bims-placeb 2025-11-09 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–11–09
nineteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

ATOH8 is crucial for the differentiation of human trophoblast stem cells into extravillous trophoblasts.
Organoids in modeling human trophoblast development.
Variations in blood levels of the anti-fusogenic endogenous retroviral protein suppressyn are associated with fetal growth outcome in preeclampsia.
Delta 9-Tetrahydrocannabinol Signaling Through Cannabinoid Receptor 1 Alters Trophoblast Differentiation.
Urban air pollution disrupts placental microarchitecture and shifts hofbauer cells towards a pro-inflammatory state.
Resveratrol Activates SIRT1 to Inhibit Trophoblast Pyroptosis in Preeclampsia.
Sexually dimorphic responses in androgen metabolism and signalling in the non-human primate placenta to moderate maternal undernutrition.
Deconvoluting the heterogeneities of immune cells at the maternal-fetal interface of mice across pregnancy.
Role of ubiquitin‑proteasome system in preeclampsia (Review).
Placental Steroid Hormones in Preeclampsia: Multilayered Regulation of Endocrine Pathogenesis.
Mapping the placental galectin-3 interactome identifies CD9 and ITGB1 as functional glycoprotein counterreceptors during syncytialization.
Micro- and nanoplastic (MNPs) exposure at single-cell resolution impaired placental function and cellular dynamics.
Placental gene expression of the AMPK signaling pathway in association with gestational exposure to ambient air pollution.
Methionine induced placental angiogenesis through activating WNT3A/CTNNB1-PIGF-VEGFR1 pathway.
Metformin mitigates placental dysfunction by modulating gene expressions in a high-fat diet-induced rat model.
Single-cell characterization of trophoblast-epithelial interactions at the human maternal-fetal interface during early implantation.
Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.
Maternal exercise alters placental proteome in an exercise mode-specific manner.
Effects of exercise during pregnancy on maternal and newborn outcomes.

Sci Rep. 2025 Nov 04. 15(1): 38582

ATOH8 is crucial for the differentiation of human trophoblast stem cells into extravillous trophoblasts.

Joudi Salamah, Mohamed Salamah, Bum-Kyu Lee.

  The transcription factor ATOH8 regulates cell fate and differentiation during development. Loss of ATOH8 leads to defects in murine placenta development, yet its specific functions in self-renewal and differentiation of human trophoblast stem cells (TSCs) remain poorly understood. Here, we reveal that ATOH8 is critical for extravillous trophoblasts (EVTs) formation while being dispensable for the self-renewal of TSCs. We show predominant ATOH8 expression in EVTs compared to syncytiotrophoblasts (STs) and TSCs. Knockdown (KD) of ATOH8 in TSCs does not alter their morphology, proliferation, or self-renewal marker expression, indicating that ATOH8 is not required for TSC maintenance. However, during EVT differentiation, ATOH8 expression gradually increases and its depletion results in pronounced morphological abnormalities, impaired expression of EVT markers, sustained TSC marker expression, and abolished invasive capacity. Conversely, ATOH8 overexpression (OE) under self-renewing conditions modestly induces EVT markers, whereas its OE during ST differentiation disrupts ST formation by reducing cell fusion and aberrantly activating EVT genes. Transcriptomic profiling reveals that the loss of ATOH8 during EVT differentiation disrupts pathways critical for placental development, including extracellular matrix organization and PI3K-AKT signaling. We also show that ATOH8 functions within a cooperative network of EVT regulators, reciprocally regulating their expression and maintaining a transcriptional circuit essential for EVT specification. Collectively, these findings establish ATOH8 as an indispensable regulator of EVT differentiation and invasive function, orchestrating EVT-specific gene programs and pathways alongside other key transcription factors to ensure proper EVT formation.

Keywords:  ATOH8; EVT differentiation; Trophoblast lineage differentiation placental development; Trophoblast stem cells

DOI:  https://doi.org/10.1038/s41598-025-22484-3
Fertil Steril. 2025 Nov 04. pii: S0015-0282(25)01955-7. [Epub ahead of print]

Organoids in modeling human trophoblast development.

Alexander G Beristain, Gina L McNeill.

   IMPORTANCE: Human trophoblast development is essential for implantation, placental formation, and pregnancy success yet has historically been challenging to study because of limited access to early human tissues and the inadequacy of animal models to capture human-specific features. Advances in stem cell and organoid technologies have now provided tractable, renewable platforms that more faithfully reproduce human trophoblast biology.
OBJECTIVE: To summarize the development of human trophoblast organoids, outline their overall fidelity and utility for dissecting trophoblast lineage specification, and discuss their emerging role as translational tools for understanding placental development and pathologies specific to pregnancy.
EVIDENCE REVIEW: We reviewed primary literature related to primary trophoblast model systems, establishment of epithelial organoid systems, and trophoblast stem cells and organoid cultures (2018-2025) and subsequent studies that benchmarked organoids against in vivo trophoblast populations using transcriptomic, epigenetic, and functional assays. Particular attention was given to work characterizing trophoblast lineage fidelity, refinements in culture conditions, and applications of trophoblast organoids to model infection.
FINDINGS: First-trimester trophoblast organoids recapitulate villous cytotrophoblast progenitors and their capacity to generate both syncytiotrophoblast and invasive extravillous trophoblast lineages, with refinements now enabling more physiologic orientation and maturation cell states. Term and pluripotent stem cell-derived organoid systems expand the developmental spectrum, although each platform carries unique strengths and limitations. These models are beginning to yield insight into pregnancy-relevant conditions, including viral pathogenesis, impaired trophoblast invasion, and disease-associated epigenetic memory. Emerging work demonstrates that trophoblast organoids can serve as patient-specific models for interrogating placental dysfunction.
CONCLUSION AND RELEVANCE: Trophoblast organoids represent state-of-the-art in vitro systems for studying human trophoblast development, bridging a critical gap between animal models and primary tissue culture systems. By enabling detailed analysis of lineage specification and patient-specific pathophysiology, they hold great promise for advancing both fundamental discovery and translational applications in reproductive medicine, with potential future use in clinical contexts such as fertility assessment and in vitro fertilization.

Keywords:  Human placenta; epithelial organoid; trophoblast; trophoblast organoid; trophoblast stem cell

DOI:  https://doi.org/10.1016/j.fertnstert.2025.10.004
Sci Rep. 2025 Nov 03. 15(1): 38360

Variations in blood levels of the anti-fusogenic endogenous retroviral protein suppressyn are associated with fetal growth outcome in preeclampsia.

Jun Sugimoto, Danny J Schust, Takeshi Nagamatsu, Eriko Yano, Makiko Sugimoto, Tomomi Yamazaki, Yoshiki Kudo.

  Suppressyn, a placenta-specific protein characterized by its inhibitory effect on trophoblast cell fusion, is considered to play a direct role in the formation and maintenance of placental villi in humans. Given the potential involvement of aberrant suppressyn expression in the development of placenta-dependent disorders, we focused our analysis on hypertensive disorders of pregnancy, with particular emphasis on preeclampsia (PE). PE is a leading cause of maternal morbidity and mortality worldwide and poses a serious risk to fetal growth and survival. As delivery remains the only definitive treatment and no effective methods for prevention or early diagnosis have been established, there is an urgent need for investigation from novel perspectives. In the present study, we investigated the expression profiles of suppressyn and fusion-associated molecules in human placental villous tissues and maternal blood samples. Our analysis revealed two key findings: (1) suppressyn protein levels are significantly reduced in placentas from pregnancies complicated by PE with fetal growth restriction (FGR), and (2) suppressyn secretion is modulated in an ASCT2 expression-dependent manner, suggesting that the intracellular balance between suppressyn and this transporter may play a critical role in the pathophysiology of PE and in maintaining placental function. Detectable alterations in maternal serum concentrations of secreted suppressyn in pregnancies affected by hypertensive disorders of pregnancy may offer a novel biomarker that monitors placental developmental status in these disease states. These findings may also provide new insights into the molecular underpinnings of PE and a mechanistic link between suppressyn dysregulation and the development of FGR.

Keywords:  ASCT2; Cell fusion; Fetal growth restriction; Pre-eclampsia; Suppressyn

DOI:  https://doi.org/10.1038/s41598-025-22275-w
Stem Cells Dev. 2025 Nov 07.

Delta 9-Tetrahydrocannabinol Signaling Through Cannabinoid Receptor 1 Alters Trophoblast Differentiation.

Jessica L Koven, Bryony V Natale, Daniel B Hardy, David R C Natale.

  Cannabis use during pregnancy is increasing. In rodent models of delta-9 tetrahydrocannabinol (Δ9-THC) exposure during pregnancy, placental pathology, including compromised labyrinth development, is reported. Cannabinoid receptor 1 (CB1/Cnr1) is the primary mediator of Δ9-THC action, with its expression reportedly limited to the placental junctional zone in the rodent. Given a Δ9-THC-induced labyrinth-specific pathology, we predicted more diverse expression. This study aimed to elucidate the spatiotemporal expression of CB1/Cnr1 in the rodent and assess whether it mediates Δ9-THC-induced alterations in trophoblast differentiation. Results revealed CB1 expression in all maternal blood-facing trophoblast cells. Furthermore, Δ9-THC exposure (at levels matching those reported in maternal serum) had a more significant effect on the expression of markers associated with differentiating trophoblast cells than on proliferating trophoblast stem (TS) cells. Δ9-THC impacted mouse (m) TS cell differentiation in a CB1-dependent manner, reducing the expression of syncytiotrophoblast (SynT) markers, driving differentiation along the junctional zone/trophoblast giant cell pathway. mTS cells without Cnr1/CB1 (mTSCnr1KO) did not express markers of SynT cells or the differentiated junctional zone cell types. However, at a higher than physiologically relevant concentration, Δ9-THC (15 μM) induced Gcm1 (SynT) expression in mTSCnr1KO cells. This study reveals a mechanism by which Δ9-THC may impact placental growth.

Keywords:  CB1; Cnr1; TS cells; cannabinoid receptor 1; cannabis; placenta; syncytiotrophoblast; trophoblast; trophoblast differentiation; trophoblast stem cells; Δ9-THC

DOI:  https://doi.org/10.1177/15473287251392544
J Environ Sci (China). 2026 Feb;pii: S1001-0742(25)00153-6. [Epub ahead of print]160 124-134

Urban air pollution disrupts placental microarchitecture and shifts hofbauer cells towards a pro-inflammatory state.

Lena Erlandsson, Birgit Hirschmugl, Eva Hansson, Monika Horvat Mercnik, Christian Wadsack, Stefan R Hansson.

  Exposure to urban air pollution during early pregnancy is associated with increased risk for adverse pregnancy outcomes, such as preeclampsia (PE), and there is an urgent need to understand how air pollution affects biological mechanisms in the placenta. Hofbauer cells (HBCs) are fetal placental macrophages that regulate immune tolerance in the placenta. They are normally polarized towards an anti-inflammatory M2 phenotype but display a more pro-inflammatory M1 phenotype in PE. The ex vivo dual placental perfusion approach uses full term human placentas to study physiological aspects of the placenta. In this study, effects of urban traffic-derived particles of size <2.5 µm (PM2.5) on placental tissue and HBC polarization was deciphered. To study changes in placental microarchitecture and cell morphology, transmission electron microscopy was applied. In addition, changes in cell surface markers on HBCs were determined by immunohistochemistry. Exposure to PM2.5 caused disrupted collagen structures and affected cell organelles in multiple cell types inside placental villi. The resident HBC marker CD163 was not affected by PM2.5 exposure, while CD206 was reduced by 60 % and CD209 remained unchanged, indicating altered M2 polarization. Additionally, the expression of pro-inflammatory M1 markers CD40 (p = 0.02) and CD80 (p = 0.03) in HBCs increased due to urban PM2.5 exposure. Urban PM2.5 showed detrimental effects on the placenta by disrupting tissue morphology and affecting HBC polarization specifically. These results extend the currently accepted view on properties of HBCs, by demonstrating their ability to react plastically and specifically to different exogenous stimuli.

Keywords:  Air pollution; Hofbauer cells; PM(2.5); Placenta; Preeclampsia

DOI:  https://doi.org/10.1016/j.jes.2025.03.043
Reprod Sci. 2025 Nov 05.

Resveratrol Activates SIRT1 to Inhibit Trophoblast Pyroptosis in Preeclampsia.

Weizhao Lin, Jiachun Wei, Zhuojun Xie, Pingping Song, Ruiman Li.

  Preeclampsia (PE) is a hypertensive disorder of severe pregnancy complication characterized by placental dysfunction and systemic inflammation. Resveratrol (RES), a natural polyphenol, has been shown to exert anti-inflammatory effects partly through the activation of SIRT1. NLRP3 inflammasome-mediated pyroptosis plays a crucial role in placental inflammation. This study aims to investigate the role of RES in regulating trophoblast pyroptosis through SIRT1 activation in PE. Placental tissues from PE patients and normal pregnancies were analyzed for SIRT1 and pyroptosis markers. A lipopolysaccharide (LPS)-induced PE mouse model and HTR-8/SVneo trophoblasts model were used to examine for pyroptosis following RES treatment. Placental tissues from PE patients exhibited significantly reduced SIRT1 expression and elevated pyroptosis markers (NLRP3, Caspase-1) compared to normal pregnancies. In a LPS-induced PE mouse model, RES treatment ameliorated pregnancy outcomes by reducing blood pressure, proteinuria, and improving renal morphology. RES also enhanced fetal and placental development, as evidenced by decreased embryo resorption rates, increased fetal weight, and improved spiral artery remodeling. Mechanistically, RES upregulated SIRT1 expression and suppressed pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, ASC) in placental tissues of PE mice. In vitro, RES attenuated LPS-induced trophoblast dysfunction by enhancing proliferation, migration, and invasion in HTR-8/SVneo cells. This was accompanied by SIRT1-mediated suppression of pyroptosis and reduced secretion of inflammatory cytokines (IL-18, IL-1β). These findings demonstrate that RES activates SIRT1 to inhibit trophoblast pyroptosis, thereby improving placental function and pregnancy outcomes in PE. This study highlights RES as a potential therapeutic agent for PE by modulating SIRT1-mediated pyroptosis pathways.

Keywords:  Preeclampsia; Pyroptosis; Resveratrol; SIRT1

DOI:  https://doi.org/10.1007/s43032-025-02003-5
Biol Sex Differ. 2025 Nov 07. 16(1): 93

Sexually dimorphic responses in androgen metabolism and signalling in the non-human primate placenta to moderate maternal undernutrition.

Ashley S Meakin, Peter W Nathanielsz, Cun Li, Vicki L Clifton, Hillary F Huber, Michael D Wiese, Janna L Morrison.

   BACKGROUND: Maternal nutrient restriction (MNR) can increase maternal androgen concentrations during pregnancy and cause placental dysfunction leading to reduced fetal growth, especially in males. Placental androgen metabolism, as well as differential expression and subcellular localisation of androgen receptor (AR) variants, modulates androgen signalling, which may benefit placental function; however, the impact of MNR on these adaptations remains undefined. We characterised the impact of MNR and fetal sex on placental androgen signalling in a non-human primate model of pregnancy.
METHODS: Pregnant baboons (Papio spp.) were randomly assigned to control diet (Ctrl; offspring female n = 5, male n = 6) or MNR diet (70% of global Ctrl; offspring female n = 5, male n = 5) at 0.16 gestation (term = ~ 180 days). Fetuses were delivered by Caesarean section at 0.9 gestation and placenta collected. Molecular measures of sex steroid signalling and placental function were quantified using established LC-MS/MS assays, Western blot, and qRT-PCR. Data were analysed using two-way ANOVA (factors: diet, sex) with Tukey's multiple comparison test.
RESULTS: CYP17A1, SRD5A1, and PGF expression was higher, whereas HSD3B1, CYP19A1, and ANGPT2 was lower in male compared to female placentae, independent of diet. KDR expression and CYP19A1 activity increased in MNR versus Ctrl in females only. Cytoplasmic expression of the antagonistic AR variant, AR-45, was higher in males, whereas MNR increased cytoplasmic and nuclear AR-45 expression independent of sex.
CONCLUSIONS: Differences in placental steroidogenic and angiogenic genes, as well as androgen metabolism and signalling, may explain sex-specific placental responses to MNR. Better understanding of molecular regulators of androgen signalling may lead to novel, targetable therapeutics that improve placental function in complicated pregnancies associated with increased androgen concentrations.

Keywords:  Androgen receptor; Androgen signalling; Baboon; Cytochrome P450; Developmental programming; Nonhuman primate; Placenta; Sex differences

DOI:  https://doi.org/10.1186/s13293-025-00771-y
Reproduction. 2025 Dec 01. pii: e250090. [Epub ahead of print]170(6):

Deconvoluting the heterogeneities of immune cells at the maternal-fetal interface of mice across pregnancy.

Jingjing Su, Yue Wang, Qian Li, Ziwei Yin, Qingbao Liu, Liangliang Yang, Xiangxiang Jiang.

   In brief: Mice often serve as valuable surrogate models for studying human reproduction. This study provides a single-cell transcriptomic profile of mouse immune cells at the maternal-fetal interface throughout pregnancy and assesses the similarities and differences between these immune cells and human decidual immune cells.
Abstract: Homeostasis of the immune microenvironment at the maternal-fetal interface is essential for pregnancy. Immune cell heterogeneity at the maternal-fetal interface in pregnant mice remains understudied. Here, we perform in-depth single-cell transcriptomic analysis with 120,238 maternal-fetal single cells of mice from embryonic day 7.5 (E7.5) to E18.5 and in vitro experiments to establish an immune cell atlas. Macrophages constitute the largest population, with some subsets resembling human counterparts, and the number of Ccr2 + macrophages in the decidua increases as pregnancy progresses. Neutrophils constitute the second largest population, and Ifit1 + N2 neutrophils are localized close to the implantation site during early pregnancy. Three NK cell subsets were identified, including the previously reported NK1.1 - subset. In combination with in vitro experiments, the presence of T and B cells within the decidua was validated. Our work profiles a comprehensive immune cell atlas of the mouse maternal-fetal interface, offering a valuable reference for further investigations.

Keywords:  NK cell; immune cell atlas; macrophage; single-cell RNA sequencing; the maternal–fetal interface of mice

DOI:  https://doi.org/10.1530/REP-25-0090
Mol Med Rep. 2026 Jan;pii: 25. [Epub ahead of print]33(1):

Role of ubiquitin‑proteasome system in preeclampsia (Review).

Chang-Zhu Pei, Xiao-Xing Song, Hao Xu, Kwang-Hyun Baek.

  Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, primarily resulting from placental abnormalities and endothelial dysfunction. The present review explores the role of ubiquitination and deubiquitination (key post‑translational modifications), in the pathogenesis of PE. Ubiquitination, catalyzed by E1, E2 and E3 enzymes, and reversed by deubiquitinating enzymes, regulates protein stability and function, thereby influencing key cellular processes in trophoblasts. Dysregulation of these pathways impairs trophoblast functions and contributes to PE development. In addition, the present review discusses emerging therapeutic strategies targeting the ubiquitin‑proteasome system, including deubiquitinase‑targeting chimera and proteolysis‑targeting chimeras. Targeting ubiquitination and deubiquitination mechanisms presents a promising avenue for the treatment of PE. Further research into these pathways may lead to novel interventions aimed at improving maternal and fetal outcomes.

Keywords:  DUBTAC; PE; PROTAC; deubiquitination; ubiquitin ligase

DOI:  https://doi.org/10.3892/mmr.2025.13735
Endocr Rev. 2025 Nov 04. pii: bnaf039. [Epub ahead of print]

Placental Steroid Hormones in Preeclampsia: Multilayered Regulation of Endocrine Pathogenesis.

Yun Yang, Shanshan Zhang, Xiao Fang, Tengqi Shao, Xuan Shao, Yan-Ling Wang.

  The human placenta serves as the predominant endocrine organ throughout pregnancy, assuming a central role in preserving endocrine homeostasis, facilitating maternal physiological adaptation, and safeguarding fetal well-being. Preeclampsia (PE), a multifaceted and systemic gestational complication, stands a primary contributor to maternal and perinatal morbidity and mortality. Defective placental development has been extensively acknowledged as the fundamental pathological foundation underlying this condition. Accumulating evidence has unveiled a disruption in the balance of steroid hormone production within placentas affected by early-onset PE (E-PE). Considerable endeavors have been undertaken to decipher the endocrine mechanisms driving E-PE. Recent investigations have illuminated a complex, multi-tiered regulatory system that governs placental steroidogenesis, encompassing epigenetic controls such as microRNAs (miRNAs) activity and metabolic flux-conjugated histone acetylation, post-translational modifications including O-linked β-N-acetylglucosamine (O-GlcNAc), as well as intricate endocrine feedback loops among steroids and other signaling molecules like melatonin. Notably, a growing body of evidence robustly supports a causal link between elevated placental testosterone (T0) synthesis and the onset of PE. Nevertheless, comprehensive studies exploring the endocrine pathophysiology of PE remain essential to illuminate novel therapeutic avenues for mitigating this adverse pregnancy outcome.

Keywords:  estradiol; glycolysis; glycosylation; placenta; testosterone; trophoblast

DOI:  https://doi.org/10.1210/endrev/bnaf039
Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2511042122

Mapping the placental galectin-3 interactome identifies CD9 and ITGB1 as functional glycoprotein counterreceptors during syncytialization.

Abigail E Reeves, Gil-Suk Yang, Sabyasachi Baboo, Jolene K Diedrich, Pranali Bedekar, Shaheen A Farhadi, Arun Wanchoo, Christopher Bratcher, Gregory A Hudalla, John R Yates, Mia L Huang.

  The fetomaternal interface is replete with glycan-binding proteins (GBPs) that can interact with cell surface glycoprotein counterreceptors to regulate placental function. Here, we interrogate the role of galectin-3, a GBP that controls placental trophoblast syncytialization, an important differentiation process where progenitor cytotrophoblast cells fuse to produce the multinucleated syncytiotrophoblast. The molecular mechanism of galectin-3-mediated fusion has not yet been elucidated in part due to the difficulty of studying glycan-GBP binding events in live cells. To overcome these challenges, we employ a proximity labeling strategy to identify the galectin-3 interactome. From this interactome dataset, we selected and validated CD9 and integrin beta 1 as functional counterreceptors of galectin-3 and showed that CD9 is glycosylated with an N-linked glycan at a rare noncanonical sequon. Furthermore, we present evidence that galectin-3 acts to physically alter the fluidity of the cellular membrane, and it does not activate canonical syncytialization signaling pathways. Overall, we report that galectin-mediated binding events and their corresponding functions in cell biology can be precisely regulated by select glycoproteins at specific glycosites.

Keywords:  galectin-3; glycan; glycan-binding protein; proximity labeling; trophoblast

DOI:  https://doi.org/10.1073/pnas.2511042122
Ecotoxicol Environ Saf. 2025 Nov 04. pii: S0147-6513(25)01677-X. [Epub ahead of print]306 119332

Micro- and nanoplastic (MNPs) exposure at single-cell resolution impaired placental function and cellular dynamics.

Tingting Zhang, Hao Tian, Yunfei Teng, Zhao Duan, Han Dai, Dong Cheng, Jie Han, Ming Liu.

  The placenta is crucial for a successful pregnancy, acting as a protective barrier for fetal health. Growing evidence suggests that pregnant women are widely exposed to micro- and nanoplastics (MNPs), which have been implicated in placental dysfunction associated with pregnancy complications and adverse offspring outcomes. To investigate this, we characterized MNPs-induced placental cellular dynamics at the single-cell level. Our analysis of placental tissue identified 14 major cell types, including trophoblasts and immune cells. Comparative transcriptomics between control and MNPs-exposed groups revealed significant alterations in subpopulations of trophoblasts, macrophages, and fibroblasts, indicating an adaptive response to toxic stress. Specifically, we observed a marked upregulation of genes related to endoplasmic reticulum stress and xenobiotic clearance in trophoblasts, and of ECM remodeling pathways in fibroblasts. This was supported by the integration of metabolomic and proteomic data, which detailed the accompanying molecular cascades. We propose that while these processes represent an attempt to maintain placental homeostasis, prolonged or high-level MNP exposure may overwhelm such compensatory mechanisms, ultimately leading to dysfunction. Consequently, our study provides a foundational resource for understanding the cellular mechanisms of MNP-induced placental toxicity and establishes a basis for future research into protective strategies against environmental reproductive toxicants.

Keywords:  Cellular stress response; Microplastics and nanoplastics (MNPs); Placental dysfunction; Reproductive Toxicity; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119332
Environ Res. 2025 Nov 05. pii: S0013-9351(25)02533-2. [Epub ahead of print] 123280

Placental gene expression of the AMPK signaling pathway in association with gestational exposure to ambient air pollution.

Joline L Millen, Dries S Martens, Rossella Alfano, Theo M de Kok, Michelle Plusquin, Florence Debacq-Chainiaux, Thierry Arnould, Tim S Nawrot.

   OBJECTIVE: Prenatal ambient air pollution exposure is able to reach the fetus by crossing the placenta, a highly metabolically active organ. The adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is a crucial regulator of the placental cellular metabolism, necessary for normal placental and fetal development. This study investigates the association between in utero exposure to BC, NO2, and PM2.5, and differences in placental gene expression of the AMPK signaling pathway at birth.
MATERIAL AND METHODS: Transcription data from 182 placentas of the ENVIRONAGE birth cohort were obtained through microarray analysis. Exposure levels were estimated using a spatio-temporal model for the mothers' residential address during pregnancy. The associations between transcription levels of 76 genes, clustered by the cascades of the AMPK signaling pathway, and the air pollution exposures during different time windows of pregnancy were analyzed using a mixed-effects model adjusting for potential confounders.
RESULTS: Higher prenatal levels of BC, NO2, and PM2.5 were associated with downregulated gene expression of the central AMPK gene cluster and multiple upstream and downstream cascades of the AMPK signaling pathway. In a multi-pollutant model, the observed patterns of downregulation remained, supporting the robustness of the associations when considering co-exposure to different air pollutants.
CONCLUSION: This study provides new insights into the possible adverse effects of ambient air pollution exposure on placental development, affecting the placental metabolism at the transcript level. Whether reduced placental AMPK signaling may play a role in air pollution-induced birth outcomes and their long-term consequences needs to be further addressed.

Keywords:  AMPK signaling pathway; air pollution; gene expression; gestation; metabolism; placenta

DOI:  https://doi.org/10.1016/j.envres.2025.123280
Cell Commun Signal. 2025 Nov 07. 23(1): 481

Methionine induced placental angiogenesis through activating WNT3A/CTNNB1-PIGF-VEGFR1 pathway.

Yijin Zou, Jiayu Tu, Ziqi Wang, Shuang Quan, Linlu Zhao, Yiwen Yang, Xiangzhou Zeng, Shiyan Qiao, Xiangfang Zeng, Shuang Cai.

BACKGROUND: Placenta is highly susceptible to oxidative stress during pregnancy, which is a major cause of abnormal vascular development, fetal growth restriction and preterm birth. Methionine exhibits remarkable efficacy in promoting embryonic development and pregnancy outcomes, yet the role of methionine in placental antioxidant capacity and angiogenesis remains unclear.
METHODS: Pregnant rats and porcine iliac artery endothelial cells (PIECs) were used in our study. Pregnant rats were fed with methionine supplementation or methionine free diet. PIECs were treated with methionine, ROS inducer, VEGFR1 inhibitor, CTNNB1 knockdown or overexpressing.
RESULTS: Our findings revealed that dietary methionine supplementation significantly increased the levels of glutathione, while reducing the levels of malondialdehyde in rat placentae. Moreover, experiments from PIECs treatment with ROS inducer, VEGFR1 inhibitor, knockdown or overexpressing of CTNNB1 revealed that methionine regulated angiogenesis in the placenta by modulating ROS levels and the CTNNB1 signaling pathway. Mechanistically, methionine enhanced the transsulfuration metabolism in placental vascular cells, leading to the production of the antioxidant glutathione and a reduction in ROS levels, followed by activating the WNT3A/CTNNB1 signaling pathway. CTNNB1 bind to PIGF, which promoted the phosphorylation of VEGFR1, thereby enhancing angiogenesis.
CONCLUSIONS: This study elucidated that methionine promoted placental angiogenesis through the ROS-WNT3A/CTNNB1-PIGF-VEGFR1 axis, providing new therapeutic targets for pregnancy complications.

DOI: https://doi.org/10.1186/s12964-025-02488-2
Placenta. 2025 Oct 28. pii: S0143-4004(25)00728-3. [Epub ahead of print]172 114-119

Metformin mitigates placental dysfunction by modulating gene expressions in a high-fat diet-induced rat model.

Yu-Ju Lin, Yin-Hua Cheng, Ni-Chin Tsai, Li-Tung Huang, Hong-Ren Yu, You-Lin Tain, I-Chun Lin, Kuo-Chung Lan.

   BACKGROUND: Maternal obesity impairs placental development and function, contributing to adverse fetal outcomes through disrupted gene regulation and metabolic homeostasis. Metformin, an insulin-sensitizing agent, may mitigate these effects by modulating placental molecular pathways, but its comprehensive impact under obesity-complicated pregnancy remains unclear.
OBJECTIVE: To investigate whether metformin restores placental gene expression and improves placental and maternal metabolic outcomes in a rat model of maternal obesity induced by a high-fat diet (HFD).
METHODS: Female Sprague-Dawley rats were fed either a control diet or a HFD for six weeks prior to and throughout pregnancy. During gestation, a subset of HFD-fed rats received metformin (500 mg/kg/day) administered via drinking water. Maternal glucose tolerance was assessed in late pregnancy. On gestational day 21, maternal metabolic parameters, placental and fetal weights were assessed. Placental mRNA expression of genes involved in the renin-angiotensin system (RAS), nutrient-sensing (AMPK/SIRT), and nutrient transport (GLUTs, SNATs, AdipoRs) was quantified using qPCR.
RESULTS: HFD-fed dams exhibited increased maternal body weight, total fat mass, GPT levels, glucose intolerance, and placental overgrowth. Metformin significantly reversed these effects and improved glucose tolerance without affecting insulin sensitivity. At the molecular level, HFD downregulated key genes involved in RAS, AMPK/SIRT, and nutrient transport. Metformin treatment restored or upregulated the expression of these genes to near-control levels.
CONCLUSION: Metformin mitigates HFD-induced placental dysfunction by restoring vascular, metabolic, and transport gene networks, improving placental efficiency and maternal metabolic status. These findings support metformin's potential to enhance intrauterine conditions in obesity-complicated pregnancies and align with the DOHaD hypothesis, though long-term offspring outcomes require further investigation.

Keywords:  High-fat diet; Maternal obesity; Metformin; Nutrient transporters; Placenta; Renin-angiotensin system

DOI:  https://doi.org/10.1016/j.placenta.2025.10.020
Biol Reprod. 2025 Nov 04. pii: ioaf246. [Epub ahead of print]

Single-cell characterization of trophoblast-epithelial interactions at the human maternal-fetal interface during early implantation.

Suming Xu, Shimin Wang, Yaoqin Wang, Xingyu Bi, Pengfei Zhu, Yonglian Wang, Xianping Wang, Xueqing Wu.

  Human embryo implantation is crucial for successful pregnancy, yet its molecular mechanisms remain poorly understood due to ethical and technological limitations. In this study, we constructed an embryo implantation model using Single-cell RNA Sequencing (scRNA-seq) data from the implantation sites (IS) of patients with tubal ectopic pregnancy (TEP) to infer the embryo implantation mechanisms at the maternal-fetal interface during early human pregnancy. Based on scRNA-seq data from normal intrauterine pregnancies (IUP) in the public database (GSE214607), we identified and validated marker genes for trophoblast cells and their subtypes. We applied CellPhoneDB and CellChat to map intercellular communication networks at the maternal-fetal interface in the TEP model. By validating the predicted ligand-receptor interacting pairs against IUP data, we assessed the utility of the TEP model as a reference for studying implantation mechanisms. Results revealed similar gene expression patterns at the transcriptional level between trophoblast cells in TEP and IUP, and Immunofluorescence staining further supported the conserved expression of key marker genes in the two types of pregnancy tissues. Cell-cell interaction analysis suggested bidirectional ligand-receptor communications between extravillous trophoblasts (EVTs) and non-ciliated secretory epithelial cells, involving extracellular matrix remodeling, angiogenesis, and immune regulation. Meanwhile, macrophages may participate in trophoblast-immune interactions through the IL-1 signaling pathway. These signaling pathways showed a certain degree of conservation between TEP and IUP. The TEP model provides a complementary tool for studying early implantation, offering new perspectives for elucidating molecular mechanisms at the maternal-fetal interface and for preventing and treating infertility.

Keywords:  embryo implantation; maternal-fetal interface; single-cell RNA sequencing; tubal ectopic pregnancy

DOI:  https://doi.org/10.1093/biolre/ioaf246
Cell Death Discov. 2025 Nov 07. 11(1): 513

Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.

Ellen C Francis, Hiroshi Shimada, Theresa L Powell, Kristen E Boyle, Dana Dabelea, Thomas Jansson, Fredrick J Rosario.

Fetal growth restriction (FGR) is associated with inhibition of placental mTOR signaling and amino acid transport. mTOR is a positive regulator of amino acid transport mediated by controlling the plasma membrane trafficking of SNAT2, a System A amino acid transporter isoform, and LAT1 an isoform involved in System L amino acid transport. Inhibition of mTOR complex 1 decreases SNAT2 and LAT1 plasma membrane trafficking by activating of Nedd4-2, an E3 ubiquitin ligase, and inhibition of mTOR Complex 2 decreases the protein expression of Cdc42 which limits transporter trafficking to the plasma membrane. We isolated human primary trophoblast (PHT) cells from FGR placentas and demonstrate that they maintain the in vivo FGR phenotype with increased expression of DEPTOR, an endogenous inhibitor of mTOR, reduced mTOR signaling, increased Nedd4-2 expression, lower expression of Cdc42, and decreased SNAT2 and LAT 1 protein expression in the plasma membrane, and decreased System A and L activity. We silenced DEPTOR in FGR PHT cells using siRNA and found normalized mTOR signaling, Nedd4-2 and Cdc42 protein expression, SNAT2 and LAT1 plasma membrane trafficking and System A and L amino acid transport activity. We also show that hypoxia induces DEPTOR upregulation in PHT cells. In the Healthy Start Study, a longitudinal pre-birth cohort, placental DEPTOR expression was correlated with lower birth weight percentile and with higher systolic and diastolic blood pressure in children at 4-6 years of age. Together, our studies provide mechanistic and translational insight into how placental DEPTOR may serve as potential mediator of fetal growth and long-term health risk. We identify a mechanistic link between increased trophoblast DEPTOR expression in FGR and decreased placental mTOR signaling and amino acid transport. Intervention strategies aimed at normalizing trophoblast mTOR signaling may be effective to improve trophoblast nutrient transport and fetal growth in FGR.

DOI: https://doi.org/10.1038/s41420-025-02801-5
Am J Physiol Endocrinol Metab. 2025 Nov 04.

Maternal exercise alters placental proteome in an exercise mode-specific manner.

Filip Jevtovic, Breanna L Wisseman, Fahmida Jahan, Alex Claiborne, David N Collier, James E DeVente, Steven Mouro, Tonya Zeczycki, Anna Szumilewicz, Kristi Adamo, Laurie J Goodyear, Linda E May.

  Maternal exercise is a widely recommended and safe intervention associated with the improvement of maternal gestational and infant metabolic health. While various modes of exercise are deemed safe during pregnancy, the effects of supervised maternal aerobic, resistance, and combination (aerobic+resistance) exercise remain understudied. Specifically, it remains unknown how different modes of maternal exercise affect the placenta, an organ central to maternal-fetal communication and successful pregnancy outcomes. This study aimed to characterize the placental proteomic changes in response to controlled and supervised maternal exercise during gestation. Results demonstrate that the placental proteomic landscape changes in a maternal exercise mode-specific way. Additionally, proteomics revealed that ~20% of the identified placental proteins were associated with maternal exercise volume during gestation. These results highlight the differential effect maternal exercise modes have on the placental proteome and further implicate the placenta in mediating the effects of maternal exercise on maternal and infant health.

Keywords:  maternal exercise modes; placenta; pregnancy; proteomics

DOI:  https://doi.org/10.1152/ajpendo.00052.2025
BMC Pregnancy Childbirth. 2025 Nov 03. 25(1): 1158

Effects of exercise during pregnancy on maternal and newborn outcomes.

Yu Shen, Yi Wang, Peng Huang.

  There is some debate over whether exercising during pregnancy has any impact on the health of the mother or baby. While most studies indicate that moderate exercise during pregnancy is beneficial for mothers and does not harm newborns, some studies suggest that it may divert oxygen and nutrients away from the baby, which could negatively affect development. However, due to variations in the type and amount of exercise, as well as different measures used, it is difficult to compare studies. Nevertheless, most studies on the relationship between exercise and pregnancy have not reported the effects of exercise on maternal or fetal health. This review concludes that moderate exercise can benefit both mothers and babies and recommends that uncomplicated mothers exercise at a moderate level throughout their pregnancy without risk to maternal or fetal health.

Keywords:  Exercise during pregnancy; Maternal; Newborn outcome

DOI:  https://doi.org/10.1186/s12884-025-08285-6