bims-placeb 2026-02-08 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–02–08
twenty papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Exploring placental ultrastructure: A review of electron microscopy techniques and emerging methods for resolving 3D organelle architecture.
Characterization, organoid formation and differentiation potential of the novel term trophoblast cell line TB/SVTERT350.
A review of xenobiotic membrane transporter expression within the human placenta: Lessons gained from primary tissue and in vitro methodologies.
Trophoblast-specific overexpression of Slc7a5 increases fetal amino acid availability and hepatic mTOR signalling and causes increased fetal growth.
Longitudinal ultrasonographic assessment of placentome diameter and maternal ovine placental lactogen across gestation in sheep.
Determinants of Placental Versus Maternal Preeclampsia.
ESRRG downregulation in early spontaneous abortion induces mitochondrial damage, leading to impaired trophoblast function.
Maternal PM2.5 exposure causes fetal growth restriction and alters placental morphology: Role of uterine inflammation.
Oxygen and TGF-β1 jointly regulate fibronectin and trophoblast behavior highlighting a potential role for matrix signalingin severe preeclampsia.
High sensitivity ultrasound microvessel imaging for the assessment of placental health.
Molecular Signatures of Preeclampsia: The Role of Post-Translational Protein Modifications.
Dulaglutide and pregnancy: a comprehensive safety assessment using the ex vivo placenta perfusion and in vitro models.
Placental crises: disruptive selection and maternal under-investment as the foundations of mammalian placental evolution and dysfunction.
Pregnancy Outcomes Associated With Anemia in the First Trimester and Anemia Resolution by Late Pregnancy.
In vivo imaging of the rodent placenta.
Mediating role of maternal cortisol in the association between maternal serum creatinine and fetal cortisol exposure.
Early identification of umbilical blood flow restriction and maternal placental hypoperfusion with photoacoustic imaging.
Contributing to a (cell) cultural shift: Human platelet lysate is a suitable replacement for fetal calf serum when culturing the HTR8/SVneo extravillous trophoblast cell line.
Oxidative stress-mediated impairment of human trophoblast cell proliferation by zinc pyrithione exposure.
Maternal high-fat diet and its multigenerational impact on hypertension and metabolic alterations in Wistar rat offspring.

Placenta. 2026 Jan 16. pii: S0143-4004(26)00021-4. [Epub ahead of print]

Exploring placental ultrastructure: A review of electron microscopy techniques and emerging methods for resolving 3D organelle architecture.

Siddharth Acharya, Eric Hanssen, James C Bouwer, John E Schjenken, Kirsty G Pringle, Roger Smith, Joshua J Fisher.

  Trophoblast cells line the surface of placental villi, facilitating the exchange of nutrients, gases, and wastes between the maternal and fetal circulations. The fusion of cytotrophoblast (CTB) cells into the surrounding multinucleated syncytiotrophoblast (STB), is accompanied by a shift in cellular ultrastructure (subcellular architecture). Mitochondria undergo a remarkable decrease in size and alteration in morphology following trophoblast differentiation, and have thus been the subject of investigations due to their crucial role in producing energy for placental development. Observing this shift in structure has relied on the use of electron microscopy, which has offered insights into underlying mitochondrial functions. Since the initial use of electron microscopy to study villous trophoblasts in the 1950s, novel techniques have emerged that have the capacity to interrogate placental ultrastructure with unprecedented resolution. This review discusses the evolution of electron microscopy techniques to study the placenta over the last 70 years. Moreover, we discuss emerging methods for resolving 3D organelle structure within the placenta, which offer more physiologically pertinent information and context for complex topologies. Further, we discuss advanced methods of cryo-electron tomography (cryo-ET) that present the placental field with an exciting opportunity to determine the complex relationship between mitochondrial architecture and protein structure in the human placenta. By specifically focusing on mitochondrial imaging, we showcase the capacity for volume electron microscopy and cryo-ET to reveal the role of organelle structure in placental development.

Keywords:  3D structure; Cryo-EM; Mitochondria; Organelles; Placenta; Volume electron microscopy

DOI:  https://doi.org/10.1016/j.placenta.2026.01.009
Placenta. 2026 Jan 28. pii: S0143-4004(26)00030-5. [Epub ahead of print]175 73-77

Characterization, organoid formation and differentiation potential of the novel term trophoblast cell line TB/SVTERT350.

Gudrun Meinhardt, Hanna Waldhäusl, Leila Saleh, Sandra Haider, Jürgen Pollheimer, Christian Fiala, Dieter Bettelheim, Johanna Gamauf, Matthias Postl, Matthias Wieser, Regina Grillari-Voglauer, Martin Knöfler.

  Herein, we molecularly characterize the novel human term trophoblast cell line TB/SVTERT350 and show that it meets the criteria for trophoblast identity and subtype specification. TB/SVTERT350, cultured under stemness conditions in 2D or 3D, express trophoblast progenitor markers such as E-cadherin, TEAD4 and YAP1 and develop into CGβ-producing syncytiotrophoblast and HLA-G-expressing extravillous trophoblasts in the respective differentiation media. Expanding TB/SVTERT350 organoids share structural similarities with primary trophoblast organoids and express NOTCH1 suggesting that the cell line exhibits phenotypic traits of proximal cell column trophoblasts. In summary, TB/SVTERT350 could represent a reliable model for studying mechanisms of placental growth and differentiation.

Keywords:  Differentiation; Human placenta; Organoid formation; Trophoblast cell line

DOI:  https://doi.org/10.1016/j.placenta.2026.01.018
J Physiol. 2026 Feb 06.

A review of xenobiotic membrane transporter expression within the human placenta: Lessons gained from primary tissue and in vitro methodologies.

Rhiannon Pass, Kathryn Wolton, Amanda N Sferruzzi-Perri.

  The human placenta acts as a critical barrier within the body, protecting the fetus from the potentially harmful effects of xenobiotics encountered by the mother during pregnancy. Membrane transporter proteins play a central role in this protective function, yet their expression patterns and how this changes across gestation remains poorly understood. A range of in vitro models have been generated to try and understand human placental transport processes; however, uncertainties persist regarding the developmental stage and cellular composition that each model represents. This review summarises the current understanding of membrane transporter expression in the most widely used in vitro systems, including primary placental tissue, choriocarcinoma cell lines and trophoblast stem cells. It also highlights recent advances in culturing techniques. Key gaps in the knowledge are identified, and opportunities for refining experimental approaches to study xenobiotic uptake and transport across the placenta in vitro are discussed.

Keywords:  fetus; placenta; pregnancy; transport; xenobiotic

DOI:  https://doi.org/10.1113/JP289607
J Physiol. 2026 Jan 31.

Trophoblast-specific overexpression of Slc7a5 increases fetal amino acid availability and hepatic mTOR signalling and causes increased fetal growth.

Fredrick J Rosario, Hiroshi Shimada, Sam Blessen J Fredrick, Kenneth Barentsen, Theresa L Powell, Johann Urschitz, Thomas L Brown, Laura Brown, Thomas Jansson.

  Abnormal fetal growth is linked to perinatal complications and increased risk of metabolic and cardiovascular diseases, yet the underlying mechanisms remain unclear. Placental System L amino acid transport is decreased in human pregnancies complicated by fetal growth restriction and increased in fetal overgrowth. We previously demonstrated that trophoblast-specific overexpression (OX) of Slc7a5/LAT1 enhances transplacental leucine transport and fetal growth. However, the mechanistic link between increased placental transfer of leucine and stimulation of fetal growth remains unclear. We hypothesized that trophoblast-specific Slc7a5 OX in mice increases fetal plasma levels of essential amino acids, which are associated with elevated fetal circulating levels of insulin and IGF-1 and activation of fetal liver insulin/IGF-1 and mTOR signalling. Trophoblast-specific Slc7a5 OX in mice was generated by lentiviral transduction of embryonic day (E) 3.5 mouse blastocysts followed by embryo transfer. Maternal and pooled fetal plasma samples and fetal livers were collected at E18.5. Slc7a5 OX significantly increased fetal weight and fetal plasma levels of essential amino acids, including leucine, phenylalanine, tryptophan, lysine, histidine, valine, methionine and isoleucine. Insulin and IGF-1 concentrations were elevated in fetal plasma, and fetal liver showed an increased phosphorylation of p70S6K1-Threonine-389, S6-Serine-235/236 and Akt-Serine-473, indicating activation of insulin/IGF-1 and mTORC1 and mTORC2 pathways. These results support the hypothesis that placental LAT1 overexpression enhances fetal amino acid supply, driving endocrine responses and anabolic signalling that promote accelerated fetal growth. We speculate that targeting placental LAT1 may represent a novel intervention in cases of pathological fetal growth. KEY POINTS: Placental amino acid transport is critical for fetal growth and serves as a link between maternal nutrition, placental function and fetal development. Trophoblast-specific overexpression of Slc7a5 (LAT1) in mice increases placental transport of essential amino acids, including leucine and lysine. Fetal plasma amino acids, insulin and IGF-1 concentrations were elevated following LAT1 overexpression. Fetal hepatic signalling was activated, with increased mTORC1 (p-S6 Ser235/236) and mTORC2 (p-Akt Ser473) phosphorylation, while Akt Thr308 phosphorylation was unaffected. Fetuses exposed to LAT1 overexpression were larger, with increased fetal and placental weights, consistent with a fetal overgrowth phenotype. These findings demonstrate that placental LAT1 functions as a nutrient-sensing regulator of fetal growth via endocrine and metabolic signalling pathways.

Keywords:  fetal development; leucine; maternal–fetal exchange; mechanistic target of rapamycin; placenta; pregnancy complications

DOI:  https://doi.org/10.1113/JP289970
Front Vet Sci. 2026 ;13 1769704

Longitudinal ultrasonographic assessment of placentome diameter and maternal ovine placental lactogen across gestation in sheep.

Kerem Baykal, Ahmet Sabuncu, Gamze Evkuran Dal, Sinem Özlem Enginler, Aslıhan Baykal Uğur, Merve Yılmaz, Mert Sarılar.

   Introduction: Placental development in sheep involves closely coordinated morphological and endocrine processes. Ultrasonographic placentome measurements and maternal ovine placental lactogen (oPL) profiles reflect distinct components of pregnancy progression; however, their longitudinal relationship across gestation has not been clearly defined. This study aimed to characterize temporal changes in placentome diameter and maternal oPL concentrations and to evaluate how their association evolves throughout pregnancy.
Methods: Fifty clinically healthy, multiparous Kivircik ewes carrying singleton pregnancies were monitored longitudinally from Day 26 to Day 145 of gestation. Serial transabdominal ultrasonography was performed at two-week intervals to measure placentome diameter using consistent anatomical landmarks. Maternal blood samples collected at each examination were analyzed for serum oPL concentrations using validated immunoassays. Gestational changes were assessed using non-parametric repeated-measures analyses. Associations between structural and endocrine variables were examined using day-specific correlation analyses and within-ewe models that accounted for repeated observations and individual baseline variability.
Results: Placentome diameter increased rapidly during early gestation, rising from approximately 1.3 cm at Day 26 to around 3.5 cm by mid-gestation, after which values stabilised and showed only minor fluctuations toward term. Maternal oPL concentrations increased progressively from early pregnancy, reaching peak values of approximately 15-16 μg/mL in late gestation before declining near parturition. No significant association between placentome diameter and oPL concentration was detected during early gestation. Transient inverse relationships were observed at selected mid-gestational time points, whereas from late gestation onward, a consistent positive association emerged. Within-ewe analyses demonstrated a strong positive co-variation between placentome diameter and circulating oPL concentrations after controlling for inter-individual differences.
Discussion: These findings indicate that placentome growth and oPL secretion follow distinct yet interrelated developmental trajectories during sheep gestation, with increasing structural-endocrine concordance in late pregnancy. The integrated longitudinal evaluation of placentome biometry and maternal oPL profiles provides a refined framework for interpreting placental development and may support improved assessment of gestational progression in both research and clinical settings.

Keywords:  gestation; placental development; placental lactogen (PL); placentome diameter; sheep; ultrasonography

DOI:  https://doi.org/10.3389/fvets.2026.1769704
Hypertension. 2026 Feb 04.

Determinants of Placental Versus Maternal Preeclampsia.

Omonigho Aisagbonhi, Marni B Jacobs, Morgan Meads, Valentina Stanley, Leah M Lamale-Smith, Ukachi N Emeruwa, Louise C Laurent, Kathleen M Fisch, Mariko Horii.

   BACKGROUND: The placenta is known to be critical in the cause of preeclampsia. However, there is a subset of preeclampsia cases without identifiable placental pathology. We evaluated which clinical preeclampsia classification system best distinguishes preeclampsia with placental pathology from preeclampsia without placental pathology.
METHODS: We evaluated 5 placental pathological features in 197 placentas from patients with preeclampsia grouped by 3 clinical preeclampsia subclasses: (1) preeclampsia with calculated infant birthweight <10th percentile for gestational age (small for gestational age [SGA] preeclampsia) versus preeclampsia with birthweight ≥10th percentile for gestational age (not SGA preeclampsia); (2) preeclampsia with delivery before 34 weeks of gestation (early delivery preeclampsia) versus preeclampsia with delivery at or after 34 weeks of gestation (late delivery preeclampsia); and (3) preeclampsia with severe features versus preeclampsia without severe features. Clinical, histological and molecular findings in patients with preeclampsia were compared with normotensive patients, with and without SGA infants (N=1078 total).
RESULTS: The SGA versus not small for gestational age preeclampsia classification system performed best (likelihood ratios [95% CI] for ≥3 of 5 placental pathological findings: 15.7 [6.5-38.1] in SGA preeclampsia versus not small for gestational age preeclampsia; 6.8 [4.3-10.8] in early delivery preeclampsia versus late delivery preeclampsia; and 5.2 [1.95-14.1] in preeclampsia with severe features versus preeclampsia without severe features; all P<0.0001). SGA preeclampsia and SGA normotensive placentas were abnormal and shared alterations in hypoxia, TNFα, glycolysis, unfolded protein response, estrogen response, UV response, p53, TGFβ, and mTORC1 signaling pathways.
CONCLUSIONS: Classifying preeclampsia based on birthweight percentile for gestational age is the most useful system for consistently identifying preeclampsia associated with placental pathology.

Keywords:  birth weight; glycolysis; humans; infants; pregnancy

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.26236
Ann Med. 2026 Dec;58(1): 2622749

ESRRG downregulation in early spontaneous abortion induces mitochondrial damage, leading to impaired trophoblast function.

Sha Lv, Lieyang Li, Xiaoxiao Xu, Zhengwei Liang, Rongrui Zhang, Zunlun Zhou, Deqin Lu.

   BACKGROUND: Early spontaneous abortion (ESA) is recognized as the most common complication during pregnancy and is often linked to dysfunction in the trophoblast and placenta. Studies suggest that downregulation of trophoblast oestrogen-related receptor gamma (ESRRG) may play a significant role in the impairment of placental function. In light of these findings, we evaluated the impact of ESRRG on trophoblast and placental function in ESAs, aiming to uncover new targets for diagnosis and treatment.
PATIENTS/MATERIALS AND METHODS: Bioinformatics methods were used to analyse differentially expressed genes in the trophoblast of ESA patients and normal controls. ESA Patients and controls were recruited and the villus tissues were collected. Protein and mRNA levels were determined by western blot and qRT-PCR, respectively. Mitochondrial morphological changes in trophoblasts were observed via transmission electron microscopy. CCK8 and Transwell assays were conducted with ESRRG-knockdown HTR-8/SVneo cells. MitoSOX staining, JC-1 assays and ATP quantification were used to assess mitochondrial function in vitro. In addition, Esrrg was overexpressed in ICR female mice, and the number of embryos in the uterus was determined.
RESULTS: The expression of ESRRG was significantly decreased in the placental villous tissue of ESA patients, accompanied by abnormal mitochondrial morphology and decreased ATP levels in trophoblast cells. Impaired proliferation, invasion, migration and tube formation abilities were observed in ESRRG-downregulated HTR-8/SVneo cells, as well as impaired mitochondrial function. ESRRG overexpression was associated with improved trophoblast functionality in a lipopolysaccharide-induced abortion model in ICR mice, leading to an increased number of retained embryos in the uterus.
CONCLUSION: In summary, this study revealed that ESRRG downregulation plays an important role in ESA, providing new targets for diagnosis and treatment.

Keywords:  ESRRG; Early spontaneous abortion; mitochondria; trophoblast dysfunction

DOI:  https://doi.org/10.1080/07853890.2026.2622749
Reprod Toxicol. 2026 Jan 28. pii: S0890-6238(26)00020-1. [Epub ahead of print]140 109177

Maternal PM2.5 exposure causes fetal growth restriction and alters placental morphology: Role of uterine inflammation.

Shan Wang, Hongxia Chen, Aryamann Singh, Niralkumar Ghevariya, Zhekang Ying.

  Maternal exposure to fine particulate matter (PM2.5) correlates with low birthweight. The mechanism, however, remains elusive. We thus investigated the effects of maternal PM2.5 exposure on maternal uterus and placenta. To this end, female C57BL/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 20 weeks and then mated with normal males. Placentas and fetus of gestation day 18.5 were harvested and analyzed. Pregnancy outcomes were also assessed, and after weaning, the uteri of those subgroups of dams were collected and analyzed either at estrus or diestrus stage. Maternal CAP exposure significantly reduced the fetal and placental weights but not fetal-placental weight ratio. Histological analysis of placenta showed smaller junction zone and bigger decidua due to maternal CAP exposure, accompanied by uterine natural killer (uNK) cell infiltration in decidua but not remarkable changes in vasculature and mRNA expression of nutrient transporters. Moreover, CAP exposure reduced uterine mass and increased uterine macrophage infiltration at estrus, but not diestrus, stage. As such, we demonstrate that PM2.5 exposure provokes endometritis, which may be responsible for the development of placental abnormalities and fetal growth restriction due to maternal PM2.5 exposure, shedding light on the mechanism whereby maternal PM2.5 exposure causes adverse reproductive outcomes.

Keywords:  Endometritis; Fetal growth restriction; Maternal exposure; PM(2.5); Placenta

DOI:  https://doi.org/10.1016/j.reprotox.2026.109177
Matrix Biol. 2026 Jan 31. pii: S0945-053X(26)00010-7. [Epub ahead of print]

Oxygen and TGF-β1 jointly regulate fibronectin and trophoblast behavior highlighting a potential role for matrix signalingin severe preeclampsia.

Felipe Gallardo, Delia I Chiarello, Ivo Carrasco-Wong, Sebastián San Martín, Andrea Leiva, Rocío Salsoso, Jaime Gutiérrez.

  Fibronectin is a key component of the extracellular matrix whose abundance and organization depend on both environmental conditions and intracellular signaling. In this study we show that oxygen tension modifies the response of extravillous trophoblasts to TGF-β1 and thereby controls fibronectin output and matrix dependent cell behavior. TGF-β1 increased fibronectin transcripts and protein through SMAD3, p38 and AKT, while hypoxia altered this response by reducing fibronectin protein despite preserved mRNA and by shifting downstream phosphorylation toward SMAD3, ERK and p38 with reduced AKT activity. These changes influenced functional outcomes: fibronectin rich conditions and TGF-β1 suppressed invasion and supported endothelial-like organization, and interference with fibronectin integrin binding preserved invasiveness and prevented network formation. Analysis of placental tissue showed that the spatial pattern of fibronectin expression differs in severe preeclampsia, where fibronectin appears earlier along the trophoblast trajectory compared with normal pregnancy. Together, these findings define how oxygen and TGF-β1 jointly regulate fibronectin and trophoblast behavior, while descriptive observations in human placental tissue provide histological context consistent with these cellular responses and suggest a potential role for matrix-associated signaling in severe preeclampsia.

Keywords:  1.Fibronectin regulation; 2.Trophoblast invasion; 3.TGF-β1 signalling; 4.Oxygen tension; 5.Preeclampsia

DOI:  https://doi.org/10.1016/j.matbio.2026.01.002
Placenta. 2026 Feb 01. pii: S0143-4004(26)00047-0. [Epub ahead of print]

High sensitivity ultrasound microvessel imaging for the assessment of placental health.

Janelle Santos, U-Wai Lok, Shigao Chen, Chengwu Huang, Elizabeth Ann L Enninga.

  Placental insufficiency underlies common and clinically challenging pregnancy complications including fetal growth restriction, preeclampsia, and preterm birth. Although these disorders share impaired placental function, current clinical tools cannot reliably detect early or subtle vascular abnormalities while pregnancy is ongoing. Standard obstetric ultrasound lacks the sensitivity needed to visualize small vessel development; however, high sensitivity microvessel imaging has emerged as a promising tool that overcomes many limitations of conventional Doppler ultrasound. By leveraging high frame rate or ultrafast ultrasound, together with advanced clutter filtering techniques, these highly sensitive ultrasound methods (often referred to as ultrafast Doppler or ultrasound microvessel imaging) can detect slow blood flow within small vessels that are invisible to conventional Doppler. The microvessel imaging has demonstrated promise in various clinical applications, such as assessing tumor vasculogenesis and autoimmune diseases. Only recently has microvessel imaging been applied to the placenta. Early studies show that it can visualize patterns of villous branching and vascular density that differ between healthy and complicated pregnancies. Some work has also linked microvessel imaging findings to placental pathology after delivery, suggesting the technique may allow clinicians to detect placental injury while pregnancy is ongoing. As the placenta cannot be directly assessed during gestation, a safe, non-invasive, and repeatable imaging tool is urgently needed. Ultrasound microvessel imaging has the potential to fill this gap by enabling earlier identification of at-risk pregnancies, improving monitoring and clinical decision-making throughout gestation.

Keywords:  Microvessels; Pathology; Placenta; Pregnancy; Ultrasound

DOI:  https://doi.org/10.1016/j.placenta.2026.01.020
Compr Physiol. 2026 Feb;16(1): e70107

Molecular Signatures of Preeclampsia: The Role of Post-Translational Protein Modifications.

Sarah G Rodrigues, Karine A Assis, João Lucas M Silva, Daniel J T Privado, Juliano V Alves, Jessica L Faulkner, Thiago Bruder-Nascimento, Rafael M Costa.

  Preeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by placental dysfunction, systemic inflammation, oxidative stress, and widespread maternal endothelial injury. Although multiple molecular pathways have been implicated in its pathogenesis, the regulatory mechanisms that integrate placental stress with vascular and immune maladaptation remain incompletely understood. Post-translational modifications (PTMs) have emerged as critical regulators of protein function, stability, localization, and signaling, positioning them as key molecular integrators of the pathological processes underlying PE. In this review, we synthesize current evidence linking PTM dysregulation to the major biological processes disrupted in PE, with a particular focus on SUMOylation, ubiquitination, S-nitrosylation, acetylation, and glycosylation. These modifications modulate trophoblast invasion, angiogenic balance, redox homeostasis, immune tolerance, and endothelial signaling across placental, and maternal vascular compartments. We highlight how hypoxia, inflammation, and metabolic stress converge to disrupt PTM-regulating enzyme systems, thereby amplifying placental dysfunction and maternal vascular injury. Emerging evidence supporting PTM crosstalk further underscores the existence of coordinated regulatory networks rather than isolated molecular events. Advances in proteomics, systems biology, and extracellular vesicle profiling have revealed PTM-enriched molecular signatures in maternal circulation that precede clinical disease onset, offering opportunities for early diagnosis and risk stratification. We critically address current limitations in the field, including the predominance of cross-sectional studies, challenges in cell type-specific and temporal resolution, and barriers to clinical implementation. This review positions PTMs as central molecular hubs linking placental stress to systemic vascular dysfunction and highlights their potential to inform future precision medicine approaches in PE.

Keywords:  placental dysfunction; post‐translational modifications; preeclampsia

DOI:  https://doi.org/10.1002/cph4.70107
Front Pharmacol. 2025 ;16 1765815

Dulaglutide and pregnancy: a comprehensive safety assessment using the ex vivo placenta perfusion and in vitro models.

Sabrina Kuoni, Sara Caviglia, Alexandra Dolder, Joanna Gawinecka, Nicole Ochsenbein-Kölble, Ana Paula Simões-Wüst.

  The use of glucagon-like peptide-1 (GLP-1) receptor agonists by young populations is rapidly increasing worldwide, thereby exposing more women of childbearing age. Dulaglutide, a long-acting GLP-1 receptor agonist designed to bind to the neonatal Fc receptor (FcRn) and approved for type 2 diabetes mellitus, reflects this trend. In this study, we wanted to evaluate transplacental passage of dulaglutide and its potential effects on placental function. Transplacental transfer was investigated both with human placenta perfusions, a model for term transfer and expressing FcRn; and with permeability assays across BeWo b30 cell layers, a model for the early pregnancy placental barrier and characterised by negligible FcRn expression. Additional in vitro experiments were performed with human placental explants and BeWo cells. Placenta perfusions revealed minimal but consistent transplacental passage of dulaglutide (0.2%-0.7%; at 1.9 nM and 19.1 nM, over 4 hours); fluorescently labelled dulaglutide was detected within foetal villi of perfused tissue, with co-localisation to the early endosome marker Rab5. Permeability assays revealed negligible transfer. Dulaglutide exposure did not impair viability, alter the secretion of pregnancy-related hormones, nor affect glycolytic metabolism neither in human placental explants nor in BeWo cells. Our results suggest that dulaglutide has no adverse effects on placental viability and functions and is not able to cross the placental barrier at earlier gestation stages. However, its ability to cross the placental barrier at term in minimal amounts, but consistently, indicates foetal exposure during late pregnancy, when FcRn is expressed.

Keywords:  BeWo cells; diabetes mellitus; dulaglutide; ex vivo placenta perfusion; placenta explants; placental transfer; pregnancy

DOI:  https://doi.org/10.3389/fphar.2025.1765815
Biol Rev Camb Philos Soc. 2026 Jan 31.

Placental crises: disruptive selection and maternal under-investment as the foundations of mammalian placental evolution and dysfunction.

Davis Laundon, Neil J Gostling, Ian G Reddin, Bram G Sengers, Pascale Chavatte-Palmer, Rohan M Lewis.

  Among the vertebrates, mammals are notable for the dominance of live birth and placental nutrition. The structural diversity of the mammalian placenta is remarkable, despite sharing a single common ancestor and conserved physiological functions. Historically, investigations into the evolution of the mammalian placenta have been grounded in 'the efficiency paradigm', i.e. the assumption that certain placental configurations permit easier nutrient exchange, but this paradigm has struggled to explain the diversity of mammalian placentation strategies. Here, we propose a new paradigm to understand mammalian placental evolution. Using multidimensional plotting of recorded placental structures, quantitative metrics for mammalian maternal investment, and illustrative computational modelling of physiological processes, we argue that the ancestral mammalian placenta is not a streamlined 'highly efficient' design, but rather a product of low maternal investment, with fitness costs that manifest as gestational demand increases. Expansion of small mammals into larger-bodied, longer-lived niches induces a 'placental crisis' characterised by maternal under-investment and chronic gestational dysfunction, triggering an arms race through the interaction of disruptive selection and materno-fetal conflict. We propose the acute severity of the placental crisis is the foundation of placental evolution. We go on to argue that some primates are currently in a state of placental crisis and that maternal under-investment and inappropriate placentation are the evolutionary foundations of human gestational dysfunctions such as pre-eclampsia. We conclude that the ancestral mammalian placenta was not an efficiently optimised design that allowed placentation to dominate the clade, but rather an idiosyncrasy of mammal-specific biology, which likely hindered mammalian expansion into larger-bodied niches.

Keywords:  disruptive selection; mammal; maternal investment; placenta; reproductive dysfunction

DOI:  https://doi.org/10.1002/brv.70139
Obstet Gynecol. 2026 Feb 06.

Pregnancy Outcomes Associated With Anemia in the First Trimester and Anemia Resolution by Late Pregnancy.

Anna Booman, Brian T Bateman, Sara Siadat, Caroline Berube, Irogue Igbinosa, Cecilia Leggett, Deirdre J Lyell, Elliott K Main, Stephanie A Leonard.

OBJECTIVE: Evidence related to anemia in early pregnancy, and its resolution or persistence by late pregnancy, is limited. We evaluated pregnancy outcomes associated with anemia in early pregnancy and resolution compared with persistence in late pregnancy.
METHODS: We used the Merative™ Marketscan® Commercial Database of nationwide insurance claims (2018-2023) and included pregnant individuals without hereditary anemias. We used hemoglobin and hematocrit to identify anemia in early pregnancy (before 14 weeks of gestation) and late pregnancy (at or after 24 weeks of gestation). Pregnancy outcomes included preeclampsia, placenta previa, placental abruption, severe postpartum hemorrhage, blood products transfusion, cesarean birth, nontransfusion severe maternal morbidity (SMM), spontaneous preterm birth, medically indicated preterm birth, and small-for-gestational-age (SGA) birth weight. We used modified Poisson regression to estimate associations between: 1) anemia in early pregnancy and pregnancy outcomes; and 2) anemia resolution by late pregnancy and pregnancy outcomes, adjusting for confounders by inverse probability weighting.
RESULTS: Among 73,586 individuals, 4.4% (95% CI, 4.3-4.6%) had anemia in early pregnancy. Early pregnancy anemia was associated with higher risk of each outcome assessed, with the exception of placenta previa, with the highest associated risk of blood products transfusion (2.4% vs 0.8%; adjusted risk ratio [aRR] 2.45; 95% CI, 1.91-3.13). Of those with early pregnancy anemia and laboratory values in late pregnancy (72.1%), 53.4% had persistent anemia and 46.6% had resolved anemia. Persistent anemia was associated with nontransfusion SMM (2.6% vs 1.1%, aRR 1.64; 95% CI, 1.13-2.37), blood products transfusion (2.9% vs 0.8%, aRR 2.60; 95% CI, 1.84-3.69), and SGA birth weight (8.5% vs 6.8%, aRR 1.23; 95% CI, 1.01-1.50), compared with those without anemia in the first trimester. The resolution of anemia by late pregnancy was not associated with nontransfusion SMM (1.6% vs 1.1%; aRR 1.07; 95% CI, 0.65-1.74) but was associated with blood products transfusion (1.6% vs 0.8%; aRR 1.64; 95% CI, 1.01-2.67) and SGA birth weight (10.0% vs 6.8%; aRR 1.38; 95% CI, 1.15-1.67) compared with those without anemia in the first trimester.
CONCLUSION: Anemia in the first trimester was associated with adverse maternal and neonatal outcomes. The resolution of anemia by late pregnancy eliminated the association with nontransfusion SMM but not other outcomes, emphasizing the importance of treating anemia in early pregnancy and before pregnancy.

DOI: https://doi.org/10.1097/AOG.0000000000006183
Placenta. 2026 Jan 29. pii: S0143-4004(26)00046-9. [Epub ahead of print]

In vivo imaging of the rodent placenta.

Lindsay S Cahill, Sarah Debebe, Jessica Peng, John G Sled.

  Our understanding of the structure and function of the placenta and of placental disease have been enhanced by the use of in vivo imaging technologies and rodent models of pregnancy. These technologies share similarities with those used in the clinic to assess and diagnose complications of human pregnancies, providing an easy pathway for advances in rodent imaging and the findings from rodent studies to be translated to humans. Here, we review the available in vivo imaging technologies used in rodent studies of the placenta including magnetic resonance, ultrasound, positron emission tomography, and optical techniques. We synthesize the studies that have used these techniques to investigate placental perfusion, microvascular imaging, metabolism and structure. We also discuss the benefits and limitations of the technologies and provide future directions based on gaps in the present knowledge and limitations of the techniques.

Keywords:  Blood flow; Magnetic resonance imaging; Metabolism; Microvasculature; Ultrasound imaging

DOI:  https://doi.org/10.1016/j.placenta.2026.01.019
Psychoneuroendocrinology. 2026 Jan 30. pii: S0306-4530(26)00031-4. [Epub ahead of print]186 107772

Mediating role of maternal cortisol in the association between maternal serum creatinine and fetal cortisol exposure.

Ziyan Lin, Zhiqi Zhang, Guoping Yang, Nan Wang, Jinfu Peng.

   BACKGROUND: Cortisol is the principal glucocorticoid regulated by the hypothalamic-pituitary-adrenal (HPA) axis and plays a crucial role in maintaining pregnancy and promoting fetal growth and development. Renal function is a key determinant of cortisol exposure. Given that serum creatinine serves as a key biomarker of renal function, it is plausible that maternal creatinine levels contribute to the regulation of fetal cortisol exposure, although the underlying mechanisms remain to be fully elucidated.
OBJECTIVE: This study was designed to (1) examine the association between maternal serum creatinine and umbilical cord blood cortisol levels, (2) assess the potential mediating role of maternal cortisol in this relationship, and (3) investigate corresponding changes in the protein expression of placental 11β-HSD1 and 11β-HSD2.
METHODS: This study employed a paired maternal-fetal design. At delivery, maternal serum, umbilical cord blood, and placental tissue were collected simultaneously from 103 mother-newborn pairs. Cortisol and cortisone levels in maternal and cord blood were measured, and protein expression of 11β-HSD1 and 11β-HSD2 in placental tissue was analyzed. Correlation and mediation analyses were performed to assess the relationships among maternal serum creatinine, maternal cortisol, and cord blood cortisol.
RESULTS: Each unit increase in maternal serum creatinine was associated with a significant decrease in cord blood cortisol levels. Maternal cortisol levels were positively correlated with cord blood cortisol. Mediation analysis showed that maternal cortisol mediated 31.75 % of the association between maternal creatinine and cord blood cortisol. In the high-creatinine conditions, placental expression of 11β-HSD1 was significantly decreased, while expression of 11β-HSD2 was increased.
CONCLUSION: Maternal cortisol showed evidence of partial mediation in the association between maternal renal function and fetal cortisol exposure. This observational finding highlights a potential link between maternal renal function and fetal glucocorticoid exposure and provides a basis for future studies to investigate the role of placental glucocorticoid regulation and fetal HPA axis development.

Keywords:  11β-HSD1; 11β-HSD2; Cortisol; Pregnancy; Serum creatinine

DOI:  https://doi.org/10.1016/j.psyneuen.2026.107772
Photoacoustics. 2026 Apr;48 100803

Early identification of umbilical blood flow restriction and maternal placental hypoperfusion with photoacoustic imaging.

Luting Zhang, Mengyu Zhou, Qiufang Ouyang, Fan Meng, Zhen Yuan, Min Chen, Zongjie Weng, Jian Zhang.

  In clinical practice, the prompt and accurate identification of acute fetal distress (AFD) is critical. Although cardiotocography and ultrasonography are the cornerstone clinical tools for fetal monitoring, they cannot quantitatively assess fetal cerebral hypoxia and carry inherent risks of underdiagnosis or false-positive interpretations. This study evaluates photoacoustic imaging (PAI) for early AFD detection. In mouse models, oxygen saturation (sO2) in the fetal brain and placenta was measured using PAI, demonstrating a significant sO2 decrease following placental blood flow obstruction - with more pronounced reductions observed in complete versus partial restriction cases. Crucially, a novel two-step PAI approach differentiated placental hypoperfusion from umbilical cord obstruction by analyzing distinct sO2 patterns in both placenta and fetal brain tissues. This distinction is clinically vital, as placental and cord-related AFD require different urgent interventions. PAI's ability to pinpoint the underlying cause highlights its potential for guiding precise treatment decisions.

Keywords:  Acute fetal distress; Blood oxygen saturation; Brain; Photoacoustic imaging; sO2 map

DOI:  https://doi.org/10.1016/j.pacs.2026.100803
Toxicol In Vitro. 2026 Jan 31. pii: S0887-2333(26)00012-3. [Epub ahead of print]113 106204

Contributing to a (cell) cultural shift: Human platelet lysate is a suitable replacement for fetal calf serum when culturing the HTR8/SVneo extravillous trophoblast cell line.

B C Hameete, A Hogenkamp, L Groenink.

  While suitable as a universal supplement in cell culture, fetal calf serum (FCS) has several downsides, including its bovine origin and batch-to-batch variability. In this study, we investigated human platelet lysate (HPL) as a potential replacement for FCS when culturing an extravillous trophoblast cell line. HTR8/SVneo cells were cultured in conventional medium supplemented with 10% FCS or serum-free medium supplemented with varying concentrations of HPL for 24 h or 3 weeks, whereafter LDH release, metabolic activity and cytokine release were assessed. Cellular viability and cell counts were measured for each passage during the 3 weeks of culturing. Cells were successfully cultured in all media. Media with 1% and 10% HPL provided the best yields, but culturing in 10% HPL also increased LDH release. Medium composition had a direct effect on IL-6 release and affected IL-8 release after three weeks of culturing. Furthermore, HPL interfered with the detection of RANTES at higher HPL concentrations. Based on our findings, we recommend culturing HTR8/SVneo cells in serum-free medium with 1% HPL. However, we suggest that researchers assess how medium composition affects relevant outcomes before implementing a serum free culture protocol.

Keywords:  Fetal calf serum; Human platelet lysate; Serum free media; Trophoblast; animal use alternatives; cell line

DOI:  https://doi.org/10.1016/j.tiv.2026.106204
Sci Rep. 2026 Feb 05.

Oxidative stress-mediated impairment of human trophoblast cell proliferation by zinc pyrithione exposure.

Xiumei Wang, Bingbing Luo, Ziqin Lu, Xiangxue Cai, Junling Wang, Junbiao Mao.



Keywords:  Apoptosis; Oxidative stress; Transcriptome; Trophoblast cells; Zinc pyrithione

DOI:  https://doi.org/10.1038/s41598-026-38895-9
J Mol Histol. 2026 Feb 04. 57(1): 68

Maternal high-fat diet and its multigenerational impact on hypertension and metabolic alterations in Wistar rat offspring.

Maghawry Hegazy, Mahmoud Mohamed Mokhtar, Elsayed G E Elsakka, Hesham A El-Mahdy, Samy Y Elkhawaga, Mohamed A Elkady, Amr Mohamed Yehia, Ahmed Aglan, Ahmed M Mansour, Salama Abdo Salama, Hamada Ahmed Mokhlis, Hesham Fathy Hassan, Adel I Abdelaziz, Maher Hassan Gomaa, Ahmed A El-Husseiny, Mahmoud Eldeib, Hesham Shaaban, Rasha M Alnefaie, Ahmed Ismail.

  This study investigates the impact of maternal high-fat diet (HFD) on the development of hypertension and associated metabolic changes in offspring across multiple generations of Wistar rats. Pregnant female rats were assigned to either a normal standard diet or a HFD during gestation. We assessed body weight, heart weight, systolic blood pressure (SBP), catechol-O-methyl transferase (COMT), and vanillyl mandelic acid (VMA) in first, second, and third-generation offspring. Our findings revealed that HFD offspring exhibited significantly elevated SBP compared to controls in all generations, with the most pronounced increase in F1. In addition, plasma EP, NE, and urinary VMA were markedly increased in F1, attenuated in F2, and remained elevated though less pronounced in F3. Also, the cardiac COMT expression was downregulated in all HFD offspring, most strongly in F1. Furthermore, the body weights were significantly higher in F1 compared to controls, whereas differences were minimal in F2 and F3. Moreover, dyslipidemia (elevated TC, TG, LDL; reduced HDL) was observed in F1 and partially persisted in F2 and F3. Finally, histopathological analysis revealed cardiac hypertrophy, cytoplasmic vacuolation, and pyknotic nuclei in F1, with milder alterations in F2 and F3. These results suggest that maternal HFD during pregnancy might affect the offspring cardiovascular health, potentially mediated by alterations in catecholamine dynamics. The study underscores the importance of maternal nutrition in the context of fetal programming and its implications for the prevention of hypertension and related metabolic disorders in future generations.

Keywords:  COMT; Fetal programming; Generations; HFD; Hypertension; VMA

DOI:  https://doi.org/10.1007/s10735-025-10693-z