. These findings reveal unique dynamics and functional consequences of abnormal 5hmC remodeling in SCNT embryos, highlighting the precise regulation of 5hmC generation as a key epigenetic event for successful mammalian cloning.

Keywords:  5‐hydroxymethylcytosine; embryonic development; epigenetic barrier; somatic cell nuclear transfer

DOI:  https://doi.org/10.1002/advs.202509682
Reprod Toxicol. 2025 Nov 19. pii: S0890-6238(25)00284-9. [Epub ahead of print]139 109113

Polystyrene nanoparticles induced adverse pregnancy outcomes via the activation of placental ferroptosis and gut microbiota dysfunction.

Zhilong He, Jijiao Cai, Ruitong Liu, Weici Yan, Guoqi Yang, Runxiong Yu, Lili Xin, Zhongxiao Wan.

  Maternal exposure to microplastics, particularly polystyrene nanoparticles (PS-NPs), is an emerging environmental threat associated with adverse pregnancy outcomes. However, the underlying mechanisms, especially the potential involvement of placental ferroptosis and gut microbiota, remain largely unexplored. This study aimed to elucidate whether and how maternal exposure to 50-nm PS-NPs disrupts pregnancy in a mouse model, with a focus on gut microbiota dysbiosis and placental ferroptosis. We found that PS-NPs exposure during pre-mating and gestation induced gut microbiota dysbiosis (e.g., increased Campylobacterota and Helicobacter) and triggered placental ferroptosis, as evidenced by iron accumulation, lipid peroxidation, and dysregulation of key proteins associated with ferroptosis. These cellular disruptions led to impaired placental barrier function, increased inflammation, and ultimately, adverse pregnancy outcomes, including elevated embryo resorption and reduced fetal weight. Crucially, correlation analysis linked specific gut microbiota alterations to ferroptosis and pregnancy loss. Furthermore, in vitro experiments confirmed that ferroptosis inhibitors alleviated PS-NPs-induced trophoblast dysfunction. These results suggest that maternal exposure to PS‑NPs may contribute to adverse pregnancy outcomes via inducing gut‑microbiota dysbiosis and placental ferroptosis, which might be potential focus for future mechanistic and therapeutic investigations.

Keywords:  Ferroptosis; Gut microbiota; Microplastics; Pregnancy

DOI:  https://doi.org/10.1016/j.reprotox.2025.109113
Reprod Fertil. 2025 Nov 19. pii: RAF-25-0084. [Epub ahead of print]

Melatonin mitigates Autophagy: Unlocking Conditional Resilience in Sheep Trophoblast Cells Exposed to a Hypoxic Environment.

Irene Viola, Paolo Accornero, Elisa Quarati, Isabella Manenti, Silvia Miretti, Francisco Canto, José Alfonso Abecia, Paola Toschi.

   Abstract: Melatonin is a key molecule in supporting pregnancy success in sheep, particularly under suboptimal conditions. In humans, melatonin is also known for its antioxidant properties. Additionally, it has recently been reported that melatonin differentially drives cell fate in normal vs altered trophoblast cells. Given that, we hypothesize that melatonin is a potential partner for trophoblasts to overcome a hypoxic environment during the early stage of pregnancy. Here, we explore the effect of melatonin on early trophoblast cell behaviour and its potential mitigating effect in CoCl2-induced hypoxia. Cell functionality and autophagy modulation were studied on ovine primary trophoblast cells (oTCs) 24 hours treated with 250µM melatonin with/without 200µM CoCl2. First, melatonin exerts its antioxidant effects by reducing H2O2 levels under hypoxic cellular conditions (P < 0.0001). CoCl2 suppressed cell proliferation and migration (P < 0.0001); however, melatonin supplementation partially restored oTCs functionality (P < 0.05). Melatonin-mediated cytoprotective effects are manifested even through the modulation of cell fate mechanisms, particularly autophagy and apoptosis. Increased protein expression of autophagic markers (BCLN1 and LC3BII/LC3BI ratio) in concomitance with a decreased phosphorylation of mTOR was observed in CoCl2-treated cells (P < 0.01), while a reduced rate of autophagy was detected following melatonin co-treatment (P < 0.01). Similarly, melatonin attenuates the CoCl2-induced increase in apoptosis when administered concurrently (5.5 vs 1.8%, P < 0.01). These findings suggest that melatonin promotes autophagy over apoptosis, indicating a shift toward cell survival mechanisms. Additionally, melatonin enhances cell functionality under hypoxia, suggesting the conceptus benefits from melatonin, particularly when it is forced to grow in a suboptimal environment.
Lay Summary: Melatonin is known for its role in regulating reproduction in sheep; however, very little is known about the role it plays in the development of the placenta. Here, we take you through how melatonin helps the placental cells survive in a low-oxygen environment, a condition called hypoxia. In this environment, we found that melatonin helps the placental cells function and reduces their death rate by helping them recycle damaged parts to survive. Overall, our findings highlight melatonin as a powerful molecule playing a role in placental cells' survival and how they function under stressful conditions. Since hypoxia is a common cause of pregnancy complications, melatonin could be a valuable aid for both animals and humans. Indeed, this study shows that melatonin isn't just a sweet little pill-it's mighty and should only be used when truly needed.

Keywords:  autophagy; hypoxia stress; melatonin; placenta; sheep

DOI:  https://doi.org/10.1530/RAF-25-0084
Sci Rep. 2025 Nov 20. 15(1): 41140

Placenta-derived extracellular vesicles in maternal plasma of Hb Bart's fetuses.

Piya Chaemsaithong, Puntabut Warintaksa, Pornpimol Ruangvutilert, Suchaya Luewan, Chayawat Phatihattakorn, Kasem Raungrongmorakot, Noppadol Chaiyasit, Tachjaree Panchalee Tachjaree, Maneerat Prakobpanich, Jirawan Panachan, Thanasikan Kunsawat, Wararat Chiangjong, Somchai Chutipongtanate.

  Hemoglobin (Hb) Bart's disease is the most common cause of hydrops fetalis among Southeast Asians. Given its high fatality rate, prenatal diagnosis and treatment are the key. This condition is associated with placental hypoxia, which can trigger the release of placenta-derived extracellular vesicles (EVs) into the maternal circulation. We aimed to determine the levels of placenta-derived EVs and the proteomic profiles of plasma EVs in women with fetuses with Hb Bart. This prospective cohort study included women with: (1) normal term pregnancies (Group 1; n = 19); (2) Hb Bart's fetuses with hydropic features (Group 2; n = 4); (3) Hb Bart's fetuses without hydrops (Group 3; n = 7); (4) placental associated complications (a disease control group or Group 4; n = 4); and (5) hydrops fetalis from non-Bart's causes (Group 5; n = 5). Maternal plasma EVs were isolated as well as characterized, and their placental alkaline phosphatase (PLAP) content was quantified via ELISA. Proteomic profiles were determined via mass spectrometry. The EVs from the women with fetuses with Hb Bart's with hydrops were smaller than those from the women in the normal and disease control groups. Bart fetuses with hydropic features had higher PLAP levels per EV particle than normal pregnancies. However, PLAP levels per EV seemed to be highest in the patients with placenta-associated complications. Among the 16 differentially expressed EV proteins, hnRNPA2B1 showed the greatest difference between women who had fetuses with Hb Bart's hydrops and those with normal pregnancies or placenta-associated complications. The 16 proteins are involved in aberrant immune responses, pro-inflammatory cytokine regulation, and vascular injuries. These changes may be the result of placental hypoxia associated with Hb Bart's hydrops.

Keywords:  Exosomes; Extracellular vesicle; Hb Bart’s; Hydrops fetalis; Placenta-derived exosome; Proteomics

DOI:  https://doi.org/10.1038/s41598-025-24900-0
Hum Reprod. 2025 Nov 17. pii: deaf223. [Epub ahead of print]

New models of implantation: towards a whole better than the sum of parts.

T M Rawlings, S A Guttridge, E S Lucas.

  Recent advances in the development of stem-cell-based embryo models and endometrial assembloids have fuelled understanding of their respective biology. However, a faithful combined approach is required to truly advance our understanding of implantation processes. This mini-review considers the most recent developments in producing reliable in vitro models of the human endometrium and human embryo, and the next steps required to combine their respective potential. While the fundamental biology of implantation is the primary driver of in vitro model development, the combined effort of embryo and endometrial models to generate new models of implantation provides the opportunity to manipulate either compartment to further understand the aetiologies of reproductive dysfunction. Through combining both systems, their efforts are symbiotic, each extending the relevance and utility of their counterpart to generate a whole greater than the sum of its parts.

Keywords:   in vitro models; blastoid; early pregnancy; embryo; human endometrium; implantation; stem-cell-based embryo model

DOI:  https://doi.org/10.1093/humrep/deaf223