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1.
Chemosphere ; 262: 127880, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32777607

RESUMO

BACKGROUND: Bisphenol A (BPA) is a well-known endocrine disruptor that affects male fertility. However, the main biological events through which BPA affects spermatogenesis remain to be identified. METHODS: Adult male mice were treated by feeding with drinking water containing BPA (0.2 µg/ml, 20 µg/ml, 200 µg/ml, respectively) for two months. Testes were collected for protein extraction or for immunohistochemical analysis. Epididymal spermatozoa were collected for sperm quality evaluation and male fertility assay by in vitro fertility (IVF). Serums were collected for detection of testosterone levels. Proteins associated with germ cell proliferation, meiosis, blood-testis barrier, and steroidogenesis production were examined in BPA-treated and control mice testes. CCK8 assay was used to detect the effect of BPA on the proliferation of GC-1 and GC-2 cells. RESULTS: The BPA-treated mice were characterized by decreased sperm quality, serum testosterone levels and, sub-fertile phenotype characterizing with low pregnancy rates and reduced fertilization efficiency. In lower BPA (0.2 µg/ml) treatment, PCNA and PLZF were down-expressed that indicated impaired germ cell proliferation. SYCP3 was down-expressed in BPA-treated mice, but expressions of other proteins associated with meiosis and blood-testis barrier were not significantly altered. CYP11A1 and HSD3B1 were down-expressed in BPA-treated mice that demonstrated reduced steroidogenesis activity. BPA has a concentration-dependent inhibition effect on the proliferation of GC-1 and GC-2 cells. Conclusively, low doses BPA exposure reduced mice sperm quality mainly by impairing germ cell proliferation, leading to reduced male fertility. The study would provide relevant information for investigation on molecular mechanisms and protective strategy on male production.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Espermatozoides/fisiologia , Animais , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/metabolismo , Epididimo/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos , Gravidez , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testes de Toxicidade Crônica
2.
Chemosphere ; 262: 127792, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32805656

RESUMO

Tebuconazole is a triazole fungicide, used in agriculture to treat phytopathogenic fungi, and as a biocide, has been reported to be related to reproductive and developmental toxicity. The purpose of this study was to investigate the effect of tebuconazole exposure on rat fetal Leydig cells and fetal testis during pregnancy. Pregnant Sprague-Dawley rats were randomly divided into 4 groups, daily gavaged with corn oil (as a control), 25, 50, and 100 mg/kg body weight tebuconazole for 10 days (from the 12th day of pregnancy). Tebuconazole increased fetal serum testosterone and progesterone levels at a dose of 100 mg/kg. Exposure to 100 mg/kg tebuconazole significantly caused an increase in the number of fetal Leydig cells per testis without inducing cell aggregation. Tebuconazole up-regulated the expression of Star, Cyp11a1, Hsd17b3, and Fshr and their proteins. Further investigation found that tebuconazole caused increased phosphorylation of AKT1, ERK1/2, and mTOR, the level of BCL2, as well as the decrease of Beclin1, LC3B, and BAX, which may contribute to the fetal Leydig cell autophagy and proliferation. In conclusion, in utero exposure of tebuconazole causes the proliferation of fetal Leydig cells.


Assuntos
Fungicidas Industriais/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Triazóis/toxicidade , Animais , Feminino , Células Intersticiais do Testículo/metabolismo , Masculino , Fosfoproteínas/genética , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/patologia , Testosterona/sangue , Regulação para Cima
3.
Bull Environ Contam Toxicol ; 105(5): 699-704, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33006036

RESUMO

Transportation of crude oil across North America's boreal ecozone creates the potential for spills in freshwater where less is known about the sensitivity of resident fish than for marine systems. The sensitivity of wild fathead minnows (FHM) to residual concentrations (ppb range) of the water accommodated fraction (WAF) of diluted bitumen (dilbit) was assessed by exposing them for 21 days followed by a 14 days depuration. Target concentrations were well below detection limits for GC-MS, but were estimated by dilution factor (1:100,000 and 1:1,000,000 WAF:water) to contain less than 0.0003 µg/L of polycyclic aromatic compounds. Confinement and handling stress caused by transfer of wild fish into tanks much smaller than their natural range resulted in mortality and lower body condition among all groups, but interactive effects of oil exposures still resulted in females with smaller cortical alveolar oocytes, and males with larger testicular lobe lumen sizes. Additional studies examining the compounded effects of stress and environmentally relevant oil exposures in wild fishes are needed.


Assuntos
Cyprinidae/crescimento & desenvolvimento , Exposição Ambiental/análise , Hidrocarbonetos/análise , Poluição por Petróleo/análise , Petróleo/análise , Poluentes Químicos da Água/análise , Animais , Exposição Ambiental/efeitos adversos , Feminino , Água Doce/química , Hidrocarbonetos/toxicidade , Masculino , América do Norte , Óvulo/efeitos dos fármacos , Óvulo/patologia , Petróleo/toxicidade , Poluição por Petróleo/efeitos adversos , Testículo/efeitos dos fármacos , Testículo/patologia , Poluentes Químicos da Água/toxicidade
4.
Proc Natl Acad Sci U S A ; 117(38): 23751-23761, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32917815

RESUMO

Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit W-sh/W-sh mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.


Assuntos
Anafilaxia , Androgênios/farmacologia , Mastócitos/efeitos dos fármacos , Fatores Sexuais , Animais , Modelos Animais de Doenças , Feminino , Inflamação , Masculino , Mastócitos/fisiologia , Camundongos , Camundongos Transgênicos , Testículo/citologia , Testículo/efeitos dos fármacos
5.
Gen Physiol Biophys ; 39(4): 331-341, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32902403

RESUMO

Quantitative proteomic analysis was performed using iTRAQ to explore the potential regulation of differentially expressed proteins (DEPs) by bisphenol A (BPA) in murine testis. BPA was intraperitoneally injected into mice at a dose of 100 mg/kg body weight for 7 consecutive days. After BPA treatment, the histopathology changes of testis were examined. The circulating levels of testosterone (T) and estradiol (E2) were determined. iTRAQ was used to assess the expression levels of DEPs and to reveal potential interactions between different DEPs. Results showed that BPA caused histological damage in testicular tissues. The levels of T and E2 were affected by BPA exposure. The abundances of orosomucoid 1 (Orm1), haptoglobin (Hp), and insulin-like 3 (Insl3) were significantly lower in BPA-treated mice than those in control mice. The expression changes in the above-mentioned proteins were further validated at the protein level using Western blot analysis. We concluded that BPA affects histological morphology of testis and sex hormone productions. The regulation of key proteins (such as Orm1, Hp and Insl3) may reflect that these proteins may serve as important factors in male reproductive disorders caused by BPA, and these proteins are probably biomarkers for infertility caused by endocrine disrupting chemicals.


Assuntos
Compostos Benzidrílicos/toxicidade , Infertilidade Masculina , Fenóis/toxicidade , Testículo/efeitos dos fármacos , Animais , Estradiol/sangue , Infertilidade Masculina/induzido quimicamente , Masculino , Camundongos , Proteômica , Testículo/metabolismo , Testosterona/sangue
6.
Life Sci ; 260: 118472, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971106

RESUMO

AIMS: Testicular torsion/detorsion (T/D) is a critical medical condition that necessitates prompt surgical intervention to avoid testicular atrophy and infertility. The use of natural compounds may protect against the associated detrimental oxidative stress and inflammatory responses. Interestingly, acetyl-11-keto-ß-boswellic acid (AKBA), the main active constituent of Boswellia resin, has shown potent inhibitory effect on 5-lipoxygenase enzyme which converts arachidonic acid into inflammatory mediators. Therefore, this study was conducted to assess the protective mechanisms by which AKBA may protect against testicular T/D injury in rats. MAIN METHODS: Male rats were randomly distributed into five groups: Sham, AKBA (50 mg/kg, p.o.), unilateral testicular T/D, AKBA at two dose levels (25 or 50 mg/kg for 15 successive days) followed by T/D. Histological examination and Johnsen's score were performed to assess testicular injury and perturbations in spermatogenesis. Biochemical parameters included markers of testicular function (serum testosterone), oxidant/antioxidant status (malondialdehyde, glutathione), inflammation (5-lipoxygenase, leukotriene-B4, myeloperoxidase, interleukin-1ß, interleukin-6), apoptosis (Bax, Bcl2, caspase-3), DNA integrity (quantitative DNA fragmentation, DNA laddering, PARP-1), energy production (ATP), in addition to p38 MAPK and JNK protein expression. KEY FINDINGS: In a dose dependent manner, AKBA significantly inhibited testicular T/D-induced upregulation of 5-LOX/LTB4 and p38-MAPK/JNK/Bax pathways and their associated downstream inflammatory and apoptotic cascades. These effects were accompanied with ATP replenishment and DNA preservation, resulting ultimately in salvage of the testis. SIGNIFICANCE: Unprecedentedly, the present mechanistic study revealed the pathways by which AKBA may inhibit testicular T/D injury and offered a novel protective approach that may attenuate the severity of this condition.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Torção do Cordão Espermático/metabolismo , Torção do Cordão Espermático/prevenção & controle , Testículo/efeitos dos fármacos , Triterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Caspase 3/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucotrieno B4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ratos Wistar , Testículo/metabolismo , Testículo/patologia , Testosterona/metabolismo , Triterpenos/administração & dosagem , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Ecotoxicol Environ Saf ; 203: 111053, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888615

RESUMO

Vinclozolin is a common dicarboximide fungicide used to protect crops from diseases. It is also an endocrine disruptor and is thought to be related to abnormalities of the reproductive tract. However, its mechanism of inducing abnormalities of the male reproductive tract is still unclear. The purpose of this study was to study the effect of gestational vinclozolin exposure on the development of rat fetal Leydig cells. Female pregnant Sprague-Dawley rats were exposed to vinclozolin (0, 25, 50, and 100 mg/kg body weight/day) by gavage from gestational day 14-21. Vinclozolin dose-dependently reduced serum testosterone levels at doses of 50 and 100 mg/kg and the anogenital distance at 100 mg/kg. RNA-seq, qPCR, and Western blotting showed that vinclozolin down-regulated the expression of Nr5a1, Sox9, Lhcgr, Cyp11a1, Hsd3b1, Hsd17b3, Amh, Pdgfa, and Dhh and their encoded proteins. Vinclozolin reduced the number of NR2F2-positive stem Leydig cells at a dose of 100 mg/kg and enhanced autophagy in the testes. In conclusion, vinclozolin disrupts reproductive tract development and testis development in male fetal rats via several pathways.


Assuntos
Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Organogênese/efeitos dos fármacos , Oxazóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Testículo/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Testículo/embriologia , Testículo/patologia , Testosterona/sangue
8.
Ecotoxicol Environ Saf ; 205: 111176, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846301

RESUMO

The effects of 17α-ethinylestradiol (EE2) on sex ratio, gonopodium morphology, and gonadal histology of C. decemmaculatus were assessed by a full-lifecycle exposure experiment. Newborn fish were waterborne exposed to 30, 100, and 300 ng EE2/L for 90 d, using 50 fish per treatment. Additionally, in December of 2016, a field survey was conducted on a C. decemmaculatus population inhabiting the Girado Creek downstream of the Chascomus city wastewater effluent discharge. After 90 d of exposure, EE2 was able to histologically skew the sex ratio toward females and inhibit the full gonopodium development since the lowest tested concentration (LOEC = 30 ng/L). At higher concentrations, EE2 was toxic, inducing mortality in a concentration-dependent fashion (90 d-LC50 = 109.9 ng/L) and altering the gonadal histoarchitecture, causing neither testes nor ovaries discernible histologically (LOEC = 100 ng/L). In addition, a novel response, perianal hyperpigmentation, was discovered been induced by the EE2 exposure in a concentration-dependent fashion (90 d-EC50 = 39.3 ng/L). A higher proportion of females and perianal hyperpigmentation were observed in wild fish collected from the Girado Creek. The major reached conclusions are: i) EE2 induce different effects on the sexual traits of C. decemmaculatus when exposed from early-life or adult stages. ii) The most sensitive effects observed in the laboratory occur in a creek receiving wastewater effluent. iii) The perianal hyperpigmentation comes-up as a promising biomarker of exposure to estrogenic compounds.


Assuntos
Ciprinodontiformes/crescimento & desenvolvimento , Disruptores Endócrinos/toxicidade , Etinilestradiol/toxicidade , Gônadas/efeitos dos fármacos , Hiperpigmentação/induzido quimicamente , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Gônadas/crescimento & desenvolvimento , Gônadas/patologia , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/patologia , Fenótipo , Razão de Masculinidade , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/patologia
9.
Life Sci ; 261: 118301, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32827546

RESUMO

AIM: Acrylamide (AC) is a carcinogenic substance which is formed during the heating of starchy foods at high temperatures and constitutes an important risk for human health. Therefore, reducing the detrimental effects of AC has become an important research topic. This study was performed to evaluate the protective effect of morin against the testicular toxicity induced by AC in male rats. MATERIALS AND METHODS: Testicular damage was evaluated after the rats were treated orally with AC (38.27 mg/kg body weight) alone or with morin (50 and 100 mg/kg body weight) for 10 consecutive days. KEY FINDINGS: Our results showed that treatment with morin could significantly decrease MDA level and considerably increase the activity of antioxidant enzymes (SOD, CAT, GPx) and GSH level in the testicular tissue of the AC-treated rats. Morin supplementation also suppressed the activation of inflammatory, apoptotic and autophagic pathways by increasing Bcl-2 and decreasing p38α MAPK, TNF-α, NF-κB, IL-1ß, IL-6, COX-2, cytochrome c, Bax, caspase-3, LC3A, LC3B and beclin-1 protein levels. Morin also alleviated the side effects caused by AC by regulating the PI3K/Akt/mTOR signaling pathway. SIGNIFICANCE: Collectively, our results have shown the possible protective mechanism of morin, a potential therapeutic agent for AC-induced testicular toxicity.


Assuntos
Acrilamida/toxicidade , Flavonoides/farmacologia , NF-kappa B/metabolismo , Testículo/patologia , Animais , Antioxidantes/metabolismo , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Masculino , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Testículo/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
10.
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
11.
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
12.
Aquat Toxicol ; 226: 105557, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32645606

RESUMO

Extensive studies have shown that estrogenic endocrine-disrupting chemicals (EDCs) can disrupt testis differentiation and even cause feminization in vertebrates. However, little is known about the mechanisms by which estrogenic EDCs disrupt testis differentiation. Here, we employed Xenopus laevis, a model amphibian species sensitive to estrogenic EDCs, to explore the molecular and cellular events by which 17ß-estradiol (E2) disrupts testis differentiation and causes feminization. Following waterborne exposure to E2 from stage 45/46, genetically male X. laevis were confirmed to undergo testis differentiation inhibition and ovary differentiation activation at stages 52 and 53, ultimately displaying gonadal feminization at stage 66. Using a time-course RNA sequencing approach, we then identified thousands of differentially expressed transcripts (DETs) in genetically male gonad-mesonephros complexes at stages 48, 50 and 52 (the window for testis differentiation) between E2 treatment and the control. Enrichment analysis suggests alterations in cell proliferation, extracellular matrix, and cell motility following E2 exposure. Further verification by multiple methods demonstrated that E2 inhibited cell proliferation, disrupted extracellular matrix, and altered cell motility in the genetically male gonads compared with controls, implying that these events together contributed to testis differentiation disruptions and feminization in X. laevis. This study for the first time uncovered some of the early molecular and cellular events by which estrogen disrupts testicular differentiation and causes feminization in X. laevis. These new findings improve our understanding of the mechanisms by which estrogenic EDCs disrupt testicular differentiation in vertebrates.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Feminização , Testículo/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Feminização/induzido quimicamente , Feminização/genética , Perfilação da Expressão Gênica , Humanos , Larva/efeitos dos fármacos , Larva/genética , Masculino , Ovário/efeitos dos fármacos , Xenopus laevis
13.
Aquat Toxicol ; 226: 105580, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32712368

RESUMO

Bisphenol A (BPA), a well-known estrogenic endocrine disruptor, is ubiquitously present in the environment, possessing the potential to interfere with the reproductive endocrine system in male mammals. However, there are limited studies on the reproductive toxicity in male aquatic animals associated with epigenetic modifications. In order to evaluate the potential effects of BPA on reproduction and better understand the underlying mechanism, adult male rare minnow (Gobiocypris rarus) were exposed to 15 µg L-1 BPA over a period of 63 d. Results showed that BPA induced congestion of blood vessels and infiltration of inflammatory cells after 21 d exposure, and decreased sperm fertilization after 63 d exposure. The genome DNA methylation levels were significantly increased throughout the treatment, and a strong positive stain were found in the spermatocyte, spermatid and sperm. The H3K4me3 level in all types of germ cell were increased by 21 d exposure while decreased following 63 d exposure. The positive stain of H3K9me3 was decreased in sperms while increased in spermatids by 21 d exposure. In addition, the H3K9me3 level was significantly increased after 63 d exposure, and a strong positive stain were found in spermatocytes, spermatids, and sperms. Our result also revealed that the transcripts of DNA methyltransferase genes (dnmt1 and dnmt3-8) and histone methyltransferase genes (mll2-5, setdb1-2 and ezh2) were also markedly changed under BPA exposure for 21-63 d. These findings indicated that BPA had toxicity in male reproductive, and DNA/histone methylation might play a vital role in the regulation of BPA-triggered the decreased of sperm quality.


Assuntos
Compostos Benzidrílicos/toxicidade , Cyprinidae/metabolismo , Metilação de DNA/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Histonas/metabolismo , Fenóis/toxicidade , Espermatozoides/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , DNA/metabolismo , Feminino , Humanos , Masculino , Análise do Sêmen , Espermatozoides/metabolismo , Testículo/efeitos dos fármacos
14.
Chemosphere ; 259: 127221, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32615454

RESUMO

Due to its unique properties, graphene oxide (GO) has potential for biomedical and electronic applications, however environmental contamination including aquatic ecosystem is inevitable. Moreover, potential risks of GO in aquatic life are inadequately explored. Present study was designed to evaluate GO as an endocrine disrupting chemical (EDC) using the model Japanese medaka (Oryzias latipes). GO was injected intraperitoneally (25-200 µg/g) once to breeding pairs and continued pair breeding an additional 21 days. Eggs laid were analyzed for fecundity and the fertilized eggs were evaluated for developmental abnormalities including hatching. Histopathological evaluation of gonads, liver, and kidneys was made 21 days post-injection. LD50 was found to be sex-dependent. Fecundity tended to reduce in a dose-dependent manner during early post-injection days; however, the overall evaluation showed no significant difference. The hatchability of embryos was reduced significantly in the 200 µg/g group; edema (yolk and cardiovascular) and embryo-mortality remained unaltered. Histopathological assessment identified black particles, probably agglomerated GO, in the gonads of GO-treated fish. However, folliculogenesis in stromal compartments of ovary and the composition of germinal elements in testis remained almost unaltered. Moreover, granulosa and Leydig cells morphology did not indicate any significant EDC-related effects. Although liver and kidney histopathology did not show GO as an EDC, some GO-treated fish accumulated proteinaceous fluid in hepatic vessels and induced hyperplasia in interstitial lymphoid cells (HIL) located in kidneys. GO agglomerated in medaka gonads after 21-days post-injection. However, gonad histopathology including granulosa and Leydig cells alterations were associated with GO toxicity rather than EDC effects.


Assuntos
Grafite/toxicidade , Oryzias/fisiologia , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Ecossistema , Disruptores Endócrinos/toxicidade , Feminino , Fertilidade/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Testículo/efeitos dos fármacos
15.
Int J Nanomedicine ; 15: 4191-4203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606672

RESUMO

Purpose: To characterize the nanoparticle of antroquinonol from A. cinnamomea and its ameliorative effects on the reproductive dysfunction in the diabetic male rat. Material and Methods: The chitosan-silicate nanoparticle was used as the carrier for the delivery of antroquinonol from solid-state-cultured A. cinnamomea extract (AC). The rats were fed with a high-fat diet and intraperitoneally injected with streptozotocin to induce diabetes. The rats were daily oral gavage by water [Diabetes (DM) and Control groups], three different doses of chitosan-silicate nanoparticle of antroquinonol from solid-state-cultured A. cinnamomea (nano-SAC, NAC): (DM+NAC1x, 4 mg/kg of body weight; DM+NAC2x, 8 mg/kg; and DM+NAC5x, 20 mg/kg), solid-state-cultured AC (DM+AC5x, 20 mg/kg), or metformin (DM+Met, 200 mg/kg) for 7 weeks. Results: The nano-SAC size was 37.68±5.91 nm, the zeta potential was 4.13±0.49 mV, encapsulation efficiency was 79.29±0.77%, and loading capacity was 32.45±0.02%. The nano-SAC can improve diabetes-induced reproductive dysfunction by regulating glucose, insulin, and oxidative enzyme and by increasing the level of testosterone, follicle-stimulating hormone, luteinizing hormone, and sperm count as well as sperm mobility. In testicular histopathology, the seminiferous tubules of A. cinnamomea-supplemented diabetic rats showed similar morphology with the control group. Conclusion: The nanoparticle of antroquinonol from Antrodia cinnamomea can be used as an effective strategy to improve diabetes-induced testicular dysfunction.


Assuntos
Antrodia/química , Diabetes Mellitus Experimental/tratamento farmacológico , Nanopartículas/química , Reprodução , Ubiquinona/análogos & derivados , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Jejum/sangue , Glutationa Peroxidase/metabolismo , Humanos , Insulina/efeitos adversos , Insulina/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Estreptozocina , Superóxido Dismutase/metabolismo , Testículo/efeitos dos fármacos , Testículo/patologia , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
16.
Aquat Toxicol ; 225: 105553, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32622090

RESUMO

Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 µg/L) or EE2 (0.01 µg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.


Assuntos
Compostos Benzidrílicos/toxicidade , Etinilestradiol/toxicidade , Oryzias/fisiologia , Fenóis/toxicidade , Testículo/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Disruptores Endócrinos/metabolismo , Estrogênios/metabolismo , Etinilestradiol/metabolismo , Feminino , Perfilação da Expressão Gênica , Larva/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos
17.
Arch Environ Contam Toxicol ; 79(2): 258-269, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32666217

RESUMO

Phenothiazine (PTZ) is a heterocyclic thiazine compound used for industrial and medical purposes. Through environmental surveillance studies, PTZ was found being discharged into a local river in Connecticut. Phenothiazine has been shown to act similarly to endocrine disrupting chemicals. This study sought to identify sex specific hormone receptor changes in Fundulus heteroclitus in response to PTZ exposure. Fundulus heteroclitus, also known as mummichog, are small fish native to the Atlantic coast of the United States and Canada. They reside in brackish waters and can survive harsh toxic environments. This model organism is native to the polluted waters found in Connecticut. In this study, fish were exposed to PTZ concentrations of 0.5 ppm, 1.0 ppm, and 2.0 ppm for 1 week. Following exposure, brain, liver, and gonad tissues were harvested; cDNA was synthesized; and mRNA expression was assessed for 6 different hormone receptors. Compared with vehicle control (ethanol) differences in mRNA expression, levels of hormone receptors were observed in various tissues from male and female fish. Many of the tissues assessed showed changes in expression level, while only female liver and testis showed no change. These results implicate PTZ as a potential endocrine disrupting compound to mummichog at environmentally relevant concentrations.


Assuntos
Fundulidae/fisiologia , Fenotiazinas/toxicidade , Receptores de Esteroides/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Canadá , Disruptores Endócrinos/metabolismo , Monitoramento Ambiental , Feminino , Fundulidae/metabolismo , Fígado/química , Masculino , Fenotiazinas/metabolismo , Testículo/efeitos dos fármacos , Poluentes Químicos da Água/análise
18.
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
19.
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
20.
Toxicol Appl Pharmacol ; 401: 115077, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479917

RESUMO

Triclocarban (TCC) is an antimicrobial compound, widely used in personal care products, such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Studies show that TCC has been associated with some endocrine disruptions. In vitro, TCC demonstrated potent androgen-augmenting activity and aromatase inhibition. In this sense, exposure during critical periods of development (gestation and lactation) could lead to some adverse health outcomes in offspring. Therefore, the present study evaluated if maternal exposure to three different doses of TCC could interfere in the reproductive parameters of male offspring. Pregnant female Wistar rats were separated into four groups: vehicle Control (CTR); TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg (TCC 1.5); TCC 3.0 mg/kg (TCC 3.0). Dams were treated daily by oral gavage from gestational day 0 to lactational day 21. The males were evaluated in different timepoint: infancy (PND 21), puberty (PND 50) and adult life (PND 90-120). The histomorphometric analysis of testis and testosterone level were assessed on PND 21, 50, 120; sexual behavior and sperm parameters at adulthood. In the TCC 3.0 group, a decrease in the testis interstitial volume and an increase in testosterone levels were observed on PND 21. Moreover, there was a decrease in the diameter of the seminiferous tubules on PND 50, and a decrease in sexual competency in adulthood. These results suggest that exposure to a human relevant dose of TCC may interfere with reproduction and could have implications for human health.


Assuntos
Anti-Infecciosos Locais/toxicidade , Carbanilidas/toxicidade , Lactação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Fatores Etários , Animais , Feminino , Lactação/fisiologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Reprodução/fisiologia , Comportamento Sexual Animal/fisiologia , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
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