bims-placeb 2026-07-12 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–07–12
fourteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss.
Conserved and divergent DNA methylation features of extraembryonic tissues between human, mouse and chicken.
Sex-Specific Placental Adaptations Associated with Fetal Growth Restriction: A Review.
Effects of hyperlipidic diet-induced obesity on placental transcriptome and fetal development: FTO-related biological processes.
The mTOR/AMPK signaling axis in placental dysfunction and preeclampsia: mechanisms and therapeutic targeting with metformin.
Modeling human embryo adhesion using a microfluidic platform.
Proteomic profiling of xenobiotic and nutrient transporters in human placenta of different gestational ages.
Embryo quality control via lineage-specific aneuploid cell elimination in embryos and stem cell-derived embryo models.
Associations of Placental Oxidative Stress with Exposure to Gestational Air Pollution: Evidence from the UPSIDE ECHO BABIES Cohort.
Lumican deficiency dysregulates trophoblast function via PI3K/AKT and P53 signaling in preeclampsia.
Electron tomography reveals mitochondrial network and cristae remodelling during cell differentiation in the human placenta.
PD-L1 expression in trophoblasts contributes to maternal-fetal immune tolerance in the canine placenta.
Epigenetic, Environmental, and Sex-Specific Programming of Long-Term Health in ART-Conceived Offspring.
Brain sparing in fetal growth restriction: The double-edged sword of fetal hypoxaemia.

Nat Commun. 2026 Jul 10.

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

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

Idiopathic recurrent pregnancy loss (RPL) affects 1-2% of human pregnancies, yet the underlying molecular causes are poorly understood. Here we identify defective Protein Arginine Methyltransferase 1 (PRMT1) function in trophoblast progenitors as a cause of early pregnancy failure. PRMT1 is highly conserved in mammalian trophoblast progenitors, and conditional deletion of Prmt1 in mouse trophoblast progenitors arrests placental and embryonic development, resulting in lethality at ~E7.5. In humans, a subset of idiopathic RPL cases exhibits loss of PRMT1 in cytotrophoblast progenitors (CTBs). Human trophoblast stem cells (hTSCs) derived from these RPL placentas, together with PRMT1-depleted hTSCs, demonstrate an essential role for PRMT1 in maintaining trophoblast progenitor self-renewal. RNA-seq and CUT&RUN analyses reveal that PRMT1 promotes expression of stem-state regulators, including TEAD4 and MYBL2, through enrichment of histone H4 arginine 3 asymmetric dimethylation (H4R3Me2a) at their chromatin loci. PRMT1 is required for extravillous trophoblast (EVT) development, whereas its loss promotes spontaneous syncytiotrophoblast (STB) differentiation. Together, these findings identify the PRMT1-H4R3Me2a axis as a conserved epigenetic regulator of trophoblast development and pregnancy maintenance.

DOI: https://doi.org/10.1038/s41467-026-75452-4
BMC Genomics. 2026 Jul 06.

Conserved and divergent DNA methylation features of extraembryonic tissues between human, mouse and chicken.

Georgia Lea, Yuxin Gu, Fengzhu Xiong, Courtney W Hanna.

   BACKGROUND: The first cell fate decisions in embryogenesis give rise to extraembryonic tissues, such as the yolk sac and placenta, which are essential for embryo survival. In mammals, extraembryonic cell types arising from these first lineage decisions show distinct DNA methylation patterning, including large partially methylated domains, gene body methylation and accumulation across developmental CpG island (CGI) promoters. Analysis of extraembryonic membranes beyond mammalian species has been limited. Using bisulphite-seq and RNA-seq, we comparatively define these epigenetic characteristics of extraembryonic tissues in both mouse and human. We then tested whether these features are conserved in the chicken extraembryonic membranes (EEMs) including the yolk sac, chorion and chorioallantoic membrane (CAM).
RESULTS: Transcriptomic analysis revealed that embryonic day (E)4 yolk sac/chorion and E14 CAM express similar marker genes to the mouse chorionic trophoblast, supporting that the chicken chorionic ectoderm shares a 'trophoblast-like' cell identity. We find that partially methylated domains and transcription-linked gene body methylation patterning are highly conserved between mouse and human proliferative multipotent trophoblast cells but were not evident in the chicken EEMs. However, we find that methylation of CGIs associated with developmental genes was a conserved feature of mouse, human and chicken EEMs.
CONCLUSIONS: These findings support that features of the extraembryonic DNA methylation landscape have distinct underlying mechanisms. We find that only one feature is conserved across extant amniotes, suggesting distinct evolutionary pressures are associated with different features of EEM epigenetic landscape.

Keywords:  Amniotes; Chorion; Cross-species; DNA methylation; Extraembryonic; Methylome; Trophoblast

DOI:  https://doi.org/10.1186/s12864-026-13123-w
J Anim Sci. 2026 Jul 10. pii: skag210. [Epub ahead of print]

Sex-Specific Placental Adaptations Associated with Fetal Growth Restriction: A Review.

Leticia T Casarotto, Alexa M Holtzapple, Helen N Jones.

  Fetal growth restriction (FGR) is a major obstetric complication linked to placental insufficiency, increasing the risk of perinatal morbidity, mortality, and long-term health issues. The placenta is central to fetal development and maternal-fetal communication; its dysfunction leads to impaired fetal development. Numerous experimental FGR models exist, from rodents to large animals, but most studies, despite changes to some federal funding requirements, have historically overlooked the impact of fetal sex on placental development, function, and adaptation. Recent evidence indicates that male and female placentas employ distinct adaptive strategies in response to adverse intrauterine conditions, potentially contributing to observed sex differences in neonatal outcomes and adult disease risk. Male fetuses often prioritize growth, reducing resilience to environmental stress, while female fetuses exhibit more pronounced growth restriction but greater placental adaptability, such as altered expression of insulin-like growth factors, angiogenic regulators, and nutrient transporters. This review synthesizes data from human studies and animal models to highlight sex-specific placental adaptations to nutrient restriction, hypoxia, maternal hyperthermia, and other stressors. Understanding these differences is critical for both developing future interventions in humans and enhancing livestock productivity/neonatal survival in agriculture.

Keywords:  fetal growth restriction; placenta; sex specific

DOI:  https://doi.org/10.1093/jas/skag210
Placenta. 2026 Jul 02. pii: S0143-4004(26)00303-6. [Epub ahead of print]182 279-292

Effects of hyperlipidic diet-induced obesity on placental transcriptome and fetal development: FTO-related biological processes.

Maíra Schuchter Ferreira, Josilene Lopes de Oliveira, Ana Paula Varela Sanches, Bruna de Souza Lima, Josiane Érica Miyamoto, Ana Carolina Lima Camargo, Márcio Alberto Torsoni, Adriana Souza Torsoni, Marciane Milanski, Letícia Ignacio-Souza.

   INTRODUCTION: The FTO gene is strongly linked to obesity, but its mechanisms in fetal growth and placental function under maternal obesity remain unclear. This study investigated FTO-related biological processes in the placental transcriptome and fetal development using a diet-induced obesity model.
METHODS: Swiss mice were fed a 45% high-fat diet for 4 weeks and classified as obesity-prone (HFP) or obesity-resistant (HFR). Transcriptomic analysis identified differentially expressed genes (DEGs) in placentas. Maternal and fetal parameters were correlated with placental FTO expression, and in vitro analyses evaluated obesogenic conditions on FTO mRNA in placental cells.
RESULTS: Distinct transcriptomic profiles were observed between groups. HFP mice showed increased DEGs linked to placental development and anatomical structure, but a reduction in response to growth factors and cell differentiation. In HFP mice, placental FTO expression correlated negatively with pre-gestational weight gain and placental weight, but positively with fetal weight, crown-rump length, biparietal diameter, and transverse abdominal diameter. These associations were absent in HFR mice. In vitro, obesogenic conditions significantly reduced FTO mRNA expression.
DISCUSSION: The obesity phenotype modulates the relationship between placental FTO expression and fetal development. These findings highlight FTO as a potential mediator of placental adaptations and fetal growth under maternal obesogenic conditions.

Keywords:  Development; Obesity; Perinatal outcomes; Placenta; Pregnancy; Transcriptome

DOI:  https://doi.org/10.1016/j.placenta.2026.06.014
Mol Biol Rep. 2026 Jul 10. pii: 1145. [Epub ahead of print]53(1):

The mTOR/AMPK signaling axis in placental dysfunction and preeclampsia: mechanisms and therapeutic targeting with metformin.

Mohammad Hassan Albar, Hayder M Al-Kuraishy, Ahmed Baker A Alshaikh, Souzan Kafy, Mustafa M Shokr, Gaber El-Saber Batiha.

  Preeclampsia continues to be one of the main causes of maternal and fetal complications in the absence of any effective treatment apart from placental expulsion. The present review presents a systematic evaluation of the involvement of mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) in preeclampsia through a discussion of mechanisms, pathophysiology, and clinical features, and explores the possible role of metformin as a therapeutic agent. In normal pregnancy, the physiological interaction between mTORC1 and AMPK enables appropriate trophoblast invasion and nutrition. However, in preeclampsia, chronic placental hypoxia and oxidative stress affect this delicate balance, resulting in a pathological situation characterized by increased AMPK activation and reduced mTORC1 activity, which adversely affects the function of trophoblasts and leads to increased anti-angiogenic factor production. However, the interaction is mutual because, while low doses of AMPK activation might restore metabolic equilibrium, higher doses, especially in combination with metformin, may further inhibit mTORC1. Thus, identifying the mTOR/AMPK axis as a key mechanism offers a new paradigm for understanding preeclampsia, yet therapeutic targeting with metformin requires careful titration to avoid aggravating the very imbalance it aims to correct. This nuanced perspective supports the future development of safe, placenta-directed therapies for preeclampsia.

Keywords:  AMP activated protein kinase; Mammalian target of rapamycin; anti-angiogenic factors; metformin; nutrient sensing; trophoblast

DOI:  https://doi.org/10.1007/s11033-026-12273-0
Sci Adv. 2026 Jul 10. 12(28): eadz2249

Modeling human embryo adhesion using a microfluidic platform.

Sofía Zaragozano, María Pardo-Figuerez, Ana Monteagudo-Sanchez, Anna Quirant, Javier Moncayo-Arlandi, Javier Gonzalez-Fernandez, Jaime Llera-Oyola, Petr Volkov, Sara Maggi, Luis Quintero, Francisco Raga, Pablo Grases, Xavier Santamaria, Inmaculada Moreno, Nicolas Plachta, Carlos Simon, Felipe Vilella.

Embryo adhesion represents a critical step of implantation, yet understanding this process has been hindered by the lack of human in vitro platforms that replicate endometrial physiology. Here, we present a dual-channel microfluidic platform containing organoid-derived endometrial epithelium and primary stromal cells. Our model recapitulates important endometrial hallmarks including epithelial polarization, stromal decidualization, extracellular vesicle release, and hormone-induced receptivity. We validated the model using mouse embryos and human blastocysts, where we showed that embryos displayed features of initial adhesion. These included establishment of embryo-epithelial contacts initiated via the polar trophectoderm, inner cell mass repositioning, and lineage reorganization. Moreover, human embryos secreted βhCG indicating a functional trophoblast. Thus, this work provides a platform to study key features of embryo adhesion and endometrial receptivity and disorders affecting embryo-endometrium interactions.

DOI: https://doi.org/10.1126/sciadv.adz2249
bioRxiv. 2026 Jun 30. pii: 2026.06.25.730994. [Epub ahead of print]

Proteomic profiling of xenobiotic and nutrient transporters in human placenta of different gestational ages.

Eric M Weaver, Ariel Topletz-Erickson, Nina Isoherranen, Jashvant D Unadkat, Samuel L M Arnold.

Background: The placenta serves a critical role in nutrient uptake and waste elimination for the developing fetus. The placenta is also responsible for the uptake and/or exchange of xenobiotics, including medications, between the maternal and fetal bloodstreams. An estimated 40-80% of women take medications or drugs during pregnancy for a variety of conditions. Very little is understood about fetal drug and nutrient exposure during pregnancy and how it may change over the course of fetal development.
Objective: This study aimed to characterize the abundance of transport proteins in placental tissue, which are important in modulating fetal nutrient and drug exposure, over the duration of pregnancy. Mass spectrometry-based global proteomic analysis revealed trends in the expression of thousands of proteins throughout gestation. Focusing on the membrane-associated proteome enabled an increased emphasis on the solute carrier and ATP-binding cassette families of transporter proteins that are critical for nutrient and xenobiotic transport across the maternal-fetal barrier.
Study Design: Using data-independent acquisition proteomics, relative abundance of proteins in placental tissue samples was profiled across all three trimesters of pregnancy (Trimester 1 = 16, Trimester 2 = 9, and Term = 9). Membrane fractions were generated to enrich membrane-associated proteins for proteomic analysis. Placental samples were grouped into randomized batches for membrane fraction generation and mass spectrometry analysis. Proteomic search results from each batch were imported into the R programming environment from Skyline, concatenated, and normalized as one data set for downstream analysis.
Results: A total of 6,331 proteins were detected across all samples with 4,210 proteins identified in every sample. Pathway analysis revealed that as gestational age increases, membrane-associated proteins involved in more complex metabolic pathways increase in relative abundance while those involved in extracellular remodeling events and simple organic ion transport tended to decrease. A total of 139 solute carrier and ATP-binding cassette transport proteins were identified in all samples, and 80 were identified in every sample. In general, membrane-associated proteins, including solute carrier and ATP-binding cassette transport proteins, were significantly enriched in placental tissue collected during early gestation compared to term placental tissue.
Conclusion: This study presents a comprehensive profiling of membrane-associated proteomic changes during gestation and identifies significant gestational age associated abundance changes at the protein level in several transport protein families. The application of data-independent acquisition global proteomic techniques enabled in-depth analysis of thousands of proteomic changes across pregnancy in a single experiment. These data provide critical information to support future studies into the understanding of fetal exposure to xenobiotics and nutrients circulating in the maternal bloodstream.

DOI: https://doi.org/10.64898/2026.06.25.730994
Nat Commun. 2026 Jul 06.

Embryo quality control via lineage-specific aneuploid cell elimination in embryos and stem cell-derived embryo models.

Lisa K Iwamoto-Stohl, Laura Amaya, Pallavi Panda, Yuqi Wang, Ninadini Sharma, Catherine King, Magdalena Zernicka-Goetz.

Aneuploidy is frequent in human pre-implantation embryos and a leading cause of early pregnancy loss, yet is rarely observed at birth, implying robust embryonic surveillance. Here we define how this surveillance operates after implantation using an integrated, three-lineage stem cell-derived embryo model that recapitulates the epiblast (EPI), visceral endoderm (VE), and extraembryonic ectoderm (ExE). Seeding of aneuploid cells into each lineage independently reveals lineage-specific fates: aneuploid cells are selectively depleted from EPI and VE but persist within ExE. Live imaging captures their removal by apoptosis or physical extrusion. Single-cell RNA sequencing shows p53 activation and Myc repression in aneuploid cells, and pathway perturbations modulate their clearance, confirming causality. Together, these findings demonstrate a post-implantation, lineage-restricted quality-control program that eliminates aneuploid cells from the embryo proper while permitting extraembryonic tolerance. They also establish integrated embryo models as a tractable platform to dissect the molecular logic of developmental quality control.

DOI: https://doi.org/10.1038/s41467-026-75054-0
Environ Res. 2026 Jul 09. pii: S0013-9351(26)01561-6. [Epub ahead of print] 125230

Associations of Placental Oxidative Stress with Exposure to Gestational Air Pollution: Evidence from the UPSIDE ECHO BABIES Cohort.

Emily A Craig, Yan Lin, Yihui Ge, Xiangtian Wang, Otgondelger Enkhtaivan, Don K Harrington, Richard K Miller, Susan K Murphy, Sally W Thurston, Philip K Hopke, Emily S Barrett, Thomas G O'Connor, David Q Rich, Junfeng Jim Zhang.

   BACKGROUND: Increased placental oxidative stress is frequently documented in pregnant women with adverse maternal outcomes such as preeclampsia. However, environmental determinants of placental oxidative stress remain poorly understood.
OBJECTIVES: To determine whether exposure to air pollution and polycyclic aromatic hydrocarbons (PAHs) are associated with placental levels of malondialdehyde (MDA), a biomarker of oxidative stress; to assess whether placental MDA reflects short-term (lag days 0-7) or longer-term (trimester-specific) exposure; and to evaluate whether these associations differ by fetal sex.
METHODS: Participants were drawn from the UPSIDE ECHO BABIES cohort (n = 222). Placental MDA concentrations were quantified using an HPLC method. The ambient PM2.5 and NO2 exposures were estimated using high-resolution random forest models. PAH exposure was assessed using trimester-specific maternal blood concentration of PAH-hemoglobin adducts. Associations between exposure and placental MDA were evaluated using multivariable linear regression and distributed lag non-linear models (DLNMs), adjusting for maternal and demographic covariates.
RESULTS: A 1-IQR increase in the second trimester, specifically month 5 PM2.5, was associated with a 24.8% (95% CI: 3.3-50.7), and 13.7% (95% CI: 0.1-29.16) increase in MDA concentration, respectively. Similarly, the second-trimester hemoglobin adduct of benzo[a]pyrene showed a positive, non-significant association with MDA. Although week-specific DLNM estimates were not statistically significant, the analysis showed that exposure to PM2.5 during gestational weeks 16-20 was positively associated with MDA concentration. When stratified by placenta sex, female placentas had increased MDA in the second trimester associated with PM2.5 , and male placentas had increased MDA in the second trimester associated with PAH-hemoglobin adducts. No significant associations were observed for either pollutant when estimated one lag week before birth. No significant associations were observed for NO2 exposure.
CONCLUSIONS: Second-trimester PM2.5 exposure was linked to elevated placental MDA concentration at delivery, indicating that placental MDA may reflect longer-term air pollution exposure. These findings emphasize the importance of investigating specific gestational windows through which air pollution induces oxidative injury to the placenta.

Keywords:  Air pollution; Malondialdehyde; Oxidative stress; PM(2).(5); Placenta; Pregnancy

DOI:  https://doi.org/10.1016/j.envres.2026.125230
NPJ Regen Med. 2026 Jul 07.

Lumican deficiency dysregulates trophoblast function via PI3K/AKT and P53 signaling in preeclampsia.

Xin Wang, Qi Zhang, Yi Ren, Kunzheng Fan, Chao Liu, Huijie Gao.

Lumican, an extracellular matrix (ECM) component highly expressed in placenta, is implicated in preeclampsia (PE) pathogenesis, though its precise mechanisms in trophoblast function and PE development remain unclear. Transcriptomic analysis of a PE rat model induced by L-NAME revealed altered placental gene expression. Lumican expression progressively increased throughout rat and human gestation but was significantly downregulated in PE patient and model placentas. Functional assays showed shRNA-mediated lumican knockdown inhibited trophoblast proliferation, migration, and invasion while promoting apoptosis. This knockdown also influenced the phosphorylation of key proteins within the PI3K/AKT and P53 signaling pathways. Co-treatment with the PI3K agonist 740 Y-P activated this pathway, enhancing trophoblast proliferation and invasion, effects antagonized by lumican knockdown. In vivo, adenovirus-mediated lumican shRNA induced PE-like phenotypes: elevated systolic blood pressure, increased 24 h urinary protein, higher plasma sFlt-1 levels and sFlt-1/PlGF ratio. Histopathological analyses demonstrated abnormal placental villi development and renal glomerular endothelial damage. Immunohistochemistry confirmed lumican deficiency reduced PI3K, AKT, and MDM2 while upregulating P53 in placental tissues. Collectively, our findings demonstrate that reduced lumican expression contributes to PE by impairing trophoblast function via disruption of the PI3K/AKT and P53 signaling pathway, thus providing a mechanistic basis for its further exploration as a diagnostic marker and therapeutic target.

DOI: https://doi.org/10.1038/s41536-026-00493-8
Nat Commun. 2026 Jul 08.

Electron tomography reveals mitochondrial network and cristae remodelling during cell differentiation in the human placenta.

Siddharth Acharya, Eric Hanssen, Veronica B Botha, Tia M Smith, Sahan Jayatissa, Zlatan Trifunovic, Lucy A Bartho, John E Schjenken, Tu'uhevaha J Kaitu'u-Lino, Anthony V Perkins, Joanna L James, Kirsty G Pringle, James C Bouwer, Roger Smith, Joshua J Fisher.

Mitochondria adapt their structure through fusion and fission, yet how their morphology and cristae architecture change as cells differentiate remains unclear. The human placenta is a valuable model for studying mitochondrial diversity within a single tissue. As epithelial trophoblast cells of the placenta differentiate, their accompanying mitochondria morphologically and functionally transform. We use array tomography to characterise mitochondrial volume and network complexity. Cryo-electron tomography reveals two distinct subpopulations of mitochondria within preparations enriched for progenitor cytotrophoblasts, and a singular, homogeneous population in the differentiated syncytiotrophoblast. We showcase the 3D topology of individual cristae through a standardised metric of "curvedness". Proteomic analysis of isolated mitochondria identifies reduced levels of proteins involved in mitochondrial dynamics and cristae organisation complexes in the syncytiotrophoblast, accompanied by variations in electron transport chain subunits, ATP synthase, and supercomplex components. This study highlights the advantages of combining multimodal imaging with proteomic analyses, to elucidate the process of mitochondrial morphology and cristae architecture remodelling as cells differentiate.

DOI: https://doi.org/10.1038/s41467-026-75408-8
Theriogenology. 2026 Jul 07. pii: S0093-691X(26)00261-X. [Epub ahead of print]265 118071

PD-L1 expression in trophoblasts contributes to maternal-fetal immune tolerance in the canine placenta.

Masato Kobayashi, Takayuki Obuki, Risa Yazaki, Rino Ishimoto, Sara Naito, Mami Kobayashi, Yukino Machida, Tomokazu Nagashima, Masanori Kobayashi, Tatsuya Hori.

  To elucidate the mechanisms of maternal-fetal immune tolerance in the canine endotheliochorial placenta, we investigated the localization and functional significance of programmed death-ligand 1 (PD-L1). Immunohistochemical analysis revealed region-specific PD-L1 expression, with negative staining in syncytiotrophoblasts and cytotrophoblasts within the labyrinth zone, and positive staining in monolayered columnar trophoblasts within the junctional zone. As the junctional zone is the primary interface for maternal tissue invasion, this site-specific expression suggests that PD-L1 functions as an immunological barrier. To verify this mechanism at the cellular level, we established primary canine trophoblast cells (CD45-/CD90-/Pan-cytokeratin+) purified from placental tissues. These cells were PD-L1 negative under unstimulated conditions; however, PD-L1 expression was markedly increased upon stimulation by the addition of with culture supernatants containing T-cell-derived cytokines, including interferon-gamma (IFN-γ). Furthermore, functional analysis by co-culture with canine peripheral blood mononuclear cells revealed that trophoblasts significantly inhibited Concanavalin A-stimulated proliferation of CD4+ and CD8+ T cells and IFN-γ production in the culture supernatant. This immunosuppressive effect was significantly reversed by administration of a neutralizing anti-canine PD-L1 antibody. Therefore, trophoblasts actively suppress T-cell responses via the PD-L1 pathway. These findings highlight the importance of local immune regulation in canine pregnancy maintenance and provide a novel perspective for understanding the pathophysiology of reproductive disorders such as abortion.

Keywords:  Canine; Maternal–fetal immune tolerance; PD-L1; Placenta; Trophoblasts

DOI:  https://doi.org/10.1016/j.theriogenology.2026.118071
Biol Reprod. 2026 Jul 01. pii: ioag137. [Epub ahead of print]

Epigenetic, Environmental, and Sex-Specific Programming of Long-Term Health in ART-Conceived Offspring.

Eric A Rhon-Calderon, Cassidy N Hemphill, Marisa S Bartolomei.

  Assisted Reproductive Technologies (ART) are non-coital methods of conception widely used to address infertility. These procedures include conventional in vitro fertilization (IVF), intracytoplasmic sperm injection, gamete and embryo cryopreservation, trophectoderm biopsy for preimplantation genetic testing, and newer mitochondrial replacement techniques. Since the first IVF birth in 1978, the global use of ART has increased rapidly, contributing to more than 13 million births worldwide. Although ongoing technological advances have improved safety and increased pregnancy and live-birth rates, ART has also been associated with adverse placental and fetal outcomes, some of which persist into later life and, in certain cases, across generations. The mechanisms underlying these outcomes are not fully understood, but studies suggest that altered epigenetic reprogramming, environmental influences, and sex-specific factors are major contributors. In this review, we examine how long-term health outcomes in ART-conceived offspring are shaped by the interplay of epigenetic mechanisms, environmental influences, and sex-specific responses in both humans and mice.

Keywords:  ART; development; environment; epigenetics; sex

DOI:  https://doi.org/10.1093/biolre/ioag137
J Physiol. 2026 Jul 06.

Brain sparing in fetal growth restriction: The double-edged sword of fetal hypoxaemia.

Beth J Allison, Tegan A White, Emily J Camm, Suzanne L Miller.

  Fetal hypoxaemia during pregnancy is not uncommon, arising from chronic placental insufficiency or acute stressors. In the case of placental insufficiency and chronic fetal hypoxia, fetal growth is reduced, resulting in fetal growth restriction (FGR). Fetal hypoxaemia initiates an immediate adaptive strategy to preserve brain oxygen delivery - the brain sparing response. Asymmetric FGR, in which head size is relatively larger than body size, is evidence of prolonged brain sparing. The acute physiology of the brain sparing response is well-defined in preclinical studies, involving peripheral vasoconstriction and reduced cerebral resistance to promote cerebral vasodilatation. Yet, the mechanisms that maintain fetal brain sparing during sustained hypoxaemia remain incompletely understood. Furthermore, although brain sparing has historically been interpreted as protective, this concept is being challenged, with its presence linked to increased risk of death or neonatal morbidity and neuropathology. This contradiction reflects that brain sparing is not static but evolves with the severity of fetal hypoxaemia; clinical evidence points to a front-to-back pattern of brain vasodilatation that initially prioritises cortical perfusion for higher-order function, whereas prolonged or severe hypoxaemia drives a shift towards brainstem preservation and survival. Thus, the brain sparing response is initiated by fetal hypoxaemia and is a unique indicator of fetal compromise, but it progresses from a compensatory to a maladaptive response. The mechanisms, multisystem physiology and ontogeny of sustained brain sparing in severe FGR are not well characterised, but advancing this knowledge affords new opportunities to diagnose and manage FGR, and to intervene to prevent adverse consequences.

Keywords:  brain sparing; cardiovascular; fetal growth restriction; hypoxia; neuropathology; small for gestational age

DOI:  https://doi.org/10.1113/JP291253