bims-placeb 2025-08-24 papers

Sci Rep. 2025 Aug 18. 15(1): 30275

Dynamic shifts in trophoblast nucleos(t)ide metabolism, transport, and adenosine signaling during gestation and preterm birth.

Mohammed Ali, Mariia Adler, Antonin Libra, Ivan Vokral, Rona Karahoda, Eva Cifkova, Miroslav Lisa, Jakub Tomek, Magdalena Novotna, Frantisek Staud, Lukas Cerveny.

Nucleos(t)ides are essential for DNA/RNA synthesis, energy metabolism, and signaling, yet their roles in placental development remain poorly understood. The placenta undergoes dynamic metabolic adaptations throughout gestation to support fetal growth. This study investigates gene expression shifts in nucleos(t)ide metabolism, transport, and adenosine signaling during placental development and in the pathological condition of spontaneous preterm birth (PTB). We analyzed gene expression in first-trimester (n = 10) and term (n = 10), and PTB (n = 10) human placentas, and in cytotrophoblast and syncytiotrophoblast stage in primary human trophoblasts (n = 3) and BeWo (n = 5) cells. For developmental context, rat placentas were examined at gestation days (GD) GD12, GD15, and GD20 (n = 5 per group) that correspond to early second trimester in the human placenta. We found that genes involved in nucleos(t)ide metabolism and adenosine signaling were dominantly upregulated from early gestation to term in the human placenta. PTB placentas revealed further elevation compared to the term placenta. Differentiation from cytotrophoblast to syncytiotrophoblast was accompanied by only minor changes. Pearson's correlation analysis revealed strong gene-metabolite and gene-gene associations, highlighting an integrated metabolic network regulating placental function. Gene expression also differed among the tested GDs in the rat placenta. These findings demonstrate dynamic changes of nucleos(t)ide metabolism during healthy placental development and enhanced expression in PTB placentas, suggesting increasing needs for nucleos(t)ides during placental growth and metabolic shifts in the PTB placenta. Our data also indicate that nucleos(t)ide metabolism is preserved in both proliferative and differentiated states.

Keywords: Adenosine receptors; Cytotrophoblast and syncytiotrophoblast; Nucleoside transporters; Nucleotide and nucleoside metabolism in placenta; Placental gene expression; Preterm birth

DOI: https://doi.org/10.1038/s41598-025-16183-2

Biol Reprod. 2025 Aug 19. pii: ioaf191. [Epub ahead of print]

Identifying Established Human Placental Markers of Schizophrenia in Rodents after Gestational Delta-9-Tetrahydrocannabinol Exposure.

Andrea M Kocsis, Enzo Perez-Valenzuela, Mar Rodríguez-Ruiz, Mohammed H Sarikahya, Anubha Dembla, David R C Natale, Steven R Laviolette, Daniel B Hardy.

Placental complications resulting in fetal growth restriction (FGR) have been associated with dysregulated placental gene expression tied to an increased risk of schizophrenia (SCZ). In rat offspring, it has been demonstrated that THC exposure in pregnancy results in FGR and SCZ-like phenotypes (e.g. decreased pre-pulse inhibition of the acoustic startle response). However, it remains elusive if prenatal THC exposure induces this SCZ signature of placental gene expression. Therefore, our objective was to determine if these established predictive markers of SCZ are altered in a preclinical model of gestational oral THC exposure in rodents. We observed significantly reduced fetal weights in male and female prenatal THC-exposed offspring in the absence of maternal alterations. Placentae from THC-exposed males and females revealed altered expression of genes previously identified in human transcriptomic datasets of SCZ (i.e. Furin, Rccd1, Atp5mk), with some expression changes being sex-specific (i.e. Eif5, Rps10, Vps33b, Iqgap1). A subset of these genes was found altered in human BeWo cells exposed to THC. Targets were examined in the adult rodent (PND70) brain, and a subgroup of these genes (i.e. Furin, Rccd1) were altered concomitant with SCZ-like behaviour (decreased PPI). We further detected THC-induced upregulation of FURIN in patient-derived cerebral organoids, an effect observed in control and SCZ cell lines. Collectively, these findings demonstrate prenatal THC exposure can lead to altered gene expression in established prioritized markers of SCZ in the placenta in both animal and human models.

Keywords: Cannabis; Dohad; Fetal growth restriction; Placenta; Schizophrenia (scz); Δ9-tetrahydrocannabinol (thc)

DOI: https://doi.org/10.1093/biolre/ioaf191

Compr Physiol. 2025 Aug;15(4): e70040

Deciphering the Molecular Dialogue: Mitochondria, Epigenetics, and Extracellular Vesicles in Placental Function and Pregnancy Complications.

Yu-Chin Lien, Rebecca A Simmons.

Placental dysfunction is implicated in the pathogenesis of multiple pregnancy complications. Mitochondria are the powerhouse of the cell and are critical for placental metabolism and function. Several pregnancy complications are associated with oxidative stress and mitochondrial alterations. Mitochondrial function is also essential for epigenetic modifications, which are pivotal in regulating gene expression during pregnancy. Extracellular vesicles (EVs) carry and transfer a variety of biological molecules, including intact mitochondria and mitochondrial components, and act as modifiers of epigenetics in recipient cells. Changes in the EV profile may serve as biomarkers for pregnancy complications. In the present review, we summarize the associations of mitochondrial dysfunction, epigenetic alterations, and changes in EVs that are associated with pregnancy complications. We also describe the link between mitochondria and epigenetics, mitochondria in EVs, and EVs in epigenetic modifications, which provide insight into the possible implications of crosstalk among mitochondria, epigenetics, and EVs in regulating placental function and adverse pregnancy outcomes.

DOI: https://doi.org/10.1002/cph4.70040

Reprod Sci. 2025 Aug 18.

SPI1 Transcriptional Activates TXNRD1 to Protect Trophoblast Cell from Ferroptosis.

Tiantian Chen, Ruxiu Ge, Jie Bai, Haiteng Ye.

Preeclampsia (PE) is a severe complication of pregnancy characterized by hypertension and organ dysfunction. Abnormal low expression of thioredoxin reductase 1 (TXNRD1) in the placenta has been implicated in the pathogenesis of PE. This study aimed to investigate the role of TXNRD1 in PE and its association with ferroptosis. In our study, placental tissues collected from healthy pregnant women and PE patients, as well as trophoblast cell lines (HTR-8 and JEG-3) were employed in this study. QPCR, Western blot, and immunohistochemistry (IHC) were performed to detect the genes expression. Additionally, ferroptosis level was tested by assessing cell activity, reactive oxygen species (ROS) levels, lipid oxidation, and key ferroptosis-related proteins. The transcriptional regulation mechanism of TXNRD1 was explored using bioinformatics tools, dual luciferase reporter assay, ChIP-qPCR, and electrophoretic mobility shift assay (EMSA). Our results showed that TXNRD1 expression was significantly lower in the placenta of PE patients compared to healthy controls. Consistently, the protein levels of GPX4 and SLC7A11, which are inhibitors of ferroptosis, were reduced in PE, while the levels of COX2 and ACSL4, promoters of ferroptosis, was increased. Overexpression of TXNRD1 in trophoblast cells enhanced ferroptosis resistance, as evidenced by increased cell activity, reduced ROS levels, inhibited lipid oxidation, and altered expression of ferroptosis-related proteins. Conversely, knocking down TXNRD1 exacerbated erastin-induced ferroptosis. Furthermore, we identified SPI1 as a transcriptional activator of TXNRD1, which was also abnormally low expressed in the placenta of PE patients. Overexpression of SPI1 protected trophoblast cells from ferroptosis, which was reversed by inhibiting TXNRD1 expression. Collectively, our findings reveal that SPI1-mediated transcriptional regulation of TXNRD1 plays a protective role in ferroptosis of trophoblast cell, and impeded TXNRD1 expression might involve in PE, advancing our understanding of its pathogenesis.

DOI: https://doi.org/10.1007/s43032-025-01945-0

Acta Physiol (Oxf). 2025 Sep;241(9): e70093

AMPK: Accumulating Evidence in Support of its role in Dual Regulation of Vascular Function and Metabolism During Human Pregnancy.

Lorna G Moore, Stephanie R Wesolowski, Ramón A Lorca, Colleen G Julian.

Adenosine monophosphate-activated protein kinase (AMPK) serves to match perfusion with metabolism. Since pregnancy necessitates significant changes in both perfusion and metabolism for supporting fetal growth, surprising is that AMPK has received scant attention during pregnancy, perhaps due to the complexity of its actions and multiple maternal, placental, and fetal targets. Here we review human as well as experimental animal studies documenting AMPK activation's broad-ranging maternal effects. Emphasized are those affecting vascular control and blood flow to the uteroplacental circulation under conditions of chronic hypoxia. Time and dosage-dependent effects on the placenta and the fetus are also reviewed, revealing that AMPK activation affects all three-maternal, placental, and fetal-pregnancy compartments. We point to the need for an integrated study of AMPK's effects in each compartment during normal as well as fetal growth-restricted (FGR) pregnancies. Since there are currently no therapies for FGR apart from early delivery, whereas there are drugs or nutritional substances activating AMPK approved for human use, such agents may represent new treatments. However, understanding their molecular mechanisms and specific actions in pregnancy compartments is required before conducting such trials.

Keywords: blood flow; carbohydrate metabolism; fetal growth restriction; high altitude; hypoxia; preeclampsia

DOI: https://doi.org/10.1111/apha.70093

Genes Dis. 2025 Nov;12(6): 101665

Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion.

Cong Li, Shengya Wang, Jing Tang, Xin Luo, Luxing Ge, Youlong Xie, Lijuan Fu, Lingling Ruan, Enoch Appiah Adu-Gyamfi, Fangfang Li, Yingxiong Wang, Hongbo Qi, Yubin Ding.

Successful placental development and pregnancy rely on effective extravillous trophoblast (EVT) invasion. The mechanisms underlying inadequate EVT invasion in recurrent spontaneous abortion (RSA) remain unclear. WAS/WASL interacting protein family member 1 (WIPF1), the key regulator of cytoskeletal dynamics, is exclusively expressed in first-trimester placental EVTs. Knockdown experiments revealed WIPF1's crucial involvement in successful placental development; reduced levels impaired cell migration, while overexpression induced the opposite effects. Moreover, WIPF1 knockdown in hTSC-derived EVTs hampered trophoblast differentiation. WIPF1 interacted with ACTN4 to regulate podosome formation, matrix degradation, and actin polymerization, potentially mediated by its ARG54 site. Notably, WIPF1 was significantly down-regulated in human RSA patient EVTs and RSA mice trophoblast giant cells (CBA/J × DBA/2). This association suggests WIPF1 as a potential key player in RSA pathogenesis. In conclusion, our study spotlights WIPF1 as a pivotal factor in EVT invasion, emphasizing its multifaceted roles and implications in pregnancy complications like RSA.

Keywords: Extravillous trophoblasts; Invasion; Podosome formation; Recurrentspontaneous abortion; WIPF1

DOI: https://doi.org/10.1016/j.gendis.2025.101665

Hum Genomics. 2025 Aug 19. 19(1): 94

Variants of NLRP genes encoding subcortical maternal complex components are linked to biparental placental mesenchymal dysplasia.

Ayaka Murase, Hiroyuki Mishima, Saori Aoki, Satoshi Hara, Musashi Kubiura-Ichimaru, Takashi Ohba, Koh-Ichiro Yoshiura, Hidenobu Soejima.

BACKGROUND: Placental mesenchymal dysplasia (PMD) is a placental abnormality resembling partial hydatidiform moles without trophoblastic proliferation. Although many PMD cases involve androgenetic/biparental mosaicism or chimerism, we recently reported that approximately 30% of cases retain biparental genomes (BiPMD) and exhibit aberrant methylation at multiple imprinted differentially methylated regions (DMRs). This resembles multilocus imprinting disturbances (MLIDs) and biparental hydatidiform moles (BiHMs), which are associated with pathogenic variants in subcortical maternal complex (SCMC) genes. However, the involvement of SCMC variants in BiPMD pathogenesis remains unclear.
RESULTS: We performed whole-exome sequencing on seven mothers with BiPMD during pregnancy, focusing on SCMC-related and DNA methylation maintenance genes. We identified compound heterozygous frameshift and missense variants in NLRP5 in one mother, and a heterozygous missense variant in NLRP2 in another. In silico predictions suggested that the NLRP5 frameshift variant was pathogenic, whereas the missense variants were deemed likely benign. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) of placental tissues revealed aberrant methylation patterns in multiple imprinted DMRs. The affected DMRs varied between cases and within the same case, with abnormalities also observed in macroscopically normal placental regions.
CONCLUSIONS: These findings suggest that maternal variants in NLRP genes, which encode components of the SCMC, may contribute to the development of BiPMD with MLIDs. SCMC dysfunction due to SCMC gene mutations may cause aberrant methylation at imprinted DMRs in early embryos with cell-to-cell variation in the affected DMRs among cells, leading to a mosaic pattern of abnormal cells and normal cells. Through differentiation into placental tissues in this mosaic condition, BiPMD with aberrant methylation of multiple DMRs can occur. Taken together, our findings support the hypothesis that MLID in live-born individuals, BiPMD, and BiHMs may collectively represent a continuum within the MLID spectrum. Further studies are needed to elucidate how SCMC dysfunction leads to imprinting errors and to improve the diagnosis and understanding of PMD and related imprinting disorders.

Keywords: DNA methylation; Differentially methylated regions; Genomic imprinting; Hydatidiform mole; Multilocus imprinting disturbances; Placental mesenchymal dysplasia; Subcortical maternal complex

DOI: https://doi.org/10.1186/s40246-025-00814-w

iScience. 2025 Aug 15. 28(8): 113181

Placental epigenetic clocks derived from crowdsourcing: Implications for the study of accelerated aging in obstetrics.

DREAM Placenta Clock Challenge Consortium

Epigenetic gestational age acceleration has been implicated in obstetric syndromes including preeclampsia, yet robust conclusions require accurate and unbiased epigenetic age models. Herein, we curated 1,842 public placental methylomes and organized a DREAM challenge to develop models of gestational age. Participants were blinded to the test data that we generated from 384 placentas encompassing normal and complicated pregnancies. Models developed during and post-challenge compared favorably to existing models in terms of accuracy, yet they were better calibrated throughout gestation and indicated that reports of accelerated epigenetic aging in preterm preeclampsia were likely due to modeling artifacts. The models show that accelerated aging is associated with a decrease in birthweight percentiles in male neonates delivered at term. By contrast, preterm accelerated aging was protective against delivery of a small-for-gestational-age neonate regardless of fetal sex. This work informs our understanding of the fetal sex-dimorphic role of the placenta epigenome in obstetrics.

Keywords: Epigenetics; Pregnancy

DOI: https://doi.org/10.1016/j.isci.2025.113181

Hum Reprod. 2025 Aug 18. pii: deaf116. [Epub ahead of print]

Paracetamol (N-acetyl-para-aminophenol) disrupts early embryogenesis by cell cycle inhibition.

STUDY QUESTION: Does paracetamol (N-acetyl-para-aminophenol (APAP) also known as acetaminophen) interfere with cell division and thereby disrupt pre-implantation embryonic development?
SUMMARY ANSWER: Our findings suggest that APAP exposure inhibits cell cycling during pre-implantation development (PID) through the reduction of DNA synthesis, potentially resulting in early embryonic loss.
WHAT IS KNOWN ALREADY: It is estimated that 10-40% of all human conceptions fail around the time of implantation. Genetic factors explain ∼50% of early embryonic loss, leaving a substantial portion of early losses without a known cause. Smoking and alcohol are established risk factors for spontaneous abortion, underscoring the importance of the chemical environment during embryonic development.
STUDY DESIGN, SIZE, DURATION: To address the challenges in determining the mechanism of action and the effects of APAP during PID, we utilized a range of approaches, including in vitro, ex vivo, and in vivo methods across various models ranging from yeasts to human embryos and women of fertile age.
PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 90 human embryos were exposed in vitro (22 cleavage stage and 68 blastocyst-stage embryos). Endometrial tissue and uterine fluid were collected from seven women as part of an endometrial scratching procedure. Follicular fluid was collected from 26 women during transvaginal ultrasound guided aspiration of the pre-ovulatory follicles. All human material was sampled in accordance with relevant guidelines and regulations with consent from the regional scientific ethical committee of the Capital Region of Denmark and signed informed patient consent given prior to donation. All mouse experiments were approved by the Danish Animal Experiments Inspectorate and under EU directive 2010/63/EU on the protection of animals used for scientific purposes. The cultivation of the human embryonic stem cell lines H1 and HUES4 was conducted in compliance with relevant guidelines and regulations, following approval from the regional scientific ethical committee of the Capital Region of Denmark.
MAIN RESULTS AND THE ROLE OF CHANCE: After exposure to APAP, we found an unequivocal repression of cell division across all used model systems. APAP exposure hindered cell cycle progression, likely by inhibiting ribonucleotide reductase, leading to reduced DNA synthesis and accumulation in the S-phase. At concentrations found in the reproductive system of women after standard dosing, APAP exposure decreased cell numbers in mouse and human cleavage-stage embryos or caused direct embryonic death. Similar exposure to mouse and human blastocyst-stage embryos resulted in a reduced inner cell mass and decreased DNA synthesis, respectively.
LIMITATIONS, REASONS FOR CAUTION: A limitation of the study is the low number of available human cleavage-stage embryos. However, the high number of human blastocysts and our translational approach, which demonstrated reproducibility across various model systems, partly addressed this limitation. Further studies are needed to confirm the potential association between APAP use and pregnancy loss in prospective cohorts.
WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that the widely used mild analgesic APAP could contribute to early embryonic loss by impairing initial cell divisions. These results suggest that APAP should be used with caution by women attempting to conceive. Given that cell division is fundamental to all development, further investigation is now warranted to substantiate these findings and to elucidate possible implications for other developmental processes, such as gonadal and brain differentiation.
STUDY FUNDING/COMPETING INTEREST(S): The research was funded by the Lundbeck Foundation (R324-2019-1881). Authors P.S. and H.K.M. were affiliated with the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW; NNF21CC0073729). H.K.M. received a fellowship from the Novo Nordisk Foundation as part of the Copenhagen Bioscience PhD Program, supported by grant NNF19SA003544. M.H and A.D. are part of the National French Research Infrastructure France Exposome and have received funding from the European Regional Development Fund and Britanny region (Contrat Plan Etat Region, project Exposome, AIDEN 106201).
TRIAL REGISTRATION NUMBER: N/A.

Keywords: DNA synthesis inhibition; acetaminophen; cell cycle; early embryo development; embryonic loss; paracetamol; ribonucleotide reductase

DOI: https://doi.org/10.1093/humrep/deaf116

FASEB J. 2025 Aug 31. 39(16): e70961

WTAP Dysregulation Mediates HLF-m6A Modification to Inhibit Trophoblast Ferroptosis in Preeclampsia.

Shuang Liu, Li Zhang, Yan Li, Xi Jia, Junling Kang, Manni Sun, Xiaoxuan Zhang, Jun Tang, Tao Meng.

Preeclampsia (PE) is a severe pregnancy-specific disorder that poses significant risks to maternal and perinatal health. The pathophysiological mechanisms underlying PE are complex and not yet fully elucidated. This study focuses on the role of ferroptosis in PE and identifies a significant downregulation of the transcription factor hepatic leukemia factor (HLF) in PE placental tissues. Further investigations reveal that HLF transcriptionally activates solute carrier family 7 member 11 (SLC7A11) to inhibit trophoblast ferroptosis, thereby maintaining their proliferation, migration, and invasion functions. Additionally, Wilms' tumor 1-associating protein (WTAP), a key factor in N6-methyladenosine (m6A) methylation, regulates HLF mRNA stability in an m6A-dependent manner, influencing the expression of its downstream target SLC7A11. This study, for the first time, systematically clarifies the critical role of the WTAP/HLF/SLC7A11 signaling axis in the pathogenesis of PE from the perspective of ferroptosis. The findings offer a novel theoretical basis for further exploration of the molecular mechanisms of PE and potential intervention targets for precision therapy.

Keywords: HLF; SLC7A11; WTAP; ferroptosis; preeclampsia

DOI: https://doi.org/10.1096/fj.202500937RR