Camille Couture, Marie-Eve Brien, Jacqueline Piché, Elizabeth Cervantes, Thuy Mai Luu, Sylvie Girard
{"title":"Adverse neonatal outcomes are associated with a sex-specific placental inflammatory profile†.","authors":"Camille Couture, Marie-Eve Brien, Jacqueline Piché, Elizabeth Cervantes, Thuy Mai Luu, Sylvie Girard","doi":"10.1093/biolre/ioaf158","DOIUrl":"https://doi.org/10.1093/biolre/ioaf158","url":null,"abstract":"<p><strong>Background and objective: </strong>The placenta is crucial for fetal development; altered function is associated with complications and adverse neonatal outcomes. Our goal was to ascertain changes in the placental transcriptome in relation to neonatal outcome and fetal/placental sex.</p><p><strong>Study design: </strong>72 mother-baby dyads were included. Demographic, obstetrical, neonatal and infant health data were obtained through medical charts. Adverse neonatal outcome was defined as the presence of a pulmonary, cardiac, neurological or other health complication. Bulk RNA-sequencing of placental biopsies was obtained. P-value < 0.05 was considered statistically significant.</p><p><strong>Results: </strong>Neonates experiencing adverse outcomes were more likely to be premature or have lower birth weights. Analysis of the placental transcriptome revealed a predominant inflammatory profile in pregnancies associated with adverse neonatal outcomes with the top pathways being related to immune and inflammatory responses. Amongst differently expressed genes (DEGs), 1237 were upregulated and 239 were downregulated in adverse vs no adverse outcomes. Furthermore, sex-specific differences in gene expression were observed and indicated that male and female placentas displayed unique DEGs in association with adverse outcomes. Indeed, no DEG was observed in female placentas when comparing those without vs with adverse neonatal outcomes, as opposed to 1279 DEGs in male placentas, of which 91% were up-regulated in adverse subgroups.</p><p><strong>Conclusions: </strong>These findings highlight that inflammatory pathways are upregulated in placentas in association with adverse neonatal outcomes, and showcase the importance of the fetal sex in understanding neonatal health. The placenta provides a unique tool for early identification of high-risk infants rapidly after delivery.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658277","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":"Development of male contraceptives is critical for women's health†.","authors":"Wei Yan","doi":"10.1093/biolre/ioaf115","DOIUrl":"10.1093/biolre/ioaf115","url":null,"abstract":"<p><p>Despite decades of advancement in reproductive medicine, the development of effective, reversible male contraceptives remains strikingly underfunded and underprioritized. This neglect has direct consequences for women, who disproportionately bear the burden of preventing pregnancy and managing the outcomes when contraception fails or is unavailable. Approximately half of all pregnancies globally are unintended, and the lack of male contraceptive options contributes substantially to this statistic. In this commentary, I argue that male contraceptive development should be recognized as an essential component of women's health research and policy-on par with gynecological and maternal health concerns. Without access to contraceptives for men, it is women-and by extension, their children and families-who ultimately bear the physical, emotional, and economic consequences of unintended pregnancy. Reproductive responsibility must be equitably shared, and that shift requires urgent investment in male contraceptive research.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"3-4"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092742","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":"New insight in human sperm pro-survival and pro-apoptotic pathways: potential new therapeutical targets in male infertility†.","authors":"Saveria Aquila, Adele Vivacqua, Giuseppina Peluso, Roberto Castiglione, Rosario D'Agata","doi":"10.1093/biolre/ioaf078","DOIUrl":"10.1093/biolre/ioaf078","url":null,"abstract":"<p><p>Over the past two decades, others and our group have explored the different signaling cascade in human spermatozoa and observed that their deregulation might lead to sperm dysfunctions, contributing to infertility. Studies of patients with infertility have reported variations in sperm features, such as asthenozoospermia, either alone or in combination with other pathologies, more specifically in patients with genital tract infections, sperm metabolic diseases, varicocele, and anatomic/molecular sperm anomalies. Infertility is idiopathic and multifactorial in most patients. Although several studies have elucidated many of the components and mechanisms involved in the human sperm signaling pathways, their role in defective spermatozoa or systemic pathologies remains nebulous. In this review, we focused on transducing signals, the underlying regulatory mechanisms in human spermatozoa and explored the known pro-survival and pro-apoptotic pathways as well as the factors involved.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"34-48"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794525","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}
Krzysztof Damaziak, Agata Marzec, Wojciech Wójcik, Beata Horecka, Mateusz Osiadacz, Julia Riedel, Paweł Pstrokoński, Sebastian Mielnicki
{"title":"Elongated shape and unusual eggshell microstructure enable first confirmed hatching of avian twins†.","authors":"Krzysztof Damaziak, Agata Marzec, Wojciech Wójcik, Beata Horecka, Mateusz Osiadacz, Julia Riedel, Paweł Pstrokoński, Sebastian Mielnicki","doi":"10.1093/biolre/ioaf100","DOIUrl":"10.1093/biolre/ioaf100","url":null,"abstract":"<p><p>The aim of the study was to elucidate the causes that led to the hatching of goose twins for the first time. Analyses included the reconstruction of the egg's dimensions based on preserved fragments of shell and characterization of its microstructure. Sequencing of the genome of the twins was performed. Based on the results, the dimensions of the egg were recreated, while the structure and porosity of the shell were characterized. The main factors that allowed the twins to survive to the end of incubation were, first, the highly elongated shape of the egg, which \"forced\" the embryos to adopt a parallel position in line with the long axis of the egg, and second, the shell's altered porosity indices. The pores in the twins' post-hatching shell had a smaller surface area, but there were significantly more of them than in the control shells. As a result, for the twins' egg, the total pore area of the shell and the ratio of total pore area to shell thickness was low. These changes contributed to changes in the dynamics of water diffusion from the egg, adapting it to the needs of the two embryos. Analyses, including whole-genome sequencing, indicate that most of the single nucleotide polymorphism (SNP) variants, and insertions, and deletions in both twins' cases were located within introns and in the intergenic parts of the genome. A comparison of the type and frequency of SNP and InDel variations showed that the twins are characterized by high level of genetic similarity.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"49-60"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964562","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":"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, 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 Ovochymase 2 influences sperm functionality. Deletion of Ovochymase 2 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 between Ovochymase 2 and sperm surface proteins critical for fertilization, highlighting its essential protease domain and the transient, and finely regulated nature of its substrates. Collectively, these findings position Ovochymase 2 as an orchestrator of sperm surface remodeling, with broad implications for fertility diagnostics and therapeutic interventions. By revealing a multifaceted network of Ovochymase 2-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":"127-140"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260502/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The role(s) of HE4 and other WAP factors for sperm functions and male urogenital diseases†.","authors":"Xiaolun Xu, Huaiyun Tang, Shuai Zhang, Lingjin Tuo, Lisha Tang, Shi-Wen Jiang","doi":"10.1093/biolre/ioaf063","DOIUrl":"10.1093/biolre/ioaf063","url":null,"abstract":"<p><p>Human epididymis protein 4 (HE4) is a secretory glycoprotein with protease inhibitor activity. HE4 is constitutively expressed in the epididymis, testis, prostate, and other male urogenital organs. By its overexpression in the lesion and serum of cancer patients, HE4 is used as a biomarker for patient triage prognosis and recurrent surveillance of gynecologic malignancies. Elevated seminal plasma levels of HE4 have been correlated to oligoasthenozoospermia, and genetic overexpression of HE4 gene in mice led to the development of small testis, Leydig cell hyperplasia, structural anomalies of seminiferous tubules, elevated serum testosterone level, and decreased male fecundity. Since proteases and their endogenous inhibitors are deeply involved in semen liquefaction and sperm maturation/capacitation, motility, acrosomal reaction, and fertilization, HE4 and other WAP domain protease inhibitors may participate in the regulation of various sperm functions and male fertility. In addition, increasing data have implicated HE4 and other whey acidic protein (WAP) domain factors such as Secretory Leucocyte Protease Inhibitor (SLPI) in innate immunity and inflammation, and these factors may play a role(s) in male urogenital inflammatory disorders such as epididymitis, testitis, and prostatitis. This review summarizes relevant observations from in vitro, in vivo, and clinical studies, and analyzes the potential role(s) of HE4 in male infertility and other urogenital diseases. Critical issues concerning HE4 physiopathological functions, mechanisms as well as the current/future research efforts are raised and discussed.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"8-18"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717917","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}
Paula R Brown, Martin A Estermann, Artiom Gruzdev, Gregory J Scott, Thomas B Hagler, Manas K Ray, Humphrey Hung-Chang Yao
{"title":"Generation of a Nr2f2-driven inducible Cre mouse to target interstitial cells in the reproductive system†.","authors":"Paula R Brown, Martin A Estermann, Artiom Gruzdev, Gregory J Scott, Thomas B Hagler, Manas K Ray, Humphrey Hung-Chang Yao","doi":"10.1093/biolre/ioaf094","DOIUrl":"10.1093/biolre/ioaf094","url":null,"abstract":"<p><p>The orphan nuclear receptor Nr2f2, also known as COUP-TFII, plays important roles in the development and function of multiple organs, including the reproductive system. NR2F2 is expressed in the interstitial cells of both embryonic and adult testes, ovaries, and reproductive tracts. Taking advantage of such unique expression pattern, we have developed a tamoxifen inducible Cre mouse model, Nr2f2-iCreERT2, which specifically and efficiently targets interstitial cells in both male and female reproductive organs across embryonic and adult stages. This model offers a powerful tool for gene knockout studies specifically in the interstitial compartment, without affecting the supporting or germ cells. Additionally, it enables interstitial cell lineage tracing, facilitating the assessment of the interstitial's contribution to non-interstitial cell types during development and differentiation.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"220-230"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961046","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}
Alexandria Ross, Joe W Cain, Bryan A McLendon, Avery C Kramer, Fuller W Bazer, Guoyao Wu, Gregory A Johnson
{"title":"Progesterone Regulates Endometrial Expression of SLC6A9 to Potentially Increase Glycine Transport to the Developing Pig Conceptus†.","authors":"Alexandria Ross, Joe W Cain, Bryan A McLendon, Avery C Kramer, Fuller W Bazer, Guoyao Wu, Gregory A Johnson","doi":"10.1093/biolre/ioaf154","DOIUrl":"https://doi.org/10.1093/biolre/ioaf154","url":null,"abstract":"<p><p>Histotroph is regulated by progesterone (P4) and other paracrine factors and contains amino acids essential for porcine conceptus (embryo/fetus and placental membranes) development. We hypothesized that P4 contributes to amino acid transport during pregnancy in pigs. Ovariectomized gilts received daily P4 or corn oil (CO) injections from Days 12 through 39 post-estrus. High-performance liquid chromatography (HPLC) determined increased abundances of several amino acids, including glycine, in uterine flushings from P4-treated gilts. Solute carrier transporters (SLCs) transport amino acids across membranes. Quantitative real-time PCR (qPCR) analyses revealed endometrial expression of SLC6A9 mRNA increased during the peri-implantation period of pregnancy. SLC7A8 and SLC38A1 mRNA expression also increased during that period but decreased later in pregnancy. SLC1A4, SLC1A5 and SLC7A10 mRNA expression was greatest later in pregnancy. Immunofluorescence analyses localized SLC6A9, which transports glycine exclusively, to the endometrial luminal epithelium from Day 12 through 25, uterine glandular epithelium throughout gestation, conceptus trophectoderm and endoderm between Days 15 and 20, and chorionic epithelia of inter-areolar and areolar chorionic epithelia (CE) between Days 40 and 60. Expression in inter-areolar regions decreased by Day 60 but remained high in the areolae. Expression of SLC6A9 was greater for endometrium from P4-treated than CO-treated pigs. These results illustrate the complexity of, and stage-dependent changes in, expression of amino acid transporters in endometria from pregnant pigs. The results suggest that transport of glycine into the uterine lumen and across the chorioallantois by SLC6A9 may be critical for delivery of this amino acid that is essential for conceptus development.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616127","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}
Julia C Young, Penny A F Whiley, Jessie M Sutherland, Michael Luu, Dan Garama, Mark A Baker, Cathryn A Hogarth, Elizabeth A Richards, David A Jans, Eileen A McLaughlin, Kate L Loveland
{"title":"The nuclear transport factor IPO5 revealed as a critical mediator of male germline development†.","authors":"Julia C Young, Penny A F Whiley, Jessie M Sutherland, Michael Luu, Dan Garama, Mark A Baker, Cathryn A Hogarth, Elizabeth A Richards, David A Jans, Eileen A McLaughlin, Kate L Loveland","doi":"10.1093/biolre/ioaf134","DOIUrl":"https://doi.org/10.1093/biolre/ioaf134","url":null,"abstract":"<p><p>The highly conserved nuclear transport protein Importin 5 (IPO5) binds cargo implicated in fundamental processes including virus and chromatin assembly, germline development and cell signalling. It also anchors cell-specific cargo for functional outcomes in development and immune responses. IPO5 displays both spatial and temporal regulation in the male germline, from fetal through to adult ages. Because it transports key early developmental/reproductive factors, including Stella and the BMP signalling SMADs 1/5/9, we hypothesized that targeted IPO5 deletion would impair germline development and viability at specific stages. Here we demonstrate in vivo functional importance of IPO5 by generating global and conditional IPO5 knockout mice using an Ipo5FL/FL allele flanking exons 9 and 10. Global deletion using CMVCre produced no null embryos at embryonic day (E)12.5, while heterozygous embryo numbers were reduced to 50%, demonstrating it is essential for early embryogenesis. A sex-specific germline requirement for IPO5 was demonstrated following deletion using VasaCre (active from E15.5); adult testes lacked germ cells, while oocytes developed and female fertility was unaffected. Stra8Cre-directed IPO5 deletion (active from postnatal day (PND) 3) caused meiotic failure evident at PND 14; no IPO5-deficient germ cells were present in adults, although niche integrity and function supported emergence of rare IPO5-positive spermatozoa. Novel IPO5 binding proteins identified by immunoprecipitation and mass-spectrometry included SFPQ in fetal testes and XPO2 (exportin 2) in both isolated spermatocytes and spermatids. Remarkably, most IPO5 potential binding proteins are essential for male fertility. These results define IPO5 as crucial for in vivo embryonic development and male fertility.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616128","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":"Suppression of oocyte glycine transporter activity in mouse cumulus-oocyte complexes before resumption of meiosis†.","authors":"Allison K Tscherner, Jay M Baltz","doi":"10.1093/biolre/ioaf080","DOIUrl":"10.1093/biolre/ioaf080","url":null,"abstract":"<p><p>Glycine is a key regulator of cell volume in early preimplantation mouse embryos and supports embryo viability. Its accumulation is initiated when the GLYT1 glycine transporter (SLC6A9) is activated in oocytes at about the same time the oocyte is released from meiotic arrest at the germinal vesicle (GV) stage. The mechanism by which GLYT1 is maintained in an inactive state before ovulation is triggered is unknown. Here, we have shown that GLYT1 activity can remain suppressed in isolated cumulus-oocyte complexes (COCs) under defined culture conditions that include keeping COCs physically separated and using the physiological mediator of GV arrest, natriuretic peptide precursor C. When GV arrest is instead maintained in oocytes within COCs by inhibiting phosphodiesterase 3A or cyclin-dependent kinase 1, GLYT1 similarly remains inactive. However, GLYT1 becomes activated in isolated GV oocytes similarly maintained in GV arrest, indicating that cumulus cells are required for suppressing GLYT1 activity. This implies that meiotic arrest is necessary but not sufficient for preventing GLYT1 activation and that an inhibitory factor likely arising from the cumulus is also required. Finally, we have found that pyrrophenone, a selective inhibitor of arachidonic acid production by cytoplasmic phospholipase A alpha, causes GLYT1 to become activated in oocytes within COCs despite maintenance of meiotic arrest of the oocyte. Since arachidonic acid levels decrease in oocytes after release from GV arrest, we propose that arachidonic acid may be a candidate for the inhibitory factor in COCs that regulates GLYT1 activity.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"97-108"},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810365","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}