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Andrologia Apr 2021Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an evolutionarily conserved protein related to spermatozoa. To clarify its role and mechanism of action in...
Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an evolutionarily conserved protein related to spermatozoa. To clarify its role and mechanism of action in spermatozoa, qRT-PCR was used to analyse the expression of TBL1XR1 in human spermatozoa and mouse testes. The mice were established as an animal model by injecting the mice testes with small interfering RNA against TBL1XR1 or control siRNA. Our results indicated that deficiency of TBL1XR1 in mice reduced the motility of spermatozoa and disrupted the histone-to-protamine transition. We also found the decreased expression of TBL1XR1 in the spermatozoa of human patients with asthenozoospermia (AZ) compared with that in the spermatozoa of healthy males. Moreover, we carried out chromatin immunoprecipitation analyses and found that genes downstream of TBL1XR1 were related to sperm motility. Thus, TBL1XR1 might be related to sperm motility and might function through its downstream genes. Our data highlight the role of TBL1XR1 involved in spermatozoa and provide new molecular insights into the intricate systems required for male fertility.
Topics: Animals; Asthenozoospermia; Humans; Male; Mice; Nuclear Proteins; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Sperm Motility; Spermatozoa
PubMed: 33528066
DOI: 10.1111/and.13980 -
International Journal of Molecular... Apr 2022In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is... (Review)
Review
In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle that provides the mechanical force for sperm propulsion and motility. Importantly several functional maturation events that occur during the journey of the sperm cells through the genital tracts are necessary for the activation of flagellar beating and the acquisition of fertilization potential. Ion transporters and channels located at the surface of the sperm cells have been demonstrated to be involved in these processes, in particular, through the activation of downstream signaling pathways and the promotion of novel biochemical and electrophysiological properties in the sperm cells. We performed a systematic literature review to describe the currently known genetic alterations in humans that affect sperm ion transporters and channels and result in asthenozoospermia, a pathophysiological condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. We also present the physiological relevance and functional mechanisms of additional ion channels identified in the mouse. Finally, considering the state-of-the art, we discuss future perspectives in terms of therapeutics of asthenozoospermia and male contraception.
Topics: Animals; Asthenozoospermia; Female; Humans; Ion Channels; Male; Mammals; Mice; Models, Animal; Sperm Motility; Spermatozoa
PubMed: 35409285
DOI: 10.3390/ijms23073926 -
Human Reproduction (Oxford, England) Jan 2023Can new genetic factors responsible for male infertility be identified, especially for those characterized by asthenospermia despite normal sperm morphology?
STUDY QUESTION
Can new genetic factors responsible for male infertility be identified, especially for those characterized by asthenospermia despite normal sperm morphology?
SUMMARY ANSWER
We identified the novel pathogenetic gene IQ motif and ubiquitin-like domain-containing (IQUB) as responsible for male infertility characterized by asthenospermia, involving sperm radial spoke defects.
WHAT IS KNOWN ALREADY
To date, only a few genes have been found to be responsible for asthenospermia with normal sperm morphology. Iqub, encoding the IQUB protein, is highly and specifically expressed in murine testes and interacts with the proteins radial spoke head 3 (RSPH3), CEP295 N-terminal like (CEP295NL or DDC8), glutathione S-transferase mu 1 (GSTM1) and outer dense fiber of sperm tails 1 (ODF1) in the yeast two-hybrid system.
STUDY DESIGN, SIZE, DURATION
The IQUB variant was identified by whole-exome sequencing in a cohort of 126 male infertility patients with typical asthenospermia recruited between 2015 and 2020. Knockout (KO) and knockin (KI) mouse models, scanning and transmission electron microscopy (TEM), and other functional assays were performed, between 2019 and 2021.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The IQUB variant was identified by whole-exome sequencing and confirmed by Sanger sequencing. Iqub KO and KI mice were constructed to mimic the phenotype of the affected individual. After recapitulating the phenotype of human male infertility, scanning and TEM were performed to check the ultrastructure of the sperm. Western blot and co-immunoprecipitation were performed to clarify the pathological mechanism of the IQUB variant.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified a homozygous nonsense IQUB variant (NM_001282855.2:c.942T> G(p.Tyr314*)) from an infertile male. Iqub KO and KI mice mimicked the infertility phenotype and confirmed IQUB to be the pathogenetic gene. Scanning and TEM showed that sperm of both the mouse models and the affected individual had radial spoke defects. The functional assay suggested that IQUB may recruit calmodulin in lower Ca2+ environments to facilitate the normal assembly of radial spokes by inhibiting the activity of RSPH3/p-ERK1/2 (a nontypical AKAP (A-Kinase Anchoring Protein) forming by RSPH3 and phosphorylation of extracellular signal-regulated kinase 1 and 2 (p-ERK1/2)).
LIMITATIONS, REASONS FOR CAUTION
Additional cases are needed to confirm the genetic contribution of IQUB variants to male infertility. In addition, because no IQUB antibody is available for immunofluorescence and the polyclonal antibody we generated was only effective in western blotting, immunostaining for IQUB was not performed in this study. Therefore, this study lacks direct in vivo proof to confirm the effect of the variant on IQUB protein level.
WIDER IMPLICATIONS OF THE FINDINGS
Our results suggest a causal relation between IQUB variants and male infertility owing to asthenospermia, and partly clarify the pathological mechanism of IQUB variants. This expands our knowledge of the genes involved in human sperm asthenospermia and potentially provides a new genetic marker for male infertility.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the National Key Research and Development Program of China (2021YFC2700100), the National Natural Science Foundation of China (32130029, 82171643, 81971450, 82001538, and 81971382) and the Guangdong Science and Technology Department Guangdong-Hong Kong-Macao Joint Innovation Project (2020A0505140003). There are no competing interests to declare.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Male; Animals; Mice; Phosphorylation; Mitogen-Activated Protein Kinase 3; MAP Kinase Signaling System; Semen; Mice, Knockout; Infertility, Male; Spermatozoa; Asthenozoospermia
PubMed: 36355624
DOI: 10.1093/humrep/deac244 -
Asian Journal of Andrology 2020The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is a specific kind of asthenoteratozoospermia with a mosaic of flagellar morphological... (Review)
Review
The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is a specific kind of asthenoteratozoospermia with a mosaic of flagellar morphological abnormalities (absent, short, bent, coiled, and irregular flagella). MMAF was proposed in 2014 and has attracted increasing attention; however, it has not been clearly understood. In this review, we elucidate the definition of MMAF from a systematical view, the difference between MMAF and other conditions with asthenoteratozoospermia or asthenozoospermia (such as primary mitochondrial sheath defects and primary ciliary dyskinesia), the knowledge regarding its etiological mechanism and related genetic findings, and the clinical significance of MMAF for intracytoplasmic sperm injection and genetic counseling. This review provides the basic knowledge for MMAF and puts forward some suggestions for further investigations.
Topics: A Kinase Anchor Proteins; Adenylate Kinase; Animals; Asthenozoospermia; Cytoskeletal Proteins; Dyneins; Genetic Counseling; Humans; Infertility, Male; Male; Microtubule Proteins; Peptide Hydrolases; Sperm Injections, Intracytoplasmic; Sperm Tail; Teratozoospermia
PubMed: 31210147
DOI: 10.4103/aja.aja_53_19 -
Bioscience Reports Jul 2020Asthenozoospermia is one of the major causes of human male infertility. Long noncoding RNAs (lncRNAs) play critical roles in the spermatogenesis processes. The present... (Observational Study)
Observational Study
Asthenozoospermia is one of the major causes of human male infertility. Long noncoding RNAs (lncRNAs) play critical roles in the spermatogenesis processes. The present study aims to investigate the intricate regulatory network associated with asthenozoospermia. The lncRNAs expression profile was analyzed in the asthenozoospermia seminal plasma exosomes by RNA-sequencing, and the functions of differentially expressed genes (DEGs) were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and DO (Disease Ontology) enrichment analyses. Pearson's correlation test was utilized to calculate the correlation coefficients between lncRNA and mRNAs. Moreover, the lncRNA-miRNA-mRNA co-expression network was constructed with bioinformatics. From the co-expression analyses, we identified the cis regulated correlation pairs lncRNA-mRNA. To confirm sequencing results with five of the identified DElncRNAs were verified with quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We identified 4228 significantly DEGs, 995 known DElncRNAs, 2338 DEmRNAs and 11,706 novel DElncRNAs between asthenozoospermia and normal group. GO and KEGG analyses showed that the DEGs were mainly associated with metabolism, transcription, ribosome and channel activity. We found 254,981 positive correlations lncRNA-mRNA pairs through correlation analysis. The detailed lncRNA-miRNA-mRNA regulatory network included 11 lncRNAs, 35 miRNAs and 59 mRNAs. From the co-expression analyses, we identified 7 cis-regulated correlation pairs lncRNA-mRNA. Additionally, the qRT-PCR analysis confirmed our sequencing results. Our study constructed the lncRNA-mRNA-miRNA regulation networks in asthenozoospermia. Therefore, the study findings provide a set of pivotal lncRNAs for future investigation into the molecular mechanisms of asthenozoospermia.
Topics: Adult; Asthenozoospermia; Case-Control Studies; Computational Biology; Exosomes; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; MicroRNAs; RNA, Long Noncoding; RNA, Messenger; Semen; Semen Analysis; Sequence Analysis, RNA
PubMed: 32614449
DOI: 10.1042/BSR20194041 -
Scientific Reports Feb 2023Asthenozoospermia (AZS) is a severe form of male infertility with no clear pathogenesis, despite numerous research efforts, there is no consensus on this. This study was...
Asthenozoospermia (AZS) is a severe form of male infertility with no clear pathogenesis, despite numerous research efforts, there is no consensus on this. This study was to investigate the expression of gene-associated with retinoid-interferon-induced mortality 19 (GRIM-19) in the sperm of patients with asthenozoospermia and the regulation of GC-2 spd cell proliferation, apoptosis and migration. We analyzed the sperm samples from 82 asthenozoospermia and normal patients were collected in the First People's Hospital of Shangqiu and the First Affiliated Hospital of Zhengzhou University. Immunofluorescence, western blots and RT-qPCR analyses were used to verify the expressions of GRIM-19. MTT assays were used to assess cell proliferations, flow cytometry was performed to assess cell apoptosis, wound‑healing was performed to measure cell migration. Immunofluorescence showed that GRIM-19 is predominantly expressed in the sperm mid-piece, the mRNA expressions of GRIM-19 in sperms of the asthenozoospermia group were significantly low, relative to the normal group (OR 0.266; 95% CI = 0.081-0.868; P = 0.028). The protein expressions of GRIM-19 in sperms of the asthenozoospermia group were significantly lower than that of the normal group as well (GRIM-19/GAPDH: 0.827 ± 0.063 vs 0.458 ± 0.033; P < 0.001). GRIM-19 overexpression promotes GC-2 spd cell proliferation and migration and reduces apoptosis, while GRIM-19-silenced reduces GC-2 spd cell proliferation and migration and increased apoptosis. GRIM-19 is closely related to the occurrence of asthenozoospermia and promotes GC-2 spd cell proliferation and migration and reduces apoptosis.
Topics: Humans; Male; Asthenozoospermia; Semen; Apoptosis; Apoptosis Regulatory Proteins; Cell Proliferation
PubMed: 36813832
DOI: 10.1038/s41598-023-29775-7 -
Medicine Apr 2021According to the World Health Organization, the global incidence of infertility is about 15%, and more than 50% of infertility cases are caused by male infertility....
BACKGROUND
According to the World Health Organization, the global incidence of infertility is about 15%, and more than 50% of infertility cases are caused by male infertility. Asthenozoospermia is caused by male fertility decline and male infertility. Due to work pressure, environmental pollution, sexual diseases, and other factors, the number of patients with asthenozoospermia has increased in recent years. It has been confirmed that acupuncture has a certain effect on patients with asthenozoospermia. Acupuncture and moxibustion can be an adjuvant treatment plan for the treatment of asthenozoospermia in addition to drug treatment.
METHODS
Randomized controlled trials of acupuncture for asthenozoospermia will be searched in the relevant database, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), and Chinese Scientific Journal Database (VIP database). The studies of electronic searches will be exported to EndNote V.9.1 software. We will run meta-analyses using the Review Manager (RevMan) V.5.3 software. Any disagreements will be solved in consultation with a third reviewer.
RESULTS
Our study aims to explore the efficacy of acupuncture for asthenozoospermia and to provide up-to-date evidence for clinical of asthenozoospermia.
CONCLUSION
This study will perform a comprehensive systematic review and meta-analysis on the efficacy of acupuncture for asthenozoospermia, making up for the lack of relevant evidence of the clinical use of acupuncture.
INPLASY REGISTRATION NUMBER
INPLASY 202140032.
Topics: Acupuncture Therapy; Asthenozoospermia; Humans; Male; Meta-Analysis as Topic; Moxibustion; Research Design; Systematic Reviews as Topic; Treatment Outcome
PubMed: 33907155
DOI: 10.1097/MD.0000000000025711 -
Human Reproduction (Oxford, England) Jul 2023Can whole-exome sequencing (WES) reveal new genetic factors responsible for male infertility characterized by oligozoospermia?
STUDY QUESTION
Can whole-exome sequencing (WES) reveal new genetic factors responsible for male infertility characterized by oligozoospermia?
SUMMARY ANSWER
We identified biallelic missense variants in the Potassium Channel Tetramerization Domain Containing 19 gene (KCTD19) and confirmed it to be a novel pathogenic gene for male infertility.
WHAT IS KNOWN ALREADY
KCTD19 is a key transcriptional regulator that plays an indispensable role in male fertility by regulating meiotic progression. Kctd19 gene-disrupted male mice exhibit infertility due to meiotic arrest.
STUDY DESIGN, SIZE, DURATION
We recruited a cohort of 536 individuals with idiopathic oligozoospermia from 2014 to 2022 and focused on five infertile males from three unrelated families. Semen analysis data and ICSI outcomes were collected. WES and homozygosity mapping were performed to identify potential pathogenic variants. The pathogenicity of the identified variants was investigated in silico and in vitro.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Male patients diagnosed with primary infertility were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Genomic DNA extracted from affected individuals was used for WES and Sanger sequencing. Sperm phenotype, sperm nuclear maturity, chromosome aneuploidy, and sperm ultrastructure were assessed using hematoxylin and eosin staining and toluidine blue staining, FISH and transmission electron microscopy. The functional effects of the identified variants in HEK293T cells were investigated via western blotting and immunofluorescence.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified three homozygous missense variants (NM_001100915, c.G628A:p.E210K, c.C893T:p.P298L, and c.G2309A:p.G770D) in KCTD19 in five infertile males from three unrelated families. Abnormal morphology of the sperm heads with immature nuclei and/or nuclear aneuploidy were frequently observed in individuals with biallelic KCTD19 variants, and ICSI was unable to rescue these deficiencies. These variants reduced the abundance of KCTD19 due to increased ubiquitination and impaired its nuclear colocalization with its functional partner, zinc finger protein 541 (ZFP541), in HEK293T cells.
LIMITATIONS, REASONS FOR CAUTION
The exact pathogenic mechanism remains unclear, and warrants further studies using knock-in mice that mimic the missense mutations found in individuals with biallelic KCTD19 variants.
WIDER IMPLICATIONS OF THE FINDINGS
Our study is the first to report a likely causal relationship between KCTD19 deficiency and male infertility, confirming the critical role of KCTD19 in human reproduction. Additionally, this study provided evidence for the poor ICSI clinical outcomes in individuals with biallelic KCTD19 variants, which may guide clinical treatment strategies.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the National Key Research and Developmental Program of China (2022YFC2702604 to Y.-Q.T.), the National Natural Science Foundation of China (81971447 and 82171608 to Y.-Q.T., 82101961 to C.T.), a key grant from the Prevention and Treatment of Birth Defects from Hunan Province (2019SK1012 to Y.-Q.T.), a Hunan Provincial Grant for Innovative Province Construction (2019SK4012), and the China Postdoctoral Science Foundation (2022M721124 to W.W.). The authors declare no conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Animals; Humans; Male; Mice; Asthenozoospermia; Chromosomal Proteins, Non-Histone; HEK293 Cells; Infertility, Male; Oligospermia; Semen; Transcription Factors; Nuclear Proteins
PubMed: 37192818
DOI: 10.1093/humrep/dead095 -
Reproductive Biology Jun 2022Advances in transcriptomic technologies are contributing to an increased understanding of the role of spermatozoal RNA in sperm physiology. Although sperm transcriptomic... (Review)
Review
Advances in transcriptomic technologies are contributing to an increased understanding of the role of spermatozoal RNA in sperm physiology. Although sperm transcriptomic studies have delivered large amounts of valuable information, no new male fertility biomarkers have emerged from such studies to date. This review summarizes current knowledge about the potential relevance of certain mRNA as biomarkers, focusing on comparative studies of human spermatozoa transcriptomic profiles from fertile and pathological semen samples. Asthenozoospermia is the semen aberrant condition that has been most exhaustively investigated to date. We cross-analyzed findings from three different studies on the transcriptome of asthenozoospermic semen samples and identified 100 transcripts that were consistently differentially expressed and that consequently are candidates for characterizing the molecular source of this sperm anomaly. The potential use of sperm mRNAs as predictors of outcomes of assisted reproductive technologies (ART) is also reviewed. Improving the understanding of the human spermatozoa mRNA content is expected to improve the evaluation and diagnosis of infertile men, and ultimately facilitate the selection of the best treatment to overcome infertility.
Topics: Asthenozoospermia; Biomarkers; Fertility; Humans; Infertility, Male; Male; RNA, Messenger; Semen; Sperm Motility; Spermatozoa
PubMed: 35338912
DOI: 10.1016/j.repbio.2022.100636 -
Zhonghua Nan Ke Xue = National Journal...Studies show that acupuncture can significantly elevate the level of serum testosterone (T), reduce the concentrations of follicle-stimulating hormone (FSH), luteinizing... (Review)
Review
Studies show that acupuncture can significantly elevate the level of serum testosterone (T), reduce the concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), initiate spermatogenesis, enhance testicular blood flow, maintain a relative low temperature in the testis, increase the concentration, motility and antioxidative injury capability of spermatozoa by raising the levels of seminal α-glucosidase, fructose and super oxide dismutase, and eventually improve semen quality and the rate of conception in the treatment of oligoasthenozoospermia. Currently, the quality of the clinical studies of acupuncture treatment of oligoasthenozoospermia is relatively poor, the existing evidence remains at a low level, its clinical application is limited, and its therapeutic effect has to be further verified. The present paper summarizes the literature from domestic and international databases about acupuncture treatment of oligoasthenozoospermia, and offers an overview of the effects of acupuncture on the reproductive endocrine system, testicular blood flow, semen quality, and rate of conception in the treatment of the patient.
Topics: Acupuncture Therapy; Asthenozoospermia; Estradiol; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Oligospermia; Semen Analysis; Sperm Count; Spermatogenesis; Spermatozoa; Testis; Testosterone
PubMed: 30157368
DOI: No ID Found