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1.
Am J Hum Genet ; 108(2): 309-323, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33472045

RESUMO

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.


Assuntos
Astenozoospermia/genética , Infertilidade Masculina/genética , Animais , Astenozoospermia/patologia , Astenozoospermia/fisiopatologia , Estudos de Coortes , Feminino , Deleção de Genes , Genes Ligados ao Cromossomo X , Hemizigoto , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Injeções de Esperma Intracitoplásmicas , Motilidade Espermática , Cauda do Espermatozoide/ultraestrutura , Espermatozoides/patologia , Espermatozoides/fisiologia , Espermatozoides/ultraestrutura , Sequenciamento Completo do Exoma
2.
Biomed Pharmacother ; 133: 111085, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378981

RESUMO

Obesity is a significant global health and socio-economic challenge, and considered an important risk factor for poor health outcomes including male reproductive dysfunction and infertility. As excess adiposity causes testicular dysfunction and infertility, novel therapeutic strategies require investigation. Nigella sativa (Ns) seed oil and metformin have both demonstrated a potential positive effect on obesity, although both remain poorly investigated in male fertility. Therefore, this study aimed to determine the effect of Ns oil and metformin on total body weight (TBW), mitochondrial membrane potential (MMP), serum testosterone and semen parameters in an obese animal model. Wistar rats (n = 54) were divided into six groups: normal chow (NC), high sugar diet (HSD) only, HSD and saline, HSD and metformin (75 mg/Kg/day), HSD and Ns (200 mg/Kg/day) (NS200), HSD and Ns (400 mg/Kg/day) (NS400). Intervention was force fed for the last 8 weeks of the 14 weeks dietary exposures. Results showed that the HSD increased TBW (P = 0.001) and reduced sperm concentration (P = 0.013) and progressive motility (P = 0.009) compared to the NC group. Metformin, NS200 and NS400 improved TBW (P = 0.035, P = 0.006 and P = 0.005, respectively) and testosterone (P < 0.001) compared to the HSD saline group, where metformin and NS400 improved sperm concentration (P < 0.001 and P = 0.049, respectively) and MMP (P < 0.001). There were no changes in sperm motility and viability for all experimental exposures, although NS400 (P = 0.047) negatively affected sperm viability. Metformin and Ns may be novel treatment options in obesity-induced infertility, although a potential negative impact on viability is cautioned for high dose Ns. These results warrant further investigation of Ns and Metformin for the management of obese infertile males.


Assuntos
Fármacos Antiobesidade/farmacologia , Fármacos para a Fertilidade Masculina/farmacologia , Fertilidade/efeitos dos fármacos , Infertilidade Masculina/prevenção & controle , Metformina/farmacologia , Obesidade/tratamento farmacológico , Óleos Vegetais/farmacologia , Espermatozoides/efeitos dos fármacos , Testosterona/sangue , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Infertilidade Masculina/sangue , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Obesidade/sangue , Obesidade/patologia , Ratos Wistar , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-33006953

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes COVID-19 infections penetrates body cells by binding to angiotensin-converting enzyme-2 (ACE2) receptors. Evidence shows that SARS-CoV-2 can also affect the urogenital tract. Hence, it should be given serious attention when treating COVID-19-infected male patients of reproductive age group. Other viruses like HIV, mumps, papilloma and Epstein-Barr can induce viral orchitis, germ cell apoptosis, inflammation and germ cell destruction with attending infertility and tumors. The blood-testis barrier (BTB) and blood-epididymis barrier (BEB) are essential physical barricades in the male reproductive tract located between the blood vessel and seminiferous tubules in the testes. Despite the significant role of these barriers in male reproductive function, studies have shown that a wide range of viruses can still penetrate the barriers and induce testicular dysfunctions. Therefore, this mini-review highlights the role of ACE2 receptors in promoting SARS-CoV-2-induced blood-testis/epididymal barrier infiltration and testicular dysfunction.


Assuntos
Barreira Hematotesticular/enzimologia , Barreira Hematotesticular/patologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/patologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Pneumonia Viral/patologia , Humanos , Infertilidade Masculina/enzimologia , Masculino , Pandemias , Testículo/metabolismo
4.
PLoS Genet ; 16(8): e1008954, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32785227

RESUMO

The flagellum is essential for sperm motility and fertilization in vivo. The axoneme is the main component of the flagella, extending through its entire length. An axoneme is comprised of two central microtubules surrounded by nine doublets, the nexin-dynein regulatory complex, radial spokes, and dynein arms. Failure to properly assemble components of the axoneme in a sperm flagellum, leads to fertility alterations. To understand this process in detail, we have defined the function of an uncharacterized gene, Cfap97 domain containing 1 (Cfap97d1). This gene is evolutionarily conserved in mammals and multiple other species, including Chlamydomonas. We have used two independently generated Cfap97d1 knockout mouse models to study the gene function in vivo. Cfap97d1 is exclusively expressed in testes starting from post-natal day 20 and continuing throughout adulthood. Deletion of the Cfap97d1 gene in both mouse models leads to sperm motility defects (asthenozoospermia) and male subfertility. In vitro fertilization (IVF) of cumulus-intact oocytes with Cfap97d1 deficient sperm yielded few embryos whereas IVF with zona pellucida-free oocytes resulted in embryo numbers comparable to that of the control. Knockout spermatozoa showed abnormal motility characterized by frequent stalling in the anti-hook position. Uniquely, Cfap97d1 loss caused a phenotype associated with axonemal doublet heterogeneity linked with frequent loss of the fourth doublet in the sperm stored in the epididymis. This study demonstrates that Cfap97d1 is required for sperm flagellum ultra-structure maintenance, thereby playing a critical role in sperm function and male fertility in mice.


Assuntos
Axonema/genética , Proteínas do Citoesqueleto/genética , Dineínas/genética , Infertilidade Masculina/genética , Animais , Chlamydomonas/genética , Cílios/genética , Cílios/patologia , Fertilização In Vitro , Humanos , Infertilidade Masculina/patologia , Masculino , Camundongos , Camundongos Knockout , Motilidade Espermática/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/patologia , Testículo/crescimento & desenvolvimento , Testículo/patologia
5.
Andrologia ; 52(9): e13791, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32790205

RESUMO

Male infertility is linked to some viral infections including human papillomavirus (HPV), herpes simplex viruses (HSV) and human immunodeficiency viruses (HIVs). Almost nothing is known about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effect on fertility. The possible risk factors of coronavirus disease 2019 (COVID-19) infection on fertility comes from the abundance of angiotensin-Converting Enzyme-2 (ACE2), receptor entry of the virus, on testes, a reduction in important sex hormone ratios and COVID-19-associated fever. Recent studies have shown a gender difference for COVID-19 rates and comorbidity. In this review, we will discuss the potential effect of COVID-19 on male fertility and talk about what needs to be done by the scientific community to tackle our limited understanding of the disease. On the other side, we will focus on what is known so far about the risk of COVID-19 on pregnancy, neonatal health and the vertical transfer of the virus between mothers and their neonates. Finally, because reproduction is a human right and infertility is considered a health disease, we will discuss how assisted reproductive clinics can cope with the pandemic and what guidelines they should follow to minimise the risk of viral transmission.


Assuntos
Infecções por Coronavirus/complicações , Transmissão Vertical de Doença Infecciosa , Infertilidade Masculina/virologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/virologia , Saúde Reprodutiva , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/transmissão , Infecções por HIV/virologia , Herpes Simples/complicações , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Infertilidade Masculina/patologia , Masculino , Pandemias , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/transmissão , Infecções por Papillomavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Fatores de Risco , Glicoproteína da Espícula de Coronavírus/metabolismo , Testículo/metabolismo , Testículo/patologia
6.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
7.
Med Hypotheses ; 143: 110083, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32679425

RESUMO

The outbreak of CoronaVirus Disease19 (COVID19) in December 2019 posed a serious threat to public safety, and its rapid spread caused a global health emergency. Clinical data show that in addition to respiratory system damage, some male patients with COVID-19 are also accompanied by abnormal renal function and even renal damage. As the main receptor of syndrome coronavirus 2 (SARS-CoV-2), angiotensin converting enzyme 2 (ACE2) is also found to be highly expressed not only in respiratory mucosa and alveolar epithelial cells, but also in renal tubule cells, testicular Leydig cells and seminiferous tubule cells. This suggests that SARS-CoV-2 has the possibility of infecting the male reproductive system, and the recent detection of SARS-CoV-2 in the patient's semen further confirms this theory. In previous studies, it has been found that ACE2 has the ability to regulate autophagy. Not only that, recent studies have also found that SARS-CoV-2 infection can also lead to a reduction in autophagy. All of these associate SARS-CoV-2 with autophagy. Furthermore, autophagy has been shown to have an effect on male reproduction in many studies. Based on these, we propose the hypothesis that SARS-CoV-2 affects male reproductive function by regulating autophagy. This hypothesis may provide a new idea for future treatment of COVID-19 male patients with reproductive function injury, and it can also prompt medical staff and patients to consciously check their reproductive function.


Assuntos
Autofagia/fisiologia , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Reprodução/fisiologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Genitália Masculina/patologia , Genitália Masculina/fisiopatologia , Genitália Masculina/virologia , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Modelos Biológicos , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Espermatozoides/patologia , Espermatozoides/virologia
8.
Andrologia ; 52(9): e13712, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32578263

RESUMO

We performed this systematic review to evaluate the possibility of an impact of SARS-CoV-2 infection on male fertility. SARS-CoV-2 enters the cells with the help of ACE2; therefore, testicular expression of ACE2 was analysed from transcriptome sequencing studies and our unpublished data. Literature suggested that SARS-CoV-1 (2002-2004 SARS) had a significant adverse impact on testicular architecture, suggesting a high possibility of the impact of SARS-CoV-2 as well. Out of two studies on semen samples from COVID-19 affected patients, one reported the presence of SARS-CoV-2 in the semen samples while the other denied it, raising conflict about its presence in the semen samples and the possibility of sexual transmission. Our transcriptome sequencing studies on rat testicular germ cells showed ACE expression in rat testicular germ cells. We also found ACE2 expression in transcriptome sequencing data for human spermatozoa, corroborating its presence in the testicular germ cells. Transcriptome sequencing data from literature search revealed ACE2 expression in the germ, Sertoli and Leydig cells. The presence of ACE2 on almost all testicular cells and the report of a significant impact of previous SARS coronavirus on testes suggest that SARS-CoV-2 is highly likely to affect testicular tissue, semen parameters and male fertility.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infertilidade Masculina/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Testículo/metabolismo , Animais , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Perfilação da Expressão Gênica , Humanos , Infertilidade Masculina/patologia , Masculino , Modelos Animais , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ratos , Sêmen/virologia , Espermatozoides/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Testículo/patologia
9.
PLoS One ; 15(4): e0232357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353040

RESUMO

One of the main molecular causes that contributes to varicocele-related male infertility is excess production of reactive oxygen species (ROS). It is believed that hypoxia is an important stimulator of ROS in this condition. Recently, the significant roles of long non-coding RNAs (lncRNAs) in hypoxia response have emerged. Despite the investigation of hypoxia, there is scant information about the role of hypoxia-responding lncRNAs in varicocele-related male infertility. In the present study, we deduced eight hypoxia-responding lncRNAs based on high-throughput RNA sequencing data from two Gene Expression Omnibus (GEO) datasets. We used qRT-PCR to assess the expression levels of some of these lncRNAs in 42 ejaculated spermatozoa samples from 25 infertile men with varicocele and 17 fertile men as controls. We identified significant increases in expression levels of hypoxia-related lncRNAs, MIR210HG and MLLT4-AS1 in ejaculated spermatozoa of infertile men with varicocele. These lncRNAs also showed significant positive correlations with ROS levels and meaningful negative correlations with sperm parameters (count and motility). Besides, in silico studies identified several hypoxia response elements (HREs) within selected lncRNAs promoters. Delineation of hypoxia-related lncRNAs in varicocele-related infertility provides a valuable insight into male infertility.


Assuntos
Infertilidade Masculina/genética , RNA Longo não Codificante/genética , Varicocele/complicações , Adulto , Hipóxia Celular , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Masculino , RNA Longo não Codificante/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Elementos de Resposta , Motilidade Espermática , Espermatozoides/metabolismo , Espermatozoides/fisiologia
10.
Life Sci ; 254: 117767, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407848

RESUMO

OBJECTIVE: Heat stress shock affects the generation of free radicals and can have a harmful effect on spermatogenesis. Photobiomodulation (PBM) is very effective in andrology for treating male infertility. This research aimed at the evaluation of the impacts of PBM on spermatogenesis on the transient scrotal hyperthermia-induced oligospermia mouse model. MATERIALS AND METHODS: This experimental research divided 24 mice into the following four groups: (1) Control, (2) Scrotal hyperthermia, (3) Scrotal hyperthermia receiving laser 0.03 J/cm2 for 30 s for each testis, 35 days after induction of scrotal hyperthermia every other day for 35 days, and (4) Scrotal hyperthermia receiving laser 0.03 J/cm2 for 30 s for each testis, immediately after induction of scrotal hyperthermia every other day for 35 days. Scrotal hyperthermia was induced by water bath with 43 °C for 30 min. Then, the mice were euthanized, and their sperm samples were collected for sperm parameters analysis. Then, we took the testis samples for histopathological experimentations, serum testosterone level, reactive oxygen species (ROS), RNA extraction for the examination of IL1-α, IL6 and TNF-α genes expression as well as production and glutathione disulfide (GSH) activity. KEY FINDINGS: Our outputs indicated that PBM could largely improve the sperms parameters and stereological parameters, like spermatogonia, primary spermatocyte, round spermatid and Leydig cells together with an increasing level of the serum testosterone and GSH activity compared to the scrotal hyperthermia induced mice. In addition, it was found that the diameter of seminiferous tubules, ROS production, as well as the expression of IL1-α, IL6, and TNF-α genes significantly decreased in the treatment groups by PBM compared to the scrotal hyperthermia induced mice, but there was not a significant difference in terms of testis weight and Sertoli cells between the studied groups. SIGNIFICANCE: It could be concluded that PBM may be regarded as an alternative treatment for improving the spermatogenesis process in the scrotal hyperthermia induced mice.


Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Escroto/metabolismo , Espermatogênese/efeitos dos fármacos , Animais , Febre/metabolismo , Resposta ao Choque Térmico/fisiologia , Temperatura Alta , Hipertermia Induzida/métodos , Infertilidade Masculina/patologia , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Escroto/patologia , Células de Sertoli/metabolismo , Espermatozoides/patologia , Testículo/efeitos dos fármacos
11.
Tissue Cell ; 63: 101318, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223946

RESUMO

Varicocele, which is one of the causes of infertility in men, can be defined as the expansion of spermatic cord veins. The presence of apelin and apelin receptor (APJ) in many tissues and the effects of apelin have been reported in several studies. There is no study showing apelin and APJ protein expressions in normal and varicocele-induced testicular tissues. In this study, we aimed to demonstrate varicocele-induced changes in apelin and APJ expressions in testicular tissue by immunohistochemical and western blotting techniques. In our study, Wistar male rats were randomly divided into three groups as control, varicocele, and sham. While the control group rats were not subjected to any treatment, the unilateral varicocele model was created under anesthesia in the varicocele group. In the sham group, the left abdominal region was opened and closed to exclude the effect of the surgical procedure. At the 13th postoperative week, the left testes were obtained under anesthesia in all groups, and the immunohistochemistry and Western blotting techniques were used to detect apelin and APJ expressions. In our study; apelin and APJ were significantly expressed in control group's testicular tissue; apelin in testicular tissues of varicocele groups increased compared to the control group, whereas APJ expression decreased. In conclusion, the presence of apelin/APJ system in normal testis and the increased expression of apelin in varicocele-induced testicular tissue suggested that apelin may have a role in the varicocele etiopathogenesis.


Assuntos
Receptores de Apelina/genética , Apelina/genética , Cordão Espermático/metabolismo , Varicocele/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Ratos , Cordão Espermático/irrigação sanguínea , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Testículo/patologia , Varicocele/metabolismo , Varicocele/patologia
12.
Am J Physiol Cell Physiol ; 318(6): C1092-C1106, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32233951

RESUMO

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism that is indispensable for the formation and maintenance of cilia and flagella; however, the implications and functions of IFT81 remain unknown. In this study, we disrupted IFT81 expression in male germ cells starting from the spermatocyte stage. As a result, homozygous mutant males were completely infertile and displayed abnormal sperm parameters. In addition to oligozoospermia, spermatozoa presented dysmorphic and nonfunctional flagella. Histological examination of testes from homozygous mutant mice revealed abnormal spermiogenesis associated with sloughing of germ cells and the presence of numerous multinucleated giant germ cells (symblasts) in the lumen of seminiferous tubules and epididymis. Moreover, only few elongated spermatids and spermatozoa were seen in analyzed cross sections. Transmission electron microscopy showed a complete disorganization of the axoneme and para-axonemal structures such as the mitochondrial sheath, fibrous sheath, and outer dense fibers. In addition, numerous vesicles that contain unassembled microtubules were observed within developing spermatids. Acrosome structure analysis showed normal appearance, thus excluding a crucial role of IFT81 in acrosome biogenesis. These observations showed that IFT81 is an important member of the IFT process during spermatogenesis and that its absence is associated with abnormal flagellum formation leading to male infertility. The expression levels of several IFT components in testes, including IFT20, IFT25, IFT27, IFT57, IFT74, and IFT88, but not IFT140, were significantly reduced in homozygous mutant mice. Overall, our study demonstrates that IFT81 plays an essential role during spermatogenesis by modulating the assembly and elongation of the sperm flagella.


Assuntos
Fertilidade , Flagelos/metabolismo , Infertilidade Masculina/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/metabolismo , Espermatócitos/metabolismo , Espermatogênese , Testículo/metabolismo , Animais , Proteínas do Citoesqueleto/metabolismo , Epididimo/metabolismo , Epididimo/fisiopatologia , Epididimo/ultraestrutura , Flagelos/ultraestrutura , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Transdução de Sinais , Contagem de Espermatozoides , Motilidade Espermática , Espermatócitos/ultraestrutura , Testículo/fisiopatologia , Testículo/ultraestrutura
13.
Biochim Biophys Acta Mol Cell Res ; 1867(7): 118708, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32240712

RESUMO

Spermatogonia migrate to the microenvironment during the establishment from gonocytes and leave it when they differentiate. However, the mechanisms underlying the regulation of spermatogonial differentiation-associated migration remain mostly unknown. In this study, we show that spermatogonial differentiation induced by retinoic acid (RA) was accompanied with increased migration ability and elevated expression of connective tissue growth factor (CTGF), a member of the CCN family. CTGF was mainly expressed in the testicular somatic cells and committed spermatogonial progenitors. Recombinant CTGF (rCTGF) promoted the spermatogonial migration and silencing of endogenous CTGF suppressed the migration of homogenous spermatogonial cell lines. Moreover, depletion of CTGF by neutralizing antibody inhibited the elevated migration ability induced by RA, suggesting both the paracrine and autocrine roles of CTGF in spermatogonial migration associated with differentiation. Finally, CTGF interacted with ß1-integrin and regulated its level in spermatogonial cell lines. Together, our study provides novel insights into the regulation of spermatogonial migration by CTGF, which may shed light on the diagnosis and treatment of male infertility.


Assuntos
Movimento Celular/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Integrina beta1/genética , Espermatogônias/crescimento & desenvolvimento , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Camundongos , Espermatogônias/metabolismo , Tretinoína/farmacologia
14.
Urol Clin North Am ; 47(2): 175-183, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32272989

RESUMO

From a fertility perspective, men with azoospermia represent a challenging patient population. When no mature spermatozoa are obtained during a testicular sperm extraction, patients are often left with limited options, such as adoption or the use of donor sperm. However, it has been reported that round spermatids can be successfully injected into human oocytes and used as an alternative to mature spermatozoa. This technique is known as round spermatid injection (ROSI). Despite the limitations of ROSI and diminished clinical success rates, the use of round spermatids for fertilization may have potential as a treatment modality for men with azoospermia.


Assuntos
Azoospermia/patologia , Infertilidade Masculina/terapia , Injeções de Esperma Intracitoplásmicas , Recuperação Espermática , Espermátides/patologia , Azoospermia/etiologia , Azoospermia/fisiopatologia , Feminino , Fertilização In Vitro , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Microdissecção , Gravidez , Resultado da Gravidez , Análise do Sêmen , Espermatogênese/fisiologia
15.
Fertil Steril ; 113(3): 500-509, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32111477

RESUMO

Since the birth of the first child conceived via in vitro fertilization 40 years ago, fertility treatments and assisted reproductive technology have allowed many couples to reach their reproductive goals. As of yet, no fertility options are available for men who cannot produce functional sperm, but many experimental therapies have demonstrated promising results in animal models. Both autologous (stem cell transplantation, de novo morphogenesis, and testicular tissue grafting) and outside-the-body (xenografting and in vitro spermatogenesis) approaches exist for restoring sperm production in infertile animals with varying degrees of success. Once safety profiles are established and an ideal patient population is chosen, some of these techniques may be ready for human experimentation in the near future, with likely clinical implementation within the next decade.


Assuntos
Técnicas de Reprodução Assistida/tendências , Espermatogênese/fisiologia , Testículo/transplante , Pesquisa Médica Translacional/tendências , Animais , Criança , Criopreservação/métodos , Fertilização In Vitro , Humanos , Técnicas In Vitro , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Infertilidade Masculina/terapia , Masculino , Espermatozoides
16.
Toxicol Appl Pharmacol ; 393: 114942, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142724

RESUMO

Implications of lead (Pb) exposure in dysregulated spermatogenesis in sexually active individuals during adulthood is well established; however, the effect of Pb exposure on spermatogenesis in the early stages of puberty is not clear yet. Moreover, the mechanism of Pb mediated dysregulation of spermatogenesis in adults is also poorly understood. Exposure to environmental toxicants during puberty may cause serious consequences in adulthood causing developmental retardations, especially in the reproductive system. Here we investigated the effects of lead exposure on spermatogenesis at the onset of puberty and the underlying mechanisms of these effects. Male ICR mice were exposed to low (50 mg/L) and high (200 mg/L) doses of Pb through the drinking water for 90 days. At the end of this period, the blood Pb level of the low-dose and high-dose exposure groups were found 6.14 ± 0.34 µg/dL and 11.92 ± 2.92 µg/dL respectively which were in agreement with the US CDC-recommended (5 µg/dL) and Chinese CDC-recommended (10 µg/dL) reference blood Pb level for the children. Although no visible toxicity was observed in either group, Pb exposure caused considerable histopathological changes in testis and epididymis; increased sperm DNA fragmentation indices as well as disrupted sperm heads and head-neck conjunctions. Moreover, both low and high-dose Pb exposures caused aberrant expressions of several important spermatogenesis-related genes in epididymis and testis. These results suggest that although the blood Pb levels are close to the recommended-reference values, low dose Pb exposure at the onset of puberty can disrupt spermatogenesis-related gene expression and cause abnormal mouse spermatogenesis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Infertilidade Masculina/induzido quimicamente , Intoxicação por Chumbo/complicações , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Animais , Fragmentação do DNA , Água Potável , Epididimo/patologia , Infertilidade Masculina/patologia , Chumbo/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Maturidade Sexual , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/patologia
17.
Toxicology ; 436: 152428, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32151602

RESUMO

The increase in human infertility prevalence due to male reproductive disorders has been associated with extensive endocrine-disrupting chemical (EDC) exposure. Acrylamide (AA) is a compound formed spontaneously during heat processing of some foods that are mainly consumed by children and adolescents. In this study, we evaluated the prepubertal AA exposure effects on male adult reproductive physiology using a prepubertal experimental model to analyze the pubertal development, spermatogenesis hormones levels and genes expression involved in male reproductive function. This study is the first one to use the validated protocol to correlate the AA exposure with puberty development, as well as the AA-induced endocrine disrupting effects on reproductive axis. AA did not affect the age at puberty, the reproductive organ's weight and serum hormonal levels. AA reduces spermatogenesis, induces morphological and functional defects on sperm and alters transcript expression of sexual hormone receptors (Ar and Esr2), the transcript expression of Tnf, Egr2, Rhcg and Lrrc34. These findings suggest that excessive AA consumption may impair their reproductive capacity at adulthood, despite no changes in hormonal profile being observed.


Assuntos
Acrilamida/toxicidade , Disruptores Endócrinos/toxicidade , Contaminação de Alimentos , Infertilidade Masculina/induzido quimicamente , Desenvolvimento Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Fatores Etários , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Relação Dose-Resposta a Droga , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Medição de Risco , Espermatozoides/metabolismo , Espermatozoides/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Adv Clin Chem ; 95: 149-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122522

RESUMO

Exosomes are nanosized membrane vesicles secreted by wide variety of cells and found in abundance in biological fluids including semen. They contain cargo of lipids, proteins, microRNAs and mRNAs, and are known to play a major role in intracellular communication. Seminal exosomes mainly include epididymosomes and prostasomes. Most of the proteins associated with the epididymosomes are transferred to the sperm subcellular or membranous domains during their epididymal transit and are involved in the acquisition of fertilizing ability, modulation of motility and protection against oxidative stress. Proteins associated with prostasomes stimulate sperm motility and regulate the timing of capacitation to avoid premature induction of acrosome reaction. Furthermore, prostasomes protect the sperm from immune responses within the female reproductive tract. Overall, exosome-associated proteins play an indispensable role in maturation of spermatozoa and therefore, serve as an excellent biomarker in early diagnosis of male infertility.


Assuntos
Epididimo/metabolismo , Exossomos/metabolismo , Fertilidade/fisiologia , Animais , Epididimo/citologia , Epididimo/patologia , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Masculino , Espermatozoides/citologia , Espermatozoides/metabolismo
19.
Andrologia ; 52(3): e13523, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32017167

RESUMO

Spermatozoa are vulnerable to lack of energy and oxidative stress as a result of elevated levels of reactive oxygen species. Therefore, it is essential that appropriate nutrients are available during maturation. This randomised, double-blind, placebo-controlled trial investigated the effect of 6-month supplementation with carnitines and other micronutrients on sperm quality in 104 subjects with oligo- and/or astheno- and/or teratozoospermia with or without varicocele. Semen analyses were done at the beginning and end of the treatment. In addition to main analyses, post hoc analyses for age and body mass index (BMI) were carried out. Results were interpreted by dividing the population into two age and BMI classes. In 94 patients who completed the study, all sperm parameters increased in supplemented patients compared to the placebo group. A significant (p = .0272) difference in supplementation efficacy was observed for total motility on patients with varicocele and BMI < 25. In the same group, also the progressive motility was significantly superior (p = .0159). For Responder analysis, total motility results were confirmed in both the cited group (p = .0066) and in the varicocele group with BMI < 25 and age < 35 (p = .0078). This study suggests that supplementation is more effective in subjects with varicocele younger than 35 years with BMI < 25.


Assuntos
Antioxidantes/administração & dosagem , Índice de Massa Corporal , Suplementos Nutricionais , Infertilidade Masculina/dietoterapia , Micronutrientes/administração & dosagem , Varicocele/dietoterapia , Adolescente , Adulto , Fatores Etários , Método Duplo-Cego , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Placebos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Resultado do Tratamento , Varicocele/complicações , Varicocele/patologia , Adulto Jovem
20.
Andrologia ; 52(3): e13525, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32022285

RESUMO

The pathophysiology of varicocele remains to be unknown. Several genetic factors have been implicated in varicocele etiopathogenesis. We studied the relationship between NOS3 c.894G>T, c.786T>C and 4b/a polymorphisms to varicocele risk and their prognostic value as regards improvement of the post-operative seminal parameters &/or seminal malonaldehyde levels. The three NOS3 polymorphisms were evaluated in 100 patients with varicocele and 100 healthy subjects by RT-PCR. Seminal plasma MDA level was measured pre-operatively and 3 months after varicocelectomy by the thiobarbituric acid method. The GT, TT, TC and bb genotypes of NOS3 polymorphism were more commonly observed in varicocele patients (30%, 9%, 28% and 70% respectively) compared to normal controls (12%, 0%, 10% and 50% respectively). The mean percentage of post-varicocelectomy seminal MDA reduction was highest with the GT genotype (p < .001). Genotypes GT+TT, TC and bb were associated with varicocele occurrence in our patients. The T (c.894G>T), C (c.786T>C) and b (NOS3 intron 4 VNTR) alleles were significantly associated with varicocele occurrence in our cohort of patients. We also report a better response regarding the reduction of seminal MDA after varicocelectomy with the GT and ba genotypes.


Assuntos
Infertilidade Masculina/prevenção & controle , Óxido Nítrico Sintase Tipo III/genética , Procedimentos Cirúrgicos Urológicos Masculinos , Varicocele/genética , Procedimentos Cirúrgicos Vasculares , Adulto , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Incidência , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Malondialdeído/análise , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Sêmen/metabolismo , Cordão Espermático/irrigação sanguínea , Cordão Espermático/cirurgia , Resultado do Tratamento , Varicocele/epidemiologia , Varicocele/cirurgia
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