Search Results (33)

This study investigated the metabolic mechanisms driving physiological functional remodeling in RFM by analyzing plasma biochemical parameters and metabolomic profiles at key peripartum timepoints (21 and 7 d prepartum and 4 h postpartum), integrated with placental and fetal membrane metabolic characteristics. The results revealed that RFM cows exhibited significant negative energy balance (NEB) as early as 21 days before parturition, characterized by elevated plasma levels of non-esterified fatty acids, β-hydroxybutyrate, and malondialdehyde, alongside reduced activity of antioxidant enzymes (GSH-Px, CAT) (p ≤ 0.05). Metabolomic analysis demonstrated persistent lipid metabolism dysregulation, amino acid imbalance, and nucleotide metabolism disturbances in RFM cows from 21 days prepartum to 4 h postpartum, indicating premature mobilization of adipose and muscle tissues. Further metabolomic analyses of the placenta and fetal membranes confirmed that metabolic dysfunction compromises energy supply during parturition, adversely affecting immune homeostasis and extracellular matrix degradation in the placenta and fetal membranes of RFM dairy cows. These physiological dysfunctions have the potential to impede the timely expulsion of fetal membranes after calving. In conclusion, RFM is closely associated with early-onset metabolic dysfunction during the periparturient period, where insufficient energy supply due to NEB, oxidative stress, and immune-endocrine disruptions collectively impair normal fetal membrane detachment. Full article

Background: The placenta stands at the maternal–fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Methods: Pre-pregnancy weight loss in C57BL/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg/kg/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18–20 of gestation. Results: ¹H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p < 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation. Conclusions: These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity. Full article

Developmental programming, shaped by environmental and lifestyle stressors during prenatal life, is increasingly recognized as a major contributor to non-communicable diseases (NCDs) later in life. Oxidative stress, one of key mechanisms linking these stressors to fetal metabolomic reprogramming and disease pathogenesis, leaves measurable metabolomic signatures that reflect disrupted redox balance. Alterations in glucose, lipid, and amino acid metabolism and antioxidant response could reveal the main pathways driving NCD development. This review summarizes epidemiological studies that have investigated biochemical responses of the prenatal exposure to metals, air pollution, and tobacco smoke and e-cigarette vapor in maternal–placental–fetal compartments using a metabolomic approach. Summarized studies indicate that maternal exposure to metals primarily disrupts amino acid pathways related to one-carbon metabolism, glutathione synthesis, and oxidative stress defense, while air pollution, particularly fine particulate matter, mainly affects lipid oxidation, fatty acid β-oxidation, and amino acid and carbohydrate metabolism. Tobacco smoke and e-cigarette vapor induce widespread disturbances involving reduced citric acid cycle intermediates, altered acylcarnitines and phospholipids, and impaired antioxidant capacity, collectively promoting oxidative damage and inflammatory signaling. The identification of these metabolome alterations might contribute to a deeper understanding of the toxicity and biological impact of environmental stressors on offspring health. These results may eventually lead to the identification of early biomarkers and to the development of therapeutic strategies aimed at reducing NCD risk. Full article

Placental dysfunction underlies the major obstetric syndromes, including preeclampsia, fetal growth restriction, placenta accreta spectrum, pregnancy loss, and monochorionic twin complications. Recent molecular studies have revealed that dysregulated oxygen sensing, impaired angiogenic signaling, altered immune tolerance, and defective trophoblast fusion represent shared pathogenic pathways that converge across these disorders. Integrating morphological evidence with mechanistic data highlights how villous maldevelopment, shallow trophoblast invasion, and aberrant vascular remodeling translate into clinical disease. Advances in biomarker research have already transformed clinical care: the sFlt-1/PlGF ratio is now established in the prediction and management of preeclampsia, while placental proteins such as PAPP-A and PP13, nucleic acid signatures including cfDNA, cfRNA and miRNAs, and extracellular vesicle cargo show promising potential for early, non-invasive detection of placental pathology. Multi-omics approaches, particularly single-cell and spatial transcriptomics combined with proteomic and metabolomic profiling, are paving the way for composite diagnostic panels that capture the polygenic and multicellular nature of placental disease. This review synthesizes current knowledge of molecular mechanisms, histological correlates, and translational biomarkers, and outlines how precision obstetrics may emerge from bridging mechanistic discoveries with clinical applications. Full article

Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy, affecting up to 14% of pregnancies globally. GDM is characterized by glucose intolerance that arises or is first identified during pregnancy and is linked to significant short- and long-term adverse outcomes for both mothers and their offspring. The pathophysiology of GDM involves more than maternal insulin resistance and β-cell dysfunction. It is influenced by complex interactions among placental hormones, adipokines, inflammatory mediators, and oxidative stress pathways. Additionally, placental-derived exosomes and metabolomic signatures have emerged as promising biomarkers for early prediction and monitoring of the disease. Despite advancements in clinical diagnosis and management, including lifestyle interventions and pharmacological treatments, current strategies are still inadequate to prevent complications for both mothers and newborns entirely. Recent molecular insights into GDM development have been explored, along with emerging biomarkers and potential therapies. This synthesis also considers prospects for precision medicine strategies that could significantly improve GDM management. The urgent need for improved prevention and treatment of GDM is evident. A deeper understanding of the molecular foundations of GDM is essential and urgent, as it may enhance clinical outcomes and provide opportunities for early prevention of intergenerational metabolic disease risk. Full article

Background/Objectives: Individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy are two distinct cardiometabolic populations, each potentially necessitating alternative clinical management. However, our understanding of the unique physiological effects of uncomplicated MHO on fetoplacental growth and metabolism remains limited. In this study, we aimed to identify changes in placental morphology and metabolites associated with maternal obesity, independent of pregnancy-related cardiometabolic complications. Methods: Placentae from women with a prepregnancy body mass index (BMI) < 25 kg/m² (control; n = 15) and women with MHO (prepregnancy BMI > 30 kg/m² with no cardiometabolic diseases; n = 15) were analyzed for indices of placental growth and untargeted metabolomics. Complementary assessments were conducted on proinflammatory genes and antioxidant defense system genes, proteins, and enzymes, along with lipid peroxidation markers. Results: Clear placentomegaly without histopathological changes was observed in uncomplicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing placentae from MHO individuals from control placentae, and changes in the cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct differences identified. Conclusions: These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity, without cardiometabolic complications, may influence fetoplacental growth and metabolism. They may also represent a crucial first step towards marker identification for MHO pregnancy and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent. Full article

Identifying the specific factors secreted during early pregnancy is an effective method for pregnancy detection in cattle, helping to reduce empty pregnancies in the industry. To systematically investigate metabolic variations between early pregnancy and the estrous cycle and their relationship with pregnancy progression, this study utilized four-dimensional data-independent acquisition (4D-DIA) proteomics and liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomics to analyze serum samples collected from Chinese native yellow cattle at day 0 and day 21 post-mating, combining bioinformatics analysis with experimental validation. The platelet activation signaling pathway and angiogenesis-related proteins were significantly upregulated. Among them, fibrinogen alpha/beta/gamma chains (FG) exhibited notable differences, with their branched-chain protein FGB showing highly significant upregulation (p = 0.003, Log₂FC = 2.167) and tending to increase gradually during early pregnancy, suggesting that FGB could be one of the important indicators of early pregnancy in Chinese native yellow cattle. Among the differential metabolites, 11-Deoxy prostaglandin F1α (p < 0.001, Log₂FC = 1.563), Thromboxane B1 (p = 0.002, Log₂FC = 3.335), and Homo-Gamma-Linolenic Acid (C20:3) (p = 0.018, Log₂FC = 1.781) were also increased, indicating their involvement in the regulation of the platelet activation signaling pathway. The platelet activation signaling pathway plays a crucial role in maternal immune tolerance and placental vascularization, which are essential for embryo implantation and placental development. These findings indicate that FGB has the potential to be a valuable biomarker for early cattle pregnancy detection, thereby improving pregnancy diagnosis accuracy, reducing economic losses caused by undetected empty pregnancies and enhancing reproductive efficiency in the cattle industry. Undoubtedly, our research outcomes must be validated with future studies, and a larger sample size as well as the evaluation of the potential endocrine effects induced by the synchronized estrus treatment must be considered. Full article

Background: Prenatal alcohol exposure (PAE) can reduce fetal growth and cause neurodevelopmental disability. Prenatal choline supplements attenuate PAE-induced behavioral and growth deficits; however, the underlying mechanisms are unknown. Alcohol alters nutrient metabolism and potentially increases nutrient needs. Here, we investigate how alcohol affects choline metabolism in the maternal–fetal dyad and the role of supplemental choline. Methods: Pregnant C57BL/6J mice were assigned to one of four groups: alcohol-exposed (3 g/kg alcohol/day) or control +/− 100 mg/kg choline daily from embryonic day (E)8.5–17.5. We performed an exploratory hypothesis-generating analysis of targeted metabolomics on choline-related metabolites in the maternal liver, plasma, placenta, and fetal brain at E17.5 and Spearman correlation analyses to determine their association with gestational and fetal growth outcomes. Results: Although choline levels were largely unaffected by alcohol or choline, alcohol increased many lipid products in the CDP–choline pathway; this was not normalized by choline. Alcohol increased placental CDP–ethanolamine and reduced the maternal hepatic SAM/SAH ratio as well as dimethylglycine and the serine/glycine ratio across the dyad, suggesting a functional insufficiency in methyl donor pools. These outcomes were rescued by supplemental choline. Correlation analyses among choline metabolites and fetal growth outcomes suggest that maternal plasma methionine, serine, and the serine/glycine ratio may be predictive of maternal–fetal choline status. Conclusions: The increased hepatic lipid synthesis that characterizes chronic alcohol exposure may draw choline into phospholipid biosynthesis at the expense of its use as a methyl donor. We propose that PAE increases choline needs, and that its supplementation is necessary to fulfill these competing demands for lipid and methyl use. Full article

(1) Background: The follicular fluid (FF) comprises a large portion of ovarian follicles, and serves as both a communication and growth medium for oocytes, and thus should be representative of the metabolomic status of the follicle. This review aims to explore FF biomarkers as well as their effects on fertilization, oocyte, and embryo development, and later on implantation and maintenance of pregnancy. (2) Methods: This review was registered in the PROSPERO database with the ID: CRD42025633101. We parsed PubMed, Scopus, and Google Scholar for research on the effects of different FF biomarkers on IVF/ICSI outcomes in normo-ovulatory women. Included studies were assessed for risk of bias using the NOS scale. Data were extracted and tabulated by two independent researchers. (3) Results: 22 included articles, with a sample size range of 31 to 414 and a median of 60 participants, contained 61 biomarkers, including proteins, growth factors, steroid and polypeptide hormones, inflammation and oxidative stress markers, amino acids, vitamins, lipids of different types, and miRNAs. Most of the biomarkers studied had significant effects on IVF/ICSI outcomes, and seem to have roles in various cellular pathways responsible for oocyte and embryo growth, implantation, placental formation, and maintenance of pregnancy. The FF metabolome also seems to be interconnected, with its various components influencing the levels and activities of each other through feedback loops. (4) Conclusions: FF biomarkers can be utilized for diagnostic and therapeutic purposes in IVF; however, further studies are required for choosing the most promising ones due to heterogeneity of results. Widespread adoption of LC-MS and miRNA microarrays can help quantify a representative FF metabolome, and we see great potential for in vitro supplementation (IVS) of some FF biomarkers in improving IVF/ICSI outcomes. Full article

Postnatally, glucagon acutely lowers plasma amino acid (AA) concentrations by stimulating hepatic AA catabolism, but its fetal actions remain unclear. This study tested whether a 2 h fetal glucagon infusion would stimulate hepatic AA catabolism and inhibit placental AA transfer. Late-gestation pregnant sheep (0.9 gestation) underwent surgical, vascular catheterization and received fetal glucagon (n = 8) or vehicle infusions (n = 8) in a crossover design with a 48 h washout period. Nutrient uptake and utilization were assessed during each infusion, and fetal liver and placental tissue were collected post-infusion under hyperglucagonemic (n = 4) or vehicle (n = 4) conditions. Glucagon receptor was identified in fetal hepatocyte and trophoblast cells. Glucagon reduced fetal plasma AA concentrations by 20% (p = 0.0103) and increased plasma glucose by 47% (p = 0.0152), leading to a three-fold rise in fetal plasma insulin (p = 0.0459). Hepatic gene expression associated with AA catabolism and gluconeogenesis increased (p < 0.0500) following glucagon infusion, and hepatic metabolomic analysis showed enrichment in AA metabolism pathways. However, placental AA transfer was unaffected by 2 h fetal glucagon infusions. In conclusion, a 2 h glucagon infusion stimulates hepatic glucose production and enhances AA catabolism in the fetal liver, lowering plasma AA concentrations. The primary acute effects of fetal glucagon are hepatic, as placental AA transfer is unchanged. Full article

Chagas disease, caused by Trypanosoma cruzi, is a parasitic zoonosis with significant health impacts, particularly in Latin America. While traditionally associated with vector-borne transmission, increased migration has expanded its reach into urban and non-endemic regions. Congenital transmission has become a critical route of infection, involving intricate maternal–fetal immune interactions that challenge diagnosis and treatment. This review synthesizes findings from three RNA-seq studies that explore the molecular underpinnings of congenital Chagas disease, emphasizing differentially expressed genes (DEGs) implicated in host–pathogen interactions. The DAVID tool analysis highlighted the overexpression of genes associated with the innate immune response, including pro-inflammatory cytokines that drive chemotaxis and neutrophil activation. Additionally, calcium-dependent pathways critical for parasite invasion were modulated. T. cruzi exploits the maternal–fetal immune axis to establish a tolerogenic environment conducive to congenital transmission. Alterations in placental angiogenesis, cellular regeneration, and metabolic processes further demonstrate the parasite’s ability to manipulate host responses for its survival and persistence. These findings underscore the complex interplay between the host and pathogen that facilitates disease progression. Future research integrating transcriptomic, proteomic, and metabolomic approaches is essential to unravel the molecular mechanisms underlying congenital Chagas disease, with a particular focus on the contributions of genetic diversity and non-coding RNAs in immune evasion and disease pathogenesis. Full article

Background: Small vulnerable newborns (SVNs), including those born preterm, small for gestational age, or with low birth weight, are at higher risk of neonatal mortality and long-term health complications. Early exposure to maternal vaginal microbiota and breastfeeding plays a critical role in the development of the neonatal microbiota and immune system, especially in low-resource settings like Burkina Faso, where neonatal mortality rates remain high. Objectives: The DenBalo study aims to investigate the role of maternal and neonatal factors, such as vaginal and gut microbiota, immune development, and early nutrition, in shaping health outcomes in SVNs and healthy infants. Methods: This prospective cohort observational study will recruit 141 mother-infant pairs (70 SVNs and 71 healthy controls) from four health centers in Bobo-Dioulasso, Burkina Faso. The mother-infant pairs will be followed for six months with anthropometric measurements and biospecimen collections, including blood, breast milk, saliva, stool, vaginal swabs, and placental biopsies. Multi-omics approaches, encompassing metagenomics, metabolomics, proteomics, and immune profiling, will be used to assess vaginal and gut microbiota composition and functionality, immune cell maturation, and cytokine levels at critical developmental stages. Conclusions: This study will generate comprehensive data on how microbiota, metabolomic, and proteomic profiles, along with immune system development, differ between SVNs and healthy infants. These findings will guide targeted interventions to improve neonatal health outcomes and reduce mortality, particularly in vulnerable populations. Full article

Preeclampsia (PE) is a serious complication of pregnancy linked to endothelial dysfunction and an imbalance in the gut microbiota. While Akkermansia muciniphila (AKK) has shown promise in alleviating PE symptoms, the use of live bacteria raises safety concerns. This study explored the potential of pasteurized A. muciniphila (pAKK) as a safer alternative for treating PE, focusing on its effects on endothelial function and metabolic regulation. A PE mouse model was induced via the nitric oxide synthase inhibitor L-NAME, followed by treatment with either pAKK or live AKK. Fecal metabolomic profiling was performed via liquid chromatography–tandem mass spectrometry (LC-MS/MS), and in vivo and in vitro experiments were used to assess the effects of pAKK on endothelial function and metabolic pathways. pAKK exhibited therapeutic effects comparable to those of live AKK in improving L-NAME-induced PE-like phenotypes in mice, including enhanced gut barrier function and reduced endotoxemia. pAKK also promoted placental angiogenesis by restoring endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. The in vitro experiments further confirmed that pAKK alleviated L-NAME-induced NO reduction and endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). Metabolomic analysis revealed that both pAKK and live AKK reversed metabolic disturbances in PE by modulating key metabolites and pathways related to unsaturated fatty acid biosynthesis, folate, and linoleic acid metabolism. As a postbiotic, pAKK may support existing treatments for preeclampsia by improving gut barrier function, restoring endothelial function, and regulating metabolic dysregulation, offering a safer alternative to live bacteria. These findings highlight the potential clinical value of pAKK as an adjunctive therapy in managing PE. Full article

Ectopic pregnancy (EP) is the leading cause of maternal morbidity and mortality in the first trimester. Using an untargeted metabolomic approach, we sought to identify putative plasma biomarkers using tandem liquid chromatography–mass spectrometry for the detection of tubal EP. This case-control study included the prospective recruitment of 50 tubal EP cases and 50 early intrauterine pregnancy controls. To avoid over-fitting, logistic regression models were developed in a randomly selected discovery group (30 cases vs. 30 controls) and validated in the test group (20 cases vs. 20 controls). In total, 585 mass spectral features were detected, of which 221 molecular features were significantly altered in EP plasma (p < 0.05). Molecular networking and metabolite identification was employed using the Global Natural Products Social Molecular Networking (GNPS) database, which identified 97 metabolites at a high confidence level. Top significant metabolites include subclasses of sphingolipids, carnitines, glycerophosphocholines, and tryptophan metabolism. The top regression model, consisting of D-erythro-sphingosine and oleoyl-carnitine, was validated in a test group and achieved an area under receiving operating curve (AUC) (95% CI) = 0.962 (0.910–1) with a sensitivity of 100% and specificity of 95.9%. Metabolite alterations indicate alterations related to inflammation and abnormal placentation in EP. The validation of these metabolite biomarkers in the future could potentially result in improved early diagnosis. Full article

A major factor limiting the development of somatic cell nuclear transfer (SCNT) technology is the low success rate of pregnancy, mainly due to placental abnormalities disrupting the maternal-fetal balance during pregnancy. Although there has been some progress in research on the abnormal enlargement of cloned bovine placenta, there are still few reports on the direct regulatory mechanisms of enlarged cloned bovine placenta tissue. In this study, we conducted sequencing and analysis of transcriptomics, proteomics, and metabolomics of placental tissues from SCNT cattle (n = 3) and control (CON) cattle (n = 3). The omics analysis results indicate abnormalities in biological functions such as protein digestion and absorption, glycolysis/gluconeogenesis, the regulation of lipid breakdown, as well as glycerolipid metabolism, and arginine and proline metabolism in the placenta of SCNT cattle. Integrating these analyses highlights critical metabolic pathways affecting SCNT cattle placenta, including choline metabolism and unsaturated fatty acid biosynthesis. These findings suggest that aberrant expressions of genes, proteins, and metabolites in SCNT placentas affect key pathways in protein digestion, growth hormone function, and energy metabolism. Our results suggest that abnormal protein synthesis, growth hormone function, and energy metabolism in SCNT bovine placental tissues contribute to placental hypertrophy. These findings offer valuable insights for further investigation into the mechanisms underlying SCNT bovine placental abnormalities. Full article