bims-placeb 2026-07-05 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–07–05
seventeen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Rotational trophoblast organoids reveal biomechanical regulation of trophoblast differentiation.
Micro and nanoplastic inhalation during gestation disrupts placentation in the Sprague-Dawley rat.
Inducing physiological polarity and performing gene editing using CRISPR-Cas9 in human trophoblast organoids.
A longitudinal single-nucleus transcriptomic atlas of bovine placentation reveals dynamic cellular hierarchies and regulatory programs.
Placental iron-driven oxidative imbalance and changes in iron homeostasis in diabetes-in-pregnancy: A cross-sectional analytical study.
Resf1 is required for proper placental development and configuration of trophoblast cell-specific heterochromatin.
The pro-inflammatory cytokines IFN-α and TNF-α inhibit organoid-derived extravillous trophoblast invasion.
Tracing PFAS Transfer from Mother to the Fetoplacental Unit: Insights from Trimester-Specific Maternal Serum Profiles.
Selective silencing of placental anti-angiogenic factors in invasive trophoblasts via membrane-fusion divalent siRNA delivery for preeclampsia therapy.
Sex-specific cellular and molecular mechanisms of PFAS-induced reproductive toxicity.
The Cardiac-Fetal-Placental Unit: links between umbilical venous flow and maternal hemodynamics in fetal growth restriction.
Esomeprazole treatment targeting sFLT-1 signaling in preeclampsia improves placental and fetal outcome in mice.
Age-Associated Senescence of Decidual Macrophages: A Key Mediator of Adverse Pregnancy Outcomes in Advanced Maternal Age.
Maternal hyperhomocysteinemia compromises female offspring fertility through overactivation of primordial follicles.
Exposure to perfluorooctanoic acid accelerates Drosophila melanogaster juvenile development and disrupts mitochondrial metabolism.
Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through early ovarian failure.
Female reproductive dysfunction and transgenerational consequences following prolonged spaceflight exposure.

Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00715-1. [Epub ahead of print]45(7): 117637

Rotational trophoblast organoids reveal biomechanical regulation of trophoblast differentiation.

Shun Shibata, Yuki Ishikawa, Marina Kosaka, Hiroaki Okae, Takahiro Arima.

  Human placental development is essential for pregnancy but remains mechanistically obscure because early post-implantation tissues are inaccessible. Here, we establish a rotational trophoblast organoid platform that recapitulates selected morphogenetic features shared with early trophoblast development, including spontaneous syncytiotrophoblast (STB) differentiation and progressive fusion of lacuna-like cavities. Integrated multi-omic analyses associate this architecture with a biomechanical balance between attenuated YAP activity and peripheral CREB activation, with GCM1 stabilizing trophoblast chromatin state and POLQ supporting genome maintenance in rapidly expanding progenitors. The organoids display autonomous endocrine activity, induce an endometrial epithelial state consistent with metabolic activation, and can generate extravillous trophoblasts that directionally engage endothelial networks. This platform provides a framework for studying placental morphogenesis and tissue interactions relevant to pregnancy complications.

Keywords:  CP: developmental biology; CP: stem cell research; biomechanics; extravillous trophoblast; maternal-fetal interface; placental morphogenesis; syncytiotrophoblast; trophoblast organoids

DOI:  https://doi.org/10.1016/j.celrep.2026.117637
Res Sq. 2026 Jun 15. pii: rs.3.rs-9861614. [Epub ahead of print]

Micro and nanoplastic inhalation during gestation disrupts placentation in the Sprague-Dawley rat.

Chelsea M Cary, Nacala N Gadsden, Peihong Zhou, Laurie B Joseph, Calla Nguyen, Marianne Polunas, Michael J Goedken, Lauren M Aleksunes, Phoebe A Stapleton.

Micro and nanoplastics (MNPs) are a ubiquitous environmental contaminant that humans are exposed through multiple routes. Multiple studies have demonstrated that MNPs deposit in human placental tissues and can translocate across the placental barrier. Maternal blood enters the placenta through uterine spiral arteries. During development of the placenta, trophoblasts enter the arteriolar lumen and invade the endothelial layer. This remodeling reduces vascular contractility and maintains maternal blood flow into the placenta. Simultaneously, the placenta increases surface area through angiogenic branching, facilitating the indirect contact of maternal and fetal blood spaces and promoting maternal-fetal exchange. To date, no groups have investigated how maternal MNP exposure affects these key steps of placentation. Therefore, in this study, pregnant Sprague Dawley rats were exposed to air containing polyamide-12 MNP throughout gestation. Placental morphology, invasion of spiral arteries, and angiogenic signaling were evaluated in male and female placentas at GD16 and GD20. Maternal MNP inhalation significantly reduced the relative distance of trophoblast invasion into the placental region that houses maternal spiral arteries. Additionally, MNP exposure increased staining of smooth muscle actin around maternal spiral arteries, indicating poor remodeling and likely reducing uteroplacental blood flow. Likewise, inhalation of MNPs altered the size and number of maternal and fetal blood spaces, favoring less surface area for maternal-fetal exchange. Lastly, significant changes in the expression and spatial distribution of angiogenic and antiangiogenic mRNAs that regulate vascular branching and surface area were observed. Future studies are needed to characterize the mechanisms by which polyamide-12 MNP influences placental hemodynamics.

DOI: https://doi.org/10.21203/rs.3.rs-9861614/v1
Nat Protoc. 2026 Jun 29.

Inducing physiological polarity and performing gene editing using CRISPR-Cas9 in human trophoblast organoids.

Liheng Yang, Joshua Hatterschide, Rizban E Worota, Kaila Cooley, Carolyn B Coyne.

Human trophoblast organoids (TOs) are three-dimensional ex vivo culture models that enable the study of placental development, physiology and pathology. A major limitation of TOs grown in Matrigel or other extracellular matrices is their apical-inward polarity, in which cytotrophoblasts (CTBs) line the outer surface and the multinucleated syncytiotrophoblast (STB) forms the interior layer, opposite to their orientation in vivo. Here we present a detailed protocol to reverse TO polarity, producing organoids that recapitulate the cellular orientation of human chorionic villi. Standard TOs with inward-facing STBs (STBin) undergo polarity reversal during suspension culture to generate outward-facing STBs (STBout). In parallel, we describe a complementary protocol for CRISPR-Cas9-mediated gene editing in TOs and illustrate its application in generating CGA (hCG) knockout organoids, which disrupt placental hormone secretion, and MAVS knockouts, which impair antiviral signaling. The outward-facing STB protocol can be completed in ~2 weeks, whereas the establishment of stable gene-edited TO lines requires 2-3 months. Successful implementation requires experience in TO culture, lentiviral transduction and CRISPR-Cas9-based genome editing. Together, these protocols provide versatile and reproducible methods for modeling placental architecture and studying gene function in vitro, enabling functional interrogation of trophoblast biology within physiologically oriented organoids.

DOI: https://doi.org/10.1038/s41596-026-01402-5
Genome Biol. 2026 Jun 27.

A longitudinal single-nucleus transcriptomic atlas of bovine placentation reveals dynamic cellular hierarchies and regulatory programs.

Guanghui Tan, Xiaoru Yan, Xuesha Cao, Ao Zhang, Tao Shi, Yaqi Zhou, Xi Guo, Haoping Wang, Hengkuan Li, Jiezhang Li, Yingran Liu, Xihong Wang, Yu Jiang, Yi Zheng.

BACKGROUND: Elucidating cellular hierarchies and regulatory mechanisms of placental development across gestation is critical for understanding pregnancy maintenance and improving reproductive outcomes in mammals, including cattle. However, a comprehensive, temporally resolved single-cell characterization of the bovine placenta has remained lacking.
RESULTS: We construct a longitudinal single-nucleus transcriptomic atlas comprising 311,299 placental cells and nuclei across 13 developmental timepoints (E12, E14, E16, E18, E24, E30, E50, E60, E85, E110, E180, E240, and E280). We identify 13 major cell types and 14 trophoblast subtypes, revealing pronounced cellular heterogeneity and stage-specific transcriptional programs. Regulatory analyses highlight HAND1 and DLX5 as candidate key regulators of maternal recognition of pregnancy. Trajectory inference demonstrates that binucleate cells arise from specific uninucleate cell subpopulations around E24, with differentiation governed by genomic imprinting and metabolic reprogramming. Integration with genome-wide association study data identifies eight early trophoblast subtypes significantly associated with gestation length, along with candidate pathways and risk genes, including CYCS, HMGA1, and VDAC1, under strong evolutionary constraint. Additionally, we find that placental macrophages emerge from E30 in cattle and show significant associations with pregnancy loss in both cattle and humans, sharing conserved risk pathways.
CONCLUSIONS: This study provides a comprehensive spatiotemporal single-cell atlas of bovine placental development, defining cellular hierarchies, lineage dynamics, and regulatory networks at the maternal-fetal interface. These findings offer a valuable resource and conceptual framework for understanding pregnancy maintenance and for improving reproductive traits in ruminants.

DOI: https://doi.org/10.1186/s13059-026-04173-0
Placenta. 2026 Jun 29. pii: S0143-4004(26)00306-1. [Epub ahead of print]182 196-203

Placental iron-driven oxidative imbalance and changes in iron homeostasis in diabetes-in-pregnancy: A cross-sectional analytical study.

Kamila Thalapalliyil, Zachariah Bobby, Gowri Dorairajan, Pampa Ch Toi.

   INTRODUCTION: Diabetes in pregnancy (DIP) is associated with adverse maternal and fetal outcomes. Placental iron homeostasis is tightly regulated to ensure adequate fetal supply while preventing oxidative injury. Dysregulated iron metabolism may promote ferroptosis. Altered placental iron homeostasis in DIP may reduce the Placental Iron Deficiency Index, thereby compromising fetal iron endowment. The study evaluated alterations in placental iron homeostasis and ferroptosis-related pathways in DIP compared with healthy pregnancies (HP).
METHODS: In this cross-sectional analytical study, 120 pregnant women were recruited and divided into HP (n = 60) and DIP (n = 60) groups. Sixteen placentae from each group, at ≥34 weeks of gestation, were analysed. Placental expressions of hepcidin, ferritin, FPN1, TfR1, TGF-β, NQO1, and GPX4 were assessed by qPCR, western blotting and IHC. Further, the perinatal outcomes were measured in each group.
RESULTS: Placental gene expression of hepcidin was increased in DIP compared with HP, accompanied by reduced ferritin and TfR1 expression. Protein analyses confirmed increased hepcidin and decreased levels of ferritin, TfR1, and FPN1. Immunohistochemistry localised these alterations predominantly to the syncytiotrophoblast. TGF-β and NQO1 transcripts were elevated, whereas GPX4 protein expression was reduced in DIP placentae. The newborns of DIP had an adverse perinatal outcome compared to HP.
DISCUSSION: The DIP is associated with profound disruption of placental iron homeostasis and impaired ferroptosis defence mechanisms. Upregulation of hepcidin, alongside suppression of key iron transport proteins and reduced GPX4, suggests a pro-oxidative, iron-dysregulated placental environment. These molecular alterations may contribute to trophoblast dysfunction and adverse pregnancy outcomes, highlighting potential therapeutic targets.

Keywords:  Ferroptosis; Iron homeostasis; Oxidative stress; Placenta; Placental dysfunction

DOI:  https://doi.org/10.1016/j.placenta.2026.06.017
Genome Res. 2026 Jun 29. pii: gr.281507.125. [Epub ahead of print]

Resf1 is required for proper placental development and configuration of trophoblast cell-specific heterochromatin.

Kei Fukuda, Kimiko Inoue, Chikako Shimura, Moe Kitazawa, Michiko Hirose, Takashi Ishiuchi, Shogo Matoba, Atsuo Ogura, Yoichi Shinkai.

Resf1 (Retroelement silencing factor 1) is involved in retroelement silencing in cooperation with H3K9 methyltransferase SETDB1 by regulating H3K9 methylation in mouse embryonic stem cells (mESCs). However, it remains unknown whether Resf1 functions in retroelement silencing in vivo, and has a role in development. Here, we established Resf1-deficient mice, which exhibit developmental delay, partial embryonic lethality, and placental defects. Notably, retroelements are also upregulated in the Resf1-deficient placenta, correlating with increased expression of nearby genes. To further assess whether Resf1 functions within the trophoblast lineage, we generate Resf1-deficient trophoblast stem cell (TSC) lines. Both undifferentiated TSCs and differentiated TSCs (D-TSCs) display increased retroelement expression along with elevated levels of genes associated with placental development. Moreover, Resf1-deficient TSCs exhibit compromised maintenance of H3K9me3 domains in a manner independent of SETDB1. Collectively, our findings reveal that Resf1 plays multifaceted roles beyond retroelement silencing, underscoring its importance in development and its critical function in trophoblast lineage regulation.

DOI: https://doi.org/10.1101/gr.281507.125
iScience. 2026 Jul 17. 29(7): 116431

The pro-inflammatory cytokines IFN-α and TNF-α inhibit organoid-derived extravillous trophoblast invasion.

A Jantine van Voorden, Fangxu Lin, Souad Boussata, Remco Keijser, Liana Barenbrug, Bente Horselenberg, Ans M M van Pelt, Wendy Dankers, Susana M Chuva de Sousa Lopes, Gijs B Afink.

  Proper placental development requires extravillous trophoblast (EVT) differentiation and invasion into the maternal decidua to remodel spiral arteries and support fetal growth. Disruptions in these processes contribute to preeclampsia and fetal growth restriction. These pregnancy complications are common in women with immune-mediated inflammatory diseases, which are characterized by elevated levels of pro-inflammatory cytokines such as interferon-α (IFN-α) and tumor necrosis factor-α (TNF-α). However, the direct effects of these cytokines on EVTs remain unclear. Using human trophoblast organoid models, we demonstrate that IFN-α and TNF-α impair EVT invasion while preserving differentiation capacity. High-resolution imaging of untreated organoid-decidua co-cultures revealed extensive trophoblast invasion into decidual stroma and arteries, but invasion was substantially reduced particularly upon IFN-α treatment. Transcriptome profiling identified changes in several invasion-related pathways after cytokine exposure. These findings suggest that elevated IFN-α and TNF-α can directly impair trophoblast invasive capacity, potentially contributing to suboptimal placental development in inflammatory disorders.

Keywords:  developmental biology; immunology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.116431
bioRxiv. 2026 Jun 24. pii: 2026.02.02.703409. [Epub ahead of print]

Tracing PFAS Transfer from Mother to the Fetoplacental Unit: Insights from Trimester-Specific Maternal Serum Profiles.

Kyle Campbell, Dana Boyd Barr, Andrew J Morris, Volha Yakimavets, Parinya Panuwet, Donald Turner, Lauren A Havens, Stephanie M Eick, Kartik Shankar, Kevin J Pearson, Aline Andres, Todd M Everson.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous endocrine-disrupting pollutants that cross the placenta and affect offspring health, but the extent and timing of their transfer to placental and fetal compartments remain poorly understood. We characterized the relationship between trimester-specific prenatal maternal serum PFAS levels and paired placental and cord plasma levels at term. Data came from the Central Arkansas Glowing prospective cohort (n=151, 2010-2014). Four well-detected PFAS were measured using liquid chromatography-tandem mass spectrometry. Regression, elastic net, and parametric g-formula models tested the association between maternal levels in each trimester and placental or cord PFAS levels. In g-formula models, trimester one (T1) or trimester two (T2) measures consistently had the largest effect sizes associated with placental levels (p<0.001-0.05). Similarly, T1 (PFHxS, PFNA, PFOS, PFOA), T2 (PFNA, PFOS, PFOA), and placental PFOA were associated with cord plasma levels (p<0.05-p<0.001). Results were robust to time-varying adjustment for estimated glomerular filtration rate, serum albumin, or maternal weight. Predictive models improved with additional timepoint measures. Our findings suggest PFOA may transfer more efficiently from the placenta to cord plasma and early-to-mid gestation maternal serum PFAS measures may serve as the most robust sentinels of fetoplacental exposure burden, suggesting early exposure prevention should be prioritized.

DOI: https://doi.org/10.64898/2026.02.02.703409
J Control Release. 2026 Jul 01. pii: S0168-3659(26)00555-9. [Epub ahead of print] 115152

Selective silencing of placental anti-angiogenic factors in invasive trophoblasts via membrane-fusion divalent siRNA delivery for preeclampsia therapy.

Wenqiang Qian, Ying Zhang, Yao Yao, Xiaojun Zhu, Dongli Sun, Huidi Jiang, Peiyue Jiang, Jiaxin Shang, Weidong Fei, Caihong Zheng.

  Preeclampsia is a common and severe hypertensive disorder of pregnancy driven by placental dysfunction. In the absence of effective therapies, termination of pregnancy remains the only definitive treatment, resulting in significant maternal and fetal mortality. In this study, single-cell transcriptomic analysis of human placentae identified extravillous trophoblasts as a key pathogenic invasive cell subtype in preeclampsia, characterized by aberrant overexpression of fms-like tyrosine kinase-1 (Flt-1) and endoglin (Eng), the molecular sources of the soluble anti-angiogenic factors sFlt-1 and sEng. To coordinately modulate these pathogenic mediators, this study designed a novel dual-target divalent siRNA (dual-siRNA) to enhance molecular stability and enable simultaneous gene silencing, and further developed a ligand-functionalized membrane-fusogenic liposomal delivery system (iMFlip) targeting receptors highly expressed in invasive trophoblasts for selective dual-siRNA delivery. The optimized iMFlip@dual-siRNA exhibited favorable stability and low protein adsorption properties, and achieved efficient cytosolic siRNA delivery predominantly through membrane fusion, thereby substantially bypassing lysosomal degradation. In vitro, iMFlip@dual-siRNA markedly restored the invasion, migration and angiogenesis of hypoxia-injured HTR-8/SVneo cells. The subsequent pharmacodynamic studies showed that iMFlip@dual-siRNA simultaneously reduced circulating maternal sFlt-1 and sEng levels, alleviated placental vascular dysfunction and inflammatory microenvironment remodeling through reactivation of the PI3K/Akt/eNOS signaling pathway, and consequently improved maternal hypertension, proteinuria, and fetal growth restriction in a preeclamptic mouse model. Collectively, this study established a mechanism-driven therapeutic paradigm that integrated single-cell transcriptomic analysis-guided pathogenic target identification with advanced nucleic acid delivery strategies, offering a promising precision intervention approach for preeclampsia.

Keywords:  Anti-angiogenic factors; Divalent siRNA; Invasive trophoblasts; Membrane fusion; Preeclampsia; Single-cell transcriptomic

DOI:  https://doi.org/10.1016/j.jconrel.2026.115152
Toxicology. 2026 Jun 30. pii: S0300-483X(26)00142-3. [Epub ahead of print]526 154535

Sex-specific cellular and molecular mechanisms of PFAS-induced reproductive toxicity.

Ashiya Salim Bhagwan, A Gowtham, Devesh Kumar, Ravinder K Kaundal.

  Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in water, food, consumer products, and household dust, resulting in ongoing human exposure and bioaccumulation. Accumulating evidence increasingly implicates PFAS in reproductive dysfunction. Although PFAS-associated reproductive toxicity has been widely reviewed, critical knowledge gaps persist regarding the sex-specific cellular and molecular mechanisms mediating these effects and the reproductive toxicity of emerging replacement PFAS. Increasing epidemiological, in vivo, and in vitro evidence indicates that PFAS disrupt reproductive health through multiple mechanisms common to both sexes, including oxidative stress, mitochondrial dysfunction, endocrine perturbation, inflammation, epigenetic modifications, and dysregulation of cell survival pathways. However, emerging data reveal sex-specific differences in susceptibility and molecular responses. In males, PFAS specifically disrupt steroidogenesis, the blood-testis barrier (BTB), induce germ cell apoptosis, and impair spermatogenesis, leading to reduced sperm quality and fertility. In females, PFAS exposure perturbs ovarian homeostasis by impairing folliculogenesis, oocyte maturation, steroid hormone biosynthesis, and granulosa/cumulus cell function, thereby contributing to diminished ovarian reserve and reproductive dysfunction. Distinct alterations in hormone signaling, lipid metabolism, nuclear receptor activation, and epigenetic regulation mediate these sex-specific effects. Beyond gonadal toxicity, PFAS exposure during pregnancy disrupts placental development and endocrine signaling, contributing to placental dysfunction, adverse pregnancy outcomes, and developmental programming associated with metabolic, neurodevelopmental, and immune abnormalities in offspring. This review presents current epidemiological and mechanistic evidence to delineate shared and sex-specific pathways underlying reproductive toxicity induced by both legacy and emerging PFAS. The findings provide an updated perspective on PFAS-induced reproductive toxicity and have implications for future risk assessment and targeted interventions.

Keywords:  Bioaccumulation; Child health; Developmental toxicity; Female fertility; Male fertility; PFAS; Reproductive toxicity

DOI:  https://doi.org/10.1016/j.tox.2026.154535
Best Pract Res Clin Obstet Gynaecol. 2026 Jun 27. pii: S1521-6934(26)00045-3. [Epub ahead of print]107 102745

The Cardiac-Fetal-Placental Unit: links between umbilical venous flow and maternal hemodynamics in fetal growth restriction.

Daniele Farsetti, Francesca Pometti, Gian Paolo Novelli, Barbara Vasapollo, Herbert Valensise.

  Fetal growth restriction (FGR) is associated with significant perinatal morbidity and mortality, yet its identification remains challenging due to the limited sensitivity of conventional biometric assessment and the lack of a reliable tool for assessing placental function. Placental function depends on uteroplacental perfusion which, in turn reflects maternal cardiovascular adaptation to pregnancy. In this context, umbilical venous flow (UVF) has emerged as a quantitative parameter reflecting fetal blood supply and a potential surrogate marker of placental function. This narrative review aims to provide an overview of UVF and maternal hemodynamics, and to explore their interaction within the framework of the cardiac-fetal-placental unit. The current literature indicates that UVF is reduced in pregnancies complicated by FGR, and it correlates significantly with maternal cardiac output (CO) and systemic vascular resistance (SVR). A hypodynamic maternal profile (high SVR, low CO) is consistently associated with reduced UVF and impaired placental perfusion, regardless of fetal biometry. The integration of maternal cardiovascular assessment and UVF evaluation provides a functional perspective on placental insufficiency and may improve the identification of pregnancies at risk. Furthermore, this approach offers a potential framework for understanding the effects of maternal hemodynamic interventions on fetal growth.

Keywords:  Cardiac output; Cardiac-fetal-placental unit; Maternal hemodynamics; Placenta function; Systemic vascular resistance; Umbilical vein blood flow

DOI:  https://doi.org/10.1016/j.bpobgyn.2026.102745
Placenta. 2026 Jun 30. pii: S0143-4004(26)00310-3. [Epub ahead of print]182 229-238

Esomeprazole treatment targeting sFLT-1 signaling in preeclampsia improves placental and fetal outcome in mice.

Beatrix Reisch, Lilo Valerie Wölk, Alina Edinger, Rainer Kimmig, Antonella Iannaccone, Alexandra Gellhaus.

   INTRODUCTION: Preeclampsia (PE) is one of the leading causes of maternal and infant mortality. Increase of soluble fms-like tyrosine kinase-1 (sFLT-1) is thought to be a key player in pathophysiology. Since preclinical studies showed therapeutical effects of esomeprazole (Eso), we hypothesized treatment may target sFLT-1 in PE.
METHODS: Using the PE/FGR (fetal growth restriction) model with systemic human sFLT-1 overexpression, mice were treated with Eso or vehicle. We analyzed dams, fetal and placental tissues regarding sFLT-1 at day 18.5 dpc and determined hypoxia of placentas using the marker pimonidazole.
RESULTS: Eso led to a trend of decrease in sFLT-1 serum levels. As shown previously by us sFLT-1 increase resulted in different severity levels of FGR. Exclusive maternal sFLT-1 overexpression (PE wt) fetuses revealed a mild reduction in weights, combined maternal and feto-placental sFLT-1 (PE het) led to strong reductions in weights and non-viability of the fetuses. Upon Eso an improvement in fetal outcome shown by an increased rate of fetal viability and a significant increase in weight of PE het fetuses was observed. Furthermore, upon Eso sFLT-1 (sFLT-i13) mRNA expression significantly decreased in the mesometrial triangle tissue (MT) and in placentas of PE het fetuses and maternal kidneys. A significant decrease of pimonidazole in MT of PE wt fetuses and a trend of decrease in PE het fetuses upon Eso showed less hypoxia in the maternal compartment.
DISCUSSION: These results could indicate a potential cytoprotective effect of Eso and an improvement of the hypoxic conditions at the maternal-fetal interface during PE.

Keywords:  Esomeprazole; Fetal growth restriction; Hypoxia; Placenta; Preeclampsia; sFLT-1

DOI:  https://doi.org/10.1016/j.placenta.2026.06.021
Aging Cell. 2026 Jul;25(7): e70614

Age-Associated Senescence of Decidual Macrophages: A Key Mediator of Adverse Pregnancy Outcomes in Advanced Maternal Age.

Yujing Zhang, Yiming Zhang, Guangshun Gong, Zhijing Li, Wenjing Xiong, Xuhui Fang, Ning Lu, Di Wang, Yihui Li, Aihua Liao.

  Senescence of immune cells can drive senescence of solid organs, and reversing immune cell senescence ameliorates organismal senescence phenotypes. As the second largest subset of decidual immune cells, macrophages play a critical role in pregnancy. However, whether decidual macrophages (DM) exhibit senescence in advanced maternal age (AMA) pregnancies (≥ 35 years old) and their involvement in AMA-related adverse outcomes remain undefined. This study elucidates the phenotypic and functional characteristics of DM in AMA pregnancies through clinical samples, animal models, and in vitro experiments. It clarifies the mechanisms underlying DM aging and explores novel intervention strategies to reverse DM aging and improve pregnancy outcomes in AMA pregnancies. We found that the presence of DM senescence in AMA pregnancies, manifested by an increased proportion of the pro-inflammatory phenotype M1, increased expression of senescence markers (P53 and SA-β-Gal), and decreased phagocytic capacity-all associated with the development of adverse outcomes in AMA. The mechanistic basis of DM senescence involves two key pathways: on the one hand, low expression of forkhead box O3 causes DM senescence by downregulating mitophagy. On the other hand, elevated IL-6 in the uterine microenvironment exacerbates senescence. Adoptive transfer of young mouse bone marrow-derived macrophages significantly rescues embryo resorption rates and placental development in AMA pregnant mice. Overall, our study uncovers novel mechanisms and therapeutic strategies for AMA-related adverse pregnancy outcomes through a new perspective of uterine macrophage senescence, providing new intervention ideas to improve adverse pregnancy outcomes in AMA.

Keywords:  advanced maternal age; aging; decidual macrophages; mice; uterus

DOI:  https://doi.org/10.1111/acel.70614
iScience. 2026 Jul 17. 29(7): 116393

Maternal hyperhomocysteinemia compromises female offspring fertility through overactivation of primordial follicles.

Jinmei Gao, Lu Wang, Jie Ma, Jialing Li, Yajie Wang, Jinfang Wang, Rong Hu.

  Hyperhomocysteinemia (HHcy), characterized by plasma homocysteine concentrations exceeding 15 μmol/L, has been associated with various issues that impact personal health and offspring well-being. This study examines the effect of maternal HHcy induced by a high-methionine diet on the fertility of female offspring mice. The results showed that maternal HHcy caused the overactivation of primordial follicles in female offspring mice by promoting the phosphorylation of key factors, including RPS6, mTOR, FOXO3a, and AKT. Moreover, the number of mitochondria in mature oocytes decreases, and mitochondrial function decreases, further leading to increased reactive oxygen species (ROS) levels, a higher degree of DNA damage, and spindle abnormalities, ultimately impairing the quality of oocytes. These findings demonstrate that maternal HHcy decreases offspring fertility by inducing primordial follicle overactivation and impairing oocyte quality, providing new insights into the pathological mechanisms through which HHcy affects the reproductive potential of offspring.

Keywords:  developmental biology; female reproductive endocrinology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.116393
bioRxiv. 2026 Jun 17. pii: 2026.06.14.730922. [Epub ahead of print]

Exposure to perfluorooctanoic acid accelerates Drosophila melanogaster juvenile development and disrupts mitochondrial metabolism.

Eric A Kilbourn, Matthew R Lowe, Kanishka Panda, Akshay M Bhaskaran, Guomao Zheng, Aditi R Aalati, Adam Malave, Sophia White, Anna Graber, Nika Zulkowski, Robert Pepin, Amina Salamova, Travis Nemkov, Angelo D'Alessandro, Swathi Yadlapalli, Pramod Reddy, Edgar Meyhofer, Jason M Tennessen.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants with poorly understood sublethal effects on insects. Perfluorooctanoic acid (PFOA), one of the most widely distributed legacy PFAS is increasingly recognized for altering organismal physiology beyond traditional toxicity endpoints. Here, we use the fruit fly Drosophila melanogaster as a model to examine how PFOA exposure during larval (juvenile) development reshapes insect life-history progression and metabolic homeostasis. Our studies reveal that at environmentally relevant concentrations (nM to low µM), PFOA induces precocious expression of developmentally-regulated genes and leads to metabolic changes that persist into adulthood. At higher concentrations used to probe mechanism, PFOA accelerates larval development, disrupts mitochondrial membrane potential, and increases whole-organism metabolic heat production - results that suggest altered mitochondrial energetic efficiency. Consistent with this tradeoff, PFOA-exposed larvae that develop faster under permissive conditions exhibit heightened sensitivity to environmental stressors, including elevated temperature and reduced food hydration. Together, these findings demonstrate that PFOA disrupts metabolic and developmental processes in a dose- and context-dependent manner, highlighting sublethal effects that may influence insect resilience under environmental stress.
SYNOPSIS STATEMENT: Here we describe how PFOA alters the growth, development, and metabolism of the fruit fly Drosophila melanogaster . Specifically, we find that PFOA accelerates Drosophila juvenile growth while also rendering exposed larvae sensitive to environmental stress. These observations suggest that widespread PFOA contamination may impair the developmental fitness of insect populations.

DOI: https://doi.org/10.64898/2026.06.14.730922
J Clin Invest. 2026 Jun 30. pii: e201633. [Epub ahead of print]

Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through early ovarian failure.

Eric A Rhon-Calderon, Cassidy N Hemphill, Alexandra J Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J Krapp, Laren Riesche, Nicolas Plachta, Richard M Schultz, Marisa S Bartolomei.

  Reproductive aging is characterized by a progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF) though widely used and generally considered safe, has been associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrated that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibited altered ovarian function, reduced follicle reserve, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.

Keywords:  Development; Embryonic development; Epigenetics; Reproductive biology; Transcriptomics

DOI:  https://doi.org/10.1172/JCI201633
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2606092123

Female reproductive dysfunction and transgenerational consequences following prolonged spaceflight exposure.

Xiaoman Hong, Fereshteh Dalouchi, John C Prom, Michael E Ponte, Briana L Hockey, Jessica L Braun, Payton Nies, Avanelle Stoltz, V Praveen Chakravarthi, Molika Sinha, Sungshin Y Choi, April E Ronca, Joshua S Alwood, Val A Fajardo, E Matthew Morris, Stephanie Puukila, Lane K Christenson.

  Spaceflight presents unique gravitational, radiation, and isolation hazards for human exploration of the Moon, Mars, and beyond, yet its impact on the female reproductive system and successive generations has been largely unassessed. In the NASA Rodent Research 20 mission, we examined the impact of a 42-d spaceflight on the female reproductive axis including ovulatory capacity, implantation rate, and fecundity as well as behavioral, metabolic, and functional outcomes in F1 and F2 offspring. Females bred 5 d after return to Earth became pregnant but only exhibited a slight decline in fecundity compared to ground controls. In contrast, F1 offspring from spaceflight dams exhibited marked growth, functional, and behavioral differences compared to F1 offspring from control dams. Moreover, F1 female offspring from spaceflight dams exhibited decreased ovarian reserves as evidenced by reduced anti-Mullerian hormone levels early in life (21 d of age) and premature ovarian failure or an early loss in fertility, as indicated by reduced numbers of litters and total number of pups born to females over a 9-mo period. Strikingly, transgenerational metabolic and reproductive disturbances were also observed in F2 pups of spaceflight granddams, including persistent reductions in ovarian reserve, suggesting germline-level effects. Together these findings reveal significant short- and long-term impacts of spaceflight on the female reproductive system and on their offspring across generations, demonstrating biological transmission of reproductive vulnerability following maternal spaceflight exposure, and raising concerns for space travelers and colonization missions.

Keywords:  fertility; microgravity; reproduction; spaceflight; transgenerational inheritance

DOI:  https://doi.org/10.1073/pnas.2606092123