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1.
Cells ; 10(9)2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34572103

RESUMO

Propagation of paternal sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals due to post-fertilization degradation of sperm mitochondria, referred to as sperm mitophagy. Whole organelle sperm mitochondrion degradation is thought to be mediated by the interplay between the ubiquitin-proteasome system (UPS) and the autophagic pathway (Song et al., Proc. Natl. Acad. Sci. USA, 2016). Both porcine and primate post-fertilization sperm mitophagy rely on the ubiquitin-binding autophagy receptor, sequestosome 1 (SQSTM1), and the proteasome-interacting ubiquitinated protein dislocase, valosin-containing protein (VCP). Consequently, we anticipated that sperm mitophagy could be reconstituted in a cell-free system consisting of permeabilized mammalian spermatozoa co-incubated with porcine oocyte extracts. We found that SQSTM1 was detected in the midpiece/mitochondrial sheath of the sperm tail after, but not before, co-incubation with oocyte extracts. VCP was prominent in the sperm mitochondrial sheath both before and after the extract co-incubation and was also detected in the acrosome and postacrosomal sheath and the subacrosomal layer of the spermatozoa co-incubated with extraction buffer as control. Such patterns are consistent with our previous observation of SQSTM1 and VCP associating with sperm mitochondria inside the porcine zygote. In addition, it was observed that sperm head expansion mimicked the early stages of paternal pronucleus development in a zygote during prolonged sperm-oocyte extract co-incubation. Treatment with anti-SQSTM1 antibody during extract co-incubation prevented ooplasmic SQSTM1 binding to sperm mitochondria. Even in an interspecific cellular environment encompassing bull spermatozoa and porcine oocyte extract, ooplasmic SQSTM1 was recruited to heterospecific sperm mitochondria. Complementary with the binding of SQSTM1 and VCP to sperm mitochondria, two sperm-borne pro-mitophagy proteins, parkin co-regulated gene product (PACRG) and spermatogenesis associated 18 (SPATA18), underwent localization changes after extract coincubation, which were consistent with their degradation observed inside fertilized porcine oocytes. These results demonstrate that the early developmental events of post-fertilization sperm mitophagy observed in porcine zygote can be reconstituted in a cell-free system, which could become a useful tool for identifying additional molecules that regulate mitochondrial inheritance in mammals.


Assuntos
Sistema Livre de Células/fisiologia , Fertilização , Mitofagia , Oócitos/fisiologia , Interações Espermatozoide-Óvulo , Espermatozoides/patologia , Animais , Bovinos , Feminino , Fertilização In Vitro , Técnicas de Maturação in Vitro de Oócitos , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Oócitos/citologia , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Espermatozoides/metabolismo , Suínos , Proteína com Valosina/genética , Proteína com Valosina/metabolismo
2.
Toxicology ; 460: 152886, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34352348

RESUMO

Arsenic intoxication affects male reproductive parameters of prepubertal rats. Besides, morphological and functional alterations in their testis and epididymis may remain after withdrawal of arsenic insult, causing potential impairment in male fertility during adulthood. In this study, we aimed at analyzing the effect of prepubertal arsenic exposure on the fecundity of epididymal sperm from sexually mature Wistar rats, assessing fertility indexes, sperm parameters, and sperm phosphoproteins content. Male pups on postnatal day (PND) 21 received filtered water (controls, n = 10) and 10 mg L-1 arsenite (n = 10) daily for 30 days. From PND52 to PND81, rats from both groups received filtered water. During this period, the males mated with non-exposed females between PND72 and PND75. Our results showed that sexually mature rats presented low sperm production, epididymal sperm count, motility, and quality after prepubertal arsenic exposure. These findings possibly contributed to the low fertility potential and high preimplantation loss. Epididymal sperm proteome detected 268 proteins, which 170 were found in animals from both control and arsenic groups, 27 proteins were detected only in control animals and 71 proteins only in arsenic-exposed rats. In these animals, SPATA 18 and other five proteins were upregulated, whereas keratin type II cytoskeletal 1 was downregulated (q < 0.1). The results of KEGG pathway analysis demonstrated an enrichment of pathways related to dopaminergic response, adrenergic signaling, protein degradation, and oocyte meiosis in arsenic-exposed animals. Moreover, 26 proteins were identified by phosphoproteomic with different phosphorylation pattern in animals from both groups, but SPATA18 was phosphorylated only in arsenic-exposed animals. We concluded that prepubertal exposure to arsenic is deleterious to sperm quality and male fertility, altering the sperm phosphoproteins profile.


Assuntos
Arsênio/toxicidade , Epididimo/metabolismo , Fertilidade/fisiologia , Fosfoproteínas/metabolismo , Maturidade Sexual/fisiologia , Espermatozoides/metabolismo , Animais , Arsênio/administração & dosagem , Bovinos , Epididimo/efeitos dos fármacos , Epididimo/patologia , Fertilidade/efeitos dos fármacos , Humanos , Masculino , Camundongos , Ratos , Ratos Wistar , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Maturidade Sexual/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia
3.
Am J Hum Genet ; 108(8): 1466-1477, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34237282

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified several MMAF-associated genes, highlighting the condition's genetic heterogeneity. To further define the genetic causes underlying MMAF, we performed whole-exome sequencing in a cohort of 643 Chinese MMAF-affected men. Bi-allelic DNAH10 variants were identified in five individuals with MMAF from four unrelated families. These variants were either rare or absent in public population genome databases and were predicted to be deleterious by multiple bioinformatics tools. Morphological and ultrastructural analyses of the spermatozoa obtained from men harboring bi-allelic DNAH10 variants revealed striking flagellar defects with the absence of inner dynein arms (IDAs). DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes. Immunostaining analysis indicated that DNAH10 localized to the entire sperm flagellum of control spermatozoa. In contrast, spermatozoa from the men harboring bi-allelic DNAH10 variants exhibited an absence or markedly reduced staining intensity of DNAH10 and other IDA components, including DNAH2 and DNAH6. Furthermore, the phenotypes were recapitulated in mouse models lacking Dnah10 or expressing a disease-associated variant, confirming the involvement of DNAH10 in human MMAF. Altogether, our findings in humans and mice demonstrate that DNAH10 is essential for sperm flagellar assembly and that deleterious bi-allelic DNAH10 variants can cause male infertility with MMAF. These findings will provide guidance for genetic counseling and insights into the diagnosis of MMAF-associated asthenoteratozoospermia.


Assuntos
Astenozoospermia/complicações , Modelos Animais de Doenças , Dineínas/genética , Infertilidade Masculina/patologia , Mutação , Fenótipo , Espermatozoides/patologia , Alelos , Animais , Homozigoto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/metabolismo , Sequenciamento Completo do Exoma
4.
Reprod Fertil Dev ; 33(12): 683-690, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34324827

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus causing coronavirus disease 2019 (COVID-19). Because COVID-19 is a multisystem infection, there are some concerns regarding its possible effects on male fertility. This study aimed to investigate the effects of COVID-19 on semen oxidative status and parameters 14 and 120 days after diagnosis in patients presenting with moderate infection (defined as respiratory symptoms, with or without fever, with Spo2 <93% and >90% and lung involvement <50%). Semen samples were obtained from 20 participants at two time points: the first sample on Day 14 and the second on Day 120 after diagnosis. Semen parameters (sperm concentration, motility, morphology, and viability) were evaluated, as were levels of seminal reactive oxygen species (ROS), malondialdehyde (MDA), total antioxidant capacity (TAC) and sperm DNA fragmentation. Semen parameters, including sperm motility and DNA integrity, improved at 120 days after the COVID-19 diagnosis relative to values at 14 days. In addition, ROS and MDA levels were significantly reduced in patients 120 days after infection, and TAC increased at 120 days compared with 14 days (during the acute stage of infection). In conclusion, the present study shows that the detrimental effects of COVID-19 on sperm properties caused by oxidative stress decrease up to Day 120 after diagnosis.


Assuntos
COVID-19/metabolismo , Estresse Oxidativo , Sêmen/metabolismo , Espermatozoides/metabolismo , Adulto , COVID-19/diagnóstico , Fragmentação do DNA , Humanos , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Oxirredução , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Análise do Sêmen , Índice de Gravidade de Doença , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides/patologia , Fatores de Tempo , Adulto Jovem
5.
Urol Int ; 105(9-10): 743-748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34265771

RESUMO

INTRODUCTION: The coronavirus disease 2019 (COVID-19) is a global pandemic which may affect multiple organs and systems including testes and disrupt the gonadal functions. The current study aimed to evaluate the effect of COVID-19 on the semen parameters and sex-related hormone levels in infertile men. METHODS: The study included 21 patients who were evaluated in Ankara City Hospital, Andrology Clinic, for male infertility and have had the diagnosis of COVID-19. All the patients were evaluated in terms of semen parameters. The follicle-stimulating hormone, luteinizing hormone, and testosterone (T) levels were also evaluated in 8 of the patients. The results were presented through 2 dependent group analyses, based on the data of the patients collected before and after the diagnosis of COVID-19. RESULTS: None of the patients needed to be hospitalized at any time through the course of COVID-19. There was a significant decrease in semen volume, percentage of total motility, percentage of progressive motility, and normal sperm morphology after COVID-19 (3 [1-8] vs. 2.5 [1.5-5], p = 0.005; 48.6 ± 22.1 vs. 34.7 ± 20.7, p = 0.001; 35.1 ± 21.7 vs. 21.8 ± 15.9, p < 0.001; 6 [3-24] vs. 5 [3-18], p = 0.015; respectively). There was also a significant decline in T level of the patients after the diagnosis of COVID-19 (350.1 ± 115.5 vs. 289.8 ± 103.3, p = 0.009). CONCLUSION: COVID-19 may have unfavorable effects on the gonadal functions and may lead to further deterioration of the semen parameters in infertile men, which should be considered through the evaluation for infertility.


Assuntos
COVID-19/virologia , Infertilidade Masculina/patologia , SARS-CoV-2/patogenicidade , Análise do Sêmen , Espermatozoides/patologia , Adulto , COVID-19/diagnóstico , Fertilidade , Hormônio Foliculoestimulante Humano/sangue , Interações Hospedeiro-Patógeno , Humanos , Infertilidade Masculina/sangue , Infertilidade Masculina/virologia , Hormônio Luteinizante/sangue , Masculino , Estudos Retrospectivos , Fatores de Risco , Espermatozoides/virologia , Centros de Atenção Terciária , Testosterona/sangue , Turquia , Adulto Jovem
6.
Cells ; 10(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202084

RESUMO

Male infertility is a multifactorial disease with a strong genetic background. Abnormal sperm morphologies have been found to be closely related to male infertility. Here, we conducted whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Two novel hemizygous mutations were identified in USP26, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These USP26 variants are extremely rare in human population genome databases and have been predicted to be deleterious by multiple bioinformatics tools. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring hemizygous USP26 variants showed a highly aberrant morphology and ultrastructure of the sperm heads and flagella. Real-time quantitative PCR and immunoblotting assays revealed obviously reduced levels of USP26 mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of USP26. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous USP26 variants achieved satisfactory outcomes. Overall, our study demonstrates that USP26 is essential for normal sperm morphogenesis, and hemizygous USP26 mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.


Assuntos
Astenozoospermia/genética , Cisteína Endopeptidases/genética , Mutação/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Cisteína Endopeptidases/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Injeções de Esperma Intracitoplásmicas , Espermatozoides/metabolismo , Espermatozoides/patologia , Espermatozoides/ultraestrutura
7.
Fertil Steril ; 116(5): 1297-1307, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34253331

RESUMO

OBJECTIVE: To evaluate Deoxyribonucleic acid (DNA) methylation patterns in sperm from men with differential levels of sperm DNA fragmentation index (DFI). DESIGN: Prospective study. SETTING: University-affiliated reproductive medicine center. PATIENT(S): A total of 278 male patients consulting for couple infertility were recruited from the First Affiliated Hospital of Wenzhou Medical University. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genome-wide DNA methylation analysis was performed using Infinium MethylationEPIC BeadChip on spermatozoal DNA from 20 male patients. Differentially methylated regions (DMRs) were identified and validated using targeted bisulfite amplicon sequencing in spermatozoal DNA from 266 males. RESULT(S): Unsupervised hierarchical clustering analysis revealed three main clusters corresponding to sperm DFI levels (low, medium, or high). Between-cluster comparisons identified 959 (medium-low), 738 (high-medium), and 937 (high-low) DMRs. Sixty-six DMRs were validated in the 266-sample cohort, of which nine CpG fragments corresponding to nine genes (BLCAP, DIRAS3, FAM50B, GNAS, MEST, TSPAN32, PSMA8, SYCP1, and TEX12) exhibited significantly altered methylation in those with high DFI (≥25%) compared with those with low DFI (<25%). CONCLUSION(S): We identified and validated a distinct DNA methylation signature associated with sperm DNA damage in a large, unselected cohort. These results indicate that sperm DNA damage may affect DNA methylation patterns in human sperm.


Assuntos
Fragmentação do DNA , Metilação de DNA , Epigênese Genética , Epigenoma , Infertilidade Masculina/patologia , Espermatozoides/patologia , Ilhas de CpG , Epigenômica , Fertilidade , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Infertilidade Masculina/fisiopatologia , Masculino , Estudos Prospectivos , Reprodutibilidade dos Testes
8.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073009

RESUMO

The purpose of the current study was to analyze phenotypic and functional characteristics of common carp (Cyprinus carpio) spermatozoa during in vitro aging and to investigate whether global DNA methylation is affected by sperm aging. Milt was collected from five individual males, stored in vitro on ice in a refrigerator for up to 96 h post stripping (HPS) and used to fertilize eggs with intervals of 1, 24 and 96 h. Computer-assisted sperm analysis and a S3e Cell Sorter was employed to determine the spermatozoa phenotypic characteristics (motility, velocity, concentration and viability). In addition, pH and osmolality of the seminal fluid and the capacity of the spermatozoa to fertilize, hatching rate and health of the resulting embryos were examined at different aging times. Whole-genome bisulfite sequencing was used to compare the global and gene-specific DNA methylation in fresh and aged spermatozoa. The results demonstrated that spermatozoa aging in common carp significantly affects their performance and thus the success of artificial fertilization. The methylation level at the cytosine-phosphate-guanine (CpG) sites increased significantly with 24 HPS spermatozoa compared to the fresh group at 1 HPS and then decreased significantly at 96 HPS. A more detailed investigation of gene specific differences in the DNA methylation was hindered by incomplete annotation of the C. carpio genome in the public databases.


Assuntos
Envelhecimento/genética , Carpas/genética , Metilação de DNA/genética , Espermatozoides/metabolismo , Envelhecimento/patologia , Animais , Carpas/crescimento & desenvolvimento , Masculino , Espermatozoides/patologia
9.
FASEB J ; 35(7): e21702, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34153130

RESUMO

Perinatal smoke/nicotine exposure alters lung development and causes asthma in exposed offspring, transmitted transgenerationally. The mechanism underlying the transgenerational inheritance of perinatal smoke/nicotine-induced asthma remains unknown, but germline epigenetic modulations may play a role. Using a well-established rat model of perinatal nicotine-induced asthma, we determined the DNA methylation pattern of spermatozoa of F1 rats exposed perinatally to nicotine in F0 gestation. To identify differentially methylated regions (DMRs), reduced representation bisulfite sequencing was performed on spermatozoa of F1 litters. The top regulated gene body and promoter DMRs were tested for lung gene expression levels, and key proteins involved in lung development and repair were determined. The overall CpG methylation in F1 sperms across gene bodies, promoters, 5'-UTRs, exons, introns, and 3'-UTRs was not affected by nicotine exposure. However, the methylation levels were different between the different genomic regions. Eighty one CpG sites, 16 gene bodies, and 3 promoter regions were differentially methylated. Gene enrichment analysis of DMRs revealed pathways involved in oxidative stress, nicotine response, alveolar and brain development, and cellular signaling. Among the DMRs, Dio1 and Nmu were the most hypermethylated and hypomethylated genes, respectively. Gene expression analysis showed that the mRNA expression and DNA methylation were incongruous. Key proteins involved in lung development and repair were significantly different (FDR < 0.05) between the nicotine and placebo-treated groups. Our data show that DNA methylation is remodeled in offspring spermatozoa upon perinatal nicotine exposure. These epigenetic alterations may play a role in transgenerational inheritance of perinatal smoke/nicotine induced asthma.


Assuntos
Metilação de DNA , Epigênese Genética , Pulmão/patologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Espermatozoides/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Espermatozoides/patologia
10.
Ecotoxicol Environ Saf ; 220: 112419, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126304

RESUMO

BACKGROUND: Despite increasing evidence that particulate air pollution has adverse effects on human semen quality, few studies examine the impact of air pollution on clinically relevant thresholds used to diagnose male fertility problems. Furthermore, exposure is often assessed using average air pollution levels in a geographic area rather than individualized estimates. Finally, physiologically-informed exposure windows are inconsistent. OBJECTIVES: We sought to test the hypothesis that airborne particulate exposures during early-phase spermatogenesis will have a differential impact on spermatogenic formation compared to late-phase exposures, using an individualized model of exposure to particulate matter ≤ 2.5 µm and ≤ 10 µm (PM2.5 and PM10, respectively). METHODS: From an original cohort of 183 couples, we conducted a retrospective analysis of 130 healthy males seeking to become parents, using spermatogenesis-relevant exposure windows of 77-34 days and 37-0 days prior to semen collection to encompass sperm development stages of mitosis/meiosis and spermiogenesis, respectively. Individualized residential exposure to PM2.5 and PM10 was estimated by selecting multiple air pollution sensors within the same geographic air basin as participants and employing inverse distance weighting to calculate mean daily exposure levels. We used multiple logistic regression to assess the association between pollution, temperature, and dichotomized World Health Organization semen parameters. RESULTS: During the early phase of spermatogenesis, air pollution exposure is associated with 1.52 (95% CI: 1.04-2.32) times greater odds of < 30% normal heads per 1-unit increase in IQR for PM2.5. In the late phase of spermatogenesis, air pollution exposure is associated with 0.35 (95% CI: 0.10-0.74) times greater odds of semen concentration < 15 million/mL per 1-unit increase in IQR for PM2.5, and 0.28 (95% CI: 0.07-0.72) for PM10. CONCLUSION: Particulate exposure has a differential and more deleterious impact on sperm during early-phase spermatogenesis than late-phase.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Material Particulado/toxicidade , Espermatogênese/efeitos dos fármacos , Adulto , Poluentes Atmosféricos/química , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Exposição Ambiental/análise , Humanos , Masculino , Tamanho da Partícula , Material Particulado/química , Estudos Retrospectivos , Análise do Sêmen , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia
11.
Sci Rep ; 11(1): 12311, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112894

RESUMO

It is well established that maternal lifestyle during pregnancy and lactation affects the intrauterine programming of F1 offspring. However, despite the co-use of alcohol and nicotine is a common habit, the effects of exposure to both substances on the reproductive system of F1 male offspring and the underlying mechanisms of developmental programming have not been investigated. The present study aimed to examine pre- and postnatal concurrent exposure to these substances on genetic and epigenetic alterations of sperm cells as well as testis properties of F1 offspring compared with exposure to each substance alone. Pregnant dams in the F0 generation randomly received normal saline, nicotine, ethanol, and combinations throughout full gestation and lactation periods. Sperm cells and testes of F1 male offspring were collected at postnatal day 90 for further experiments. High levels of sperm DNA fragmentation were observed in all exposed offspring. Regarding epigenetic alterations, there was a significant increase in the relative transcript abundance of histone deacetylase 1 and 2 in all exposed sperm cells. Moreover, despite a decrease in the expression level of DNA methyltransferase (DNMT) 3A, no marked differences were found in the expression levels of DNMT1 and 3B in any of the exposed sperm cells compared to non-exposed ones. Interestingly, combined exposure had less prominent effects relative to exposure to each substance alone. The changes in the testicular and sperm parameters were compatible with genetic and epigenetic alterations. However, MDA level as an oxidative stress indicator increased in all exposed pups, which may be responsible for such outputs. In conclusion, maternal co-exposure to these substances exhibited epigenotoxicity effects on germline cells of F1 male offspring, although these effects were less marked relative to exposure to each substance alone. These counteracting effects may be explained by cross-tolerance and probably less impairment of the antioxidant defense system.


Assuntos
Efeitos Tardios da Exposição Pré-Natal/genética , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/fisiopatologia , Animais , Variações do Número de Cópias de DNA/genética , Fragmentação do DNA , Epigênese Genética/efeitos dos fármacos , Etanol/efeitos adversos , Feminino , Humanos , Lactação/efeitos dos fármacos , Masculino , Exposição Materna/efeitos adversos , Camundongos , Nicotina/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reprodução/genética , Contagem de Espermatozoides , Espermatozoides/patologia
12.
PLoS One ; 16(6): e0251608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097690

RESUMO

AIM: To assess the prevalence of isolated teratozoospermia (iTZS) in a cohort of infertile and fertile men; explore the relationship between iTZS, inflammatory parameters and sperm DNA fragmentation index (SDF) in the same cohort. MATERIALS AND METHODS: 1824 infertile men and 103 fertile controls. Semen analysis, the neutrophil-to-lymphocyte ratio (NLR) and serum hormones were investigated. DFI was tested in infertile men only. According to 2010 WHO semen analysis, patients were categorized in 3 sub-groups of isolated sperm defects: isolated oligozoospermia (iOZS), isolated asthenozoospermia (iAZS) and iTZS. Descriptive statistics and linear regression models tested the association between clinical variables and inflammatory markers. RESULTS: Among infertile men, iAZS, iTZS, and iOZS were found in 13.9%, 11.9% and 4.1% participants, respectively. iTZS was found in 37 (35.9%) fertile men. Infertile men with iTZS had higher NLR values than those with iOZS, iAZS and men with normal semen parameters (all p<0.001). FSH and LH were higher and inhibin B lower in iOZS infertile men compared to all other groups (p≤0.001). Hormonal characteristics were similar between iTZS infertile and fertile men. Similarly, iTZS infertile men had higher SDF than all other groups (all p<0.001). Infertile men with iTZS had higher NLR values than fertile men with iTZS (p<0.01). Linear regression analysis showed that, in infertile men, iTZS was associated with SDF and NLR (all p≤0.01). CONCLUSIONS: iTZS was found in 11.9% of infertile men but it was even more prevalent in fertile controls. Infertile men with iTZS had higher NLR than fertile controls and increased SDF values than infertile participant with iAZS, iOZS, or normal semen parameters. No differences in hormonal characteristics were found between infertile and fertile men with iTZS.


Assuntos
Biomarcadores/metabolismo , Infertilidade Masculina/patologia , Inflamação/metabolismo , Inflamação/patologia , Espermatozoides/patologia , Teratozoospermia/patologia , Astenozoospermia/metabolismo , Astenozoospermia/patologia , Fragmentação do DNA , Fertilidade/fisiologia , Humanos , Infertilidade Masculina/metabolismo , Masculino , Oligospermia/metabolismo , Oligospermia/patologia , Sêmen/metabolismo , Sêmen/fisiologia , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo , Teratozoospermia/metabolismo
13.
Hum Genet ; 140(8): 1169-1182, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33963445

RESUMO

Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confirm human GCNA expression from spermatogonia to elongated spermatids. Five identified SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely affecting 3D structure. For variants within GCNA's intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identified variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in > 5000 biological fathers. Considering evidence from animal models, germ-cell-specific expression, 3D modeling, and computational predictions for SNVs, we propose that identified GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the first study implicating GCNA, a key genome integrity factor, in human male infertility.


Assuntos
Azoospermia/congênito , Genes Ligados ao Cromossomo X , Infertilidade Masculina/genética , Mutação , Proteínas Nucleares/genética , Espermatozoides/metabolismo , Adulto , Animais , Azoospermia/diagnóstico , Azoospermia/genética , Azoospermia/metabolismo , Azoospermia/patologia , Sequência de Bases , Estudos de Coortes , Hormônio Foliculoestimulante/sangue , Expressão Gênica , Genoma Humano , Instabilidade Genômica , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Hormônio Luteinizante/sangue , Masculino , Meiose , Modelos Moleculares , Proteínas Nucleares/deficiência , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Espermatogênese/genética , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Sequenciamento Completo do Exoma
14.
Sci Rep ; 11(1): 9444, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941835

RESUMO

The consumption of energy-dense diets has contributed to an increase in the prevalence of obesity and its comorbidities worldwide. The adoption of unhealthy feeding habits often occurs at early age, prompting the early onset of metabolic disease with unknown consequences for reproductive function later in life. Recently, evidence has emerged regarding the intergenerational and transgenerational effects of high-fat diets (HFD) on sperm parameters and testicular metabolism. Hereby, we study the impact of high-fat feeding male mice (F0) on the testicular metabolome and function of their sons (F1) and grandsons (F2). Testicular content of metabolites related to insulin resistance, cell membrane remodeling, nutritional support and antioxidative stress (leucine, acetate, glycine, glutamine, inosine) were altered in sons and grandsons of mice fed with HFD, comparing to descendants of chow-fed mice. Sperm counts were lower in the grandsons of mice fed with HFD, even if transient. Sperm quality was correlated to testicular metabolite content in all generations. Principal Component Analysis of sperm parameters and testicular metabolites revealed an HFD-related phenotype, especially in the diet-challenged generation and their grandsons. Ancestral HFD, even if transient, causes transgenerational "inherited metabolic memory" in the testicular tissue, characterized by changes in testicular metabolome and function.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Metaboloma/fisiologia , Oligospermia/fisiopatologia , Espermatozoides/patologia , Testículo/metabolismo , Animais , Epigênese Genética/fisiologia , Comportamento Alimentar , Resistência à Insulina/fisiologia , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Estresse Oxidativo/fisiologia , Análise de Componente Principal , Análise do Sêmen , Contagem de Espermatozoides
15.
Fertil Steril ; 116(3): 833-842, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33966888

RESUMO

OBJECTIVE: To evaluate the associations of a history of diagnosed depression, current depressive symptoms, and recent use of psychotropic medications with semen quality and to consider mediation of the association between depression and semen quality by medication use. DESIGN: Prospective cohort study. SETTING: United States. PATIENT(S): The patients were 329 men aged ≥21 years (566 semen samples) who participated in a semen-testing substudy of Pregnancy Study Online. Pregnancy Study Online is an ongoing, web-based preconception cohort study of couples attempting to conceive. At baseline, participants reported information about depression diagnosis, depressive symptoms using the Major Depression Inventory, medication use in the last 4 weeks, and selected covariates. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The men used an at-home semen-testing kit (Trak; Sandstone Diagnostics, Inc., Pleasanton, California) to measure semen volume, sperm concentration, and motile sperm concentration. We calculated percent motility, total sperm count in the ejaculate, and total motile sperm count. RESULT(S): Forty-nine men (15%) reported a history of depression diagnosis, and 41 (12%) reported recent use of psychotropic medications. A history of depression diagnosis was associated with a 4.3-fold increase in the risk of low semen volume (<1.5 mL) (95% CI 1.16, 16). A 5-unit increase in Major Depression Inventory score was associated with a 1.38-fold increase in the risk of low semen volume (95% CI 0.92, 2.1). The results for other semen parameters were inconsistent. Recent use of psychotropic medications was associated with worse semen quality, and this association was confounded by a history of depression diagnosis. The observed association between depression and semen volume showed little mediation by psychotropic medication use. CONCLUSION: A history of diagnosed depression and severe depressive symptoms at enrollment were associated with low semen volume.


Assuntos
Transtorno Depressivo Maior/complicações , Psicotrópicos/uso terapêutico , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Adulto , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/patologia , Humanos , Masculino , Estudos Prospectivos , Psicotrópicos/efeitos adversos , Contagem de Espermatozoides , Espermatozoides/patologia , Estados Unidos , Adulto Jovem
16.
Fertil Steril ; 116(3): 696-712, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33985792

RESUMO

OBJECTIVE: To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile men with clinical varicocele subjected to varicocelectomy. INTERVENTION(S): Systematic search using PubMed/Medline, EMBASE, Cochrane's central database, Scielo, and Google Scholar to identify relevant studies published from inception until January 2021. We included studies comparing SDF rates before and after varicocelectomy in infertile men with clinical varicocele. MAIN OUTCOME MEASURE(S): The primary outcome was the difference between the SDF rates before and after varicocelectomy. A meta-analysis of weighted data using random-effects models was performed. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CIs). Subgroup analyses were performed on the basis of the SDF assay, varicocelectomy technique, preoperative SDF levels, varicocele grade, follow-up time, and study design. RESULT(S): Nineteen studies involving 1,070 patients provided SDF data. Varicocelectomy was associated with reduced postoperative SDF rates (WMD -7.23%; 95% CI: -8.86 to -5.59; I2 = 91%). The treatment effect size was moderate (Cohen's d = 0.68; 95% CI: 0.77 to 0.60). The pooled results were consistent for studies using sperm chromatin structure assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, sperm chromatin dispersion test, and microsurgical varicocele repair. Subgroup analyses showed that the treatment effect was more pronounced in men with elevated vs. normal preoperative SDF levels, but the impact of varicocele grade remained equivocal. Meta-regression analysis demonstrated that SDF decreased after varicocelectomy as a function of preoperative SDF levels (coefficient: 0.23; 95% CI: 0.07 to 0.39). CONCLUSION(S): We concluded that pooled results from studies including infertile men with clinical varicocele indicated that varicocelectomy reduced the SDF rates. The treatment effect was greater in men with elevated (vs. normal) preoperative SDF levels. Further research is required to determine the full clinical implications of SDF reduction for these men.


Assuntos
Fragmentação do DNA , Fertilidade , Infertilidade Masculina/cirurgia , Espermatozoides/patologia , Procedimentos Cirúrgicos Urológicos Masculinos , Varicocele/cirurgia , Adulto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos Masculinos/efeitos adversos , Varicocele/complicações , Varicocele/patologia , Varicocele/fisiopatologia
17.
EMBO J ; 40(13): e106864, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978233

RESUMO

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26-mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring.


Assuntos
Cisteína Endopeptidases/genética , Síndrome de Klinefelter/genética , Mutação/genética , Adulto , Aneuploidia , Animais , Humanos , Masculino , Camundongos , Camundongos Knockout , Cromossomos Sexuais/genética , Espermatozoides/patologia , Adulto Jovem
18.
Toxins (Basel) ; 13(4)2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806221

RESUMO

A 65-day study was undertaken to test the effects of two doses (10 and 20 mg/kg) of dietary fumonisin Bs (FB) on the rabbit male reproduction system. Body and testicular weight was not affected by the intoxication, neither the fatty acid composition of the testicular total phospholipids; the testis histological analysis failed to reveal any toxic effect. The FBs increased the testicular concentration and activity of reduced glutathione and glutathione peroxidase and decreased initial phase lipid peroxidation (conjugated dienes and trienes) in a dose dependent manner. Sperm morphology and chromatin condensation were monitored on Feulgen-stained smears. No significant differences were observed between the treatment groups and between sampling time points. The live cell ratio in the sperm (as assessed with flow cytometry) was not different among groups at any of the five sampling timepoints and was also identical within groups. Similarly, the spermatozoa membrane lipid profile was also identical in all three groups after the total intoxication period. In summary, it was demonstrated that FBs in an unrealistic and unjustified high dose still do not exert any drastic harmful effect on the leporine, male reproduction system, meanwhile slightly augmenting testicular antioxidant response.


Assuntos
Exposição Dietética/efeitos adversos , Fumonisinas/toxicidade , Fusarium/metabolismo , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Ração Animal/microbiologia , Animais , Relação Dose-Resposta a Droga , Ácidos Graxos/metabolismo , Microbiologia de Alimentos , Fumonisinas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeos/metabolismo , Coelhos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia , Fatores de Tempo
19.
PLoS Genet ; 17(4): e1009485, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33831001

RESUMO

piRNAs are small non-coding RNAs required to maintain genome integrity and preserve RNA homeostasis during male gametogenesis. In murine adult testes, the highest levels of piRNAs are present in the pachytene stage of meiosis, but their mode of action and function remain incompletely understood. We previously reported that BTBD18 binds to 50 pachytene piRNA-producing loci. Here we show that spermatozoa in gene-edited mice lacking a BTBD18 targeted pachytene piRNA cluster on Chr18 have severe sperm head dysmorphology, poor motility, impaired acrosome exocytosis, zona pellucida penetration and are sterile. The mutant phenotype arises from aberrant formation of proacrosomal vesicles, distortion of the trans-Golgi network, and up-regulation of GOLGA2 transcripts and protein associated with acrosome dysgenesis. Collectively, our findings reveal central role of pachytene piRNAs in controlling spermiogenesis and male fertility.


Assuntos
Infertilidade Masculina/genética , RNA Interferente Pequeno/genética , Espermatogênese/genética , Espermatozoides/patologia , Acrossomo/patologia , Animais , Cromossomos/genética , Humanos , Infertilidade Masculina/patologia , Masculino , Meiose/genética , Camundongos , Estágio Paquíteno/genética , Espermátides/crescimento & desenvolvimento , Espermátides/patologia , Testículo/crescimento & desenvolvimento , Testículo/patologia
20.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921254

RESUMO

Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2-rs11125529 and decreased sperm motility (p = 0.03); PXK-rs6772228 with a lower sperm count (p = 0.02); NAF1-rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208-rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.


Assuntos
Hidrolases Anidrido Ácido/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/genética , Proteínas Serina-Treonina Quinases/genética , Ribonucleoproteínas/genética , Telômero/genética , Acrossomo/metabolismo , Acrossomo/patologia , Adulto , Feminino , Estudos de Associação Genética , Humanos , Infertilidade Masculina/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Espermatogênese/genética , Espermatozoides/metabolismo , Espermatozoides/patologia , Homeostase do Telômero/genética
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