Human reproduction最新文献

{"title":"In vitro system completely restores oogenesis in congenitally infertile mice.","authors":"K Yoshida,S Kimura,M Taguchi,H Morimoto,M Kanatsu-Shinohara,T Shinohara,Y Obata","doi":"10.1093/humrep/deaf194","DOIUrl":"https://doi.org/10.1093/humrep/deaf194","url":null,"abstract":"STUDY QUESTIONCan in vitro systems, combined with transient gene expression or factor supplementation, completely restore fertility in congenitally infertile mice?SUMMARY ANSWERTransient expression of Kitl via adeno-associated virus (AAV) vectors or supplementation with recombinant KITL in KitlSl-t/KitlSl-t mice-a model of congenital infertility caused by a mutation in the Kitl locus-resulted in the production of mature oocytes and the birth of healthy, fertile offspring.WHAT IS KNOWN ALREADYAlthough in vivo gene delivery has enabled offspring production in infertile mouse models, low efficiency, unpredictability of parturition timing, inflammatory risk, possible viral genome integration, and lack of real-time oogenesis observation remain major concerns. Despite the potential of in vitro oogenesis as an alternative, complete functional restoration of gene deficiency has not been reported.STUDY DESIGN, SIZE, DURATIONAAV-mCherry was applied to wild-type mouse ovaries, and expression levels were compared across 15 serotypes (2.5 × 1011 viral genomes/ml; N = 4-12; 4-day infection, 20-day culture) to identify optimal AAV serotypes for ovarian gene delivery. The effects of AAV-Kitl infection (six doses; N = 3-5) and recombinant KITL supplementation (four doses; N = 5) on oocyte growth were evaluated in KitlSl-t/KitlSl-t mouse ovaries. On culture day 17 or 18, secondary follicles were isolated and cultured for an additional 16 days to evaluate oocyte competence for maturation, fertilization, and full-term development. Offspring were delivered 52-53 days after treatment initiation.PARTICIPANTS/MATERIALS, SETTING, METHODSOvaries from KitlSl-t/KitlSl-t mice were dissociated into single cells and reaggregated in U-bottom wells with media containing AAV8-Kitl, AAV9-Kitl, or recombinant KITL. Reconstituted ovaries were cultured on insert membranes, thereby allowing primordial follicles to develop into secondary follicles. Isolated secondary follicles were further cultured to the antral stage, and cumulus-oocyte complexes were subjected to IVM and IVF. The resulting embryos were transferred to foster mothers. Finally, the offspring were subjected to PCR screening for AAV sequences and fertility tests.MAIN RESULTS AND THE ROLE OF CHANCEAAV8, AAV9, AAVrh.10, and AAVrh.32.33 induced significantly higher levels of mCherry expression in wild-type mouse ovaries than 10 of the 15 AAV evaluated serotypes in vitro (P < 0.05). AAV8-Kitl promoted primordial follicle activation in a dose-dependent manner in KitlSl-t/KitlSl-t mouse ovaries, with the highest number of secondary follicles (80 per reconstituted ovary) obtained at 1.0 × 1011 vg/ml (P < 0.05). In contrast, AAV9-Kitl required 2.5- to 10-fold higher titers to achieve comparable levels of secondary follicle formation. Contrastingly, no secondary follicles were formed in KitlSl-t/KitlSl-t mouse ovaries following mock treatment. Furthermore, supplementation with 200 ng/ml recombinant KITL supported secondary follicl","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"56 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No anxiety or pain reduction by Virtual Reality during oocyte retrieval in IVF/ICSI treatment: results of a randomized controlled trial.","authors":"A P van Haaps,A M F Schreurs,K Rosielle,V Mijatovic,J W Kallewaard,K Dreyer","doi":"10.1093/humrep/deaf193","DOIUrl":"https://doi.org/10.1093/humrep/deaf193","url":null,"abstract":"STUDY QUESTIONWhat is the effect of Virtual Reality (VR) on anxiety and pain during oocyte retrieval in IVF/ICSI treatment?SUMMARY ANSWERThere is no significant effect of VR on anxiety and pain during oocyte retrieval in IVF/ICSI treatment.WHAT IS KNOWN ALREADYPatients undergoing oocyte retrieval in IVF/ICSI treatment often experience anxiety and pain, despite conscious sedation. VR might offer a solution since it has been successful in reducing procedural anxiety and pain during medical procedures, with the potential to replace standard analgesic care.STUDY DESIGN, SIZE, DURATIONA single-centre, open-label, randomized controlled trial was conducted between February 2023 and August 2024. Due to the nature of the intervention, the study was not blinded.PARTICIPANTS/MATERIALS, SETTING, METHODSPatients undergoing oocyte retrieval as part of IVF/ICSI treatment were screened. After providing informed consent, participants were randomized between oocyte retrieval with VR added to conscious sedation and oocyte retrieval with conscious sedation only. When assigned to the intervention group, patients received the VR intervention through a head-mounted device, showing nature films and relaxation exercises. This was added to standard care which includes analgesia and sedatives. Sounds were delivered through the head-mounted device or headphones. The primary outcome was pre- and post-procedural anxiety, measured using the STAI questionnaire. Secondary outcomes included procedural pain (NRS, scale 0-10), satisfaction scores (NRS, scale 0-10), VR preferences, and side effects.MAIN RESULTS AND THE ROLE OF CHANCEThere were 113 participants included: 57 in the intervention group receiving VR and 56 in the control group not receiving VR. We observed no differences between the intervention and control groups in pre-procedural anxiety (mean difference (MD) 0.14 (95% CI -1.78, 2.05), P = 0.885), post-procedural anxiety (MD 0.45 (95% CI -1.21, 2.11), P = 0.589), overall pain (MD -0.12 (95% CI -0.97, 0.73), P = 0.779), and peak pain (MD 0.59 (-0.51, 1.68), P = 0.287).LIMITATIONS, REASONS FOR CAUTIONVR might only be effective for a certain group of patients undergoing retrieval, or might be more effective in reducing pre-procedural anxiety, which in turn might lead to a reduction in procedural pain. Furthermore, it might reduce pain up to a certain threshold, or be effective when the duration of the procedure is short.WIDER IMPLICATIONS OF THE FINDINGSSince VR does not affect anxiety and pain for the general patient population undergoing oocyte retrieval, we do not advise incorporating VR to standard IVF/ICSI anxiety and pain management. For future studies, it is important to investigate which subgroup could benefit from VR and how it could be implemented to study interventions from a non-pharmacological approach. Patient preferences regarding anxiety and pain management during IVF/ICSI treatment should be considered.STUDY FUNDING/COMPETING INTEREST(S)External funding f","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"107 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cumulative live birth rates in women with endometriosis undergoing ART treatment.","authors":"Repon C Paul,Rebecca Deans,Amanda Henry,Cecilia Ng,Ingrid Rowlands,Gita D Mishra,Jason Abbott,Georgina M Chambers","doi":"10.1093/humrep/deaf191","DOIUrl":"https://doi.org/10.1093/humrep/deaf191","url":null,"abstract":"STUDY QUESTIONHow do cumulative live birth rates (CLBRs) in women with endometriosis compare to those with other infertility diagnoses undergoing ART?SUMMARY ANSWERWomen with endometriosis as the sole cause of infertility achieved higher CLBRs compared to those with additional infertility diagnoses (endometriosis-plus) or other non-endometriosis causes of infertility.WHAT IS KNOWN ALREADYEndometriosis affects approximately 10% of women of reproductive age and is a major cause of infertility, with many women resorting to ART treatments in the hope of achieving a pregnancy. However, the comparative success rates of ART for these women, compared to those with other causes of infertility is not well understood.STUDY DESIGN, SIZE, DURATIONThis retrospective cohort study included 79 318 women who initiated autologous ART between 2014 and 2019 in Australia and New Zealand, with follow-up through 2021 or the first live birth.PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants were categorized into three groups based on infertility diagnosis: endometriosis-only (n = 4311), endometriosis-plus (n = 6312; endometriosis with other infertility factors) and other-infertility (n = 68 695; no endometriosis). Conservative and optimal CLBRs were calculated based on assumptions made about the chance of live birth for women who discontinued treatment.MAIN RESULTS AND THE ROLE OF CHANCEEndometriosis was reported as the sole cause of infertility in 5% of women (endometriosis-only), while 8% had endometriosis with other diagnoses (endometriosis-plus). The remaining women had either other causes of infertility (63%) or unexplained infertility (24%). Depending on assumptions made regarding patients who discontinued treatment, the CLBR by the sixth complete cycle for women diagnosed with endometriosis-only ranged from 64% to 83%; for women with an endometriosis-plus diagnoses, the CLBR ranged from 54.3% to 68.7%; and for women without endometriosis, the CLBR ranged from 57.3% to 76.5%. Compared to women without endometriosis, the live birth rate was 6% higher in endometriosis-only group (RR: 1.06; 95% CI: 1.04-1.08) and 5% lower in endometriosis-plus group (RR: 0.95; 95% CI: 0.93-0.97). Compared to the endometriosis-only group, pregnancy loss was 46% higher (RR: 1.46; 95% CI: 1.35-1.59) in endometriosis-plus group.LIMITATIONS, REASONS FOR CAUTIONThe study did not assess endometriosis severity or phenotype, which may influence ART outcomes.WIDER IMPLICATIONS OF THE FINDINGSThese findings provide critical data for counselling women with endometriosis regarding ART success. The higher CLBR in the endometriosis-only group suggests that isolated endometriosis does not negatively impact ART outcomes and highlights the need for tailored management in women with additional infertility factors.STUDY FUNDING/COMPETING INTEREST(S)This study is funded through the Medical Research Future Fund (MRFF) Research Data Infrastructure grant (MRFRFD000065). The sponsors had no role in the des","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"53 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Livebirth among 5940 Danish women diagnosed with breast cancer at age 18–40 years between 1968 and 2016: a register-based cohort study","authors":"Anna Mathilde Yde, Lotte Berdiin Colmorn, Anja Pinborg, Lone Schmidt, Niels Kroman, Frederik Nikolaj Kyhl, Ditte Vassard, Kirsten Tryde Macklon","doi":"10.1093/humrep/deaf192","DOIUrl":"https://doi.org/10.1093/humrep/deaf192","url":null,"abstract":"STUDY QUESTION Does livebirth probability differ between women diagnosed with breast cancer and unaffected women and is it impacted by age at diagnosis, time trends, parity, partnership status, and the presence of lymph node metastases and distant metastases? SUMMARY ANSWER Livebirth probability was significantly reduced in 5940 women diagnosed with breast cancer aged 18–40 years during 1968–2016 compared to 1 126 478 age-matched unaffected women, particularly among women with higher diagnosis age, parity ≥ 1, marriage, and the presence of nodal involvement and distant metastases. WHAT IS KNOWN ALREADY The survival rate for women diagnosed with breast cancer has increased over the recent decades, and in Denmark, the 5-year survival rate for women diagnosed <50 years of age was 92.2% in 2022. Chemotherapy can damage the ovarian reserve, resulting in premature ovarian insufficiency and infertility. The age of first-time mothers is increasing, and many women have not yet completed family building at the time of diagnosis. Consequently, greater focus is now placed on quality-of-life following breast cancer, including the possibility of survivors to have children. Studies have shown a decreased fertility rate in women diagnosed with cancer during their reproductive lifespan, however, studies specifically focusing on the probability of livebirth in women previously diagnosed with breast cancer are scarce. STUDY DESIGN, SIZE, DURATION This is a national, register-based cohort study including women diagnosed with breast cancer from the Danish Cancer Register between 1968 and 2016, aged 18–40 years at time of diagnosis (n = 5940). Each woman was randomly matched with ∼190 unaffected women from the background population according to the age at diagnosis (n = 1 126 478). The women were followed in medical and sociodemographic national population registers until childbirth, death, immigration, or end of study (31 December 2018). PARTICIPANTS/MATERIALS, SETTING, METHODS In all analyses, we compared the probability of livebirth between women diagnosed with breast cancer and the age-matched comparison group. Analyses were stratified by parity- and partnership status at diagnosis, age-group at diagnosis, and year of diagnosis. Stratified analyses on the probability of livebirth were conducted for women with lymph-node metastases and distant metastases at the time of diagnosis. Analyses were adjusted for age, year of diagnosis, parity, educational level, and migration status. MAIN RESULTS AND THE ROLE OF CHANCE The study population consisted of 5940 women aged 18–40 years at diagnosis of breast cancer between 1968 and 2016 and 1 126 478 women in the age-matched comparison group. Breast cancer survivors had a significantly lower probability of livebirth than the age-matched comparison group (aHR 0.38 [95% CI 0.35–0.41]); negatively impacted by increasing age at diagnosis (35–40 years: aHR 0.34 [95% CI 0.28–0.40], 18–24 years: 0.66 [95% CI 0.46–0.95]), parit","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"78 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blastocyst segmental aneuploidy breakpoints are highly correlated with human genome fragile sites.","authors":"Elaine de Quadros, Jia Xu, Nathan Treff, Diego Marin, Arielle Freedman, Cristian Milevski, Kathleen Miller, Minglei Bian","doi":"10.1093/humrep/deaf151","DOIUrl":"10.1093/humrep/deaf151","url":null,"abstract":"<p><strong>Study question: </strong>Are segmental aneuploidies identified in human embryos more likely to occur within known fragile sites of the genome?</p><p><strong>Summary answer: </strong>Segmental breaks in the autosomes of human preimplantation embryos occur more frequently in known fragile areas of the genome.</p><p><strong>What is known already: </strong>Fragile sites represent specific loci in the genome characterized by inhibition of DNA synthesis when exposed to known inhibitors and are particularly sensitive to replication stress and instability.</p><p><strong>Study design, size, duration: </strong>This was a retrospective analysis of single nucleotide polymorphism (SNP) array-based preimplantation genetic testing data from biopsies performed on 2066 human blastocysts in 98 assisted reproduction laboratories around the world from September 2019 to January 2023.</p><p><strong>Participants/materials, setting, methods: </strong>This multicenter study included eligible patients undergoing IVF with preimplantation genetic testing (PGT), in which at least one embryo was diagnosed with a segmental aneuploidy. The mean maternal age was 36.4 years (SD 4.1), ranging from 25 to 44 years. These samples were processed on high-density SNP arrays. Chromosome level copy number and B allele frequency (BAF) plots from these embryos were used to determine segmental aneuploidy breakpoints. Known fragile sites catalogued by the HumCFS database were used for correlation analyses.</p><p><strong>Main results and the role of chance: </strong>Overall, a side-by-side pairing of observed breakpoints and known fragile sites demonstrated a strong concordance (r = 0.81, 95% CI [0.6, 0.92]). A chi-square test for independence for stratified groups showed a highly significant correlation between all observed breakpoints and known fragile sites (597 expected vs. 848 observed; P < 0.001) and for telomeric breaks alone (521 expected vs. 784 observed; P < 0.001). Observed interstitial breaks alone were not correlated to expected breakpoints (75 expected vs. 64 observed; P > 0.05).</p><p><strong>Limitations, reasons for caution: </strong>These findings should be interpreted with caution, as limitations in genomic resolution may bias detection and classification of smaller segmental aneuploidies. Additionally, this study touched upon the distribution of meiotic to mitotic breakpoints in human blastocysts as they relate to known fragile sites. Since meiotic aneuploidies increase with advanced maternal age and many IVF patients undergoing PGT-A testing fall in this category, a sampling bias should be considered for this specific metric.</p><p><strong>Wider implications of the findings: </strong>Demonstrating that segmental aneuploidies significantly correlate with known fragile sites highly susceptible to replication stress offers insight into the origin of subchromosomal imbalances and hints at the influence of stressors on reproductive success.</p><p><strong>Study funding","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1998-2007"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Recurrent implantation failure: when study design fails before the embryos.","authors":"Qiong Wang, Xiaoran Zhang, Can Wang","doi":"10.1093/humrep/deaf171","DOIUrl":"10.1093/humrep/deaf171","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"2022-2023"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent implantation failure: when study design fails before the embryos.","authors":"Baris Ata, Erkan Kalafat, Paul Pirtea","doi":"10.1093/humrep/deaf170","DOIUrl":"10.1093/humrep/deaf170","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"2020-2021"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stratifying IVF population endometria using a prognosis gradient independent of endometrial timing†.","authors":"Josefa Maria Sanchez-Reyes, Antonio Parraga-Leo, Patricia Sebastian-Leon, Maria Del Carmen Vidal, Diana Marti-Garcia, Katharina Spath, Imma Sanchez-Ribas, Francisco Jose Sanz, Nuria Pellicer, Jose Remohi, Dagan Wells, Antonio Pellicer, Patricia Diaz-Gimeno","doi":"10.1093/humrep/deaf156","DOIUrl":"10.1093/humrep/deaf156","url":null,"abstract":"<p><strong>Study question: </strong>Can the disrupted window of implantation (WOI) be stratified according to transcriptomic patterns associated with reproductive success in IVF patients undergoing HRT?</p><p><strong>Summary answer: </strong>There are four transcriptomic patterns independent of endometrial timing associated with a gradient of reproductive prognosis underlying different molecular pathomechanisms.</p><p><strong>What is known already: </strong>A molecular heterogeneous profile independent of endometrial timing has been discovered as a cause of implantation failure that disrupt the endometrial transcriptome in the mid-secretory phase. However, the molecular heterogeneous patterns underlying the disruption remain poorly identify and understood. Characterizing the molecular heterogeneity of this endometrial disruption is crucial to develop personalized and more accurate diagnostic tools for preventive medicine, particularly for patients with a high risk of endometrial failure.</p><p><strong>Study design, size, duration: </strong>In this multicenter prospective study, 195 IVF patients undergoing HRT with endometrial biopsy collection, during mid-secretory phase for endometrial progression evaluation, were recruited between January 2019 and August 2022. Out of 195 patients, 131 were finally included in the following analysis.</p><p><strong>Participants/materials, setting, methods: </strong>Endometrial biopsies were processed for whole endometrial transcriptome analysis using RNA-Sequencing. To identify disruptions in the WOI, the transcriptomic variation due to cyclic endometrial tissue changes was removed. Out of 195 biopsies sequenced, 131 were derived from patients that met the clinical criteria to be classified as implantation failure group (≥3 implantation failures, n = 32) or control group (<3 implantation failures, n = 99). An artificial intelligence (AI) model, based on two supervised learning algorithms: support vector machine (SVM) and k-nearest neighbors (kNN), was performed with 131 patients that were randomly allocated to training (n = 105) and test (n = 26) sets for biomarker signature discovery and assessment of predictive performance, respectively. The reproductive outcomes of the single embryo transfer immediately after biopsy collection were analyzed. Differential expression and functional analyses were performed to characterize molecular profiles. Finally, a quantitative PCR (qPCR) assay was used to corroborate the differential expression of six potential biomarkers.</p><p><strong>Main results and the role of chance: </strong>With the dichotomous clinical classification of poor or good reproductive prognosis, there was no transcriptomic distinction between patients with a history of implantation failures during HRT endometrial preparation. Alternatively, using an AI model to stratify IVF patients based on the probability of endometrial disruption revealed molecular and clinical differences between patterns. Patients we","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1928-1937"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracetamol (N-acetyl-para-aminophenol) disrupts early embryogenesis by cell cycle inhibition.","authors":"Brian S Nielsen, Morten R Petersen, Javier Martin-Gonzalez, Christian Holmberg, Heidi K Mjoseng, Hanne Frederiksen, Cristal Rosenthal, Emma M Jørgensen, Palle Serup, Sarah L Christensen, Kathrine B Petersen, Karsten Kristiansen, Niklas R Jørgensen, Jeppe Kari, Anders Hay-Schmidt, Margaux Heurte, Per A Pedersen, Anders Juul, Anja Pinborg, Søren Ziebe, Svend Lindenberg, Jimmi Elers, Arthur David, Frederikke Lindenberg, Anne Zedeler, Søren T Christensen, David M Kristensen","doi":"10.1093/humrep/deaf116","DOIUrl":"10.1093/humrep/deaf116","url":null,"abstract":"<p><strong>Study question: </strong>Does paracetamol (N-acetyl-para-aminophenol (APAP) also known as acetaminophen) interfere with cell division and thereby disrupt pre-implantation embryonic development?</p><p><strong>Summary answer: </strong>Our findings suggest that APAP exposure inhibits cell cycling during pre-implantation development (PID) through the reduction of DNA synthesis, potentially resulting in early embryonic loss.</p><p><strong>What is known already: </strong>It is estimated that 10-40% of all human conceptions fail around the time of implantation. Genetic factors explain ∼50% of early embryonic loss, leaving a substantial portion of early losses without a known cause. Smoking and alcohol are established risk factors for spontaneous abortion, underscoring the importance of the chemical environment during embryonic development.</p><p><strong>Study design, size, duration: </strong>To address the challenges in determining the mechanism of action and the effects of APAP during PID, we utilized a range of approaches, including in vitro, ex vivo, and in vivo methods across various models ranging from yeasts to human embryos and women of fertile age.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 90 human embryos were exposed in vitro (22 cleavage stage and 68 blastocyst-stage embryos). Endometrial tissue and uterine fluid were collected from seven women as part of an endometrial scratching procedure. Follicular fluid was collected from 26 women during transvaginal ultrasound guided aspiration of the pre-ovulatory follicles. All human material was sampled in accordance with relevant guidelines and regulations with consent from the regional scientific ethical committee of the Capital Region of Denmark and signed informed patient consent given prior to donation. All mouse experiments were approved by the Danish Animal Experiments Inspectorate and under EU directive 2010/63/EU on the protection of animals used for scientific purposes. The cultivation of the human embryonic stem cell lines H1 and HUES4 was conducted in compliance with relevant guidelines and regulations, following approval from the regional scientific ethical committee of the Capital Region of Denmark.</p><p><strong>Main results and the role of chance: </strong>After exposure to APAP, we found an unequivocal repression of cell division across all used model systems. APAP exposure hindered cell cycle progression, likely by inhibiting ribonucleotide reductase, leading to reduced DNA synthesis and accumulation in the S-phase. At concentrations found in the reproductive system of women after standard dosing, APAP exposure decreased cell numbers in mouse and human cleavage-stage embryos or caused direct embryonic death. Similar exposure to mouse and human blastocyst-stage embryos resulted in a reduced inner cell mass and decreased DNA synthesis, respectively.</p><p><strong>Limitations, reasons for caution: </strong>A limitation of the study is the lo","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1860-1876"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic arrest.","authors":"Huiling Hu, Xian Wan, Jiaqi Sun, Shen Zhang, Jing Guo, Yinli Zhang, Fei Meng, Shuoping Zhang, Yifan Gu, Fei Gong, Hongqing Liao, Ge Lin, Wei Zheng","doi":"10.1093/humrep/deaf158","DOIUrl":"10.1093/humrep/deaf158","url":null,"abstract":"<p><strong>Study question: </strong>What effects do DLGAP5 defects have on human early embryo development?</p><p><strong>Summary answer: </strong>DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility characterized by recurrent early embryonic arrest (REEA).</p><p><strong>What is known already: </strong>REEA is a significant contributor to failures in assisted reproductive technology. While genetic factors play a crucial role, known gene variants account for only a small proportion of affected individuals, leaving many underlying genetic factors yet to be elucidated. The relationship between spindle assembly and early embryonic development has emerged as a key research focus, however, our understanding of bipolar spindles in human oocytes and early embryos remains limited, highlighting the need for further investigation into the essential molecular players involved.</p><p><strong>Study design, size, duration: </strong>A total of 488 female patients experiencing infertility characterized as REEA were recruited from a university-affiliated center from November 2021 to December 2023.</p><p><strong>Participants/materials, setting, methods: </strong>Whole-exome sequencing was performed on the REEA cohort to identify candidate variants. HeLa cells were transiently transfected with wild-type and mutant plasmids to evaluate protein abundance and localization. Mutant mRNAs were expressed at the zygote stage to monitor subsequent embryonic development. Immunoprecipitation-mass spectrometry was employed to identify altered interacting molecules associated with the candidate variants. Additionally, a site-directed mutant mouse model was developed to investigate the pathogenic mechanisms in vivo, validated with patient oocytes and arrested embryos.</p><p><strong>Main results and the role of chance: </strong>The study identified two nonsense variants, one frameshift variant, and one missense pathogenic variant in the DLGAP5 gene of three independent families from the cohort of 488 REEA patients through whole-exome sequencing. All affected individuals displayed a Mendelian recessive inheritance pattern. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.</p><p><strong>Limitations, reasons for caution: </strong>This study was unable to observe the dynamic changes in spindle assembly in oocytes from patients with DLGAP5 variants due to ethical restrictions. Additionally, a larger patient cohort is needed, particularly multi-center and multi-ethnic studies, to further establish t","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"2008-2019"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}