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1.
Ecotoxicol Environ Saf ; 202: 110960, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800232

RESUMO

Zinc oxide nanoparticles (ZnO NPs) have been extensively used in various industries and reported to inhibit spermatogenesis, however, ZnO NPs-induced spermatogenesis failure is yet to be fully elucidated. Herein, mouse-derived spermatogonia cell line GC-1 spg cells were treated with ZnO NPs for 24 h in the presence or absence of radical scavenger N-acetyl-L-cysteine (NAC) or autophagy inhibitor 3-methyladenine (3-MA), then cell viability was observed by MTT assay; apoptosis was observed by western blotting analysis and AnnexinV-FITC/PI assay, respectively; autophagy was detected by western blotting analysis and transmission electron microscopy, respectively; and the contents of MDA and GSH and the activities of SOD and GSH-PX were measured by oxidative stress kits. The present study showed that ZnO NPs exposure inhibited viability and induced apoptosis of mouse GC-1 spg cells. Intriguingly, ZnO NPs markedly increased the protein content of LC3-II, the ratio of LC3-II/LC3-I, and the protein levels of ATG 5 and Beclin 1 in the cells. Furthermore, transmission electron microscopy (TEM) showed that autophagic vesicles in the cytoplasm increased significantly in the ZnO NPs-treated cells, indicating that ZnO NPs could induce autophagy of the cells. Oxidative stress could be induced by ZnO NPs; moreover, inhibition of oxidative stress could alleviate the induction of apoptosis and autophagy by ZnO NPs. Inhibition of autophagy by 3-MA could rescue the inhibition of cell viability and induction of apoptosis by ZnO NPs, which indicated that autophagy might have cytotoxic effect on ZnO NPs-induced apoptosis. In summary, oxidative stress was involved in ZnO NPs-induced apoptosis and autophagy of mouse GC-1 spg cells, and autophagy might play a cytotoxic role in ZnO NPs-induced apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Nanopartículas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Óxido de Zinco/toxicidade , Animais , Proteína Beclina-1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Microscopia Eletrônica de Transmissão , Espécies Reativas de Oxigênio/metabolismo , Espermatogênese/efeitos dos fármacos
2.
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
3.
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
4.
Ecotoxicol Environ Saf ; 202: 110881, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32574863

RESUMO

Exposure to ambient PM2.5 may correlate with the decline of semen quality, and the underlying biological mechanism has not been fully understood. In the present study, mice were intratracheally instilled with diesel exhaust PM2.5 (DEP), and its effects on the spermatogenic process as well as the alterations of testicular gene expression profile were assessed. Our results showed that chronic exposure to DEP impaired the fertility of male mice without influencing their libido. Compared with Vehicle-exposed group, the sperm count and motility from DEP-exposed mice were significantly decreased. In addition, immunohistological staining of γH2AX and DMC1, biomarkers for meiotic double strand breaks (DSBs), demonstrated that chronic exposure to DEP comprised the repair of meiotic DSBs, thus disrupting the spermatogenesis. Deep RNA sequencing test showed altered expressions of testicular genes including the GnRH signaling pathway. In summary, our research demonstrated that chronic exposure to DEP may disrupt spermatogenesis through targeting the meiotic recombination, providing a new perspective for the research on the male reproductive system damage caused by air pollution.


Assuntos
Poluentes Atmosféricos/toxicidade , Espermatogênese/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Fertilidade , Masculino , Camundongos , Material Particulado/toxicidade , Análise do Sêmen , Espermatozoides/efeitos dos fármacos , Testículo
5.
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
6.
Chemosphere ; 258: 127238, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32563064

RESUMO

Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) are phthalate compounds frequently detected in the environment. Despite increasing awareness of their toxicity in human and animals, the male reproductive toxicity of their combined exposure remains elusive. The purposes of this study were to investigate whether combined exposure to DBP and DiBP could induce male reproductive toxicity, and to explore the potential toxicological mechanisms. Adult male zebrafish were exposed to DBP (11, 113 and 1133 µg L-1), DiBP (10, 103 and 1038 µg L-1) and their mixtures (Mix) (11 + 10, 113 + 103, 1133 + 1038 µg L-1) for 30 days, and their effects on plasma hormone secretion, testis histology and transcriptomics were examined. Highest concentrations of Mix exposure caused greater imbalance ratio of T/E2 and more severe structural damage to testis than single exposure. These effects were consistent with the testis transcriptome analysis for which 4570 genes were differentially expressed in Mix exposure, while 2795 and 1613 genes were differentially expressed in DBP and DiBP, respectively. KEGG pathway analysis showed that both single and combined exposure of DBP and DiBP could affect cytokine-cytokine receptor interaction. The difference was that combined exposure could also affect steroid hormone synthesis, extracellular matrix receptor interaction, retinol metabolism, and PPAR signaling pathways. These results demonstrated that combined exposure to DBP and DiBP could disrupt spermatogenesis and elicit male reproductive toxicity in zebrafish.


Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/toxicidade , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Teóricos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Testículo/metabolismo
7.
Toxicology ; 441: 152504, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445656

RESUMO

Manganese (Mn) is essential for animal development and homeostasis. However, anthropogenic activities increase the concentration of Mn in the environment and lead to increased risk of exposure to high doses of the metal. Thus, this study aimed to evaluate the effect of high doses of Mn on the male reproductive system of swiss mice. The 22-day old mice were randomly sorted into four groups and exposed to 0 (control), 15, 30 and 60 mg of MnCl2/kg/day, via daily gavages for 45 days. After the exposure, the mice were euthanized and sperm, hormonal and oxidative stress endpoints were evaluated in the testis, seminal vesicle and hypothalamus. Exposure to Mn promoted weight reduction of androgen-dependent organs, as well as alteration of the levels of fecal androgenic metabolites. Sperm parameters were drastically affected in all treated groups and the antioxidants tested (catalase and glutathione-disulfide reductase activities, and non-protein thiols content) decreased in the testis. However, only a few endpoints were altered in the seminal vesicle. For the hypothalamus, there was a reduction in acetylcholinesterase activity, suggesting a neurotoxic potential of Mn. In conclusion, Mn may affect the hypothalamic-gonadal axis by impairing the development of androgen-dependent organs, testicular redox status and Leydig cell maturation.


Assuntos
Genitália Masculina/efeitos dos fármacos , Manganês/toxicidade , Reprodução/efeitos dos fármacos , Androgênios/análise , Animais , Fezes/química , Genitália Masculina/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/sangue
8.
Aquat Toxicol ; 224: 105503, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32438217

RESUMO

Tributyltin (TBT) was reported to affect sexual behavior and gametogenesis in fish. However, the modes of action involved are largely unclear. In order to elucidate the toxicological mechanisms of TBT in reproduction, zebrafish (Danio rerio) males were exposed to TBT at concentrations of 100 and 500 ng/L for 28 days. After exposure, the sperm count of the treated fish was sharply decreased though the testis weight and gonadosomatic index remained unchanged. Moreover, reduced number of spermatogonia and spermatozoa and increased spermatocytes were observed in TBT-treated fish by histological observation and PCNA-immunostaining. Increased number of apoptotic-positive spermatocytes was also present in TBT-treated fish, indicating an enhanced apoptosis in these cells. Consistent to decreased number of spermatogonia, down-regulated expressions of genes responsible for germ cell proliferation (cyclind1 and pcna) were observed in TBT-treated fish. In contrast, TBT elevated the expressions of genes involved in meiotic entry and maintenance (aldhla2, sycp3 and dmc1) while suppressed the mRNA level of gene responsible for terminus of meiotic entry (cyp26a1), in agreement with arrested meiosis and reduced sperm count. Furthermore, TBT significantly elevated the ratios of bax/bcl-2 and tnfrsf1a/tnfrsf1b in testis, which are markers for intrinsic- and extrinsic-apoptotic pathways, consistent with the enhanced TUNEL positive signals in spermatocytes. Moreover, TBT also significantly affected the parameter of reproductive behaviors in treated fish (reflected by decreased frequency of meeting, visits and time spent in spawning area). Consistently, the expressions of genes responsible for the modulation of reproductive behaviors in brain (such as cyp19a1b, kiss2, gnrh3 and ompb) were significantly down-regulated in treated-fish. Interestingly, disrupted reproductive behaviors of untreated female fish were also observed in the present study. The present study indicated that TBT might affect the reproduction of zebrafish male by disrupting the spermatogenesis and reproductive behavior of the fish.


Assuntos
Comportamento Sexual Animal/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Compostos de Trialquitina/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Meiose/efeitos dos fármacos , Meiose/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
9.
Chemosphere ; 256: 127001, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32447106

RESUMO

N, N-Dimethylacetamide is an FDA approved solvent widely used in pharmaceutical industry to facilitate the solubility of lipophilic, high molecular weight drugs with poor water solubility. However, the cytotoxic effects of DMA raises the concern about its use in clinical applications. In the present study, we address the effect of DMA on spermatogenesis. Male Sprague Dawley rats were injected intra-peritoneally for 8 weeks, once a week at a dose of 862 mg/kg. Analysis of reproductive parameters revealed that DMA treated animals exhibit spermatid formation defects within the testis describing the characteristics of oligozoospermia. A subsequent decrease in epididymal sperm concentration along with distortion of sperm morphology was observed. The mitochondrial and microtubule organization in the sperm is considerably modified by DMA. This disrupts the sperm kinetics thus decreasing the total and progressive sperm motility. Finally, DMA treatment resulted in loss of fertility. Our results indicate that exposure to DMA has a negative impact on spermatogenesis and leads to infertility in male rats by inhibiting the post meiotic stages of sperm development. Therefore, the use of DMA in humans must be closely monitored.


Assuntos
Acetamidas/toxicidade , Excipientes/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Epididimo/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Humanos , Infertilidade , Masculino , Ratos , Ratos Sprague-Dawley , Reprodução , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos
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.
Toxicology ; 438: 152463, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32294493

RESUMO

Methyl parathion (Me-Pa) is an extremely toxic organophosphorus pesticide still used in developing countries. It has been associated with decreased sperm function and fertility and with oxidative and DNA damage. The blood-testis barrier (BTB) is a structure formed by tight junction (TJ) proteins in Sertoli cells and has a critical role in spermatogenesis. We assessed the effect of repeated doses of Me-Pa (3-12 mg/kg/day for 5 days, i.p.) on sperm quality, lipid oxidation, DNA integrity, and BTB permeability in adult male mice and explored oxidation as a mechanism of toxicity. Me-Pa caused dose-dependent effects on sperm quality, lipoperoxidation, and DNA integrity. Testis histology results showed the disruption of spermatogenesis progression and atrophy of seminiferous tubules. The pesticide opened the BTB, as evidenced by the presence of a biotin tracer in the adluminal compartment of the seminiferous tubules. This effect was not observed after 45 days of exposure when a spermatogenic cycle had completed. The coadministration of the antioxidant α-tocopherol (50 mg/kg/day for 5 days, oral) prevented the effects of Me-Pa on sperm quality, DNA and the BTB, indicating the importance of oxidative stress in the damage generated by Me-Pa. As evidenced by immunochemistry, no changes were found in the localization of the TJ proteins of the BTB, although oxidation (carbonylation) of total proteins in testis homogenates was detected. Our results show that Me-Pa disturbs the BTB and that oxidation is involved in the observed toxic effects on sperm cells.


Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Dano ao DNA , Metil Paration/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Barreira Hematotesticular/metabolismo , Barreira Hematotesticular/patologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Carbonilação Proteica/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia
12.
Arch. esp. urol. (Ed. impr.) ; 73(3): 230-235, abr. 2020. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-192921

RESUMO

OBJECTIVES: Although the association between 5 alpha reductase inhibitors used for the treatment of both androgenetic alopecia and benign prostatic hyperplasia and their side effects is well established, the impact of dutasteride on testicular structure is not clear. To evaluate the alterations in spermatogenesis and serum FSH, LH, testosterone and dihydrotestosterone concentrations along with the oxidative status in testes and blood of the rats treated with daily dutasteride. METHODS: A total of 18 male Sprague-Dawley rats have been divided into 2 groups as control (n=8) and dutasteride (n=10). After chronically administered, rats were sacrificed and their testes were harvested for histopathological and biochemical evaluation. Johnsen's criteria were used to assess spermatogenesis. Serum hormone concentrations and levels of reactive oxygen species (ROS) in both testicular tissue and serum were measured by ECLIA and ELISA, respectively. Results were compared with Mann- Whitney U test. RESULTS: DHT (7.35 ± 0.35 vs. 10.54 ± 0.95, p < 0.001) and LH levels (0.32 ± 0.009 vs. 0.43 ± 0.01, <0.001) were significantly lower in treatment group compared with controls whereas testosterone levels were higher in dutasteride arm (3.41 ± 1.12 vs. 1.52 ± 0.34, p < 0.001). Johnsen score, serum FSH levels, serum and tissue ROS levels were similar between the two groups. CONCLUSIONS: According to our results, administration of dutasteride does not appear to modify spermatogenesis and oxidative burden in rats. Further investigations are required to confirm our findings


OBJETIVOS: Aunque la asociación entre los inhibidores de la 5'alfa reductasa y el tratamiento de la alopecia y de la hiperplasia benigna de próstata esta bien establecido, el impacto de dutasteride en la estructura testicular no esta claro. El objetivo de este trabajo es evaluar las alteraciones en la espermatogénesis y concentraciones de FSH, LH, testosterona y dihidrotestosterona junto con el estado oxidativo del testículo y en sangre de ratas con la administración diaria dedutasteride. MÉTODOS: Un total de 18 ratas Sprague Dawle fueron divididas en 2 grupos: control (n = 8) y dutasteride (n = 10). Después de una administración crónica de dutasteride, las ratas fueron sacrificadas y los testículos se analizaron del punto de vista anatomopatológico y bioquímico. Los criterios de Johnsen fueron utilizados para valorar la espermatogénesis. Los niveles séricos hormonales y de especias reactivas del oxigeno en el tejido testicular y serum fueron medidos con ECLIA y ELISA respectivamente. Los resultados se compararon con Test Mann-Whitney. RESULTADOS: Los niveles de DHT (7,35 ± 0,35 vs. 10,54 ± 0,95, p < 0,001) y LH (0,32 ± 0,009 vs. 0,43 ± 0,01, < 0,001) fueron significativamente menores en el grupo tratamiento en comparación con los controles, mientras que los niveles de testosterona fueron mas elevados en el brazo de dutasteride (3,41 ± 1,12 vs. 1,52 ± 0,34, p < 0,001). El score de Johansen los niveles séricos de FSH y de ROS fueron similares entre ambos grupos. CONCLUSIONES: De acuerdo con nuestros resultados, la administración de dutasterida no parece modificar la espermatogénesis y la carga oxidativa en ratas. Mas investigaciones son necesarias para confirmar nuestros hallazgos


Assuntos
Animais , Masculino , Ratos , Dutasterida/uso terapêutico , Espermatogênese/efeitos dos fármacos , Alopecia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Dutasterida/efeitos adversos , Dutasterida/farmacocinética , Ratos Sprague-Dawley , Alopecia/veterinária , Hormônio Foliculoestimulante/sangue , Testículo/anatomia & histologia , Testículo/efeitos dos fármacos
13.
Life Sci ; 253: 117704, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32339542

RESUMO

Adverse effects of drugs on male reproductive system can be categorized as pre-testicular, testicular, and post-testicular. Pre-testicular adverse effects disrupt the hypothalamic-pituitary-gonadal (HPG) axis, generally by interfering with endocrine function. It is known that the HPG axis has roles in the maintenance of spermatogenesis and sexual function. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) which enters the hypophyseal portal system to stimulate the anterior pituitary. The anterior pituitary secretes gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which are vital for spermatogenesis, into the blood. The FSH stimulates the Sertoli cells for the production of regulatory molecules and nutrients needed for the maintenance of spermatogenesis, while the LH stimulates the Leydig cells to produce and secrete testosterone. Many neurotransmitters influence the hypothalamic-pituitary regulation, consequently the HPG axis, and can consequently affect spermatogenesis and sexual function. Psychotropic drugs including antipsychotics, antidepressants, and mood stabilizers that all commonly modulate dopamine, serotonin, and GABA, can affect male spermatogenesis and sexual function by impairment of the hypothalamic-pituitary regulation, act like endocrine-disrupting chemicals. Otherwise, studies have shown the relationship between decreased sperm quality and psychotropic drugs treatment. Therefore, it is important to investigate the adverse reproductive effects of psychotropic drugs which are frequently used during reproductive ages in males and to determine the role of the hypothalamic-pituitary regulation axis on possible pathologies.


Assuntos
Disruptores Endócrinos/efeitos adversos , Psicotrópicos/efeitos adversos , Reprodução/efeitos dos fármacos , Animais , Disruptores Endócrinos/farmacologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Masculino , Hipófise/efeitos dos fármacos , Psicotrópicos/farmacologia , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
15.
Urol Clin North Am ; 47(2): 227-244, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32272995

RESUMO

Infertility caused by chemotherapy or radiation treatments negatively impacts patient-survivor quality of life. The only fertility preservation option available to prepubertal boys who are not making sperm is cryopreservation of testicular tissues that contain spermatogonial stem cells (SSCs) with potential to produce sperm and/or restore fertility. SSC transplantation to regenerate spermatogenesis in infertile adult survivors of childhood cancers is a mature technology. However, the number of SSCs obtained in a biopsy of a prepubertal testis may be small. Therefore, methods to expand SSC numbers in culture before transplantation are needed. Here we review progress with human SSC culture.


Assuntos
Células-Tronco Germinativas Adultas/transplante , Preservação da Fertilidade/métodos , Infertilidade Masculina/prevenção & controle , Neoplasias/terapia , Espermatogênese/fisiologia , Células-Tronco Germinativas Adultas/fisiologia , Humanos , Infertilidade Masculina/etiologia , Masculino , Espermatogênese/efeitos dos fármacos , Espermatogênese/efeitos da radiação , Transplante de Células-Tronco/métodos
16.
Int J Nanomedicine ; 15: 1853-1862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256064

RESUMO

Background: Curcumin has shown many pharmacological activities in both preclinical and clinical studies. Many technologies have been developed and applied to improve the solubility and bioavailability of curcumin, especially the nanotechnology-based delivery systems. However, there has been evidence that certain nanoparticles have potential reproductive toxicity in practice. Methods: Curcumin-poly (lactic-co-glycolic acid) (PLGA)-PEG nanoparticles (Cur-PLGA-NPs for short) were prepared. The Cur-PLGA-NPs were evaluated with its effect on the proliferation of mouse testicular cell lines in vitro and spermatogenesis in vivo, while PLGA-NPs were used as control. For animal experiments, male BALB/c mice were treated with 20 mg/kg of Cur-PLGA-NPs for continuous 10 days via tail vein injection. Results: We found the curcumin nanoparticles suppressed the proliferation of testicular cell lines in vitro. Furthermore, a short-term intravenous delivery of curcumin-loaded nanoparticles could be harmful to the differentiation of spermatogonia, the elongation of spermatids, as well as the motility of mature sperms. Conclusion: In the present study, we disclosed the acute damage on mouse spermatogenesis and sperm parameters by curcumin-loaded nanoparticles. Our results suggested that the reproductive toxicity of nanoformulated curcumin needs to be prudently evaluated before its application.


Assuntos
Curcumina/efeitos adversos , Nanopartículas/efeitos adversos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/química , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Células de Sertoli/efeitos dos fármacos , Espermatogônias/efeitos dos fármacos , Espermatogônias/patologia , Espermatozoides/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.
Toxicology ; 437: 152439, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32197949

RESUMO

Cyclophosphamide (CP) is widely used as chemotherapy in various cancers; however, testicular atrophy has been encountered as an associated adverse effect. Oxidative stress, enhanced endoplasmic reticulum (ER) stress, and subsequent apoptosis are involved in the molecular mechanisms of CP-induced testicular toxicity. In addition to the cardiovascular benefits of LCZ696 (sacubitril/valsartan (VAL)), neprilysin inhibition was shown to mediate Ca2+ sequestration inside the ER. Furthermore, long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) was shown to ameliorate apoptosis in various diseases. This tempted us to investigate the possible benefit of LCZ696 against CP-induced testicular dysfunction in rats through neprilysin inhibition axis, and the downstream apoptotic cascade, with highlighting the impact of lncRNA TUG1 in regulating testicular toxicity. Sixty adult male Wistar rats were randomly allocated as control, LCZ696, VAL, CP, CP + LCZ696, and CP + VAL. Testicular atrophy was induced by single-dose injection of CP (200 mg/kg; i.p.). LCZ696 treated group received LCZ696 (30 mg/kg; p.o.) for 6 days, with CP (200 mg/kg; i.p.) single-dose on day 5. LCZ696 increased lncRNA TUG1 expression, improved sperm characteristics, hormonal profile, testicular function, antioxidant defences, and Bcl-2. The histopathological picture and reduced oxidative and ER stress markers, aligned with declined Bax, caspase-3 and the expression of CHOP, PUMA, Noxa, Bim, and p53, with a subtle superior effect over VAL-treated group. In conclusion, the current study highlights the promising impact of LCZ696 in ameliorating chemotherapy-induced testicular atrophy; yet, further investigation regarding longer duration and different doses of LCZ696 is warranted.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Ciclofosfamida/toxicidade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , RNA Longo não Codificante/metabolismo , Testículo/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Atrofia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Neprilisina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/genética , Ratos Wistar , Transdução de Sinais , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/enzimologia , Testículo/patologia
19.
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
20.
Toxicol Lett ; 326: 114-122, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32199951

RESUMO

Previous studies have reported the reproductive toxicity of cadmium (Cd); however, the effect of Cd on spermatogenesis and the underlying mechanism remain to be elucidated. In this study, mouse Leydig TM3 cells were treated with CdCl2 (0, 5, 10 and 50 µM) for 24 h to evaluate cytotoxicity, and C57BL/6 mice were treated intragastrically with 0.4 mL CdCl2 (0, 0.01, 0.05 and 0.1 g/L) for 2 months to investigate changes in spermatogenesis. The results showed that Cd aggravated apoptosis and proliferation in a dose-dependent manner, concomitant with deteriorated spermatogenesis and testosterone synthesis. For mechanism exploration, RNA-seq was used to profile alterations in gene expression in response to Cd, and the results indicated focus on P53/JNK signalling pathways and membrane proteins. We found that P53/JNK signalling pathways were activated upon Cd treatment, with the Cd-triggered downregulation of the vdac2 gene. P53/JNK pathway blockade ameliorated the Cd-induced inhibition of steroidogenic acute regulatory protein (STAR) expression and testosterone synthesis. Additionally, vdac2 knockdown in TM3 cells contributed to the phosphorylation of JNK/P53 and reduced the testosterone content. Vdac2 overexpression rescued the aforementioned Cd-induced events. Collectively, our study identified an innovative biomarker of Cd exposure in mice. The results demonstrated that vdac2 downregulation inhibits spermatogenesis via the JNK/P53 cascade. This finding may contribute to our understanding of the regulatory mechanism of Cd reproductive toxicity and provide a candidate list for sperm abnormality factors and pathways.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Canal de Ânion 2 Dependente de Voltagem/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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