Fanny Morin, Camilla H K Hughes, Vickie Roussel, Nicholas Gevry, Bruce D Murphy
{"title":"Double knockout of steroidogenic factor 1 (SF-1; NR5A1) and liver receptor homolog 1 (LRH-1; NR5A2) in the mouse ovary results in infertility due to disruption of follicle development and ovulation.","authors":"Fanny Morin, Camilla H K Hughes, Vickie Roussel, Nicholas Gevry, Bruce D Murphy","doi":"10.1093/biolre/ioaf079","DOIUrl":"https://doi.org/10.1093/biolre/ioaf079","url":null,"abstract":"<p><p>Liver receptor homolog 1 (LRH-1; Nr5a2) and steroidogenic factor 1 (SF-1; Nr5a1) are two closely related orphan nuclear receptors that bind to the same genomic motif. Conditional depletion of either of these receptors in the ovary results in infertility, but through different mechanisms, with SF-1 being critical early in ovarian development and LRH-1 regulating ovulation. We conditionally depleted both LRH-1 and SF-1 from the ovary, using two different models of conditional depletion, generating two lines of double conditional knockout (dko) mice. In one, we used the Amhr2Cre (Amhr2-dko) mouse, where depletion is initiated in the prenatal ovary before the stage of germ cell nest breakdown. In the other, we employed Cyp19a1Cre (Cyp19a1-dko)-mediated depletion, which is initiated following formation of the follicular antrum. Both models were completely anovulatory and infertile, and no ovulation occurred following administration of exogenous gonadotropins. The Amhr2-dko mouse had dramatically reduced follicular populations at every stage of development, as well as disrupted extracellular matrix, characterized by dysregulation of collagen and laminin expression in reproductively mature mice, reduced expression of steroidogenic genes, dysregulated lipid metabolism, and inhibited granulosa cell proliferation. The latter resulted in a phenotype of reduced ovarian size in this model. The Cyp19al dko mouse displayed dysregulation of luteinizing hormone (LH) response and ovulatory mechanisms and increased activation of the activin/inhibin signaling axis, suggesting impaired gonadotropin responsiveness. In summary, both dko models demonstrated a phenotype of complete infertility, confirming the critical importance of both LRH-1 and SF-1 in ovarian function.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784555","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}
Mahiru Kawano, Jennifer McKey, Iordan S Batchvarov, Blanche Capel
{"title":"Granulosa Cell Death is a Significant Contributor to DNA-Damaging Chemotherapy-Induced Ovarian Insufficiency.","authors":"Mahiru Kawano, Jennifer McKey, Iordan S Batchvarov, Blanche Capel","doi":"10.1093/biolre/ioae181","DOIUrl":"https://doi.org/10.1093/biolre/ioae181","url":null,"abstract":"<p><p>Typically, DNA-damaging chemotherapy (CTx) regimens have a gonadotoxic effect and cause premature ovarian insufficiency (POI), characterized by infertility and estrogen deficiency. However, whether loss of granulosa cells killed directly by CTx contributes significantly to POI has not been determined. To address this issue, we used a previously established mouse model of CTx-induced POI. The alkylating drugs Busulfan (8.75 mg/kg) and Cyclophosphamide (100 mg/kg) were administered to 8-week-old FVB female mice by intraperitoneal (i.p.) injection three times at 48-hour intervals, after which ovarian tissues were harvested and examined by immunofluorescence. The number of primordial follicles was significantly reduced at day (d)6, whereas the number of growing follicles was relatively unchanged. CTx led to DNA double strand breaks in both oocytes and granulosa cells based on the presence of γH2AX foci. However, markers of apoptosis predominantly labeled granulosa cells in growing follicles. We next examined the effect of inhibiting apoptosis in growing granulosa cells by generating Bak-/-Baxfxfx; Cyp19a1Cre transgenic mice. On d10 after the first CTx, Bak-/-Baxfxfx; Cyp19a1Cre ovaries had fewer apoptotic granulosa cells and more surviving follicles than controls. Furthermore, Bak-/-Baxfxfx; Cyp19a1Cre mice showed better fertility than controls after CTx. Our data suggest that granulosa cell death is a significant contributor to follicle depletion and fertility loss after Cyclophosphamide and Busulfan.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771330","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":"Zinc eluted from glassware is a risk factor for embryo development in human and animal assisted reproduction†.","authors":"Tatsuma Yao, Hisato Kobayashi, Tatsuki Hirai, Yuta Tokuoka, Mikiko Tokoro, Yuta Asayama, Yuka Suzuki, Yu Hatano, Hiroki Ikeda, Satoshi Sugimura, Takuya Yamamoto, Takahiro G Yamada, Yoshihiko Hosoi, Akira Funahashi, Noritaka Fukunaga, Yoshimasa Asada, Kazuki Kurimoto, Kazuo Yamagata","doi":"10.1093/biolre/ioaf050","DOIUrl":"https://doi.org/10.1093/biolre/ioaf050","url":null,"abstract":"<p><p>In assisted reproduction, many factors in the culture environment, including light, temperature, pH, and culture media, can reduce preimplantation embryo viability. Laboratory glassware is also a known risk factor for in vitro embryos; however, the underlying mechanisms that disrupt embryonic development remain unclear. We identified Zn eluted from glassware as an embryotoxic substance. In mouse embryos, Zn induced delayed development, abnormalities in chromosome segregation, cytokinesis, zygotic gene activation (e.g. Zscan4a and murine endogenous retrovirus with leucine, also known as MERVL), and aberrantly upregulated developmental gene expression (e.g. Hoxa1, Hoxb9, T, and Fgf8) that could be mediated through metal regulatory transcription factors (e.g. Mtf1). Subsequently, Zn exposure led to significantly reduced blastocyst formation. Post-implantation, Zn-exposed embryos were associated with normal birth rates, however, the birth weight increased by an average of 18% compared with embryos cultured without Zn. Furthermore, Zn exposure affected the development of bovine and human embryos, with species-based variation in the strength and timing of these effects. To mitigate these embryotoxic effects, we identified a method to prevent glass toxicity using chelating agents. This research not only highlights the importance of risk control in embryo culture but also facilitates the development of safe and effective methods for assisted reproduction.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762866","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}
Iris Barka, Emilie Dujardin, Aurélie Dewaele, Marjolaine André, Anne Frambourg, Dominique Thépot, Luc Jouneau, Chrystelle Le Danvic, Geneviève Jolivet, Maëlle Pannetier, Béatrice Mandon-Pépin, Eric Pailhoux
{"title":"DMRT1 haploinsufficiency leads to secondary infertility in XY male rabbits.","authors":"Iris Barka, Emilie Dujardin, Aurélie Dewaele, Marjolaine André, Anne Frambourg, Dominique Thépot, Luc Jouneau, Chrystelle Le Danvic, Geneviève Jolivet, Maëlle Pannetier, Béatrice Mandon-Pépin, Eric Pailhoux","doi":"10.1093/biolre/ioaf064","DOIUrl":"https://doi.org/10.1093/biolre/ioaf064","url":null,"abstract":"<p><p>DMRT1 is a key factor in testis development, where it is involved in sex determination and fertility. Mutations in DMRT1 have been described in humans, with patients presenting 46, XY Disorders of Sex Development (46, XY DSD) or infertility. In a previous study, we demonstrated that DMRT1 is a testis-determining factor in rabbits, with DMRT1-/- rabbits exhibiting a male to female XY sex reversal. In this study, we show that DMRT1 haploinsufficiency induces secondary infertility, with XY rabbits presenting oligospermia or even azoospermia at two years of age. We observed that sperm concentration decreases and sperm anomalies increase in DMRT1+/- rabbits at adulthood. Furthermore, spermatogenesis is impacted as early as 4 months (the earliest stage where spermatozoa are detected), with dysregulation of genes involved in spermatid maturation and oocyte/spermatozoa fusion, as well as overexpression of genes involved in the mitosis/meiosis transition of spermatogonial stem cells (SSCs). Finally, DMRT1 haploinsufficiency impacts the earliest stages of germ cell differentiation, with persistent proliferation and pluripotency in the postnatal period. In conclusion, our findings underscore DMRT1 as a crucial factor at various stages of testicular development, and reinforce its role in the multiple phenotypes observed in humans.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762851","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":"The MMP2 and MMP9-Specific Inhibitor SB-3CT Significantly Decreases Blood Pressure in Pre-eclampsia Model Rats.","authors":"Bowei Li, Jianfang Luo, Wanxing Zhou","doi":"10.1093/biolre/ioaf075","DOIUrl":"https://doi.org/10.1093/biolre/ioaf075","url":null,"abstract":"<p><p>Although uterine matrix metalloproteinases (MMPs) are known to play a role in the development of pre-eclampsia (PE), it remains unclear whether increased levels of serum MMPs are the pathogenesis underlying pregnancy-induced hypertension (PIH). We aimed to investigate whether the serum levels of MMP2 and MMP9 play a role in PIH using a specific inhibitor, SB-3CT. Twenty-five nine-week-old pregnant rats were randomly divided into five groups: normal pregnancy (SHAM) group, PE (RUPP) group, as well as low, middle, and high-dose intervention groups. The intervention groups received continuous intraperitoneal injections of SB-3CT at 25 mg, 50 mg, or 75 mg/kg/d doses. The SHAM and RUPP groups were injected with equal doses of solvent. Seven days later, the arterial pressure was tested at the carotid artery and rats were sacrificed. Serum MMP2, MMP9, tissue inhibitor of metalloproteinase-1 (TIMP1), endothelin-1 (ET-1), angiotensin II (AngII), and endothelial nitric oxide synthase (eNOS) levels were tested by ELISA. Vascular wall changes in cross-sections of the aorta abdominalis were observed using H&E-staining and the activities of MMP2 and MMP9 in the aorta abdominalis were tested using gelatin zymography. There were significant increases in blood pressure, serum MMP2 and MMP9 levels, and activities of MMP2 and MMP9 in the aorta abdominalis, along with notable vascular remodeling in the RUPP group. After the SB-3CT intervention, increased blood pressure was relieved and vascular remodeling improved, while MMP2 and MMP9 levels and activities were reduced. In summary, specific inhibition of MMP2 and MMP9 can decrease blood pressure in a PIH model. This indicates that increased MMP2 and MMP9 in maternal serum might contribute to the pathogenesis of PIH.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750891","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}
Eva Held-Hoelker, Lientje Sophie Haake, Jessica Kurzella, Maibritt Schreiber, Christina Dauben, Dessie Salilew-Wondim, Nasser Ghanem, Franca Rings, Christine Große-Brinkhaus, Ernst Tholen, Dawit Tesfaye, Michael Hoelker
{"title":"Heat stress during maturation of bovine oocytes profoundly impacts the mitochondrial bioenergetic profile and causes ER-stress in subsequent blastocysts.","authors":"Eva Held-Hoelker, Lientje Sophie Haake, Jessica Kurzella, Maibritt Schreiber, Christina Dauben, Dessie Salilew-Wondim, Nasser Ghanem, Franca Rings, Christine Große-Brinkhaus, Ernst Tholen, Dawit Tesfaye, Michael Hoelker","doi":"10.1093/biolre/ioaf070","DOIUrl":"https://doi.org/10.1093/biolre/ioaf070","url":null,"abstract":"<p><p>In dairy cows, detrimental effects of global warming and intensive genetic selection for high milk yield on reproductive performance have become increasingly relevant in cooler regions. Based on the current knowledge we hypothesized that elevated temperature during oocyte maturation affects mitochondria and endoplasmic reticulum in parallel with mitochondrial dysfunction representing the mechanistic link between ROS and ER Stress. To proof that, the present study aimed to uncover the consequences of heat stress during oocyte maturation on mitochondrial health, cellular oxidative stress response and its implications for endoplasmic reticulum stress (ER-stress). Immature bovine oocytes were matured either under routine temperatures (38.8°C, Control) or exposed to elevated temperatures (41°C, HS). MII oocytes as well as subsequent blastocysts were analysed in terms of developmental capacity, mitochondrial membrane potential, the bioenergetic profile, ROS level as well as expression of candidate genes playing a role in oxidative stress, endoplasmic reticulum stress and apoptosis. While no effect on matured oocytes became obvious, HS embryos demonstrated typical alterations of the mitochondrial bioenergetic profile in terms of higher mitochondrial membrane potentials not going along with higher ATP-linked oxygen consumptions and significantly lower maximum respiration and spare capacity rates implicating less efficient mitochondria accompanied with significantly higher ROS levels. Moreover, gene expression of HS embryos supported the assumption that mitochondria are the mechanistic link between oxidative stress and endoplasmic reticulum stress, impairing early embryo development by promoting apoptosis. In summary, the present study contributes to the elucidation of the multiple negative effects of heat stress during the maturation process.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750889","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":"From sperm to offspring: epigenetic markers for dairy herd fertility.","authors":"Ying Zhang, Marc André Sirard","doi":"10.1093/biolre/ioaf056","DOIUrl":"https://doi.org/10.1093/biolre/ioaf056","url":null,"abstract":"<p><p>In recent years, the study of bovine sperm epigenetics has garnered increasing attention alongside research on biomarkers associated with dairy cattle fertility. Male gametes not only transmit the paternal haploid genome to the offspring through fertilization, but also convey epigenetic components, such as DNA methylation, small non-coding RNA, histone variants, and histone modifications to offspring. This epigenetic information may transmit an acquired phenotype leading to intergenerational inheritance. The ongoing worldwide decline in dairy herd fertility affecting both males and females causes significant economic losses for dairy farmers. Previous scientific efforts to address this issue primarily targeted genetic aspects, identifying numerous fertility-related QTLs (Quantitative trait locus) and SNPs (Single nucleotide polymorphisms). However, since fertility is influenced by genetic, epigenetic, and environmental factors, this review highlights the importance of identifying sperm epigenetic markers as additional tools for evaluating and predicting cattle fertility.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742022","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}
Eliana G Aerts, Max J Griesgraber, Ashleigh L Thomson, Malori B Brown, Elizabeth C Bowdridge, Steven L Hardy, Andrew D Seman, Robert L Goodman, Casey C Nestor, Stanley M Hileman
{"title":"Activity of KNDy Neurons and the Melanocortin System During Pubertal Development in Female Sheep.","authors":"Eliana G Aerts, Max J Griesgraber, Ashleigh L Thomson, Malori B Brown, Elizabeth C Bowdridge, Steven L Hardy, Andrew D Seman, Robert L Goodman, Casey C Nestor, Stanley M Hileman","doi":"10.1093/biolre/ioaf074","DOIUrl":"https://doi.org/10.1093/biolre/ioaf074","url":null,"abstract":"<p><p>The increase in luteinizing hormone (LH) that elicits puberty in many species results from a decrease in sensitivity to estradiol (E2) negative feedback. The neural mechanisms underlying this change are unknown, but do not occur at the gonadotropin-releasing hormone (GnRH) neurons as they lack estrogen receptor-alpha (ERα). A potentially important area is the arcuate nucleus of the hypothalamus (ARC), where neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) reside. KNDy neurons express ERα and while our previous work indicated that KNDy cells were critical for puberty, immunopositive cell numbers went unchanged during development, raising the likelihood of additional neuronal inputs. Herein, we used ovariectomized ewes implanted with E2 at prepubertal, peripubertal, or postpubertal ages to examine whether activation of KNDy neurons changed in association with increased LH secretion. Further, a potential role for the melanocortin system (proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons) was assessed. Activation of KNDy neurons increased with increased LH secretion. POMC cell numbers were unchanged, but activation of POMC cells and number of POMC-positive contacts onto KNDy neurons increased with age. In contrast, AgRP cell numbers and activity decreased. In addition, the percentage of POMC and AgRP neurons expressing Erα did not change. Thus, puberty-related increases in LH secretion are associated with activation of KNDy neurons and POMC neurons, but reduced activation and decreased numbers of AgRP neurons. To this point, no predictable changes in ERα expression within KNDy, POMC, or AgRP cell populations have been noted.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741860","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}
Jeanette V Bishop, Aydin Guzeloglu, Tom Scheller, Joshua J Docheff, Carolina L Gonzalez-Berrios, Hana Van Campen, Terry M Nett, Abigail L Zezeski, Thomas W Geary, William W Thatcher, Thomas R Hansen
{"title":"Early identification of bovine pregnancy status and embryonic mortality†.","authors":"Jeanette V Bishop, Aydin Guzeloglu, Tom Scheller, Joshua J Docheff, Carolina L Gonzalez-Berrios, Hana Van Campen, Terry M Nett, Abigail L Zezeski, Thomas W Geary, William W Thatcher, Thomas R Hansen","doi":"10.1093/biolre/ioaf066","DOIUrl":"https://doi.org/10.1093/biolre/ioaf066","url":null,"abstract":"<p><p>Interferon-tau (IFNT) is produced by the trophectoderm cells in the bovine conceptus as early as Day 12 following fertilization. It was hypothesized that IFNT detection in blood, milk and/or cervical secretions could be used to diagnose pregnancy in lactating cows. Recombinant bovine (rb) IFNT was generated to produce goat and rabbit anti-rbIFNT polyclonal antibodies and an enzyme-linked immunosorbent assay (ELISA) for bIFNT was developed using these reagents. The IFNT ELISA did not cross-react with other type I or II IFNs and had a limit of detection of 50-100 pg/ml. The IFNT ELISA detected IFNT in external os cervical swabs from Days 15 to 25 post-AI, but did not detect IFNT in serum, plasma, or milk. The time for most accurately detecting IFNT in cervical fluid was Days 16-19 after AI. A custom bovine swab device used to collect cervical secretions reduced false negative rates to 5.5% (94.5% Sensitivity) in dairy cows on Day 17 and 0 to 3.4% (100 and 96.6% Sensitivity) in beef cows on Days 18 or 16, respectively. In summary, the detection of IFNT in cervical fluid by ELISA provides an accurate indication of pregnancy status in lactating dairy cows. Early identification of the non-pregnant cow allows re-insemination on Day 21 compared to waiting until ultrasound on Day ~32-39. Also, the detection of IFNT on Day 17 followed by loss of pregnancy detected by ultrasound on Day 32 provides a novel research tool for studying pregnancy loss caused by embryonic mortality.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741863","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}
Katarzyna Kent, Kaori Nozawa, Antrix Jain, Anna Malovannaya, Thomas X Garcia, Martin M Matzuk
{"title":"Ovochymase 2 is a key regulatory factor modulating proteolytic pathways and sperm maturation in the mammalian epididymis.","authors":"Katarzyna Kent, Kaori Nozawa, Antrix Jain, Anna Malovannaya, Thomas X Garcia, Martin M Matzuk","doi":"10.1093/biolre/ioaf069","DOIUrl":"https://doi.org/10.1093/biolre/ioaf069","url":null,"abstract":"<p><p>Spermatozoa acquire fertilizing competence during epididymal transit through proteolytic, chaperone-mediated, and post-translational modifications. Ovochymase 2 (OVCH2), an epididymis-specific trypsin-like serine protease, has emerged as a central regulator of this maturation process. Here, we integrate targeted gene disruption, comprehensive proteomic profiling, and affinity-based proteome enrichment to delineate how OVCH2 influences sperm functionality. Deletion of Ovch2 disrupts the proteome of epididymal sperm, resulting in diminished levels of core fertility-related factors-including a disintegrin and metalloprotease domain 3, β-defensins, and protease-inhibitor complexes-while inducing compensatory upregulation of alternate proteases and chaperones. Interaction assays confirm direct or indirect associations of OVCH2 with sperm surface proteins critical for fertilization, highlighting both its essential protease domain and the transient, finely regulated nature of its substrates. Collectively, these findings position OVCH2 as an orchestrator of sperm surface remodeling, with broad implications for fertility diagnostics and therapeutic interventions. By revealing a multifaceted network of OVCH2-dependent pathways, this study provides a mechanistic framework for developing innovative strategies to counter idiopathic male infertility and to enhance male contraceptive design.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742024","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}