Cause Of Male Infertility Research Articles

The Effect of Scrotal PRP Injection on Testes Function and Spermatogenesis Resumed in Azoospermia Mice Model Caused by Chronic Hyperthermia.

Infertility is an important health concern that affects around 15% of couples, 40-50% of infertile cases are because of malefactors. Azoospermia is known as one of the important causes of male infertility. PRP is an autologous source of growth factors used in various therapeutic strategies. In the present study, PRP was injected into mice scrotum, after induced azoospermia caused by scrotal hyperthermia, and then therapeutic effects were evaluated. 24 adult male mice were divided into 4 groups: Control, Azoospermia (model induced by scrotal hyperthermia every other day after anesthesia for 35 days), and ketamine/xylazine (Ket/Xi) (to assess the probable effect of anesthesia), PRP (injected 10ul of PRP in the scrotum of azoospermia mice) after 16 days animals were anesthetized and sacrificed. Plasma testosterone, seminiferous diameter, oxidative stress, and sperm parameters were evaluated. Plasma testosterone level in the Azoospermia group significantly decreased and PRP treatment improved it. Also, the testicular tissue showed impairment, and oxidative stress levels increased in the testes in the Azoospermia group and PRP treatment ameliorated them. Spermatogenesis completely arrested after scrotal hyperthermia that after treatment with PRP, resumed. PRP injection in the scrotum resumed spermatogenesis and increased the production of testosterone, reduced the oxidative stress level in the testicular tissue, and resumed sperm production. PRP shows promise in promoting testicular recovery following hyperthermia-induced damage.

TMC7 is required for spermiogenesis and male fertility by regulating TGN-derived vesicles.

TMC7 is required for spermiogenesis and male fertility by regulating TGN-derived vesicles.

Analysis of genes implicated in non-obstructive azoospermia.

Analysis of genes implicated in non-obstructive azoospermia.

Recent Guidelines and Perspectives for Varicocele: A Clinical Consensus and Recommendations from the Korean Society for Sexual Medicine and Andrology.

Varicocele is a common urological disease and varicocele has long been recognized as a condition that could affect male fertility. Although varicocele is the most common surgically correctable cause of male infertility, not all varicoceles require treatment. Because the appropriate diagnosis and management of varicoceles remain less clear in many patients, it is important to diagnose clinically significant varicoceles that can benefit from treatment. Even in the era of widespread assisted reproductive techniques, varicocele has substantial implications in infertility treatment. The Korean Society for Sexual Medicine and Andrology (KSSMA) has sought to develop guidelines for varicocele treatment tailored to clinical practices in Korea. This review summarizes the latest evidence for varicocele treatment, including clinical practice guidelines from various international professional societies, and represents the consensus opinion of experts within the KSSMA.

X-Linked Gene Dosage and SOX2 Act as Key Roadblocks for Human Germ Cell Specification in Klinefelter Syndrome.

Klinefelter syndrome (KS), characterized by the presence of at least one extra X-chromosome, is a common cause of male infertility. However, the mechanism underlying the failure of germline specification is not well studied. Intriguingly, the differentiation efficiency of female human pluripotent stem cells (hPSCs)is often lower than that of male. This study investigates how X-linked gene dosage affects human primordial germ cell-like cells (hPGCLCs)specification in both healthy and diseased conditions. This work reveals that X-linked genes play a multifaceted role against the fate competency to hPGCLCs, with escape genes IGSF1 and CHRDL1 inhibiting the TGF-beta/Activin A and BMP pathways, respectively. Notably, this work identifies a previously unrecognized role of SOX2, upregulated by the escape gene USP9X, elucidating a species-specific function in the mammalian germline. The USP9X-SOX2 regulatory axis profoundly influenced cellular metabolism, mitochondrial morphology, and progenitor competence in hPGCLCs specification. Furthermore, the inability to downregulate SOX2 and upregulate SOX17 in response to BMP signaling impedes downstream gene activation due to motif binding competition. These findings shed novel insights into the human germline specification by elucidating the divergent roles of SOX2 versus SOX17 in mammals, influenced by X-linked gene dosage effects. These results offer potential applications for improving the induction efficiency of hPGCLCs, facilitating disease mechanistic studies.

Development of a predictive nomogram for testicular sperm extraction outcomes in patients with non-obstructive azoospermia using testicular volume, follicle-stimulating hormone levels, and testosterone levels as key parameters.

Non-obstructive azoospermia (NOA) is a prevalent cause of male infertility, characterized by the lack of sperm in the ejaculate due to impaired spermatogenesis. Accurate prediction of testicular sperm extraction (TESE) outcomes is pivotal for counseling and managing patients, yet remains challenging due to variability in clinical presentations. This study aimed to establish a predictive model for TESE outcomes in patients with NOA. We retrospectively analyzed 425 patients who visited the Andrology Outpatient Clinic of the First Affiliated Hospital of Soochow University between January 2010 and January 2024. Of these, 216 had positive sperm retrieval, and 209 had negative outcomes. We compared testicular volume, reproductive hormone levels, and other clinical parameters between two groups. Multivariate logistic regression was used to identify independent risk factors that were used to establish a predictive nomogram. A calibration curve was used to evaluate the model's fit, whereas receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to assess diagnostic effectiveness and net benefit. The differences were significant in serum follicle-stimulating hormone (FSH) (P<0.001), body mass index (P=0.04), elastase levels (P=0.005), and testicular microlithiasis levels (P=0.005) between the groups. Multivariate regression identified FSH (P<0.001), testicular volume (P<0.001), and testosterone levels (P=0.003) as independent risk factors for TESE outcomes. FSH levels were negatively correlated [odds ratio (OR) =0.905, 95% confidence interval (CI): 0.876-0.935, P<0.001], while testicular volume (OR =1.453, 95% CI: 1.328-1.591, P<0.001) and testosterone (OR =1.326, 95% CI: 1.098-1.601, P=0.003) were positively correlated. Nomogram based on these factors showed a good fit with an area under the ROC curve of 0.879. The DCA plot demonstrated substantial clinical benefits. In patients with NOA, low testicular volume, low testosterone levels, and high FSH levels were independent risk factors for unsuccessful TESE. The predictive nomogram provided excellent predictive power for positive TESE outcomes.

Contributions to Rare Phenotypes in Klinefelter Syndrome

Purpose: Klinefelter Syndrome (47, XXY) and Y chromosome microdeletions are the most common causes of male infertility. We aimed to evaluate the most common genetic and non-genetic factors that causes male infertility in our region. Material and Methods: In this current study, 58 patients diagnosed with azoospermia/oligozoospermia were invited to the polyclinic and 2 ml peripheral blood samples were collected. Genotyping was performed following the isolation of genomic DNA from peripheral blood samples of patients who accepted to participate in our study. Results: We found that high follicle stimulating hormone (FSH) value can be used as a predictive factor in azoospermia. We successfully revealed the potential of Klinefelter Syndrome (3.2%) but no Y chromosome microdeletions are responsible for primary male infertility. A patient with KS that having not only short height but also not-enlarged breasts were detected. Conclusion: Physicians must be aware of unexpected features such as short stature may accompanied to KS in adult patients with untreated growth hormone. Non-genetic factors such as varicocele (28%) and smoking (28%) may have more potentials to explain primary infertility in our region.

Acupuncture mediates the "gut-testis axis" to improve asthenozoospermia.

Asthenozoospermia is a common cause of male infertility. Studies have shown that sperm quality and motility are affected by the gut-testis axis that can regulate testicular metabolism and function through the gut microbiota and its metabolites. Acupuncture is an important modality of complementary and alternative medicine. It can improve sperm motility, but it remains unclear whether acupuncture can enhance sperm vitality by influencing the gut-testis axis. In this study, sperm quality, testicular pathology, and serum hormone levels were assessed using a cyclophosphamide-induced mouse model. Real-time PCR, a western blot analysis, and immunofluorescence techniques were used to assess the effects of acupuncture on the gut barrier and blood-testis barrier functions. In addition, gut microbiome and metabolomics were used to study the impact of acupuncture on the gut microbiota structure, serum, and testicular metabolites in asthenozoospermic mice. Further validation was obtained by performing a fecal microbiota transplantation (FMT). Acupuncture improved the sperm quality; ameliorated testicular pathology; increased serum testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels; and repaired gut and blood-testis barrier damage in asthenozoospermic mice. The abundances of Bacteroidota, Firmicutes, Faecalibaculum, and Dubosiella were associated with sperm motility, as shown by a gut microbiome analysis. Serum metabolomics revealed that differentially expressed metabolites (DEMs), such as cytosine and N-oleyl-leucine, were closely related to sperm motility. Testicular metabolomics analysis revealed DEMs, such as 5-fluorouridine and 1-acetylimidazole, were also associated with sperm motility. Furthermore, reproductive function improvements in asthenozoospermic mice through acupuncture were achieved via an FMT. Acupuncture may alleviate asthenozoospermia symptoms by modulating the gut-testis axis and repairing the gut-testis barrier.

Порушення іонтранспортувальних процесів у сперматозоїдах неплідних чоловіків

During the study of the plasma membrane of spermatozoa and its organelles, a great variety of specifically localized ion channels, exchangers, and ATPases was discovered. Although the activity of ion channels and membrane transporters has been studied in detail, their involvement in the mechanisms leading to the dysfunction of male germ cells remains insufficiently elucidated. Numerous scientific works show that the absence of certain transport systems of the plasma membrane due to genetic mutations or their low activity leads to a decrease or loss of sperm motility, morphological changes that worsen the quality of sperm, and is the cause of male infertility. The review examines some ion transport systems that maintain resting membrane potential and ion homeostasis in spermatogenesis. It notes the possibility of using ion channels and membrane transporters as markers to establish the functionality of spermatozoa or as molecular targets for drugs in the treatment of male infertility.

CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility

Defects in motile cilia and flagella lead to motile ciliopathies, including primary ciliary dyskinesia (PCD), which manifests as multi-organ dysfunction such as hydrocephalus, infertility, and respiratory issues. CFAP65 variants are a common cause of male infertility, but its localization and function have remained unclear. In this study, we systematically evaluated CFAP65’s role using Cfap65 knockout mice and human patients with CFAP65 variants. The knockout mice displayed severe sperm flagellar defects (MMAF), high hydrocephalus incidence, but no significant impact on respiratory cilia. Similarly, the patients exhibited MMAF and infertility without respiratory symptoms. CFAP65 was found to anchor at the base of the C2a projection of the axoneme, interacting with proteins such as CFAP70 and MYCBPAP. Loss of CFAP65 caused disorganization of the sperm head-shaping microtubule structure and impaired protamine precursor removal, leading to nuclear condensation defects and poor assisted reproductive outcomes. Importantly, the assembly of CFAP65 was unaffected in mice with defects in the radial spokes (RSs) and nexin-dynein regulatory complex (N-DRC), indicating that CFAP65 assembly is independent of these components. However, CFAP65 deficiency led to the disintegration of the C2a projection, compromising ciliary and flagellar integrity. These findings establish CFAP65 as an essential component of the C2a projection, critical for the structure and function of sperm flagella and ependymal cilia, but not respiratory cilia, underscoring the organ-specific consequences of C2a projection defects in PCD.Graphical abstract

Correlation between seminal α-glycerylphosphorylcholine and semen parameters in infertile patients pre- and post-sub-inguinal micro-varicocelectomy: a prospective study.

Varicocele (Vx) which is the most treatable cause of male infertility, is also associated with low sperm count, decreased sperm motility and increased sperm abnormal morphology. We aimed in the current study to evaluate the correlation between seminal α-Glycerylphosphorylcholine (αGPC) and semen parameters in infertile patients pre- and post- sub-inguinal micro-varicocelectomy. The current comparative prospective study was carried out on 20 male patients who presented to Kasr Al-AinyHospitals from March 2022 to March 2023 as well as 20 healthy controls. The participants were divided into groups as follows: group (1) included fertile normozoospermic men (n = 20) who served as controls. Group (2) included infertile oligoasthenoteratozoospermia (OAT) men with varicocele (n = 20). Patients in group (2) were followed up to 3 months after microsurgicalsub-inguinal Varicocelectomy. The examination included an assessment of Vx with scrotal Duplex. Semen analysis wasdone according to the 5thEdition of WHO manual for semenanalysis. The study demonstrates that αGPC level was significantly higher among fertile normozoospermic control group andinfertile OAT men post varicocelectomy when compared to infertile OAT men preoperative (p<0.001). Moreover, it demonstrates that on follow up of infertile OAT group 3 months after sub-inguinal micro-varicocelectomy, all semen parametersshowed significant improvement compared to the corresponding semen parameters pre-operatively among Vxs grade II andgrade III (p<0.001, p<0.001, respectively). A significant positive correlation was found between αGPC level and semen parameters including sperm normal forms, sperm count andsperm motility. Using ROC curve, αGPC protein showed a sensitivity of (100%) and a specificity of (100%) at cut off value(≤ 1.975 pg/ml) in differentiation between infertile OAT patients with Vx and control fertile normozoospermic men (p<0.001). αGPC may play an important role in infertility in men with Vx and correction of Vx improves the seminal αGPC level.

Gallic acid mitigates lipopolysaccharide-induced testicular inflammation via regulation of the NF-κB and PK2/PKR1 pathway.

Genital tract infections are common causes of male infertility, and most of diagnosed men are asymptomatic. This study examined the effect of gallic acid (GA) against lipopolysaccharide (LPS)-induced testicular inflammation. Thirty-two Spraque Dawley, 2.5-3 month-old male rats were separated into four groups (n = 8). Control group; saline at 3ml/kg, and in the GA group; GA was dissolved in saline, by gavage at 100mg/kg for 14 days. LPS group; LPS 5mg/kg as a single dose was given intraperitoneal on the 11th day. LPS + GA group; GA was given for 14 days and LPS 5mg/kg on the 11th day. After 72h of LPS injection, all samples were collected. Semen analysis, biochemical assays, histological evaluations, and immunohistochemical or Western blot analyses for nuclear factor-kappa B (NF-κB) and Prokineticin 2/prokineticin receptor 1(PK2/PKR1) pathways were performed. There was a significant decrease in body and testicular weight, sperm parameters, serum testosterone level, mean seminiferous tubule diameter, germinal epithelial thickness, and Johnsen score in the LPS group compared to control and GA groups. However, a significant increase was found in interstitial space width, percentage of abnormal sperm, NF-κB and PK2 immunoreactivities, and expression of PK2 and PKR1 proteins. In the LPS + GA group, GA administration was observed to significantly prevent these adverse effects. In conclusion, the inhibitory effects of GA on the NF-κB and PK2/PKR1 pathways not only suppressed the inflammatory response but also restored impaired sperm parameters and testicular structure. These findings indicate GA's potential for treating testicular inflammation and protecting male reproductive health.

Integrative Analysis of Whole-Genome and Transcriptomic Data Reveals Novel Variants in Differentially Expressed Long Noncoding RNAs Associated with Asthenozoospermia.

Background/Objectives: Asthenozoospermia, characterized by reduced sperm motility, is a common cause of male infertility. Emerging evidence suggests that noncoding RNAs, particularly long noncoding RNAs (lncRNAs), play a critical role in the regulation of spermatogenesis and sperm function. Coding regions have a well-characterized role and established predictive value in asthenozoospermia. However, this study was designed to complement previous findings and provide a more holistic understanding of asthenozoospermia, this time focusing on noncoding regions. This study aimed to identify and prioritize variants in differentially expressed (DE) lncRNAs found exclusively in asthenozoospermic men, focusing on their impact on lncRNA structure and lncRNA-miRNA-mRNA interactions. Methods: Whole-genome sequencing (WGS) was performed on samples from asthenozoospermic and normozoospermic men. Additionally, an RNA-seq dataset from normozoospermic and asthenozoospermic individuals was analyzed to identify DE lncRNAs. Bioinformatics analyses were conducted to map unique variants on DE lncRNAs, followed by prioritization based on predicted functional impact. The structural impact of the variants and their effects on lncRNA-miRNA interactions were assessed using computational tools. Gene ontology (GO) and KEGG pathway analyses were employed to investigate the affected biological processes and pathways. Results: We identified 4173 unique variants mapped to 258 DE lncRNAs. After prioritization, 5 unique variants in 5 lncRNAs were found to affect lncRNA structure, while 20 variants in 17 lncRNAs were predicted to disrupt miRNA-lncRNA interactions. Enriched pathways included Wnt signaling, phosphatase binding, and cell proliferation, all previously implicated in reproductive health. Conclusions: This study identifies specific variants in DE lncRNAs that may play a role in asthenozoospermia. Given the limited research utilizing WGS to explore the role of noncoding RNAs in male infertility, our findings provide valuable insights and a foundation for future studies.

Lower Semen Quality Among Men in the Modern Era-Is There a Role for Diet and the Microbiome?

The prevalence of infertility is increasing worldwide; poor nutrition, increased sedentary lifestyles, obesity, stress, endocrine-disrupting chemicals, and advanced age of childbearing may contribute to the disruption of ovulation and influence oocyte and sperm quality and overall reproductive health. Historically, infertility has been primarily attributed to female factors, neglecting the importance of male fertility; this has resulted in an incomplete understanding of reproductive health. Male factors account for 40-50% of infertility cases. In half of these cases, the proximal cause for male infertility is unknown. Sperm contributes half of the nuclear DNA to the embryo, and its quality is known to impact fertilisation rates, embryo quality, pregnancy rates, risk of spontaneous miscarriage, de novo autosomal-dominant conditions, psychiatric and neurodevelopment conditions, and childhood diseases. Recent studies have suggested that both the microenvironment of the testes and diet quality may play an important role in fertility; however, there is limited research on the combination of these factors. This review summarises current known causes of male infertility and then focuses on the potential roles for diet and the seminal microbiome. Future research in this area will inform dietary interventions and health advice for men with poor semen quality, potentially alleviating the need for costly and invasive assisted reproduction treatments and allowing men to take an active role in the fertility conversation which has historically focussed on women individually.

A recurrent loss-of-function variant in DRC1 causes non-syndromic severe asthenozoospermia with favorable intracytoplasmic sperm injection and pregnancy outcomes.

Asthenozoospermia, characterized by reduced sperm motility, is a common cause of male infertility. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe and genetically heterogeneous form of asthenozoospermia. Over 50 genes have been associated, but approximately half of MMAF cases remain unexplained. DRC1, a gene involved in the nexin-dynein regulatory complex (N-DRC), has been linked to MMAF and primary ciliary dyskinesia (PCD), often with significant variability in clinical presentation. His study aimed to identify novel pathogenic DRC1 variants in MMAF patients, assess their impact on sperm flagellar structure, and evaluate intracytoplasmic sperm injection (ICSI) and pregnancy outcomes. A cohort of 196 non-syndromic MMAF patients was analyzed using whole exome sequencing (WES). Functional validation of candidate variants included immunofluorescence to assess protein expression and transmission electron microscopy (TEM) to identify ultrastructural abnormalities. Assisted reproductive therapy outcomes were also evaluated. WES identified a recurrent homozygous frameshift variant in DRC1 NM_145038.5: c.109dup; p.(Gln37ProfsTer30) in four patients (2%), all of North African origin, none of whom suffer from PCD-related symptoms. The variant caused a complete absence of DRC1 protein in spermatozoa. TEM showed flagellar abnormalities, with 10% of axonemal sections revealing peripheral doublet dissociation, suggesting N-DRC instability. ICSI resulted in a 68.5% fertilization rate, with three out of four couples successfully delivering healthy children. The identification of a novel and recurrent pathogenic DRC1 variant broadens the mutation spectrum associated with MMAF. The absence of systemic PCD symptoms suggests that DRC1 deficiency may primarily affect spermatogenesis. Notably, the phenotypic spectrum might be influenced by the genetic background, varying across populations. Favorable ICSI outcomes, with a 68.5% fertilization rate and successful pregnancies in three out of four couples, highlight the effectiveness of assisted reproductive techniques for patients with this genetic defect.

Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.

The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.

Development of the membrane ceiling method for in vitro spermatogenesis

Spermatogenesis is one of the most complex processes of cell differentiation and its failure is a major cause of male infertility. Therefore, a proper model that recapitulates spermatogenesis in vitro has been long sought out for basic and clinical research. Testis organ culture using the gas-liquid interphase method has been shown to support spermatogenesis in mice and rats. However, the conventional method using agarose gel has limitations including medium replacement efficiency and live imaging because agarose absorbs medium and is not transparent. To overcome this issue, we developed a new device using microporous membranes and oxygen-permeable materials. Mouse testes sandwiched between a microporous polyethylene terephthalate (PET) membrane on top and an oxygen-permeable 4-polymethyl-1-pentene polymer (PMP) membrane base maintained spermatogenesis over months. The chamber volume was minimized to 0.1% of the culture medium. Weekly time-lapse live imaging enabled us to observe transgenically fluorescent acrosome and nuclear shape formation throughout spermatogenesis. Finally, we obtained healthy fertile offspring from spermatozoa generated in our system. The device could be used not only for basic research to understand spermatogenesis but also for applied research, such as diagnosing and treating male infertility.

Progress in the Study of TAp73 and Sperm Apoptosis.

The study of the mechanism of oligoasthenospermia, which is a major cause of male infertility, has been the focus of research in the field of male reproduction. TAp73, a member of the p53 family of oncogenes, is endowed with tumor-suppressing activity due to its structural and functional homology with p53. It has been found that TAp73, plays a key role in spermatogenesis and maintaining male reproduction. When TAp73 is low-expressed or absent, the process of spermatogenesis is severely impaired, and mice deficient in TAp73 exhibit spermatogonial DNA damage, disturbed apical cytoplasmic specialization, and spermatocyte malformations resulting in reduced male fertility. Nevertheless, when TAp73 is overexpressed, it not only drives exogenous death receptors to regulate germ cell apoptosis, but also interacts with its various substrate proteins to promote the translocation of cytoplasmic Bax proteins to the mitochondria, resulting in the upregulation of the Bax/Bcl-2 ratio on the mitochondrial membrane and triggering a series of mitochondrial apoptotic effects. In this article, we will analyze the mechanism of TAp73 and sperm apoptosis, and elaborate the mechanism of TAp73 upregulation, exogenous apoptosis pathway and mitochondrial apoptosis pathway to systematically explain that the process of apoptosis induced by high expression of TAp73 is not fixed and single, but is interconnected, so as to provide a basis for the treatment of oligoasthenospermia and the research and development of new drugs using TAp73 as a target.

Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation.

Severe oligoasthenospermia (SOA) is a prevalent cause of male infertility. However, the underlying causes of most SOA cases remain unclear due to the complexity of germ cell development and the significant genetic heterogeneity associated with male infertility. Therefore, in this study, we aimed to elucidate the genetic etiology of two cases of male infertility resulting from SOA and clarify the novel clinical phenotype associated with a heterozygous mutation at the c.346-1G>A site of the SOHLH1 gene. Through whole-exome sequencing, we found that patients with SOA carried heterozygous mutations at the c.346-1G>A site. This variant is classified as pathogenic based on disease database records and literature reports. Notably, our study demonstrated that patients with heterozygous mutations at the c.346-1G>A site exhibited severely reduced sperm counts, significantly impaired sperm motility, and pronounced morphological deformities. One patient underwent assisted reproductive treatment through an intracytoplasmic sperm injection and achieved a favorable outcome, resulting in a successful pregnancy. In conclusion, our study provides the first evidence that the heterozygous mutation at the c.346-1G>A site of SOHLH1 is associated with SOA, and elucidates the new clinical phenotype associated with this mutation.

Perspective in the Mechanisms for Repairing Sperm DNA Damage.

DNA damage in spermatozoa is a major cause of male infertility. It is also associated with adverse reproductive outcomes (including reduced fertilization rates, embryo quality and pregnancy rates, and higher rates of spontaneous miscarriage). The damage to sperm DNA occurs during the production and maturation of spermatozoa, as well as during their transit through the male reproductive tract. DNA damage repair typically occurs during spermatogenesis, oocytes after fertilization, and early embryonic development stages. The known mechanisms of sperm DNA repair mainly include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). The most severe type of sperm DNA damage is double-strand break, and it will be repaired by DSBR, including homologous recombination (HR), classical non-homologous end joining (cNHEJ), alternative end joining (aEJ), and single-strand annealing (SSA). However, the precise mechanisms of DNA repair in spermatozoa remain incompletely understood. DNA repair-associated proteins are of great value in the repair of sperm DNA. Several repair-related proteins have been identified as playing critical roles in condensing chromatin, regulating transcription, repairing DNA damage, and regulating the cell cycle. It is noteworthy that XRCC4-like factor (XLF) and paralog of XRCC4 and XLF (PAXX) -mediated dimerization promote the processing of populated ends for cNHEJ repair, which suggests that XLF and PAXX have potential value in the mechanism of sperm DNA repair. This review summarizes the classic and potential repair mechanisms of sperm DNA damage, aiming to provide a perspective for further research on DNA damage repair mechanisms.