{"title":"PDK4 is critical for metabolic regulation and progesterone production in bovine granulosa cells†.","authors":"Xuelian Tao, Dirk Koczan, Julia Brenmoehl, Jens Vanselow, Vijay Simha Baddela","doi":"10.1093/biolre/ioaf238","DOIUrl":"10.1093/biolre/ioaf238","url":null,"abstract":"<p><p>Non-esterified fatty acids (NEFAs) influence ovarian cell function, but the underlying molecular mechanisms remain incompletely understood. Our previous work showed that NEFA induces lipid accumulation and inhibits glucose uptake in bovine granulosa cells. Here, we investigated the effect of NEFA on energy metabolism and the transcriptome, with a focus on pyruvate dehydrogenase kinase 4 (PDK4). NEFA treatment significantly increased ATP levels and mitochondrial membrane potential. Transcriptome analysis revealed differential expression of 176 genes, with downregulation of steroidogenesis and fatty acid synthesis pathways, and upregulation of apoptosis, fatty acid oxidation, and innate immune responses in NEFA treated cells. Specifically, genes involved in fatty acid oxidation (e.g. CPT1A, CPT1B, HADHA, and SLC25A20) were upregulated, whereas those related to glucose metabolism remained largely unchanged except for the marked upregulation of PDK4. Silencing PDK4 expression induced glucose utilization by upregulating glucose transporters (SLC2A1, SLC2A10) and glycolytic enzymes (GAPDH, ENO1, and LDHA). In contrast, genes associated with fatty acid oxidation (SLC27A1 and CPT1B) showed downregulation upon PDK4 silencing compared with controls, suggesting a metabolic shift favoring glucose oxidation even in the presence of NEFA. We observed that expression of PDK4, CPT1A, and CPT1B was significantly upregulated in large luteal cells compared to granulosa cells. PDK4 knockdown significantly downregulated steroidogenic genes (STAR, HSD3B1, and CYP11A1) and decreased progesterone production, suggesting that increased expression of PDK4 in luteal cells may supports steroidogenesis. Together, these findings identify PDK4 as a critical regulator of metabolic flexibility and progesterone production in granulosa cells.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"952-965"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ADAM5 is required for sperm-zona pellucida binding and sperm oviduct migration†.","authors":"Daisuke Mashiko, Shingo Tonai, Masahito Ikawa","doi":"10.1093/biolre/ioaf254","DOIUrl":"10.1093/biolre/ioaf254","url":null,"abstract":"<p><p>ADAM5 is a testis-specific transmembrane protein whose role in male fertility remains poorly understood. In this study, we report that Adam5 knockout (KO) male mice are severely subfertile, despite exhibiting normal testicular morphology, sperm structure, and motility. Adam5 KO sperm failed to transit the uterotubal junction (UTJ) and displayed severe defects in zona pellucida (ZP) binding, phenotypes that resemble those observed in Adam2 and Adam3 knockout mice. Western blot analysis revealed a significant reduction in the levels of ADAM2 and ADAM3 in Adam5 KO spermatozoa, supporting the previous finding that ADAM5 interacts with these proteins to form a complex. Additionally, Adam5 KO spermatozoa exhibited reduced binding to extracellular matrix (ECM) components, including Laminin I and Fibronectin. These findings suggest that ADAM5 plays a crucial role in sperm ECM interaction, a process likely critical for successful UTJ transit and ZP binding. While ADAM5 is a pseudogene in humans, our results provide valuable insights into the function of ADAM family proteins in mammalian reproduction.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1091-1100"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ting Wang, Qiuyao Li, Yidan Liu, Xinyuan Li, Lingyu Zhang, Chenchen Jia, Feng Yue, Lili Zhang, Xiaoling Ma, Lin Liu
{"title":"Recombinant human granulocyte colony-stimulating factor improves implantation partly by downregulating Hsa_circ_0001550†.","authors":"Ting Wang, Qiuyao Li, Yidan Liu, Xinyuan Li, Lingyu Zhang, Chenchen Jia, Feng Yue, Lili Zhang, Xiaoling Ma, Lin Liu","doi":"10.1093/biolre/ioaf288","DOIUrl":"10.1093/biolre/ioaf288","url":null,"abstract":"<p><p>Embryonic implantation is a crucial developmental phase characterized by intricate molecular crosstalk between the embryo and endometrium, with emerging evidence implicating circular RNAs (circRNAs) as important regulators. This study elucidated the role of hsa_circ_0001550 in impairing embryo adhesion and evaluated recombinant human granulocyte colony-stimulating factor (rhG-CSF) as a therapeutic strategy. Overexpression of hsa_circ_0001550 in an in vitro adhesion model using Ishikawa cells reduced the adhesion capacity of BeWo or JAR spheroids and diminished the murine blastocyst implantation rate. Knocking down hsa_circ_0001550 increased the adhesive ability of BeWo spheroids. Crucially, administration of rhG-CSF downregulated hsa_circ_0001550 expression and upregulated homeobox A10 and leukemia inhibitory factor, thereby restoring the adhesive capacity. In an endometrial injury model, administration of rhG-CSF enhanced epithelial proliferation (as measured by Ki67), suppressed apoptosis (based on the TUNEL assay), and activated mesenchymal-to-epithelial transition pathways, ultimately improving the embryo implantation rate. Collectively, this study reveals that rhG-CSF improves implantation partly by downregulating hsa_circ_0001550. These findings provide new perspectives for understanding implantation mechanisms and developing therapeutic strategies.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"810-826"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Victor A Absalón-Medina, Rodrigo V Sala, Daniela C Pereira, Vanessa C Fricke, Iebu Devkota, Zachary L Bonomo, Dailin M Fuego, Michael McDonald, José M Sánchez, Maria B Rabaglino, Antonios Matsakas, Anastasios Vourekas, Xing Fu, Rocio M Rivera, Patrick Lonergan, Pablo J Ross, Constantine A Simintiras
{"title":"Amniotic fluid metabolic biomarkers of fetal physiology and pregnancy success†.","authors":"Victor A Absalón-Medina, Rodrigo V Sala, Daniela C Pereira, Vanessa C Fricke, Iebu Devkota, Zachary L Bonomo, Dailin M Fuego, Michael McDonald, José M Sánchez, Maria B Rabaglino, Antonios Matsakas, Anastasios Vourekas, Xing Fu, Rocio M Rivera, Patrick Lonergan, Pablo J Ross, Constantine A Simintiras","doi":"10.1093/biolre/ioaf236","DOIUrl":"10.1093/biolre/ioaf236","url":null,"abstract":"<p><p>Amniotic fluid (AF) profiling provides a minimally invasive window into early fetal physiology. We characterized the AF metabolome from first trimester (Day 68) Holstein dairy heifers (n = 45), considering fetal sex, conception method [in vitro fertilization vs. artificial insemination (AI)], and eventual pregnancy outcome as key variables. Multivariate statistics uncovered differentially abundant metabolites for each comparison-including markers that preceded spontaneous abortion-independently of recipient age, weight, gestation length, or fetal genetics. Thereafter, a machine learning algorithm using panels of six metabolites accurately predicted fetal sex (AUROC = 0.76; P = 0.023) and pregnancy viability (AUROC = 0.81; P = 0.018), while corroborating conception method (AUROC = 0.91; P = 0.001). External validation using AF (Day 42) from an independent cohort of beef heifers (n = 22) reproduced the fetal sex classifier with similarly high sensitivity and specificity (AUROC = 0.85, P = 0.029). These findings reveal metabolic signatures that forecast fetal sex and pregnancy viability, while confirming distinct metabolic imprints of assisted-conception modalities. These data lay the groundwork for next-generation AF prenatal diagnostics in veterinary and human obstetrics.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"998-1017"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gülbahar Zehra Kutlutürk, Trenton L Place, Michael S Awadalla, Rachel B Danis, Sue Ann Ingles, Isaac Asante, Rita Li, Stan Louie, Frank Z Stanczyk, Lynda K McGinnis
{"title":"Long-term tamoxifen impacts the ovary but not preimplantation embryo development†.","authors":"Gülbahar Zehra Kutlutürk, Trenton L Place, Michael S Awadalla, Rachel B Danis, Sue Ann Ingles, Isaac Asante, Rita Li, Stan Louie, Frank Z Stanczyk, Lynda K McGinnis","doi":"10.1093/biolre/ioaf281","DOIUrl":"10.1093/biolre/ioaf281","url":null,"abstract":"<p><p>Many studies have examined the acute effects of chemotherapies and radiation on the ovary; however, few address the impact of long-term chemotherapeutic agents on future reproduction for cancer survivors. The purpose of our study was to determine the effect of long-term tamoxifen (TAM) treatment on follicle development, ovarian reserve, and embryogenesis in a murine model. Adult female mice were treated with TAM (250 mg/kg fed ad libitum in mouse chow) or control chow for three weeks, followed by 0-, 1-, or 3-weeks of TAM washout. Mice were then superovulated, mated, and their oviducts flushed to determine ovulation, fertilization, and in vitro embryo development rates. At specific timepoints, one ovary from each animal was harvested, sectioned, and stained with H&E, while the other ovary was evaluated for gene expression of targeted genes. Ovarian size was calculated based on average surface area over six slices. Follicles (primordial, primary, secondary, antral / pre-ovulatory), and corpora lutea (CL) were counted and averaged for each slice. All data were analyzed using mixed-effects analysis of variance (ANOVA), with treatment group as the fixed effect and ovary treated as a random effect nested within treatment. Ovaries of TAM treated mice were 36% smaller on average than control ovaries (P = 0.01). Primordial follicle counts were 35% lower than control ovaries (P = 0.007) and there were 3.4x more atretic follicles in the ovaries of TAM treated mice (P < 0.001). There were no significant differences in the number of primary, secondary, antral or pre-ovulatory follicles. The number of oocytes and embryos flushed from control mice (total ovulated) was 1.65x greater than TAM treated mice. However, fertilization rates and in vitro embryo blastulation rates were not significantly different between controls and TAM groups. In summary, for this murine model, long-term TAM negatively impacted ovarian reserve (primordial follicle number) without overtly affecting the in vitro embryo development to the blastocyst.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1115-1126"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Madison Lauryl Newman, Victória Alice Bastos Primo, Maria Belen Ugarte Marin, Phillip Martins Gondim Peixoto, Tomás Delfin Gonzalez, Alexandra Bennett, Cecilia Constantino Rocha, Mário Binelli, Jeanette Victoria Bishop, Aydin Guzeloglu, Thomas Ross Hansen, William Watters Thatcher, Rafael Sisconeto Bisinotto
{"title":"Interferon-tau concentration at the vaginal fornix and cervical ostium predicted early pregnancy outcomes in lactating dairy cows†.","authors":"Madison Lauryl Newman, Victória Alice Bastos Primo, Maria Belen Ugarte Marin, Phillip Martins Gondim Peixoto, Tomás Delfin Gonzalez, Alexandra Bennett, Cecilia Constantino Rocha, Mário Binelli, Jeanette Victoria Bishop, Aydin Guzeloglu, Thomas Ross Hansen, William Watters Thatcher, Rafael Sisconeto Bisinotto","doi":"10.1093/biolre/ioaf251","DOIUrl":"10.1093/biolre/ioaf251","url":null,"abstract":"<p><p>Concentrations of interferon-tau (IFNT) are likely the best proxy for early pregnancy diagnosis in cattle. Objectives were to compare the concentration of IFNT at the vaginal fornix and cervical ostium 18 days after artificial insemination (AI) and evaluate the use of IFNT for early identification of non-pregnant lactating dairy cows. Holstein cows (n = 251) from two dairies were enrolled. Expression of interferon-stimulated gene 15 (ISG15), myxovirus 2 (MX2), and viperin (RSAD2) were assessed in peripheral blood mononuclear cells (PBMC) by RT-qPCR. Expression of interferon-stimulated genes (ISG) and IFNT concentration in swab samples collected at the cervical ostium and vaginal fornix were measured by RT-qPCR and sandwich ELISA validated for bovine IFNT, respectively. Cervical IFNT concentration was 7.5-fold greater than the vaginal fornix on day 18 after AI in cows diagnosed as pregnant by ultrasonography on day 35 after AI. Concentrations of IFNT in the cervical ostium and vaginal fornix were positively correlated with ISG expression in cervical cytology of pregnant cows, however, ISG expression in PBMC was not correlated with cervical IFNT concentration. Assessment of cervical IFNT concentrations for identification of non-pregnant cows on day 18 after AI yielded reasonable specificity (0.84; 95% CI = 0.78-0.90) and negative predictive value (0.87; 95% CI = 0.81-0.93) based on ultrasound examination on day 35 after AI. These results support the feasibility of using cervical IFNT measurement for identification of non-pregnant cows, providing the basis for early resynchronization and increased insemination rates in dairy farms.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1045-1057"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yingdan Huang, Liang Ren, Nana Ma, Xiaoqian Fu, Yuehui Du, Bo Liu
{"title":"Potential role of extracellular vesicles from different sources in unexplained recurrent pregnancy loss†.","authors":"Yingdan Huang, Liang Ren, Nana Ma, Xiaoqian Fu, Yuehui Du, Bo Liu","doi":"10.1093/biolre/ioaf286","DOIUrl":"10.1093/biolre/ioaf286","url":null,"abstract":"<p><p>Unexplained recurrent pregnancy loss (URPL) is complex and has unknown etiologies, simultaneously endangering the patient's physical and mental health. Despite significant advancements in shifting from conventional treatments to cell therapy, clinical research and application in cell therapy have been constrained by its immunogenic properties and biosafety. As a new cell-cell communication pathway, extracellular vesicles (EVs) can transfer their bioactive cargos to other cells by endocytosis, ligand-receptor engagement, or direct fusion, thereby executing diverse biological functions both in proximity and across great distances. It is noteworthy that the role of EVs as a cell-free therapy in the form of a drug transporter has garnered increased attention, and some studies have demonstrated EVs involvement in the key pathology of URPL. This review methodically summarizes the functions of EVs from various sources in URPL, including mesenchymal stem cells, placenta, and other sources of EVs. Furthermore, we discuss the significance of EVs as possible diagnostic biomarkers and therapeutic strategies for URPL and the key questions that need to be addressed in future research.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"744-754"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ezrin, radixin, and moesin are novel citrullinated proteins in the decidua during pregnancy†.","authors":"Kouhei Yamashita, Shinji Ito, Junko Satoh, Akifumi Takaori-Kondo, Kiyomi Mizugishi","doi":"10.1093/biolre/ioaf241","DOIUrl":"10.1093/biolre/ioaf241","url":null,"abstract":"<p><p>For a successful pregnancy, decidualization is a crucial process involving the significant transformation of endometrial stromal cells surrounding the implanting blastocysts. Disruption of this process can lead to the breakdown of the fetomaternal interface and result in early pregnancy loss. However, the precise mechanisms governing this process remain incompletely understood. This study aimed to elucidate the impact of citrullination, a post-translational modification, on decidualization in mice and humans. Immunohistochemical analysis and immunoprecipitation followed by immunoblotting were performed on mouse and human uterine tissues. In this study, we showed that ezrin/radixin/moesin (ERM) proteins are expressed in decidual and endothelial cells within the decidua during pregnancy, with their expression patterns significantly influenced by two factors: citrullination mediated by peptidylarginine deiminase enzymes and sphingosine kinase activity. Notably, ERM proteins were found to undergo citrullination exclusively in the decidua during pregnancy, but not in interimplantation tissues during pregnancy or in nonpregnant uteri in mice. Similar findings were observed in human decidual tissues from cases of spontaneous abortion and elective termination. In conclusion, this study demonstrates that ERM proteins undergo citrullination in the decidua during early pregnancy in both mice and humans. Our findings provide important insights into the molecular changes involved in pregnancy, particularly decidualization.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1018-1029"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145372115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lipid nanoparticle-mediated mRNA delivery system into preimplantation embryos†.","authors":"Chihiro Emori, Hiroki Tanaka, Tatsuya Nakagawa, Hidetaka Akita, Masahito Ikawa","doi":"10.1093/biolre/ioaf262","DOIUrl":"10.1093/biolre/ioaf262","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) have emerged as a nonviral mRNA delivery vehicle for both basic and clinical applications. In the present study, we showed that the LNPs passed through the zona pellucida, the extracellular matrix surrounding the egg, and efficiently transduced preimplantation embryos. We first tested different types of surface polarity in LNPs carrying Enhanced Green Fluorescent Protein (EGFP) (LNP-EGFP) by changing cholesterol and found that the LNPs composed with neutral or anionic cholesterol are less toxic and more suitable for mRNA delivery into zygotes. Next, we transferred Cre mRNA using neutral LNP (LNP-Cre) and saw the floxed allele recombination in reporter mTmG transgenic embryos. After treatment with LNP-Cre at a 10 ng/μL concentration for 20 h at the zygote stage, about 76% mTmG embryos expressed the reporter EGFP at the blastocyst stage, and about 82% of embryos expressed EGFP in both the placenta and fetus at E12.5. Finally, we treated mTmG blastocyst stage embryos with LNP-Cre at a 50 ng/μL concentration for 20 h and found that about 86% of them expressed the reporter EGFP. Intriguingly, the EGFP fluorescence was only observed in trophectoderm cells, but not in the inner cell mass. Subsequently, we observed placenta-specific reporter EGFP expression in about 65% of the later-stage embryos (E12.5). Collectively, our study shows that LNPs provide a novel mRNA delivery system into preimplantation embryos that can be used for studying gene functions in pre-, peri-, and post-implantation development.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1070-1078"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145629063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dan Zhu, Dezhi Ma, Mengyun Wu, Jiayao Sun, Tian He, Yuan Qin, Xin Wang, Bingrui Yang, Xiaocui Zhong, Shan-An Chan, Shufang Chang, Boris Novakovic, Sergey Tumanov, Silas Villas Bôas, Heng Zou, Yang Yang, Ting-Li Han
{"title":"Oxylipins from n-6 and n-3 fatty acids modulate uterine decidualization†.","authors":"Dan Zhu, Dezhi Ma, Mengyun Wu, Jiayao Sun, Tian He, Yuan Qin, Xin Wang, Bingrui Yang, Xiaocui Zhong, Shan-An Chan, Shufang Chang, Boris Novakovic, Sergey Tumanov, Silas Villas Bôas, Heng Zou, Yang Yang, Ting-Li Han","doi":"10.1093/biolre/ioaf256","DOIUrl":"10.1093/biolre/ioaf256","url":null,"abstract":"<p><strong>Background: </strong>Metabolic remodeling is crucial for successful decidualization, but the mechanisms coordinating the tricarboxylic acid (TCA) cycle, fatty acids, and oxylipins with energy demands and pro-inflammatory responses during peri-implantation are unclear.</p><p><strong>Methods: </strong>This study analyzed temporal metabolic changes and pro-inflammatory factors at the implantation site (IS) and inter-implantation site (IIS) from days 5 to 7 post-implantation in mice using GC-MS, UPLC-MS/MS, immunofluorescence, quantitative real-time PCR and ELISA, ANOVA, Tukey HSD, mixed-effects models, and Pearson correlation were used for statistical analysis.</p><p><strong>Results: </strong>Our findings reveal dynamic metabolic changes in the IS and IIS from days 5 to 7 of pregnancy. During transition to the secondary decidual zone (SDZ), the IS exhibited metabolic adaptation, with higher TCA cycle activity compared to the IIS. On day 7, the IS also showed significantly elevated activity in the citric acid cycle, glycolysis, and pyruvate metabolism compared to day 5. Additionally, during the SDZ phase, n-3 and n-6 fatty acids and their oxylipins, particularly prostanoids like PGE2 from arachidonic acid, were upregulated in the IS, exhibiting a similar expression pattern of pro-inflammatory factors such as IL-6 and IL-8. The mRNA expression of COX-2 and mPGES-1, key enzymes related to PGE2 biosynthesis, showed a sustained increase from day 5 to day 7 of pregnancy. This suggests that PGE2 plays a key role in maintaining the pro-inflammatory environment necessary for decidualization.</p><p><strong>Conclusion: </strong>This study highlights the importance of metabolic adaptations and fatty acid-derived oxylipins in ensuring energy supply and sustaining the pro-inflammatory environment during successful decidualization.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"794-809"},"PeriodicalIF":3.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}