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1.
J Toxicol Sci ; 45(8): 411-422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741894

RESUMO

Lanthanum oxide (La2O3) nanoparticles (NPs) have been widely used in photoelectric and catalytic applications. However, their exposure and reproductive toxicity is unknown. In this study, the effect of the intragastric administration of two different-sized La2O3 particles in the testes of mice for 60 days was investigated. Although the body weight of mice treated or not treated with La2O3 NPs was not different and La2O3 NPs were distributed in the organs including the testis, liver, kidney, spleen, heart and brain. La2O3 NPs accumulate more than micro-sized La2O3 (MPs) in mice testes. The histopathological evaluation showed that moderate reproductive toxicity induced by La2O3 NPs in the testicle tissues. Furthermore, increased MDA, 8-OHdG levels and decreased SOD activities were detected in the La2O3 NP-treated groups. Moreover, qRT-PCR and western blotting data indicated that La2O3 NPs affecting the blood-testis barrier (BTB)-related genes in mice testes. Taken together, these findings suggested that La2O3 NPs activated inflammation responses and cross the BTB in the murine testes. This study provided useful information for risk analysis and regulation of La2O3 NPs by administrative agencies.


Assuntos
Lantânio/administração & dosagem , Lantânio/toxicidade , Nanopartículas Metálicas/toxicidade , Óxidos/administração & dosagem , Óxidos/toxicidade , Tamanho da Partícula , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Administração Oral , Animais , Barreira Hematotesticular/metabolismo , Desoxiadenosinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação , Lantânio/metabolismo , Masculino , Malondialdeído/metabolismo , Nanopartículas Metálicas/administração & dosagem , Camundongos , Óxidos/metabolismo , Superóxido Dismutase/metabolismo , Testículo/metabolismo , Distribuição Tecidual
2.
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
3.
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
4.
Gene ; 763: 144956, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32739586

RESUMO

Sox transcription factors play essential roles in a variety of critical physiological processes. Still, members of the sox gene family have not yet been genome-wide identified in shrimps. In this study, a total of five members of the sox gene family were identified from the genome of Pacific white shrimp Litopenaeus vannamei and classified into three subgroups based on the conserved HMG-box domain. Among them, three belong to the SoxB subgroup (one in B1 and two in B2), one in the SoxC subgroup, and one in the SoxE subgroup. The five sox genes had different sex-biased expression in some tissues. Sox21, soxB1, and sox14 had a higher expression in ovary than in testis. In comparison, sox4 had a male-biased specific expression in the gonad, hepatopancreas, gill, and eyestalk. There was no difference in soxE gene expression between testis and ovary. During embryonic development, the expression level of three sox genes (soxB1, sox21, and soxE) was higher in gastrulation stage compared to previous stages, declined in limb bud stage and then increased in intramembrane nauplius stage; the expression of sox4 was detected in blastula stage and continued to increase in the following two stages and then surged in intramembrane nauplius stage; the highest expression of sox14 was in the fertilized egg stage, and the expression level decreased with the development of the embryo. These results suggest that the shrimp sox gene family may be involved in gametogenesis, tridermogenesis, and neurogenesis.


Assuntos
Proteínas de Artrópodes/genética , Penaeidae/genética , Fatores de Transcrição SOX/genética , Animais , Proteínas de Artrópodes/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Brânquias/embriologia , Brânquias/metabolismo , Hepatopâncreas/embriologia , Hepatopâncreas/metabolismo , Masculino , Especificidade de Órgãos , Ovário/embriologia , Ovário/metabolismo , Penaeidae/embriologia , Fatores de Transcrição SOX/metabolismo , Testículo/embriologia , Testículo/metabolismo
5.
Gene ; 760: 145029, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758578

RESUMO

Heat shock protein 70 (HSP70) has been widely reported to play a vital role in maintaining intracellular homeostasis, mainly through cellular protection and immune regulation. The expression and function of HSP70 can vary depending upon species and age. To explore the expression signatures and regulatory functions of HSP70 in the reproductive organs of male sheep, we evaluated the expression and distribution patterns of HSP70 in the testes and epididymides (caput, corpus, and cauda) of Tibetan sheep at three developmental stages (i.e., 3 months, 1 year and 3 years after birth) by qRT-PCR, Western blot and immunofluorescence. HSP70 was found to be expressed in testes, caput, corpus, and cauda epididymides throughout the developmental stages but is mainly expressed postpuberty (1 year and 3 years old). Immunofluorescence results revealed that in the testes, a positive reaction for HSP70 protein was mainly seen in round spermatids and luminal sperms from the groups aged 1 year and 3 years. In caput epididymides, the positive signals for HSP70 protein was notably observed in sperm and principal cells of the epididymal epithelium from the groups aged 1 year and 3 years, and positive signals in the epididymal interstitium were found in all three age groups. In corpus and cauda epididymides, HSP70 protein was present in the epididymal epithelium and interstitium, and the positive signals gradually increased with age. In conclusion, these findings suggest that Tibetan sheep HSP70 may play a crucial role in further development and maturation of postmeiotic germ cells and participate in regulation of intraepididymal homeostasis maintenance in Tibetan sheep.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Genitália/crescimento & desenvolvimento , Proteínas de Choque Térmico HSP70/metabolismo , Animais , Epididimo/metabolismo , Genitália/metabolismo , Proteínas de Choque Térmico HSP70/genética , Masculino , Ovinos , Carneiro Doméstico/metabolismo , Espermátides/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo
6.
Life Sci ; 258: 118192, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781062

RESUMO

The present study was conducted to identify possible health - promoting effects of wogonin (Wog) on testicular dysfunction in rats caused by cadmium. Pre-treatment of cadmium chloride (Cd: 5 mg/kg b.wt.) administered rats with wogonin (10 mg/kg b.wt) resulted in significant improvement in Cd-induced decrease in body and organ (testes and epididymides) weights. Wogonin treatment significantly improved Cd-induced reduction in sperm quality and quantity, steroidogenic gene (SFI, StAR, CYP11A1, 3ß-HSD, CYP17A1 and 17ß-HSD) and protein (SF1, StAR and CYP17A1) expressions and serum testosterone levels. Wogonin treatment provided significant protection to Cd-induced aggression in testicular oxidative (elevated levels of MDA) and anti-oxidative (diminished activities of SOD, CAT and GPx) status. Wog significantly up-regulated mRNA levels of Nrf2, NQO1 and HO-1 and down-regulation of Keap1 in cadmium treated testes. Wogonin administration significantly suppressed Cd-stimulated increase in inflammatory reactions (increase in NF-κB p65 DNA, p-IKKß, TNF-α levels and decrease in IL-10 levels). Wogonin prevented apoptotic damage by enhanced protein distribution of caspase-9, caspase-3, and Bax due to Cd exposure. Furthermore, Wogonin presented significant protection to histo-morphometric changes resulted after Cd administration. Taken together, the findings of this study provided clear evidence of the therapeutic potential of Cd-induced testicular toxicity at least partly due to its antioxidant, anti-inflammatory and anti-apoptotic properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Flavanonas/farmacologia , Substâncias Protetoras/farmacologia , Transdução de Sinais , Testículo/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Epididimo/patologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/sangue , Inflamação/patologia , Masculino , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
7.
Nat Commun ; 11(1): 3739, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719317

RESUMO

The PIWI protein MIWI2 and its associated PIWI-interacting RNAs (piRNAs) instruct DNA methylation of young active transposable elements (TEs) in the male germline. piRNAs are proposed to recruit MIWI2 to the transcriptionally active TE loci by base pairing to nascent transcripts, however the downstream mechanisms and effector proteins utilized by MIWI2 in directing de novo TE methylation remain incompletely understood. Here, we show that MIWI2 associates with TEX15 in foetal gonocytes. TEX15 is predominantly a nuclear protein that is not required for piRNA biogenesis but is essential for piRNA-directed TE de novo methylation and silencing. In summary, TEX15 is an essential executor of mammalian piRNA-directed DNA methylation.


Assuntos
Proteínas Argonauta/metabolismo , Proteínas de Ciclo Celular/metabolismo , Metilação de DNA/genética , Elementos de DNA Transponíveis/genética , Inativação Gênica , Animais , Proteínas Argonauta/genética , Feminino , Feto/citologia , Genoma , Células Germinativas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Testículo/metabolismo
8.
Mol Syst Biol ; 16(7): e9610, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32715618

RESUMO

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.


Assuntos
Peptidil Dipeptidase A/metabolismo , Sistema Respiratório/metabolismo , Betacoronavirus , Vasos Sanguíneos/metabolismo , Túnica Conjuntiva/metabolismo , Enterócitos/metabolismo , Feminino , Vesícula Biliar/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Imuno-Histoquímica , Túbulos Renais Proximais/metabolismo , Masculino , Espectrometria de Massas , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Peptidil Dipeptidase A/genética , Placenta/metabolismo , Gravidez , RNA-Seq , Análise de Célula Única , Testículo/metabolismo
9.
Fertil Steril ; 114(1): 33-43, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32622411

RESUMO

OBJECTIVE: To identify cell types in the male and female reproductive systems at risk for SARS-CoV-2 infection because of the expression of host genes and proteins used by the virus for cell entry. DESIGN: Descriptive analysis of transcriptomic and proteomic data. SETTING: Academic research department and clinical diagnostic laboratory. PATIENT(S): Not applicable (focus was on previously generated gene and protein expression data). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of cell types coexpressing the key angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) genes and proteins as well as other candidates potentially involved in SARS-CoV-2 cell entry. RESULT(S): On the basis of single-cell RNA sequencing data, coexpression of ACE2 and TMPRSS2 was not detected in testicular cells, including sperm. A subpopulation of oocytes in nonhuman primate ovarian tissue was found to express ACE2 and TMPRSS2, but coexpression was not observed in ovarian somatic cells. RNA expression of TMPRSS2 in 18 samples of human cumulus cells was shown to be low or absent. There was general agreement between publicly available bulk RNA and protein datasets in terms of ACE2 and TMPRSS2 expression patterns in testis, ovary, endometrial, and placental cells. CONCLUSION(S): These analyses suggest that SARS-CoV-2 infection is unlikely to have long-term effects on male and female reproductive function. Although the results cannot be considered definitive, they imply that procedures in which oocytes are collected and fertilized in vitro are associated with very little risk of viral transmission from gametes to embryos and may indeed have the potential to minimize exposure of susceptible reproductive cell types to infection in comparison with natural conception.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Fertilidade/fisiologia , Regulação Viral da Expressão Gênica/fisiologia , Pneumonia Viral/metabolismo , Reprodução/fisiologia , Internalização do Vírus , Adolescente , Adulto , Animais , Betacoronavirus/genética , Linhagem Celular , Infecções por Coronavirus/genética , Feminino , Humanos , Macaca fascicularis , Masculino , Ovário/citologia , Ovário/metabolismo , Ovário/virologia , Pandemias , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Gravidez , Proteômica/métodos , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Testículo/citologia , Testículo/metabolismo , Testículo/virologia , Transcriptoma/fisiologia , Adulto Jovem
10.
Nature ; 585(7823): 79-84, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32663838

RESUMO

After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.


Assuntos
Cromossomos Humanos X/genética , Genoma Humano/genética , Telômero/genética , Centrômero/genética , Ilhas de CpG/genética , Metilação de DNA , DNA Satélite/genética , Feminino , Humanos , Mola Hidatiforme/genética , Masculino , Gravidez , Reprodutibilidade dos Testes , Testículo/metabolismo
11.
Mol Cell ; 79(4): 645-659.e9, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32692974

RESUMO

Stress granules (SGs) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SGs act as a protective mechanism to cope with acute stress, but persistent SGs have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP1 confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermosensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress and could aid in the development of male fertility therapies.


Assuntos
Grânulos Citoplasmáticos/genética , DNA Helicases/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Biossíntese de Proteínas , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Estresse Fisiológico/genética , Regiões 5' não Traduzidas , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/patologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/metabolismo , Feminino , Células HCT116 , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Espermatogônias/citologia , Espermatogônias/patologia , Testículo/citologia , Testículo/metabolismo
12.
Aging Cell ; 19(7)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32558150

RESUMO

The COVID-19 coronavirus is now spreading worldwide. Its pathogen, SARS-CoV-2, has been shown to use angiotensin-converting enzyme 2 (ACE2) as its host cell receptor, same as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. Epidemiology studies found males although only slightly more likely to be infected than females account for the majority of the severely ill and fatality, which also bias for people older than 60 years or with metabolic and cardiovascular diseases. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found a significantly higher level in Asian females, an age-dependent decrease in all ethnic groups, and a highly significant decrease in type II diabetic patients of ACE2 expression. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. A shockingly common enrichment of viral infection pathways was found among ACE2 anti-expressed genes, and multiple binding sites of virus infection related transcription factors and sex hormone receptors locate at ACE2 regulatory regions. Human and mice data analysis further revealed ACE2 expression is reduced in T2D patients and with inflammatory cytokine treatment and upregulated by estrogen and androgen (both decrease with age). Our findings revealed a negative correlation between ACE2 expression and COVID-19 fatality at both population and molecular levels. These results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica , Variação Genética/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/virologia , Betacoronavirus/patogenicidade , Biologia Computacional , Feminino , Humanos , Masculino , Pandemias , Receptores Virais/genética , Receptores Virais/metabolismo , Testículo/metabolismo , Testículo/virologia
13.
Toxicology ; 441: 152528, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565124

RESUMO

Cisplatin (Cis) is an effective chemotherapeutic intervention against many cancer types. However, the oxidative stress-related toxicities associated with cancer cell resistance-induced dose scaling has limited its long-term use. In the present study, we explored the benefits of the antioxidant, tert-butylhydroquinone (tBHQ; 50 mg/kg b.w./day, for 14 days) against Cis single dose injection (7 mg/kg b.w., i.p on Day 8), on testicular toxicity of male Wistar rats. Cis triggered testicular and epididymal oxidative stress, testicular inflammation (upregulated NF-κB, TNF-α and IL-1ß mRNA levels, and downregulated IL-10 mRNA level), increased testicular apoptosis (increased Bax/Bcl2 and caspase-3 mRNA levels) and decreased testicular germ cells proliferation. Further, Cis decreased testicular steroidogenesis (decreased expression of StAR, CYP11A1, 3ß-HSD and 17ß-HSD mRNA and proteins) and decreased follicle stimulating hormone, luteinizing hormone and testosterone levels. Cis also decreased sperm count, motility, viability, normal morphology and Johnsen score. However, intervention with tBHQ significantly decreased oxidative stress by upregulating Nrf2 gene, suppressed inflammation, apoptosis and increased testicular germ cells proliferation. tBHQ also increased steroidogenesis and improved sperm parameters. Taken together, tBHQ improves steroidogenesis and spermatogenesis in Cis-intoxicated rats by improving antioxidant status, dampening inflammation and apoptosis, thus improving the proliferative capacity of spermatogenic cells.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Hidroquinonas/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Cisplatino/antagonistas & inibidores , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Ratos , Ratos Wistar , Testículo/metabolismo , Testosterona/metabolismo
14.
Science ; 368(6495): 1132-1135, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32499443

RESUMO

The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell-secreted epidermal growth factor-like protein, neural epidermal growth factor-like-like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which Nell2 had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.


Assuntos
Comunicação Celular/fisiologia , Endopeptidases/metabolismo , Epididimo/metabolismo , Fertilidade , Infertilidade Masculina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo , Proteínas ADAM/metabolismo , Animais , Comunicação Celular/genética , Endopeptidases/genética , Infertilidade Masculina/genética , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
15.
Proc Natl Acad Sci U S A ; 117(24): 13680-13688, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32493750

RESUMO

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P = 4.4 × 10-6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 × 10-4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1 Arg495Gly/Arg495Gly XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor ß-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.


Assuntos
Transtornos Testiculares 46, XX do Desenvolvimento Sexual/metabolismo , Testículo/metabolismo , Proteínas WT1/metabolismo , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/genética , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/patologia , Animais , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Testículo/crescimento & desenvolvimento , Testículo/patologia , Proteínas WT1/química , Proteínas WT1/genética , Dedos de Zinco , beta Catenina/genética , beta Catenina/metabolismo
16.
Life Sci ; 256: 117982, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32562693

RESUMO

AIMS: This study was designed to evaluate the protective and therapeutic efficacy of platelet-rich plasma (PRP) against testicular degeneration and germ cell apoptosis after induced spermatic cord torsion/detorsion (TD) in rats. MATERIALS: Forty rats were allocated into 5 groups: 1) control, 2) short torsion/detorsion (STD), 3) long torsion detorsion (LTD), 4) protective (PRP/P) and 5) treatment (PRP/T). Testicular ischemia was induced by twisting the right testis 1080° clockwise for 2.5 h. PRP (10 µl) was injected intra-testicular 5 min before (PRP/P) and 3 h after (PRP/T) detorsion. At the end of the experiment, rats were euthanized at 2, 30, 2, and 30 days for groups 2-5 respectively. Nitric oxide, malondialdehyde, catalase, total antioxidant capacity, reduced glutathione, glutathione-S-transferase, interleukin1 beta, tumor necrosis factor, caspase-3, and B-cell lymphoma 2 expressions were assessed in the testes. Moreover, histological examination was performed. KEY FINDINGS: PRP treatment significantly mitigated the torsion-detorsion induced testicular degeneration. Particularly, by improving the state of oxidative stress (NO, P = 0.0001) and antioxidant markers (TAC, GSH, GST, P = 0.0001-0.01) and decreasing the expression of IL-1ß, TNF-α and cas 3 and increase the BCL2 fold changes (P = 0.0001). The protective use of PRP is superior to the therapeutic use of PRP in the restoration of the testicular histoarchitecture following TD. SIGNIFICANCE: This study illustrates the cyto-protective role of PRP against TD induced testicular cell injury that highlight possible application of PRP as a complementary therapy in different testicular degenerative diseases which might attribute to its ability to ameliorate the oxidative stress and inhibit induced apoptosis.


Assuntos
Plasma Rico em Plaquetas/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Torção do Cordão Espermático/metabolismo , Torção do Cordão Espermático/prevenção & controle , Testículo/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Torção do Cordão Espermático/patologia , Testículo/patologia , Resultado do Tratamento
17.
Ecotoxicol Environ Saf ; 202: 110876, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32563953

RESUMO

This study investigated the acute in vitro effect of low-concentration bisphenol A (BPA) on calcium (45Ca2+) influx in zebrafish (Danio rerio) testis and examined whether intracellular Ca2+ was involved in the effects of BPA on testicular toxicity. In vitro studies on 45Ca2+ influx were performed in the testes after incubation with BPA for 30 min. Inhibitors were added 15 min before the addition of 45Ca2+ and BPA to testes to study the mechanism of action of BPA. The involvement of intracellular calcium from stores on lactate dehydrogenase (LDH) release and on triacylglycerol (TAG) content were carried out after in vitro incubation of testes with BPA for 1 h. Furthermore, gamma-glutamyl transpeptidase (GGT) and aspartate aminotransferase (AST) activities were analyzed in the liver at 1 h after in vitro BPA incubation of D. rerio. Our data show that the acute in vitro treatment of D. rerio testes with BPA at very low concentration activates plasma membrane ionic channels, such as voltage-dependent calcium channels and calcium-dependent chloride channels, and protein kinase C (PKC), which stimulates Ca2+ influx. In addition, BPA increased cytosolic Ca2+ by activating inositol triphosphate receptor (IP3R) and inhibiting sarco/endoplasmic reticulum calcium ATPase (SERCA) at the endoplasmic reticulum, contributing to intracellular Ca2+ overload. The protein kinases, PKC, MEK 1/2 and PI3K, are involved in the mechanism of action of BPA, which may indicate a crosstalk between the non-genomic initiation effects mediated by PLC/PKC/IP3R signaling and genomic responses of BPA mediated by the estrogen receptor (ESR). In vitro exposure to a higher concentration of BPA caused cell damage and plasma membrane injury with increased LDH release and TAG content; both effects were dependent on intracellular Ca2+ and mediated by IP3R. Furthermore, BPA potentially induced liver damage, as demonstrated by increased GGT activity. In conclusion, in vitro effect of BPA in a low concentration triggers cytosolic Ca2+ overload and activates downstream protein kinases pointing to a crosstalk between its non-genomic and genomic effects of BPA mediated by ESR. Moreover, in vitro exposure to a higher concentration of BPA caused intracellular Ca2+-dependent testicular cell damage and plasma membrane injury. This acute toxicity was reinforced by increased testicular LDH release and GGT activity in the liver.


Assuntos
Compostos Benzidrílicos/toxicidade , Cálcio/metabolismo , Fenóis/toxicidade , Testículo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Membrana Celular/metabolismo , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Canais Iônicos , Masculino , Proteína Quinase C/metabolismo , Proteína Quinase C/farmacologia , Transdução de Sinais/efeitos dos fármacos , Testículo/metabolismo , Peixe-Zebra/metabolismo
18.
Gene ; 755: 144906, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32554048

RESUMO

The olive flounder Paralichthys olivaceus, an important marine fish, shows gender differences in growth. The mechanism on its gonadal differentiation direction affected with exogenous factors still needs to be clarified. The anti-Müllerian hormone (amh) gene is involved in fish testicular differentiation and maintenance. The aim of this study was to investigate the expression of the flounder amh in tissues and the gonads. The quantitative expression analysis results showed that it was highly expressed in the testis, especially in the testis at stages I - IV (P < 0.05). Also, amh was detected in Sertoli cells surrounding spermatogonia and peripheral seminiferous lobule of the testis with in situ hybridization (ISH) and immunohistochemistry (IHC). During the differentiation period, the amh expression in the testis of the tamoxifen treatment group (100 ppm) was higher than that in the ovary of the 17ß-estradiol (E2, 5 ppm) group, and the expression levels of amh during process of the male differentiation in the tamoxifen group were higher than those in the 17ɑ-methyltestosterone (MT, 5 ppm) group (P < 0.05). ISH results also exhibited that amh was expressed in the somatic cells that surrounded the germ cells of juvenile flounder similar to adult ones. Furthermore, the flounder gonads in the tamoxifen group maintained more germ cells and somatic cells than those in the MT group from 20 to 80 mm total length (TL). Especially, at 60 and 80 mm TL, the numbers of germ and somatic cells in the tamoxifen group were significantly higher than those in the MT group (P < 0.05). In summary, amh might initiate the process of testicular differentiation, and is involved in the early development and maintenance of testis.


Assuntos
Hormônio Antimülleriano/genética , Linguado/genética , Células de Sertoli/metabolismo , Animais , Hormônio Antimülleriano/metabolismo , Diferenciação Celular , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Gônadas/metabolismo , Hibridização In Situ/métodos , Masculino , Metiltestosterona/farmacologia , Ovário/metabolismo , Diferenciação Sexual/genética , Espermatogônias/metabolismo , Tamoxifeno/farmacologia , Testículo/metabolismo
19.
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
20.
Nanotoxicology ; 14(7): 893-907, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32529924

RESUMO

This study aimed to evaluate the effects of an intratesticular injection of silver nanoparticles (AgNPs) on reproductive parameters and health of rats, and to evaluate the AgNPs biodistribution in order to develop a nanotechnological contraceptive agent for male animals. Treated animals received 220 µL of AgNPs solution (0.46 µg-Ag/ml) in each testicle and were euthanized: seven, 14, 28, and 56 days after injection. A significant decrease (p < 0.05) in the percentage of motile sperm in D7 (8.8%) was observed, comparing to the control (73.3%), D14 (86.0%), D28 (68.2%), and D56 (90.0%) groups. D7 group also presented a decrease (p < 0.05) in the percentage of normal spermatozoa. Additionally, D7 group showed an increase (p < 0.05) in abnormal midpiece and sperm head morphology compared to the Control group. Seminiferous tubules presented all germline cell types and spermatozoa for all groups. However, D7 group did not present spermatozoa in the epididymis, whereas some spermatozoa and cellular debris were visible in D14 and D28 groups. All animals presented hematological parameters, creatinine, and alanine aminotransferase values within the normal limits for Wistar rats. The percentage of silver found in the liver was always higher than in the other organs analyzed. A pioneering mathematical model is proposed, from which the half-life time of silver in the liver (17 days), spleen (23 days), lungs (30 days), and kidneys (35 days) was extracted. In conclusion, some acute and severe toxic effects were observed in sperm cells following intratesticular injection of AgNPs, although these effects were reversible. No adverse effects to general animal health were observed.


Assuntos
Nanopartículas Metálicas/toxicidade , Reprodução/efeitos dos fármacos , Prata/toxicidade , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nanopartículas Metálicas/administração & dosagem , Ratos , Ratos Wistar , Prata/administração & dosagem , Prata/farmacocinética , Espermatozoides/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Testículo/metabolismo , Distribuição Tecidual
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