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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.
Zhonghua Nan Ke Xue ; 26(8): 708-712, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-33377731

RESUMO

Objective: To explore the correlation of the sperm DNA fragmentation index (DFI) with age and other semen parameters in infertile men and its influence on the outcomes of in vitro fertilization and embryo transplantation (IVF-ET). METHODS: Semen samples were obtained from 6 162 infertile males in our hospital between July 2017 and December 2018. Sperm concentration, the percentages of progressively motile sperm (PMS) and morphologically normal sperm (MNS) and sperm DFI were determined by computer-assisted semen analysis, modified Papanicolaou staining and sperm chromatin structure assay, respectively. According to the sperm DFI, the samples were divided into three groups: DFI≤15%, 15%30%. Comparisons were made among different groups in the rates of fertilization, embryo cleavage, embryo formation and pregnancy. RESULTS: Spearman correlation analysis showed that DFI was correlated positively with age (r = 0.508, P < 0.05), but negatively with sperm concentration (r = -0.155, P < 0.05) and the percentages of PMS (r = -0.111, P < 0.05) and MNS (r = -0.315, P < 0.05). With sperm DFI >20%, the clinical pregnancy rate of IVF-ET was significantly reduced, while with sperm DFI >30%, the rate of available embryos markedly decreased and that of biochemical pregnancy remarkably increased. No correlation was found between sperm DFI and the rates of fertilization, embryo cleavage and high-quality embryos in IVF-ET. CONCLUSIONS: In infertile males, sperm DFI is correlated positively with age but negatively with sperm concentration and the percentages of PMS and MNS, and it significantly affects the outcomes of IVF-ET.


Assuntos
Fatores Etários , Fragmentação do DNA , Transferência Embrionária , Fertilização In Vitro , Infertilidade Masculina/fisiopatologia , Espermatozoides , Feminino , Humanos , Infertilidade Masculina/terapia , Masculino , Gravidez , Taxa de Gravidez , Sêmen , Contagem de Espermatozoides
4.
Urologiia ; (4): 157-164, 2020 Sep.
Artigo em Russo | MEDLINE | ID: mdl-32897031

RESUMO

The causes, some pathogenetic mechanisms and possibilities for correcting the decrease in male reproductive potential in Russia are discussed in the lecture. Particular attention is paid to oxidative stress as one of the main causes for subfertility and male infertility, as well as the role of trace elements (zinc, selenium) and antioxidants (vitamins A, E and C) in the pathogenesis of male infertility and opportunities for the correction of fertility issues. Some aspects of COVID-19 influence on the problems of reproductive medicine, andrology and urology are highlighted.


Assuntos
Antioxidantes , Infertilidade Masculina/fisiopatologia , Estresse Oxidativo , Oligoelementos , Betacoronavirus , Infecções por Coronavirus/complicações , Humanos , Infertilidade Masculina/virologia , Masculino , Pandemias , Pneumonia Viral/complicações , Reprodução , Federação Russa , Selênio , Zinco
5.
Life Sci ; 258: 118242, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32784056

RESUMO

AIMS: As the spermatogenesis process is targeted by cisplatin (Cis) that changes testicular morphology, alters sperm quality, and hence causes male infertility. This study investigated the possible therapeutic effects of l-carnitine (LC) on Cis impaired spermatogenesis's establishment during the prepubertal phase. MATERIALS AND METHODS: Ninety-six prepubertal Sprague Dawley male rats were divided into four groups. CONTROL GROUP: rats were injected with 0.9% saline solution intraperitoneally (i.p.). LC group: animals were injected for eight weeks, with 250 mg/kg/wk. LC (i.p.). Cis group: animals were injected with a single dose of 5 mg/kg Cis (i.p.). LC + Cis group: animals were pre-injected with LC 250 mg/kg 2 h before Cis injection. The rats were sacrificed at 37, 60, and 90 days old, and their testes were taken for biochemical, molecular, and histopathological studies. The motility, viability, morphology, and DNA fragmentation of sperm in adult rats were also measured. KEY FINDINGS: Group treated with LC and Cis showed an increase in antioxidant and hormonal activity compared to the Cis treated group in the pre and post-pubertal period. Moreover, there was an increase in sperm survival, motility, and DNA integrity. Furthermore, LC showed an increase in the anti-apoptotic and chromatin remodeling genes and a decrease in the pro-inflammatory genes. SIGNIFICANCE: LC could enhance the spermatogenesis process after exposure to Cis during the prepubertal phase by restoring the balance between reactive oxygen species and antioxidant activity, improving hormonal activity, sperm quality and DNA integrity, promoting protamination and blood-testis barrier integrity, and maintaining the testicular architecture.


Assuntos
Carnitina/farmacologia , Cisplatino/toxicidade , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carnitina/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Espermatogênese/fisiologia
6.
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
7.
Proc Natl Acad Sci U S A ; 117(29): 17094-17103, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611817

RESUMO

Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, between reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending interventions could ameliorate the declining performance of the ejaculate as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration contributes to male reproductive decline via mating-dependent mechanisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproductive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling results in improved late-life ejaculate performance, indicating simultaneous amelioration of both somatic and reproductive aging.


Assuntos
Envelhecimento , Drosophila melanogaster , Proteínas de Plasma Seminal , Espermatozoides , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Masculino , Proteoma/análise , Proteoma/genética , Proteoma/fisiologia , Proteínas de Plasma Seminal/análise , Proteínas de Plasma Seminal/fisiologia , Comportamento Sexual Animal/fisiologia , Espermatozoides/química , Espermatozoides/fisiologia
8.
Fertil Steril ; 113(6): 1140-1149, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32482250

RESUMO

OBJECTIVE: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. DESIGN: Review of English publications in PubMed and Embase to April 6, 2020. METHOD(S): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. RESULT(S): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. CONCLUSION(S): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Infertilidade Feminina/virologia , Infertilidade Masculina/virologia , Orquite/virologia , Pneumonia Viral/virologia , Reprodução , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Feminino , Fertilidade , Interações Hospedeiro-Patógeno , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/fisiopatologia , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/fisiopatologia , Masculino , Orquite/diagnóstico , Orquite/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Medição de Risco , Fatores de Risco , Contagem de Espermatozoides , Motilidade Espermática
9.
Am J Clin Nutr ; 112(3): 707-719, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32453396

RESUMO

BACKGROUND: It is unknown which compounds in spermatozoa or seminal plasma may be involved in the regulation of sperm motility. OBJECTIVES: The aim of this study was to investigate the effects of DHA (22:6n-3), vitamin E, and their probable interactions in men with asthenozoospermia. METHODS: A factorial, randomized, double-blind, placebo-controlled trial was conducted in infertility clinics in Tehran, Iran. The participants were idiopathic asthenozoospermic men aged 20-45 y, with normal endocrine function. Their concentration of spermatozoa and percentage of morphologically normal spermatozoa were equal to or above the lower reference limits, according to the fifth edition of the WHO guideline. Out of 717 men referred to the infertility clinics, 180 asthenozoospermic men were randomly assigned to 1 of 4 groups according to stratified blocked randomization by age and sperm concentration. Participants took daily 465 mg DHA plus 600 IU vitamin E (DE), 465 mg DHA plus placebo (DP), 600 IU vitamin E plus placebo (EP), or both placebo capsules (PP) for 12 wk. Sperm characteristics, oxidative stress of seminal plasma, serum and sperm membrane fatty acids, dietary intakes, anthropometric measurements, and physical activity were measured at baseline and after 12 wk. RESULTS: After the intervention, mean ± SD sperm progressive motility was greater in the DE group (27.9 ± 2.8) than in the DP (25.7 ± 3.4), EP (26.1 ± 2.8), and PP (25.8 ± 2.6) groups (P < 0.05). Sperm count (P = 0.001) and concentration (P = 0.044) increased significantly in the DE group compared with the other 3 groups, whereas other semen parameters were not significantly different between the groups after the intervention. Serum concentrations of n-3 PUFAs were significantly higher in the DE and DP groups than in the EP and PP groups. CONCLUSIONS: Combined DHA and vitamin E supplements led to increased sperm motility; however, no significant changes occurred in sperm morphology and vitality in asthenozoospermic men.This trial was registered at clinicaltrials.gov as NCT01846325.


Assuntos
Astenozoospermia/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/administração & dosagem , Infertilidade Masculina/tratamento farmacológico , Fosfolipídeos/metabolismo , Sêmen/metabolismo , Espermatozoides/citologia , Vitamina E/administração & dosagem , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeos/química , Sêmen/química , Sêmen/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Adulto Jovem
10.
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
11.
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
12.
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
13.
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
14.
Andrologia ; 52(3): e13519, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32003032

RESUMO

The declining trend of male fecundity is a major global health and social concern. Among numerous other confounding factors, variations in male fertility parameters in different regions have repeatedly been suggested to be influenced by geographic locations. The impact of overall lifestyle, behavioural patterns, ethnicity, work stress and associated factors upon health differ greatly between developed and developing countries. These factors, individually or in combination, affect male reproductive functions ensuing the discrepancies in semen qualities in connection with geographic variations. However, reports comparing semen characteristics between developed and developing countries are sparse. The present study finds its novelty in presenting a comparison in semen parameters of infertile men in the United States (n = 76) that fairly represents the population of a highly developed region and Iraq (n = 102), the representative of male populations of a developing region. Samples were collected and analysed according to WHO (WHO laboratory manual for the examination and processing of human semen, WHO; 2010) criteria by means of the Mann-Whitney test. The US population demonstrated lower sperm concentration, total count, and total and progressive sperm motility with a higher seminal total antioxidant capacity (TAC) as compared to the Iraqi population. This report encourages further investigations concerning the confounding factors leading to such alterations in semen qualities between these two geographic areas.


Assuntos
Fertilidade/fisiologia , Infertilidade Masculina/patologia , Espermatozoides/patologia , Adulto , Fatores de Confusão Epidemiológicos , Geografia , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/fisiopatologia , Iraque/epidemiologia , Masculino , Pessoa de Meia-Idade , Sêmen/fisiologia , Contagem de Espermatozoides , Motilidade Espermática/fisiologia , Estados Unidos/epidemiologia
15.
Genes Dev ; 34(5-6): 398-412, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001511

RESUMO

Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.


Assuntos
DNA Helicases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Recombinação Homóloga/genética , Meiose/fisiologia , Animais , Morte Celular/genética , Quebras de DNA de Cadeia Dupla , Células Germinativas/patologia , Código das Histonas/genética , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Substâncias Macromoleculares/metabolismo , Masculino , Meiose/genética , Camundongos
16.
Oxid Med Cell Longev ; 2020: 7038124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089776

RESUMO

Almost 50% of infertility cases are associated with human male infertility. The sperm membrane is a key structure influencing sperm morphology and function in normal and pathological conditions. The fatty acid profile determines the performance not only of sperm motility but also of acrosomal reaction and sperm-oocyte fusion. This review presents available knowledge on the role of fatty acid composition in human sperm and spermatogenesis and discusses the influence of dietary fatty acids on the sperm fatty acid profile. Recent studies in biological sciences and clinical researches in this field are also reported. The topic object of this review has potential application in medicine by identifying potential causes of infertility.


Assuntos
Ácidos Graxos/metabolismo , Infertilidade Masculina/fisiopatologia , Maturação do Esperma/fisiologia , Motilidade Espermática/fisiologia , Animais , Humanos , Masculino , Ratos
17.
Cell Mol Life Sci ; 77(1): 93-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31377843

RESUMO

Infertility is a global health problem involving about 15% of couples. Approximately half of the infertility cases are related to male factors. The oxidative stress, which refers to an imbalance in levels of reactive oxygen species (ROS) and antioxidants, is one of the main causes of infertility in men. A small amount of ROS is necessary for the physiological function of sperm including the capacitation, hyperactivation and acrosomal reaction. However, high levels of ROS can cause infertility through not only by lipid peroxidation or DNA damage but inactivation of enzymes and oxidation of proteins in spermatozoa. Oxidative stress (OS) is mainly caused by factors associated with lifestyle. Besides, immature spermatozoa, inflammatory factors, genetic mutations and altering levels of sex hormones are other main source of ROS. Since OS occurs due to the lack of antioxidants and its side effects in semen, lifestyle changes and antioxidant regimens can be helpful therapeutic approaches to overcome this problem. The present study aimed to describe physiological ROS production, roles of genetic and epigenetic factors on the OS and male infertility with various mechanisms such as lipid peroxidation, DNA damage, and disorder of male hormone profile, inflammation, and varicocele. Finally, the roles of oral antioxidants and herbs were explained in coping with OS in male infertility.


Assuntos
Antioxidantes/uso terapêutico , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Gerenciamento Clínico , Humanos , Infertilidade Masculina/fisiopatologia , Masculino , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia
18.
Eur J Endocrinol ; 182(1): 67-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705791

RESUMO

Objective: Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design: Male partners of infertile couples referred to four medical French centers were enrolled in years 2013-2016. Methods: Subjects (n = 160) aged 18-45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results: Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions: These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.


Assuntos
Adipocinas/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/fisiopatologia , Adipocinas/sangue , Adolescente , Adulto , Quimiocinas/sangue , Quimiocinas/metabolismo , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Leptina/sangue , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/sangue , Nicotinamida Fosforribosiltransferase/metabolismo , Reprodução/fisiologia , Sêmen/metabolismo , Sêmen/fisiologia , Contagem de Espermatozoides , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo , Espermatozoides/fisiologia , Adulto Jovem
19.
Mol Cell Biol ; 40(3)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31712393

RESUMO

During spermatogenesis, up to 75% of germ cells in the testes undergo apoptosis and are cleared by Sertoli cells. X-linked XK blood group-related 8 (Xkr8) is a plasma membrane protein that scrambles phospholipids in response to apoptotic signals, exposing phosphatidylserine (PtdSer). Here, we found that Xkr8 -/- male mice were infertile due to reduced sperm counts in their epididymides. Apoptotic stimuli could not induce PtdSer exposure in Xkr8 -/- germ cells. Consistent with the hypothesis that PtdSer functions as an "eat-me" signal to phagocytes, cells expressing phosphatidylserine receptor TIM4 and MER tyrosine kinase receptor efficiently engulfed apoptotic wild-type male germ cells but not Xkr8 -/- germ cells. Fluorescence and electron microscopy revealed Sertoli cells carrying engulfed and degenerated dead cells. However, many unengulfed apoptotic cells and residual bodies and much cell debris were present in Xkr8 -/- testes and epididymides. These results indicate that Xkr8-mediated PtdSer exposure is essential for the clearance of apoptotic germ cells by Sertoli cells. There was no apparent inflammation in Xkr8 -/- testes, suggesting that the unengulfed apoptotic cells may have undergone secondary necrosis, releasing noxious materials that affected the germ cells. Alternatively, failure to engulf the apoptotic germ cells may have caused the Sertoli cells to starve and lose their ability to support spermatogenesis.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose , Células Germinativas/patologia , Infertilidade Masculina/genética , Proteínas de Membrana/genética , Animais , Deleção de Genes , Células Germinativas/citologia , Células Germinativas/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espermatogênese , Testículo/citologia , Testículo/metabolismo , Testículo/patologia
20.
Lab Invest ; 100(4): 583-595, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31857692

RESUMO

Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase (CS) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial CS (eCS) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of eCS in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca2+ oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of eCS enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that eCS suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.


Assuntos
Envelhecimento/metabolismo , Sinalização do Cálcio/fisiologia , Citrato (si)-Sintase , Infertilidade Masculina/metabolismo , Espermatozoides , Animais , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Feminino , Infertilidade Masculina/fisiopatologia , Masculino , Metaboloma/fisiologia , Camundongos , Óvulo/metabolismo , Espermatozoides/enzimologia , Espermatozoides/metabolismo
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