Reproductive Sciences最新文献

{"title":"Beclin1 Regulates Sertoli Cell Function to Maintain Mouse Spermatogenesis.","authors":"Yuqing Cai, Wanzhen Li, Yifeilong He, Zhifeng Zhao, Xinyi Lin, Jing Wang, Yuchuan Luo, Yinghe Qin, Yingjie Wu","doi":"10.1007/s43032-026-02202-8","DOIUrl":"10.1007/s43032-026-02202-8","url":null,"abstract":"<p><p>Besides providing nutrients, Sertoli cells support spermatogenic cells development by maintaining seminiferous epithelial polarity, forming the blood-testis barrier (BTB), and phagocytosing residual bodies. Beclin1, a core component of the autophagy initiation complex, is critical for autophagic flux in many cell types. However, its role in Sertoli cells remains unclear. Here, we generated a Sertoli cell-specific Becn1 knockout (cKO) mouse model and found that 9-week-old male cKO mice exhibited reduced fertility with decreased sperm quality and vacuolated seminiferous tubules, and became completely infertile by 12 weeks of age. These defects were associated with disrupted BTB integrity and reduced expression of Claudin-11 in the testes. Further analysis revealed that loss of Beclin1led to impaired autophagosome formation, evidenced by reduced LC3-II/LC3-I ratio. In summary, these findings demonstrate that Beclin1 in Sertoli cells is vital for spermatogenesis and male fertility.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2068-2080"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of Early Pregnancy Loss: Reproductive Outcome in Subsequent Euploid Embryo Transfers.","authors":"Emily A Clarke, Sarah C Roger, Raina Kishan, Morgan Baird, Joseph A Lee, Eric Flisser, Tanmoy Mukherjee, Alan B Copperman","doi":"10.1007/s43032-026-02200-w","DOIUrl":"10.1007/s43032-026-02200-w","url":null,"abstract":"<p><p>Early pregnancy loss (EPL) is commonly managed with medical or surgical intervention, with comparable outcomes described in the general population. However, intrauterine instrumentation including dilation and curettage has been linked to endometrial thinning, associated with inferior in vitro fertilization (IVF) outcomes. Limited data exists on how EPL management influences subsequent IVF outcomes, particular in patients undergoing single euploid embryo transfer (SEET). This single-center, retrospective cohort study compared endometrial thickness and outcomes in the subsequent SEET cycle between patients with EPL who underwent either medical or surgical management. A total of 203 patients were included: 88 patients who underwent medical and 115 who underwent surgical management. The primary outcome was change in endometrial thickness between the initial and subsequent SEET cycle. Secondary outcomes included SEET cycle cancellation due to thin endometrium (< 7 mm) and subsequent SEET outcomes. Between the initial and subsequent SEET cycle, change in endometrial thickness was similar between groups (Medical + 0.3 ± 1.4 mm, Surgical + 0.1 ± 1.5 mm; P = 0.65). Endometrial thickness in the subsequent cycle was also comparable (Medical 9.4 ± 1.5 mm, Surgical 9.1 ± 1.2 mm; P = 0.20). SEET cycle cancellation due to thin endometrium was low and similar between groups (Medical 3.4% [95% CI 1.0-9.6] (n = 3), Surgical 2.6% [95% CI 1.0-7.4] (n = 3); P = 0.74). While surgical management was associated with higher subsequent clinical pregnancy loss (15.7% vs. 4.9%; P < 0.05; aOR 3.72 [95% CI 1.11-12.47]), subsequent live birth rates were similar between groups (Medical 48.8%, Surgical 40.7%; P = 0.27; aOR 0.67 [95% CI 0.35-1.28]). These findings may help guide counseling patients undergoing IVF regarding management decision-making when facing EPL.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2148-2154"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning and Functional Analysis of Placental DNA Methylation Signatures for Early-Onset Preeclampsia.","authors":"Raunak Sharda, Valentina L Kouznetsova, Igor F Tsigelny","doi":"10.1007/s43032-026-02183-8","DOIUrl":"10.1007/s43032-026-02183-8","url":null,"abstract":"<p><p>Early-onset preeclampsia (EOPE) is a pregnancy disorder characterized by abnormal placental development and substantial maternal and fetal risk. DNA methylation at CpG sites has emerged as a key epigenetic mechanism in EOPE. In this study, we developed machine learning models for EOPE classification using β-values from CpG sites in placental tissue. Starting from 599 EOPE-associated CpG sites reported earlier, we used attribute selection in WEKA to identify 30 statistically significant descriptors, which mapped to 19 unique genes. Multiple classifiers were trained and evaluated, and the SPegasos classifier demonstrated the best performance, achieving 95.45% accuracy and an area under the receiver operating characteristic curve of 0.9545 in tenfold cross‑validation, and 95% accuracy in an independent validation dataset. These findings suggest a potentially high correlation between the CpG methylation signatures and EOPE. By creating a machine learning model, we can potentially classify a sample as having EOPE or a normal pregnancy using DNA methylation data at specific CpG sites in placental tissue. Furthermore, we identified the adipogenesis pathway to be central to the disease's pathophysiology. Gain ratio analysis highlighted a subset of CpG sites with particularly strong discriminative power between EOPE and control placentas. Functional annotation of the 19 CpG‑associated genes using protein and pathway enrichment analyses revealed enrichment in signal transduction, steroid and lipid metabolism, and cell developmental processes. Pathway analysis identified adipogenesis as a central pathway, consistent with dysregulated adipokine signaling and systemic inflammation in EOPE. These findings demonstrate that placental CpG methylation signatures can accurately distinguish EOPE from normal pregnancies and provide mechanistic insight into disrupted adipogenesis‑related pathways. The identified CpG methylation signature may serve as a basis for developing early molecular biomarkers and targeted strategies to improve EOPE diagnosis and management.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2094-2108"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Profiling of IgG and IgA Glycosylation in Pregnancy Reveals Early Associations with BMI, Nulliparity and Conception Mode: The Rotterdam Periconception Cohort.","authors":"Lotte W Voskamp, Anna Daniels, Melek Rousian, Mandy van Hoek, Manfred Wuhrer, Régine P M Steegers-Theunissen, A H Jan Danser, Koen Verdonk","doi":"10.1007/s43032-026-02190-9","DOIUrl":"10.1007/s43032-026-02190-9","url":null,"abstract":"<p><p>During early pregnancy, the maternal immune system recalibrates to tolerate the semi-allogeneic fetus. Immunoglobulin (Ig) function is modulated by glycosylation. Prior studies showed increases in anti-inflammatory glycosylation traits (galactosylation and sialylation) in IgG and to a lesser extent in IgA towards the third trimester. This study aimed to characterize IgG and IgA glycosylation patterns throughout pregnancy and assess associations with maternal age, gravidity, body mass index (BMI) and conception mode. In the Rotterdam Periconception Cohort, serum samples from 202 women with singleton pregnancies were collected at 9, 11, 13, 22, and 32 weeks'' gestation. IgG and IgA glycopeptides were analyzed using validated liquid chromatography-mass spectrometry and summarized into galactosylation, sialylation, fucosylation, and bisection traits. Longitudinal changes were assessed with linear mixed-effects models and FDR correction and associations with maternal factors were derived from model estimates. Already in the first trimester, galactosylation and sialylation increased and bisection decreased for both IgG and IgA. IgG galactosylation and sialylation continued rising throughout pregnancy, whereas most IgA traits reversed after the first trimester. Higher BMI was associated with a pro-inflammatory profile (lower IgG galactosylation; higher IgG and IgA fucosylation). Assisted reproduction and nulliparity were associated with anti-inflammatory changes, including higher galactosylation and sialylation. In conclusion, IgG and IgA glycosylation shifts towards an anti-inflammatory profile as early as the first trimester, potentially promoting immune tolerance. Pro-inflammatory changes with higher BMI, and distinct profiles in nulliparous and ART pregnancies, may represent biological pathways linking maternal factors to pregnancy outcomes, supporting glycosylation as a candidate biomarker.Trial registration number: This study is registered at the Dutch Trial Register (NTR6854).</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2081-2093"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin in Pregnancy-Related Disorders: A Review of Protective Mechanisms and Therapeutic Potential.","authors":"Shanza Waseem, Jun Zhan, Lei Yu, Xue Xiao","doi":"10.1007/s43032-026-02196-3","DOIUrl":"10.1007/s43032-026-02196-3","url":null,"abstract":"<p><p>Melatonin (N-acetyl-5-methoxytryptamine), classically known as a pineal neurohormone regulating circadian rhythms, has emerged as a critical pleiotropic molecule in reproductive physiology. Beyond its role in establishing circadian entrainment, it acts as a potent antioxidant, anti-inflammatory agent, and mitochondrial function modulator. This review synthesizes current knowledge on the multifaceted roles of melatonin in normal pregnancy and its pathophysiological implications in major gestational disorders, including preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB). Distinct from prior reviews, this work provides a structured, disorder-specific analysis of translational evidence with a critical evaluation of pharmacological optimization strategies, biomarker-driven trial design, and long-term developmental safety considerations. We highlight the dual source of melatonin maternal and placental and its receptor-mediated and receptor-independent actions. Compelling preclinical data and emerging clinical studies suggest that melatonin supplementation may represent a novel, safe, and effective therapeutic strategy for mitigating oxidative stress and inflammation at the maternal-fetal interface. This article reviews the mechanistic underpinnings, summarizes existing evidence in a structured format, and identifies critical gaps for future translational research.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"1978-1990"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obstetric and Neonatal Outcomes in Deep Infiltrating Versus Superficial Endometriosis: A Retrospective Cohort Study.","authors":"İsmail Baglar, Tamer Topaloglu, Esra Keles, Aylin Yılmaz, Sule Yildirim Kopuk, Buket Yigit Civi, Khayala Alakbarli Guliyeva, Ece Nokay, Mehmet Karahan, Dilanur Agir","doi":"10.1007/s43032-026-02215-3","DOIUrl":"10.1007/s43032-026-02215-3","url":null,"abstract":"<p><p>To compare obstetric and neonatal outcomes between women with surgically confirmed deep infiltrating endometriosis (DIE) and superficial endometriosis, focusing on lesion-specific risk profiles. This retrospective cohort study included women with surgically confirmed endometriosis who achieved singleton pregnancies at a tertiary referral center between 2015 and 2024. Patients were classified as having deep infiltrating or superficial endometriosis. Obstetric and neonatal outcomes were obtained from medical records. Primary outcomes were placenta previa and preterm birth before 37 gestational weeks. Secondary outcomes included placenta-related complications, maternal perinatal outcomes, and neonatal morbidity. Multivariable logistic regression analyses were performed adjusting for maternal age, pre-pregnancy body mass index, parity, assisted reproductive technology use, adenomyosis, and previous uterine surgery. A total of 268 pregnancies were analyzed (102 DIE, 166 superficial endometriosis). Placenta previa was significantly more frequent in the DIE group and remained independently associated after adjustment (adjusted odds ratio 2.41, 95% confidence interval 1.02-5.68). Preterm birth was more common among women with DIE, but this association did not remain significant. A placenta-related composite outcome, including placenta previa and placental abruption, was independently associated with DIE. Neonatal intensive care unit admission was also more frequent in the DIE group and remained independently associated (adjusted odds ratio 1.89, 95% confidence interval 1.01-3.54). Deep infiltrating endometriosis is associated with higher risks of placenta-related complications and adverse neonatal outcomes compared with superficial endometriosis. Lesion-based phenotyping may support clinically relevant perinatal risk stratification in pregnancies complicated by endometriosis.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2010-2017"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Biological Disease-Staging Model of Polyendocrine Metabolic Ovarian Syndrome: From Plasticity-Dominant States to Pathological Remodeling.","authors":"Hiroshi Kobayashi","doi":"10.1007/s43032-026-02191-8","DOIUrl":"10.1007/s43032-026-02191-8","url":null,"abstract":"<p><p>Polyendocrine metabolic ovarian syndrome (PMOS) is a heterogeneous endocrine-metabolic disorder characterized by reproductive dysfunction, metabolic abnormalities, and hormonal dysregulation. Although the Rotterdam criteria are widely used for phenotypic classification, accumulating evidence suggests that disease heterogeneity reflects varying contributions of insulin resistance, hyperandrogenism, chronic inflammation, mitochondrial dysfunction, autophagy dysregulation, and cellular senescence. To review the role of integrated intracellular signaling networks in PMOS and propose a conceptual model that explains disease progression and heterogeneity. A narrative review of studies published through December 2025 was conducted, focusing on insulin resistance, androgen excess, inflammation, autophagy, mitochondrial dysfunction, cellular senescence, and reproductive dysfunction. The present review proposes a three-stage disease spectrum consisting of a plasticity-dominant state, an adaptive-transition state, and a pathological-remodeling state. The plasticity-dominant state is characterized by preserved tissue adaptability despite metabolic and endocrine abnormalities. The adaptive-transition state involves persistent signaling dysregulation accompanied by impaired autophagy and mitochondrial dysfunction. In the pathological-remodeling state, cellular senescence, senescence-associated secretory phenotype (SASP)-driven inflammation, fibrosis, and tissue remodeling become increasingly prominent, resulting in reduced tissue plasticity and sustained disease maintenance. In conclusion, PMOS may be better understood as a dynamic pathophysiological spectrum rather than a static disorder. This model integrates metabolic dysfunction, inflammation, mitochondrial impairment, cellular senescence, and tissue remodeling, providing a complementary framework to the Rotterdam classification and a potential basis for improved disease stratification and personalized therapeutic strategies.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"1931-1953"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of miRNA (miR-10a, miR-30c, miR-181a, and miR-499b) Polymorphisms and Their Interactions with PAI-1 in Recurrent Implantation Failure in Korean Women.","authors":"Hui Jeong An, Sung Hwan Cho, Ji Eun Ko, Ji Hyang Kim, Hyeon Woo Park, Young Ran Kim, Eun Hee Ahn, Jin-Bae Kim, Nam Keun Kim","doi":"10.1007/s43032-026-02188-3","DOIUrl":"10.1007/s43032-026-02188-3","url":null,"abstract":"<p><p>Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technology, and accumulating evidence suggests that genetic factors, including microRNA (miRNA) polymorphisms, may influence implantation outcomes. This study investigated the association between RIF and polymorphisms in miR-10a A > T, miR-30c A > G, miR-181a T > C, and miR-499b A > G in Korean women. Peripheral blood samples were obtained from 169 women with RIF and 281 fertile controls, and genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism and real-time polymerase chain reaction. While individual miRNA polymorphisms were not independently associated with RIF in the overall population, subgroup analyses revealed that the miR-499b AG genotype was significantly associated with increased risk in women with ≥ 4 implantation failures (AOR = 1.908, P = 0.021). Stratified analysis showed that the miR-181a TC + CC genotype increased RIF risk in women with lower platelet counts, whereas the miR-30c AG + GG genotype consistently exerted a protective effect, particularly in subjects with a BMI ≥ 25 kg/m² (AOR = 0.104, P = 0.012) and those with shorter aPTT (AOR = 0.216, P = 0.002). Since plasminogen activator inhibitor-1 (PAI-1) is a confirmed (miR-10a, -30c, -181a) or predicted (miR-499b) target of these miRNAs, we further investigated the interactions between these miRNA polymorphisms and PAI-1, a key gene in implantation. Significant synergistic effects were observed between PAI-1 and miRNA polymorphisms. The A-T-C combination of PAI-1/miR-181a was strongly associated with susceptibility (OR = 2.644, P = 0.002, FDR-p = 0.014). Conversely, the G-T-G (PAI-1/miR-30c) combination was found exclusively in controls, indicating a protective effect (OR = 0.055, P = 0.002, FDR-p = 0.014). Furthermore, certain multilocus allele combinations involving PAI-1 showed potential associations with RIF risk, although estimates for rare combinations had wide confidence intervals and should be interpreted cautiously. Conclusion: These findings suggest that miRNA- and PAI-1-related genetic variation may contribute to RIF susceptibility in Korean women; however, several multilocus findings were exploratory and require validation in larger cohorts.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2155-2168"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Observation of the Cryoprotective Effect of Chlorogenic Acid on Spermatogonial Stem Cells Transplanted into of Testicular Torsion-Induced Azoospermia Model.","authors":"Sareh Khoshbakht, Azim Hedayatpour, Tayebeh Rastegar, Alireza Ebrahimzade Bideskan, Mohsen Mir, Mohammadreza Ebrahimzade, Samiullah Safi, Farnaz Khadivi","doi":"10.1007/s43032-025-02044-w","DOIUrl":"10.1007/s43032-025-02044-w","url":null,"abstract":"<p><p>Preserving spermatogonial stem cells (SSCs) in prepubertal males, followed by long-term cryostorage for future autologous transplantation, is a promising strategy for managing male infertility. This study investigated the effects of chlorogenic acid (CGA), an antioxidant agent, on SSCs maintained in a basal cryopreservation medium, aiming to evaluate its potential role in supporting cellular preservation under storage conditions. A torsion/detorsion protocol was applied to induce azoospermia in a murine model. Mice were randomized into five groups: fresh SSC transplantation, SSC transplantation with CGA, SSC transplantation using basal cryopreservation medium, a control group, and an untreated azoospermia group. Eight weeks post-transplantation, SSC proliferation and differentiation were assessed using specific markers. In addition, the expression of apoptosis-associated genes (Bax and Bcl-2), components of the PI₃K/Akt/Nrf₂ signaling pathway, as well as seminiferous tubule diameter and germinal epithelium thickness, were evaluated to assess both molecular and structural outcomes. Flow cytometry and morphological analysis confirmed SSC colonization capacity through expression of SALL4 and PAX7. A 100 µM concentration of CGA enhanced SSC proliferation and differentiation, increased seminiferous tubule diameter, and improved germinal epithelium thickness. CGA also increased PI₃K/Akt/Nrf₂ pathway gene expression and reduced apoptosis through its effects on Bax and Bcl-2. These findings suggest that supplementation of freezing medium with CGA may offer a promising approach to preserve and restore fertility in prepubertal males.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2053-2067"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of Sphingolipid Metabolism in Non-Obstructive Azoospermia: Insights from Bioinformatics and a Busulfan-Induced Mouse Model.","authors":"Mojdeh Parvini, Fatemeh Ghasemian, Siamak Salimy","doi":"10.1007/s43032-026-02194-5","DOIUrl":"10.1007/s43032-026-02194-5","url":null,"abstract":"<p><p>Sphingolipid metabolism plays an important role in regulating essential cellular processes, including apoptosis, proliferation, differentiation, and cellular signaling, which are critical for normal spermatogenesis. However, the contribution of sphingolipid metabolic alterations to male infertility, particularly azoospermia, remains insufficiently understood. This study aimed to investigate the involvement of sphingolipid metabolism-related genes and metabolites in spermatogenic failure and their potential association with azoospermia. A publicly available human microarray dataset (GSE9210), consisting of testicular tissue samples from patients with obstructive azoospermia (OA; n = 11) and non-obstructive azoospermia (NOA; n = 47), was analyzed to identify differentially expressed sphingolipid metabolism-related genes. Candidate genes identified through bioinformatic analysis were further evaluated in a busulfan-induced mouse model of azoospermia (control group, n = 8; busulfan-treated group, n = 8) using quantitative real-time PCR, immunohistochemical analysis, and high-performance liquid chromatography (HPLC). Analysis of the GSE9210 dataset identified 23 differentially expressed sphingolipid metabolism-related genes between OA and NOA samples. Validation in busulfan-treated testes indicated significant dysregulation of key sphingolipid-related genes, including decreased expression of Asah1, Asah2, Acer1, Acer2, Cerk, Elovl1, Sgms1, and Galc, and increased expression of Smpd 1,2 & 3 (p < 0.05). HPLC analysis revealed significant reductions in ceramide species (Cer14, Cer16, Cer18, and Cer20), sphingosine, and sphingosine-1-phosphate levels in busulfan-treated testes (p < 0.05). Furthermore, immunohistochemical analysis showed increased expression of the inflammatory markers MMP-2 and MMP-9, accompanied by elevated levels of cleaved Caspase-3 and reduced expression of the anti-apoptotic protein Bcl-2 in the busulfan-treated group (p < 0.05). Overall, these findings suggest that disruption of sphingolipid metabolism may contribute to impaired spermatogenesis and azoospermia. Altered sphingolipid-related gene expression and metabolite profiles provide new insights into the molecular mechanisms underlying male infertility and may represent potential targets for future therapeutic investigation.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2133-2147"},"PeriodicalIF":2.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}