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EBioMedicine Oct 2023Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the...
BACKGROUND
Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia.
METHODS
One-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography-mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients.
FINDINGS
We identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes.
INTERPRETATION
Defects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.
FUNDING
The National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).
Topics: Humans; Pregnancy; Female; Male; Animals; Mice; Asthenozoospermia; Nucleotides; Semen; Spermatozoa; Infertility, Male
PubMed: 37713809
DOI: 10.1016/j.ebiom.2023.104798 -
Journal of Endocrinological... Feb 2024Human papillomavirus (HPV) infection is the most common sexually transmitted disease, in males and females worldwide. While the role of HPV in female diseases is well... (Review)
Review
PURPOSE
Human papillomavirus (HPV) infection is the most common sexually transmitted disease, in males and females worldwide. While the role of HPV in female diseases is well known and largely studied, males have negligibly been included in these programs, also because the proportion of women suffering and dying from HPV-related diseases is much larger than men. The aim of this review is to focus on HPV-related diseases in male patients.
METHODS
We performed a literature analysis on the electronic database PubMed. We considered randomized trials, observational and retrospective studies, original articles having as topic the relationship between HPV male infection and the following items: oral, anal penile cancers, warts, condylomas, male infertility, altered sperm parameters, anti-sperm antibodies (ASA). We also included experimental in vitro studies focused on the effects of HPV infection on oocyte fertilization, blastocyst development, and trophoblastic cell invasiveness. In addition, studies describing the adjuvant administration of the HPV vaccination as a possible strategy to promote HPV clearance from semen in infected males were included.
RESULTS
Regarding head and neck HPV-related diseases, the most important non-neoplastic disease is recurrent respiratory papillomatosis (RRP). Regarding neoplastic diseases, the proportion of head and neck cancers attributable to HPV has increased dramatically worldwide. In addition, nowadays, it is thought that half of head and neck squamous cell carcinomas (HNSCCs) cases in the United States are caused by infection with high-risk HPV. HPV is noteworthy in andrological practice too. It was described as having a high HPV prevalence, ranging between 50 and 70%, in male penile shaft, glans penis/coronal sulcus, semen as well as in scrotal, perianal, and anal regions. Moreover, in male patients, HPV infection has been associated, among other diseases, with penile cancers. HPV semen infection has been reported in about 10% in men from the general population and about 16% in men with unexplained infertility, although these data seem widely underestimated according to clinical experience. In particular, HPV semen infection seems to be most related to asthenozoospermia and to anti-sperm antibodies (ASAs).
CONCLUSIONS
HPV infection represents a health problem with a detrimental social and public impact. Despite this evidence, little has been done to date to widely promote vaccination among young males.
Topics: Humans; Male; Female; Papillomavirus Infections; Penile Neoplasms; Semen; Retrospective Studies; Spermatozoa; Antibodies
PubMed: 37770654
DOI: 10.1007/s40618-023-02192-3 -
Human Reproduction Open 2023Are dietary fat and fatty acid (FA) intakes related to the odds of asthenozoospermia?
STUDY QUESTION
Are dietary fat and fatty acid (FA) intakes related to the odds of asthenozoospermia?
SUMMARY ANSWER
Plant-based fat consumption was associated with decreased asthenozoospermia odds, while the consumption of animal-based monounsaturated fatty acid (MUFA) was positively related to asthenozoospermia odds.
WHAT IS KNOWN ALREADY
Dietary fat and FA are significant ingredients of a daily diet, which have been demonstrated to be correlated to the reproductive health of men. However, to date, evidence on fat and FA associations with the odds of asthenozoospermia is unclear.
STUDY DESIGN SIZE DURATION
The hospital-based case-control study was performed in an infertility clinic from June 2020 to December 2020. Briefly, 549 asthenozoospermia cases and 581 controls with normozoospermia were available for final analyses.
PARTICIPANTS/MATERIALS SETTING METHODS
We collected dietary data through a verified food frequency questionnaire of 110 food items. Asthenozoospermia cases were ascertained according to the World Health Organization guidelines. To investigate the correlations of dietary fat and FA consumptions with the odds of asthenozoospermia, we calculated the odds ratios (ORs) and corresponding 95% CIs through unconditional logistic regression models.
MAIN RESULTS AND THE ROLE OF CHANCE
Relative to the lowest tertile of consumption, the highest tertile of plant-based fat intake was inversely correlated to the odds of asthenozoospermia (OR = 0.68, 95% CI = 0.50-0.91), with a significant dose-response relation (OR = 0.85, 95% CI = 0.75-0.97, per standard deviation increment). Inversely, animal-based MUFA intake (OR = 1.49, 95% CI = 1.04-2.14) was significantly correlated to increased odds of asthenozoospermia, and an evident dose-response relation was also detected (OR = 1.24, 95% CI = 1.05-1.45, per standard deviation increment). Subgroup analyses showed similar patterns of associations to those of the primary results. Moreover, we observed significant interactions on both multiplicative and additive scales between animal-based MUFA and cigarette smoking.
LIMITATIONS REASONS FOR CAUTION
Selection bias and recall bias were unavoidable in any of the observational studies. As we failed to obtain the information of trans-fatty acid (TFA) consumption, the relation of TFA intake and asthenozoospermia odds was unclear.
WIDER IMPLICATIONS OF THE FINDINGS
This study indicated that different sources of fat and FAs might exert different effects on the etiology of asthenozoospermia, and cigarette smoking could exacerbate the adverse effect of high animal-based MUFA intake on asthenozoospermia. Our findings provide novel evidence pertaining to the fields of prevention of asthenozoospermia through decreasing animal-derived fat and FA consumptions and smoking cessation.
STUDY FUNDING/COMPETING INTERESTS
This work was supported by the JieBangGuaShuai Project of Liaoning Province, Natural Science Foundation of Liaoning Province, Clinical Research Cultivation Project of Shengjing Hospital, and Outstanding Scientific Fund of Shengjing Hospital. All authors have no conflict of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.
PubMed: 37547665
DOI: 10.1093/hropen/hoad030 -
Pharmaceutical Biology Dec 2023Therapeutic effects of Qiangjing tablets (QJT) on sperm vitality and asthenozoospermia (AZS) have been confirmed. However, the mechanism of action remains unclear.
CONTEXT
Therapeutic effects of Qiangjing tablets (QJT) on sperm vitality and asthenozoospermia (AZS) have been confirmed. However, the mechanism of action remains unclear.
OBJECTIVE
This study investigates the effects of QJT on AZS and the underlying mechanism of action.
MATERIALS AND METHODS
Sixty Sprague-Dawley rats were randomly divided into six groups: Control, ORN (ornidazole; 200 mg/kg), ORN + QJT-low (0.17 g/mL), ORN + QJT-middle (0.33 g/mL), ORN + QJT-high (0.67 g/mL), and ORN + QJT + Radicicol (0.67 g/mL QJT and 20 mg/kg radicicol) groups. Pathological evaluation and analysis of mitophagy were conducted by H&E staining and transmission electron microscopy, respectively. Reactive oxygen species were detected by flow cytometry. Protein expression was determined by Western blotting.
RESULTS
QJT significantly improved ORN-treated sperm motility and kinematic parameters, as well as the pathological symptoms of testicular and epididymal tissues. In particular, QJT mitigated impaired mitochondrial morphology, and increased the PHB, Beclin-1, LC3-II protein, and ROS levels ( < 0.05), and reduced the protein expression levels of LC3-I and p62 ( < 0.05). Mechanistically, QJT antagonized the downregulation of SCF and Parkin protein levels ( < 0.05). Furthermore, QJT significantly increased the protein expressions levels of LKB1, AMPKα, p-AMPKα, ULK1 and p-ULK1 ( < 0.05). The ameliorative effect of QJT on pathological manifestations, mitochondrial morphology, and the expressions of mitophagy and mitochondrial ubiquitination-related proteins was counteracted by radicicol.
DISCUSSION AND CONCLUSIONS
QJT improved AZS mitochondrial ubiquitination and mitophagy mediated by the LKB1/AMPK/ULK1 signaling pathway. Our study provides a theoretical basis for the treatment of AZS and male infertility.
Topics: Animals; Male; Rats; AMP-Activated Protein Kinases; Asthenozoospermia; Autophagy-Related Protein-1 Homolog; Drugs, Chinese Herbal; Intracellular Signaling Peptides and Proteins; Mitophagy; Rats, Sprague-Dawley; Semen; Sperm Motility; Tablets; Ubiquitination
PubMed: 36655371
DOI: 10.1080/13880209.2023.2168021 -
ELife Nov 2023Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the...
Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygous variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using the model. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygous variants. Co-immunoprecipitation and ultrastructure expansion microscopy in revealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples from and KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and . ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.
Topics: Humans; Male; Animals; Mice; Asthenozoospermia; Semen; Flagella; Infertility, Male; Fertility; Calcium-Binding Proteins; Dyneins
PubMed: 37934199
DOI: 10.7554/eLife.87698 -
Journal of Cellular and Molecular... Apr 2024Oligoasthenoteratospermia (OAT), characterized by abnormally low sperm count, poor sperm motility, and abnormally high number of deformed spermatozoa, is an important...
Oligoasthenoteratospermia (OAT), characterized by abnormally low sperm count, poor sperm motility, and abnormally high number of deformed spermatozoa, is an important cause of male infertility. Its genetic basis in many affected individuals remains unknown. Here, we found that CCDC157 variants are associated with OAT. In two cohorts, a 21-bp (g.30768132_30768152del21) and/or 24-bp (g.30772543_30772566del24) deletion of CCDC157 were identified in five sporadic OAT patients, and 2 cases within one pedigree. In a mouse model, loss of Ccdc157 led to male sterility with OAT-like phenotypes. Electron microscopy revealed misstructured acrosome and abnormal head-tail coupling apparatus in the sperm of Ccdc157-null mice. Comparative transcriptome analysis showed that the Ccdc157 mutation alters the expressions of genes involved in cell migration/motility and Golgi components. Abnormal Golgi apparatus and decreased expressions of genes involved in acrosome formation and lipid metabolism were detected in Ccdc157-deprived mouse germ cells. Interestingly, we attempted to treat infertile patients and Ccdc157 mutant mice with a Chinese medicine, Huangjin Zanyu, which improved the fertility in one patient and most mice that carried the heterozygous mutation in CCDC157. Healthy offspring were produced. Our study reveals CCDC157 is essential for sperm maturation and may serve as a marker for diagnosis of OAT.
Topics: Animals; Humans; Male; Mice; Asthenozoospermia; Infertility, Male; Mice, Knockout; Mutation; Oligospermia; Semen; Sperm Motility; Spermatozoa; Membrane Proteins
PubMed: 38509755
DOI: 10.1111/jcmm.18215 -
Scientific Reports Apr 2024The relationship between oxygen sensing and autophagy in human sperms was explored in this study. Health semen and asthenozoospermia (astheno) semen were incubated with...
The relationship between oxygen sensing and autophagy in human sperms was explored in this study. Health semen and asthenozoospermia (astheno) semen were incubated with hypoxia-inducible factor-1α (HIF-1α) interferents, i.e., lificiguat (YC-1) or cobalt chloride (CoCl), respectively. Label-free quantitative proteomic technology was used to identify the differentially expressed proteins in human semen under the hypoxia condition. Selected proteins were detected with ELISA. It was found that the autophagy levels of sperm in the YC-1 + health group or CoCl + astheno group increased while the vitality decreased. A total of 17, 34 and 35 differentially expressed proteins were observed in the Astheno group, the YC-1 + health group and the CoCl + astheno group, respectively. These proteins were primarily associated with protein processing in endoplasmic reticulum, Th17 cell differentiation, progesterone-mediated oocyte maturation, glycolysis/gluconeogenesis, HIF-1 signaling pathway, biosynthesis of amino acids, and carbon metabolism. The expression levels of protein HIF-1α, LC3B, histone H4, cathepsin L and ENO1 changed significantly in the groups. The study suggests that hypoxia can increase sperm autophagy level and reduce their vitality through HIF-1 signaling pathway and glycolysis/gluconeogenesis signaling pathway. Furthermore, proteins histone H4, cathepsin L, glutathione synthetase and ENO1 are proposed as potential biomarkers of autophagy and vitality in asthenozoospermia sperm.
Topics: Humans; Male; Cathepsin L; Histones; Cell Hypoxia; Asthenozoospermia; Proteomics; Semen; Hypoxia; Cobalt; Autophagy; Spermatozoa; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38605082
DOI: 10.1038/s41598-024-59213-1 -
The Journal of Biological Chemistry Jul 2023Asthenozoospermia characterized by decreased sperm motility is a major cause of male infertility, but the majority of the etiology remains unknown. Here, we showed that...
Asthenozoospermia characterized by decreased sperm motility is a major cause of male infertility, but the majority of the etiology remains unknown. Here, we showed that the cilia and flagella associated protein 52 (Cfap52) gene was predominantly expressed in testis and its deletion in a Cfap52 knockout mouse model resulted in decreased sperm motility and male infertility. Cfap52 knockout also led to the disorganization of the midpiece-principal piece junction of the sperm tail but had no effect on the axoneme ultrastructure in spermatozoa. Furthermore, we found that CFAP52 interacted with the cilia and flagella associated protein 45 (CFAP45) and knockout of Cfap52 decreased the expression level of CFAP45 in sperm flagellum, which further disrupted the microtubule sliding produced by dynein ATPase. Together, our studies demonstrate that CFAP52 plays an essential role in sperm motility by interacting with CFAP45 in sperm flagellum, providing insights into the potential pathogenesis of the infertility of the human CFAP52 mutations.
Topics: Animals; Humans; Male; Mice; Cilia; Flagella; Infertility, Male; Mice, Knockout; Proteins; Semen; Sperm Motility; Sperm Tail; Spermatozoa
PubMed: 37236356
DOI: 10.1016/j.jbc.2023.104858 -
Frontiers in Endocrinology 2023Asthenoteratozoospermia is one of the most common causes of male infertility. Several genes have been identified as genetic causative factors, but there is a...
INTRODUCTION
Asthenoteratozoospermia is one of the most common causes of male infertility. Several genes have been identified as genetic causative factors, but there is a considerable genetic heterogeneity underlying asthenoteratozoospermia. In this study, we performed a genetic analysis of two brothers from a consanguineous Uighur family in China to identify gene mutations causative for asthenoteratozoospermia-related male infertility.
METHODS
Two related patients with asthenoteratozoospermia from a large consanguineous family were sequenced by whole-exome sequencing and Sanger sequencing to identify disease-causing genes. Scanning and transmission electron microscopy analysis revealed ultrastructural abnormalities of spermatozoa. Quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence (IF) analysis were used to assess the expression of the mutant messenger RNA (mRNA) and protein.
RESULTS
A novel homozygous frameshift mutation (c.2823dupT, p.Val942Cysfs*21) in was identified in both affected individuals and was predicted to be pathogenic. Papanicolaou staining and electron microscopy revealed multiple morphological and ultrastructural abnormalities of affected spermatozoa. qRT-PCR and IF analysis showed abnormal expression of DNAH6 in affected sperm, probably due to premature termination code and decay of abnormal 3' untranslated region (UTR) region of mRNA. Furthermore, intracytoplasmic sperm injection could achieve successful fertilization in infertile men with mutations.
DISCUSSION
The novel frameshift mutation identified in DNAH6 may contribute to asthenoteratozoospermia. These findings expand the spectrum of genetic mutations and phenotypes associated with asthenoteratozoospermia and may be useful for genetic and reproductive counseling in male infertility.
Topics: Humans; Male; Asthenozoospermia; Frameshift Mutation; Infertility, Male; RNA, Messenger; Semen; Sperm Tail; Dyneins
PubMed: 37424858
DOI: 10.3389/fendo.2023.1122004 -
JBRA Assisted Reproduction Jun 2024Infertility is a widespread global issue that affects approximately 15% of sexually active and active couples, which contributes to about 50% of cases. Currently, the... (Review)
Review
Infertility is a widespread global issue that affects approximately 15% of sexually active and active couples, which contributes to about 50% of cases. Currently, the condition remains prevalent and often inadequately treated. This systematic review aims to evaluate existing studies investigating the effects of probiotic supplementation in men. A comprehensive search was conducted across major databases, including PubMed, Cochrane, Science Direct, and Scielo, using relevant keywords such as 'probiotic' OR 'Lactobacillus' OR 'Bifidobacterium' AND 'Male infertility' OR 'male fertility' OR 'sperm quality' OR 'sperm motility' OR 'oligoasthenoteratozoospermia' and their Portuguese equivalents. Four randomized clinical studies met the inclusion criteria, focusing on men diagnosed with idiopathic male infertility (oligozoospermia, teratozoospermia, and asthenozoospermia). The findings revealed that probiotic administration exhibited promising antioxidant properties by combating reactive oxygen species (ROS), consequently protecting sperm DNA from damage that correlates with declining sperm quality. Significant improvements were observed across all sperm parameters, with notable enhancement in motility. Consequently, probiotic supplementation emerges as a potential therapeutic alternative for men diagnosed with idiopathic infertility, demonstrating positive effects on sperm quality.
Topics: Humans; Male; Probiotics; Infertility, Male; Dietary Supplements; Sperm Motility
PubMed: 38530761
DOI: 10.5935/1518-0557.20240013