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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 Nutrition 2021Evidence of associations between a pro-inflammatory diet and asthenozoospermia risk is limited. We therefore performed a case-controlled study to investigate...
Evidence of associations between a pro-inflammatory diet and asthenozoospermia risk is limited. We therefore performed a case-controlled study to investigate associations between pro-inflammatory diet using dietary inflammatory index (DII) scores and asthenozoospermia risk in China. Our hospital-based case-controlled study comprised 549 incident asthenozoospermia men and 581 healthy controls. All were interviewed at the infertility clinic in Shengjing Hospital of China Medical University from June 2020 to December 2020. DII scores were calculated based on dietary intake which were assessed using a validated food frequency questionnaire. Semen parameters were analyzed according to World Health Organization guidelines. An unconditional logistic regression model was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for asthenozoospermia risk. The lowest tertile served as the reference category for regression analyses. After adjustment for age in the primary multivariable model, we failed to determine a significant negative association between DII and asthenozoospermia risk (for the highest tertile of DII scores compared to the lowest tertile) (OR = 0.77, 95% CI: 0.57-1.03). Similarly, non-significant associations were also identified in the multivariable model after adjusting for more potential confounders (OR = 0.86; 95% CI: 0.58-1.27). Additionally, in subgroup analyses stratified by age, body mass index, and smoking status, non-significant results were consistent with the main findings. To our knowledge, this is the first study exploring this particular topic. Our research does not support an association between DII scores and asthenozoospermia risk. Further prospective studies with more DII relevant foods and nutrients are warranted to confirm our findings.
PubMed: 34395499
DOI: 10.3389/fnut.2021.706869 -
International Journal of Molecular... Oct 2022Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and... (Review)
Review
Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p-ERK1/2/p-CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus-pituitary-gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed.
Topics: Humans; Pregnancy; Female; Male; Nerve Growth Factor; Sperm Motility; Semen; Gonadotropin-Releasing Hormone; Infertility, Male; Genitalia, Male
PubMed: 36361912
DOI: 10.3390/ijms232113127 -
Journal of Clinical Medicine Jan 2020The role of nutraceuticals in the treatment of male infertility, especially in the "idiopathic form", remains the subject of significant debate. Many antioxidants... (Review)
Review
INTRODUCTION
The role of nutraceuticals in the treatment of male infertility, especially in the "idiopathic form", remains the subject of significant debate. Many antioxidants improve sperm motility but the exact mechanism by which they act is still unclear. Although several studies have shown a correlation between sperm motility and mitochondrial function, the effects of antioxidant therapy on mitochondrial membrane potential (MMP) are poorly studied. The first aim of this review was to evaluate the efficacy of antioxidants on mitochondrial function and, consequently, on sperm motility in male infertile patients.
MATERIAL AND METHODS
we performed a systematic search of all randomized controlled and uncontrolled studies available in the literature that reported sperm motility and MMP at baseline and after antioxidant administration in-vivo and in-vitro in patients with idiopathic asthenozoospermia. Pubmed, MEDLINE, Cochrane, Academic One Files, Google Scholar and Scopus databases were used.
RESULTS
Unexpectedly, among 353 articles retrieved, only one study met our inclusion criteria and showed a significant effect of myoinositol on both MMP and sperm motility. We then summarized the main knowledge on anatomy and metabolism of sperm mitochondria, techniques allowing to assess sperm mitochondria function and its relationships with low sperm motility. Finally, we paid special attention to the effect of antioxidant/prokinetic molecules for the treatment of asthenozoospermia.
CONCLUSIONS
This is the first systematic review that has attempted to evaluate the effects of antioxidants on MMP and sperm motility. Although results are not conclusive due to the dearth of studies, the close relationship between mitochondria and sperm motility is clear. The investigation of this correlation could provide valuable information to be exploited in clinical practice for the treatment of male infertility.
PubMed: 32013061
DOI: 10.3390/jcm9020363 -
Advanced Science (Weinheim,... Apr 2022Sperm motility is a significant predictor of male fertility potential and is directly linked to fertilization success in both natural and some forms of assisted...
Sperm motility is a significant predictor of male fertility potential and is directly linked to fertilization success in both natural and some forms of assisted reproduction. Sperm motility can be impaired by both genetic and environmental factors, with asthenozoospermia being a common clinical presentation. Moreover, in the setting of assisted reproductive technology clinics, there is a distinct absence of effective and noninvasive technology to increase sperm motility without detriment to the sperm cells. Here, a new method is presented to boost sperm motility by increasing the intracellular rate of metabolic activity using high frequency ultrasound. An increase of 34% in curvilinear velocity (VCL), 10% in linearity, and 32% in the number of motile sperm cells is shown by rendering immotile sperm motile, after just 20 s exposure. A similar effect with an increase of 15% in VCL treating human sperm with the same setting is also identified. This cell level mechanotherapy approach causes no significant change in cell viability or DNA fragmentation index, and, as such, has the potential to be applied to encourage natural fertilization or less invasive treatment choices such as in vitro fertilization rather than intracytoplasmic injection.
Topics: Animals; Asthenozoospermia; Cattle; Fertilization in Vitro; Humans; Infertility, Male; Male; Sperm Motility; Spermatozoa
PubMed: 35419997
DOI: 10.1002/advs.202104362 -
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 -
International Journal of Molecular... Jan 2023Male infertility is a common and complex disease and presents as a wide range of heterogeneous phenotypes. Multiple morphological abnormalities of the sperm flagellum...
Male infertility is a common and complex disease and presents as a wide range of heterogeneous phenotypes. Multiple morphological abnormalities of the sperm flagellum (MMAF) phenotype is a peculiar condition of extreme morphological sperm defects characterized by a mosaic of sperm flagellum defects to a total asthenozoospermia. At this time, about 40 genes were associated with the MMAF phenotype. However, mutation prevalence for most genes remains individually low and about half of individuals remain without diagnosis, encouraging us to pursue the effort to identify new mutations and genes. In the present study, an a cohort of 167 MMAF patients was analyzed using whole-exome sequencing, and we identified three unrelated patients with new pathogenic mutations in , a new gene recently associated with MMAF. Immunofluorescence experiments showed that DNHD1 was totally absent from sperm cells from patients, supporting the deleterious effect of the identified mutations. Transmission electron microscopy reveals severe flagellum abnormalities of sperm cells from one mutated patient, which appeared completely disorganized with the absence of the central pair and midpiece defects with a shortened and misshapen mitochondrial sheath. Immunostaining of IFT20 was not altered in mutated patients, suggesting that IFT may be not affected by mutations. Our data confirmed the importance of DNHD1 for the function and structural integrity of the sperm flagellum. Overall, this study definitively consolidated its involvement in MMAF phenotype on a second independent cohort and enriched the mutational spectrum of the gene.
Topics: Humans; Male; Abnormalities, Multiple; Flagella; Infertility, Male; Mutation; Semen; Sperm Tail; Spermatozoa; Dyneins
PubMed: 36768883
DOI: 10.3390/ijms24032559 -
Frontiers in Nutrition 2021Evidence of an association between dairy product and main related dairy nutrient intake, and the asthenozoospermia risk have been limited and controversial. A...
Evidence of an association between dairy product and main related dairy nutrient intake, and the asthenozoospermia risk have been limited and controversial. A hospital-based case-control study including 549 men with asthenozoospermia and 581 normozoospermic controls was carried out in the infertility clinics of Shengjing Hospital of China Medical University between June, 2020 and December, 2020. Dietary intake was assessed with a validated food frequency questionnaire. According to the World Health Organization guidelines, semen parameters were collected through masturbation and were measured with WLJY9000 instrument and flow cytometry. The daily intake of dairy products and related nutrients was categorized into three groups according to control distribution, and the lowest tertile was used as the reference category. An unconditional multiple logistic regression was used to estimate the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for asthenozoospermia risk. After adjustment for potential confounders, we found no statistically significant associations between the intake of total dairy products and asthenozoospermia risk (OR = 1.19, 95%CI = 0.85-1.67). Additionally, we generated null findings regarding the main related nutrients from dairy, including protein (OR = 1.19, 95%CI = 0.85-1.68), fat (OR = 1.28, 95%CI = 0.91-1.80), calcium (OR = 1.20, 95%CI = 0.85-1.68), saturated fatty acids (OR = 1.30, 95%CI = 0.92-1.83), and phosphorous (OR = 1.18, 95%CI = 0.84-1.67), and the asthenozoospermia risk. Of note, after stratification by body mass index (BMI), and the saturated fatty acids consumption from dairy was significantly associated with a higher asthenozoospermia risk (OR = 1.76, 95%CI = 1.01-3.09) among participants with a BMI below 25 kg/m. This study provided limited evidence of an association between the intake of total dairy products and the main related dairy nutrients including protein, fat, calcium, saturated fatty acids, and phosphorus, and the asthenozoospermia risk. Further studies are warranted to confirm our findings in the future.
PubMed: 34746202
DOI: 10.3389/fnut.2021.714291 -
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 -
American Journal of Human Genetics Mar 2023Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory...
Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.
Topics: Animals; Male; Asthenozoospermia; Macaca fascicularis; Primates; Semen; Sperm Motility; Tupaia; Tupaiidae
PubMed: 36796361
DOI: 10.1016/j.ajhg.2023.01.016