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1.
Cells ; 11(23)2022 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-36497038

RESUMEN

Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before the manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Moreover, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1, and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signaling, which plays a key role in regulating the transcription process of some of these genes. In line with the findings in BACHD rats, analyses in the R6/2 mouse model of HD showed similar results. Our findings support the view that mutant huntingtin may induce abnormal growth in males via the dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.


Asunto(s)
Proteína Huntingtina , Enfermedad de Huntington , Testosterona , Animales , Femenino , Masculino , Ratones , Ratas , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Testosterona/biosíntesis , Proteína Huntingtina/genética
2.
Andrology ; 10(7): 1411-1425, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35973717

RESUMEN

BACKGROUND: Leydig cells produce testosterone and insulin-like 3, two hormones essential for male sex differentiation and reproductive function. The orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor type II (COUP-TFII), and the zinc finger factor GATA4 are two transcription factors involved in Leydig cell differentiation, gene expression, and function. OBJECTIVES: Several Leydig cell gene promoters contain binding motifs for both GATA factors and nuclear receptors. The goal of the present study is to determine whether GATA4 and COUP-TFII cooperate to regulate gene expression in Leydig cells. MATERIALS AND METHODS: The transcriptomes from GATA4- and COUP-TFII-depleted MA-10 Leydig cells were analyzed using bioinformatic tools. Functional cooperation between GATA4 and COUP-TFII, and other related family members, was assessed by transient transfections in Leydig (MA-10 and MLTC-1) and fibroblast (CV-1) cell lines on several gene promoters. Recruitment of GATA4 and COUP-TFII to gene promoters was investigated by chromatin immunoprecipitation. Co-immunoprecipitation was used to determine whether GATA4 and COUP-TFII interact in MA-10 Leydig cells. RESULTS: Transcriptomic analyses of GATA4- and COUP-TFII-depleted MA-10 Leydig cells revealed 44 commonly regulated genes including the anti-Müllerian hormone receptor type (Amhr2) gene. GATA4 and COUP-TFII independently activated the Amhr2 promoter, and their combination led to a stronger activation. A GC-rich element, located in the proximal Amhr2 promoter was found to be essential for GATA4- and COUP-TFII-dependent activation as well as for the COUP-TFII/GATA4 cooperation. COUP-TFII and GATA4 directly interacted in MA-10 Leydig cell extracts. Chromatin immunoprecipitation revealed that GATA4 and COUP-TFII are recruited to the proximal Amhr2 promoter, which contains binding sites for both factors in addition to the GC-rich element. Cooperation between COUP-TFII and GATA6, but not GATA1 and GATA3, was also observed. DISCUSSION AND CONCLUSION: Our results establish the importance of physical and functional cooperation between COUP-TFII/GATA4 in the regulation of gene expression in MA-10 Leydig cells, and more specifically the Amhr2 gene.


Asunto(s)
Factor de Transcripción COUP II , Factor de Transcripción GATA4 , Células Intersticiales del Testículo , Receptores de Factores de Crecimiento Transformadores beta , Animales , Factor de Transcripción COUP II/genética , Factor de Transcripción COUP II/metabolismo , Extractos Celulares , Factor de Transcripción GATA4/genética , Factor de Transcripción GATA4/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Insulina/biosíntesis , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Regiones Promotoras Genéticas/genética , Proteínas , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Testosterona/biosíntesis
3.
Cell Signal ; 95: 110336, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35452821

RESUMEN

The intratumoral androgen synthesis is one of the mechanisms by which androgen receptor (AR) is aberrantly re-activated in castration-resistant prostate cancer (CRPC) after androgen ablation. However, pathways controlling steroidogenic enzyme expression and de novo androgen synthesis in prostate cancer (PCa) cells are largely unknown. In this study, we explored the potential roles of DAB2IP in testosterone synthesis and CRPC tumor growth. Indeed, DAB2IP loss could maintain AR transcriptional activity, PSA re-expression and tumor growth under castrated condition in vitro and in vivo, and reprogram the expression profiles of steroidogenic enzymes, including AKR1C3. Mechanistically, DAB2IP could dramatically inhibit the AKR1C3 promoter activity and the conversion from androgen precursors (i.e., DHEA) to testosterone through PI3K/AKT/mTOR/ETS1 signaling. Consistently, there was a high co-expression of ETS1 and AKR1C3 in PCa tissues and xenografts, and their expression in prostate tissues could also restore AR nuclear staining in castrated DAB2IP-/- mice after DHEA supplement. Together, this study reveals a novel regulation of intratumoral de novo androgen synthesis in CRPC, and provides the DAB2IP/ETS1/AKR1C3 signaling as a potential therapeutic target.


Asunto(s)
Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Andrógenos , Neoplasias de la Próstata Resistentes a la Castración , Proteína Proto-Oncogénica c-ets-1 , Testosterona , Proteínas Activadoras de ras GTPasa , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Andrógenos/metabolismo , Animales , Línea Celular Tumoral , Deshidroepiandrosterona/farmacología , Humanos , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteína Proto-Oncogénica c-ets-1/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Testosterona/biosíntesis , Testosterona/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo
4.
Reproduction ; 163(6): 365-377, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35312628

RESUMEN

Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Previous studies have shown that mitochondria play an important role in human spermatozoa motility. But the related pathogenesis is far from elucidated. The aim of this study was to investigate the association between gene associated with retinoid-interferon-induced mortality 19 (GRIM19) and asthenospermia. In this study, Grim19 knockout model (Grim19+/- mouse) was created through genome engineering. We showed that compared with WT mice, the sperm count and motility of Grim19+/- mice were significantly reduced. Grim19 may contribute to sperm count and vitality by influencing the mitochondrial membrane potential, intracellular reactive oxygen species production, and increasing cell apoptosis. The spermatogenic cells of all levels in the lumen of the seminiferous tubules were sparsely arranged, and the intercellular space became larger in the testis tissue of Grim19+/- mice. The serum testosterone concentration is significantly reduced in Grim19+/- mice. The expression of steroid synthesis-related proteins STAR, CYP11A1, and HSD3B was decreased in Grim19+/- mice. To further confirm whether changes in testosterone biosynthesis were due to Grim19 downregulation, we validated this result using Leydig cells and TM3 cells. We also found that Notch signaling pathway was involved in Grim19-mediated testosterone synthesis to some extent. In conclusion, we revealed a mechanism underlying Grim19 mediated spermatozoa motility and suggested that Grim19 affected the synthesis of testosterone and steroid hormones in male mouse partly through regulating Notch signal pathways.


Asunto(s)
Astenozoospermia , Oligospermia , Animales , Astenozoospermia/metabolismo , Humanos , Masculino , Ratones , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , Oligospermia/metabolismo , Túbulos Seminíferos/metabolismo , Motilidad Espermática , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/biosíntesis
5.
Reprod Biol Endocrinol ; 20(1): 43, 2022 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-35236366

RESUMEN

The heavy metal cadmium is proposed to be one of the environmental endocrine disruptors of spermatogenesis. Cadmium-induced inhibition of spermatogenesis is associated with a hormone secretion disorder. Letrozole is an aromatase inhibitor that increases peripheral androgen levels and stimulates spermatogenesis. However, the potential protective effects of letrozole on cadmium-induced reproductive toxicity remain to be elucidated. In this study, male mice were administered CdCl2 (4 mg/kg BW) orally by gavage alone or in combination with letrozole (0.25 mg/kg BW) for 30 days. Cd exposure caused a significant decreases in body weight, sperm count, motility, vitality, and plasma testosterone levels. Histopathological changes revealed extensive vacuolization and decreased spermatozoa in the lumen. However, in the Cd + letrozole group, letrozole treatment compensated for deficits in sperm parameters (count, motility, and vitality) induced by Cd. Letrozole treatment significantly increased serum testosterone levels, which were reduced by Cd. Histopathological studies revealed a systematic array of all germ cells, a preserved basement membrane and relatively less vacuolization. For a mechanistic examination, RNA-seq was used to profile alterations in gene expression in response to letrozole. Compared with that in the Cd-treated group, RNA-Seq analysis showed that 214 genes were differentially expressed in the presence of letrozole. Gene ontology (GO) enrichment analysis and KEGG signaling pathway analysis showed that steroid biosynthetic processes were the processes most affected by letrozole treatment. Furthermore, we found that the expression of the testosterone synthesis-related genes LHCGR (luteinizing hormone/choriogonadotropin receptor) and Hsd3b6 (3 beta- and steroid delta-isomerase 6) was significantly downregulated in Cd-treated testes, but these genes maintained similar expression levels in letrozole-treated testes as those in the control group. However, the transcription levels of inflammatory cytokines, such as IL-1ß and IL-6, and oxidative stress-related genes (Nrf2, Nqo1, and Ho-1) showed no changes. The present study suggests that the potential protective effect of letrozole on Cd-induced reproductive toxicity might be mediated by the upregulation of LHCGR and Hsd3b6, which would beneficially increase testosterone synthesis to achieve optimum protection of sperm quality and spermatogenesis.


Asunto(s)
Cadmio , Letrozol , Espermatogénesis , Testosterona , Animales , Masculino , Ratones , Cadmio/toxicidad , Citoprotección/efectos de los fármacos , Citoprotección/genética , Letrozol/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Ratones Endogámicos ICR , Sustancias Protectoras/farmacología , Receptores de HL/efectos de los fármacos , Receptores de HL/genética , Receptores de HL/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Espermatogénesis/efectos de los fármacos , Espermatogénesis/genética , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Esteroide Isomerasas/efectos de los fármacos , Esteroide Isomerasas/genética , Esteroide Isomerasas/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/biosíntesis
6.
J Ethnopharmacol ; 289: 115025, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35074455

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Argyreia nervosa (Burm.f.) Bojer is used traditionally as an aphrodisiac and mentioned in the indigenous system of medicine as spermatogenic. The roots of the plant are also used as bitter, tonic, and alternative. AIM OF THE STUDY: To study the effect of n-butanol fraction (BTF) and ethyl acetate fraction (ETF) of methanol extract prepared from the roots of Argyreia nervosa and scopoletin isolated from ETF on testosterone biosynthesis in testis and spermatogenesis using rats. MATERIALS AND METHODS: The effect of BTF, ETF, and scopoletin on the testosterone biosynthesis was evaluated by determining the alteration in expression of mRNA corresponding to steroidogenic enzymes and concentration of testosterone using TM-3 cell line. The ability of BTF and ETF in altering the level of testicular cholesterol and testosterone along with mRNA expression corresponding to 3ß-Hydroxy-Δ5-steroid dehydrogenase (3ß-HSD) and Acute Steroid Regulatory Protein (StAR) was evaluated using rats as experimental animals. The sperm concentration in the seminal fluid was determined, and histological studies of testicular tissues were also carried out. RESULTS: Test solutions containing BTF, ETF, and scopoletin showed a dose-dependent and statistically significant increase in the testosterone content when incubated with TM-3 cells. The test solutions also increased the fold expression of mRNA corresponding to StAR and 3ß-HSD enzymes from TM-3 cells. BTF and ETF elevated testicular testosterone levels by 3.57 and 3.84-fold as compared to control animals, while the fractions showed 9.04 and 10.41-fold alteration in expression of mRNA corresponding to StAR, respectively. BTF and ETF altered the expression of mRNA corresponding to 3ß-HSD by 13.43 and 15.04-fold in testicular tissues; moreover, they elevated the activity of 3ß-HSD by 7.11 and 7.73 fold, respectively. The animals treated with BTF and ETF showed increased sperm concentration. Histological observations showed that the lumen of seminiferous tubules was densely populated with spermatozoa and Leydig cells were intensely stained. Extract prepared from fruits of Tribulus terrestris Linn and testosterone served as positive controls. CONCLUSION: BTF, ETF, and scopoletin could promote testosterone biosynthesis by elevating mRNA expression corresponding to StAR, 3ß-HSD, and by increasing 3ß-HSD activity in the testicular tissues. Elevated testosterone concentration in testis promoted spermatogenesis. The studies provided the probable mechanism through which the roots of A. nervosa act as spermatogenic.


Asunto(s)
Convolvulaceae/química , Extractos Vegetales/farmacología , Espermatogénesis/efectos de los fármacos , Testosterona/biosíntesis , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Raíces de Plantas , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Testículo/efectos de los fármacos , Testículo/metabolismo
7.
Molecules ; 26(23)2021 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-34885749

RESUMEN

17ß-Hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17ß-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17ß-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17ß-HSD3 and as inhibitors of prostate cancer cell growth.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/química , Bencilaminas/química , Neoplasias de la Próstata/tratamiento farmacológico , 17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 17-Hidroxiesteroide Deshidrogenasas/ultraestructura , Bencilaminas/síntesis química , Bencilaminas/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Masculino , Simulación del Acoplamiento Molecular , Próstata/efectos de los fármacos , Próstata/metabolismo , Neoplasias de la Próstata/patología , Relación Estructura-Actividad , Testosterona/biosíntesis
8.
J Lipid Res ; 62: 100152, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34808194

RESUMEN

Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17α-hydroxylase (cytochrome P450 family 17 subfamily A member 1), and 3ß-hydroxysteroid dehydrogenase. These steroidogenic enzymes are mainly regulated at the transcriptional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regulatory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 3ß-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expression of fatty acid synthase and diacylglycerol acyltransferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intracellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively promotes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Leydig cell dysfunction and subsequent testosterone deficiency.


Asunto(s)
Amodiaquina/farmacología , Colesterol/biosíntesis , Células Intersticiales del Testículo/efectos de los fármacos , Testosterona/biosíntesis , Triglicéridos/biosíntesis , Animales , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
9.
Toxins (Basel) ; 13(10)2021 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-34678978

RESUMEN

Deoxynivalenol (DON) is a type-B trichothecene mycotoxin produced by Fusarium species, reported to be the most common mycotoxin present in food and feed products. DON is known to affect the production of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) in male rats, consequently affecting reproductive endpoints. Our previous study showed that DON induces oxidative stress in prostate cancer (PCa) cells, however the effect of DON on the intratumor steroidogenesis in PCa and normal prostate cells was not investigated. In this study human normal (PNT1A) and prostate cancer cell lines with different hormonal sensitivity (PC-3, DU-145, LNCaP) were exposed to DON treatment alone or in combination with dehydroepiandrosterone (DHEA) for 48 h. The results of the study demonstrated that exposure to DON alone or in combination with DHEA had a stimulatory effect on the release of estradiol and testosterone and also affected progesterone secretion. Moreover, significant changes were observed in the expression of genes related to steroidogenesis. Taken together, these results indicate that DON might affect the process of steroidogenesis in the prostate, demonstrating potential reproductive effects in humans.


Asunto(s)
Próstata/efectos de los fármacos , Esteroides/biosíntesis , Tricotecenos/toxicidad , Línea Celular , Línea Celular Tumoral , Deshidroepiandrosterona/farmacología , Estradiol/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Progesterona/biosíntesis , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Testosterona/biosíntesis
10.
Gen Comp Endocrinol ; 314: 113906, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34534545

RESUMEN

The current study in wall lizards Hemidactylus flaviviridis was designed to ascertain that Leydig cells utilize testicular macrophage-derived 25-hydroxycholesterol (25-HC) for steroidogenesis. Leydig cells (LC) collected from regressed testes when incubated with 25-HC that was obtained from HPLC-eluted fraction of testicular macrophage-conditioned medium (TMCM), lyophilized and reconstituted in culture medium (0.5 µg/ml/well), produced considerably higher amount of testosterone. A similar observation was made when Leydig cells were incubated with varying concentrations of commercial 25-HC. Testosterone production by LC increased in a concentration-dependent manner. Taken together, it is evident that LC utilize 25-HC as a substrate for testosterone biosynthesis. To examine the gonadotropic regulation of steroid biosynthesis utilizing 25-HC as substrate, ovine follicle-stimulating hormone (FSH) that regulates both the testicular functions in lizards was used. Leydig cells were incubated with combinations of FSH and 25-HC as follows: 0 h FSH + 12 h 25-HC, 0 h 25-HC + 12 h FSH. As compared to respective controls, a marked increase in testosterone production was observed in response to FSH indicating that gonadotropin up-regulates uptake of 25-HC as a substrate for testosterone biosynthesis.


Asunto(s)
Hidroxicolesteroles , Células Intersticiales del Testículo , Lagartos , Testículo , Testosterona/biosíntesis , Animales , Hormona Folículo Estimulante , Hidroxicolesteroles/metabolismo , Células Intersticiales del Testículo/fisiología , Lagartos/fisiología , Masculino , Ovinos , Testículo/fisiología
11.
Cell Rep ; 36(8): 109579, 2021 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34433056

RESUMEN

Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.


Asunto(s)
Hormona Antimülleriana/biosíntesis , Sistema Hipotálamo-Hipofisario/metabolismo , Ovario/metabolismo , Conducta Sexual/efectos de la radiación , Piel/metabolismo , Testosterona/biosíntesis , Rayos Ultravioleta , Animales , Estro/metabolismo , Femenino , Técnicas de Inactivación de Genes , Queratinocitos/metabolismo , Masculino , Ratones
12.
Biol Reprod ; 105(5): 1307-1316, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34363387

RESUMEN

Previous studies reported that, with aging, Leydig cell intracellular antioxidants are reduced in concentration and intracellular ROS levels increase, suggesting that oxidant/antioxidant imbalance may contribute to the reduced testosterone production that characterizes the aging cells. As yet, little is known about how the Leydig cell oxidant/antioxidant environment is regulated. Sirt1, an enzyme that deacetylates transcription factors, and the transcription factor Nrf2, have been shown to be associated with cellular response to oxidative stress. We hypothesized that Sirt1 and/or Nrf2 might be involved in regulating the oxidant/antioxidant environment of Leydig cells, and therefore, the testosterone production. We found that Sirt1 and Nrf2 are present in the Leydig cells of Brown Norway rats, though reduced in aged cells. In MA-10 cells in which Sirt1 or Nrf2 were suppressed by nicotinamide (NAM) or ML385, respectively, or in which siRNAs were used for knockdown of Sirt1 or Nrf2, increased ROS levels and decreased progesterone production occurred. In rat Leydig cells, inhibition of Sirt1 by culturing the cells with NAM resulted in increased ROS and reduced testosterone production, and subsequent removal of NAM from the culture medium resulted in increased testosterone production. Activation of rat Leydig cells Sirt1 with honokiol or of Nrf2 with sulforaphane resulted in the maintenance of testosterone production despite the exposure of the cells to oxidizing agent. These results, taken together, suggest that Sirt1 and Nrf2 are involved in maintaining the Leydig cell oxidant/antioxidant environment, and thus in maintaining steroid production.


Asunto(s)
Antioxidantes , Células Intersticiales del Testículo , Factor 2 Relacionado con NF-E2 , Oxidantes , Sirtuina 1 , Testosterona , Animales , Masculino , Ratas , Antioxidantes/metabolismo , Células Intersticiales del Testículo/metabolismo , Oxidantes/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Testosterona/biosíntesis , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo
13.
Bioresour Technol ; 341: 125833, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34455250

RESUMEN

Testosterone (TS) is a critical androgenic steroid that regulates human metabolism and maintains secondary sexual characteristics. The biotransformation from 4-androstene-3,17-done (4-AD) to TS is limited by the poor catalytic activity of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3). Herein, we explored the structural characteristics and catalytic mechanism of 17ß-HSD3 and adopted the rational design strategy to improve its catalytic activity. Molecular docking and molecular dynamics simulations revealed the substrate-binding pocket and the binding mode of 4-AD to 17ß-HSD3. We located the pivotal residues and regulated their hydrophobicity and polarity. The obtained G186R/Y195W variant formed additional electrostatic interaction and hydrogen bond with 4-AD, increasing the binding affinity between the variant and 4-AD. Therefore, the G186R/Y195W variant produced 3.98 g/L of TS, which increased to 297%. The combination of structural and mechanism resolution drives the implementation of the rational design strategy, which provides guidance for bioproduction of TS catalyzed by 17ß-HSD3.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/química , Simulación de Dinámica Molecular , Testosterona , Simulación del Acoplamiento Molecular , Ingeniería de Proteínas , Saccharomycetales , Testosterona/biosíntesis
14.
In Vitro Cell Dev Biol Anim ; 57(7): 742-752, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34355300

RESUMEN

Cyclin-dependent kinase inhibitor 1B (Cdkn1b, p27) plays important regulatory roles in many cellular processes. p27 is highly expressed in the mouse testis, but its roles and underlying mechanisms for testosterone synthesis and secretion remain not well understood. In the current study, we found that p27 located in Leydig cells and Sertoli cells of adult mouse testis. To explore the function of p27 in Leydig cells, p27 inhibitor and activator were injected into the adult mice, primary Leydig cells and TM3 cells. Our in vivo and in vitro results showed that change in the expression of p27 significantly alters the testosterone in both globe serum and culture medium. Meanwhile, the steroidogenesis-related gene expression was significantly regulated too. Moreover, our in vitro study showed that luteinizing hormone (LH) significantly increased p27 mRNA levels. Furthermore, our results proved that altering the mRNA expression of p27 leads to the synchronized changes of Lhcgr, Star, Cyp11a1, Hsd3b6, Cyp11a1, and Hsd17b3. Alterations of p27 also result in synchronously changes of RAF1 and ERK1/2 phosphorylation. These findings indicate that p27 plays vital roles in LH-induced testosterone production, providing a novel mechanism that p27 acts as an upstream molecule to elevate ERK1/2 phosphorylation to promote the expression of StAR and other cholesterol-metabolizing enzymes.


Asunto(s)
Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/metabolismo , Testosterona/metabolismo , Animales , Células Cultivadas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos ICR , Fosforilación , Proteínas Proto-Oncogénicas c-raf/metabolismo , Transducción de Señal , Testículo/metabolismo , Testosterona/biosíntesis
15.
Biol Reprod ; 105(5): 1317-1329, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34401899

RESUMEN

The study investigated the effects of prolonging photoperiod on the synthesis of testosterone and melatonin in roosters, and the effect of melatonin on testosterone synthesis in rooster Leydig cells as well as its molecular mechanisms. We randomly divided one hundred and twenty 20-week-old roosters into three groups and provided 6, 12.5 and 16 h light, respectively. The results showed that prolonging photoperiod promoted testosterone synthesis, decreased melatonin production, and inhibited the expression of melatonin membrane receptors MEL1A, MEL1B, MEL1C, and aralkylamine N-acetyltransferase (AANAT) in rooster testes. Subsequently, rooster Leydig cells were isolated and treated with 0, 0.1, 1, 10, and 100 ng/mL melatonin for 36 h. The results suggested that melatonin inhibited testosterone synthesis in rooster Leydig cells, and silencing MEL1A and MEL1B relieved the inhibition of melatonin on testosterone synthesis. Additionally, melatonin reduced the intracellular cyclic adenosine monophosphate (cAMP) level and the phosphorylation level of cAMP-response element binding protein (CREB), and CREB overexpression alleviated the inhibition of melatonin on testosterone synthesis. Furthermore, pretreatment with cAMP activator forskolin or protein kinase A (PKA) activator 8-bromo-cAMP blocked the inhibition of melatonin on CREB phosphorylation and testosterone synthesis. These results indicated that prolonging photoperiod promoted testosterone synthesis associated with the decrease in melatonin production and membrane receptors and biosynthetic enzyme of melatonin in rooster testes, and melatonin inhibited testosterone synthesis of rooster Leydig cells by inhibiting the cAMP/PKA/CREB pathway via MEL1A and MEL1B. This may be evidence that prolonging photoperiod could promote testosterone synthesis through the inhibition of the local melatonin pathway in rooster testes.


Asunto(s)
Pollos/metabolismo , Células Intersticiales del Testículo/metabolismo , Melatonina/metabolismo , Fotoperiodo , Testículo/metabolismo , Testosterona/biosíntesis , Animales , Masculino
16.
Sci Rep ; 11(1): 13772, 2021 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-34215832

RESUMEN

Our present knowledge on interrelation between morphology/ultrastructure of mitochondria of the Leydig cell and its steroidogenic function is far from satisfactory and needs additional studies. Here, we analyzed the effects of blockade of androgen receptor, triggered by exposure to flutamide, on the expression of steroidogenic proteins (1) and ultrastructure of Leydig cells' constituents (2). We demonstrated that increase in the expression level of steroidogenic (StAR, CYP11A1, 3ß-HSD, and CYP19A1) proteins (and respective mRNAs) in rat testicular tissue as well as elevation of intratesticular sex steroid hormone (testosterone and estradiol) levels observed in treated animals correspond well to morphological alterations of the Leydig cell ultrastructure. Most importantly, up-regulation of steroidogenic proteins' expression apparently correlates with considerable multiplication of Leydig cell mitochondria and subsequent formation of local mitochondrial networks. Interestingly, we showed also that the above-mentioned processes were associated with elevated transcription of Drp1 and Mfn2 genes, encoding proteins implicated in mitochondrial dynamics. Collectively, our studies emphasize the importance of mitochondrial homeostasis to the steroidogenic function of Leydig cells.


Asunto(s)
Aromatasa/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Hidroxiesteroide Deshidrogenasas/genética , Receptores Androgénicos/genética , Animales , Flutamida/farmacología , Regulación del Desarrollo de la Expresión Génica , Hormonas Esteroides Gonadales/biosíntesis , Hormonas Esteroides Gonadales/genética , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/biosíntesis , Hormona Luteinizante/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/ultraestructura , Ratas , Receptores Androgénicos/metabolismo , Esteroides/biosíntesis , Esteroides/metabolismo , Testículo/crecimiento & desarrollo , Testículo/metabolismo , Testosterona/biosíntesis , Testosterona/metabolismo
17.
Toxicology ; 458: 152836, 2021 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-34147545

RESUMEN

China's clean energy and resources are mainly located in the west and north while electric load center is concentrated in the middle and east. Thus, these resources and energy need to be converted into electrical energy in situ and transported to electric load center through ultra-high voltage direct current (UHVDC) transmissions. China has built 25,000 km UHVDC transmission lines of 800 kV and 1100 kV, near which the impact of electric field on health has attracted public attention. Previous studies showed that time-varying electromagnetic field exposure could disturb testosterone secretion. To study the effect of non-time-varying electric field caused by direct current transmission lines on testosterone synthesis, male ICR mice were continually (24 h/d) exposed to static electric field of 56.3 ± 1.4 kV/m. Results showed that on the 3rd day of exposure and on the 7th day after ceasing the exposure of 28 d, serum testosterone level and testicular oxidative stress indicators didn't change significantly. On the 28th day of exposure, serum testosterone levels, testicular glutathione peroxidase (GSH-Px) activity, the mRNA and protein levels of testicular StAR, PBR, CYP11A1 decreased significantly, and testicular malondialdehyde (MDA) content increased significantly. Meanwhile, electron-dense edges and vacuolation appeared in lipid droplets of Leydig cells. The gap between inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) enlarged, which would cause the swelling of mitochondria, the rupture and deficiency of mitochondrial membranes. Analysis showed that testicular oxidative stress could induce the damage of mitochondrial structure in Leydig cells, which would decrease the rate of cholesterol transport from cytoplasm to mitochondria. Since cholesterol is the necessary precursor of testosterone synthesis, testosterone synthesis was inhibited. The decrease of the mRNA and protein expression levels of StAR and PBR in testes could diminish the cholesterol transported from OMM to IMM. The decrease of the mRNA and protein expression levels of CYP11A1 could reduce the pregnenolone required in testosterone synthesis and inhibit testosterone synthesis consequently.


Asunto(s)
Campos Electromagnéticos , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/efectos de la radiación , Testosterona/biosíntesis , Animales , Antioxidantes/metabolismo , Colesterol/metabolismo , Citoplasma/metabolismo , Citoplasma/efectos de la radiación , Glutatión Peroxidasa/metabolismo , Células Intersticiales del Testículo/ultraestructura , Masculino , Ratones , Ratones Endogámicos ICR , Membranas Mitocondriales/metabolismo , Membranas Mitocondriales/efectos de la radiación , Dilatación Mitocondrial/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , Fosfoproteínas/metabolismo , Testosterona/sangre , Vacuolas/efectos de la radiación , Vacuolas/ultraestructura
18.
Sci Rep ; 11(1): 11675, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-34083679

RESUMEN

Zinc oxide nanoparticles (ZnO NPs) demonstrate potential positive effects on reproduction. However, their protective role against the reproductive toxicity pollutants has not yet been adequately studied at the molecular level. This study was designed to assess this objective using Benzo[α]pyrene B[a]P as reproductive toxic agent . Forty-eight mature male rats were randomly distributed into six groups: Group1 (negative control); Groups 2 and 3 (positive control I and II, wherein the animals were treated with 10 and 30 mg ZnO NPs/kg BW, respectively); Group 4 (B[a]P group; treated with 150 mg B[a]P/kg BW); and Groups 5 and 6 (subjected to B[a]P treatment co-administered with different concentrations of ZnO NPs). We investigated oxidative stress biomarkers; cholesterol side-chain cleavage enzyme (CYP11A1), steroidogenic acute regulatory protein (StAR), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) gene expression; testosterone levels; and histopathology of the liver, kidney, and testicles. The B[a]P-treated group showed significant deterioration in all reproductive parameters and displayed induced oxidative stress. ZnO NPs remarkably reduced oxidative stress, effectively upregulated the mRNA levels of CY11A1, StAR, and 3ß-HSD, and improved the histological pictures in the examined organs. At their investigated doses and given their NPs properties, ZnO NPs demonstrated a marked ameliorative effect against the reproductive toxic effects of B[a]P. Further studies are needed to thoroughly investigate the molecular mechanisms of ZnO NPs.


Asunto(s)
Benzo(a)pireno/efectos adversos , Nanopartículas , Esteroides/biosíntesis , Testículo/efectos de los fármacos , Testículo/metabolismo , Óxido de Zinc/administración & dosificación , Animales , Biomarcadores , Femenino , Regulación de la Expresión Génica , Inmunohistoquímica , Masculino , Nanopartículas/ultraestructura , Especificidad de Órganos/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Testosterona/biosíntesis
19.
Acta Trop ; 220: 105938, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33932363

RESUMEN

Leydig cells play pivotal roles in eliciting male characteristics by producing testosterone and any damage to these cells can compromise male fertility Toxoplasma gondii (T. gondii) is an intracellular parasite capable to invade any nucleated cell, including cells from male reproductive system. Herein, we evaluated the capacity of RH strain of T. gondii to infect TM3 Leydig cells and the impact of this infection on testosterone and inflammatory mediators production. We first, by performing adherence, infection, and intracellular proliferation assays, we found a significant increase in the number of infected Leydig cells, peaking 48 h after the infection with T. gondii. Supernatants of TM3 infected cells exhibited, in a time-dependent manner, increased levels of testosterone as well as monocyte chemoattractant protein-1 (MCP-1) and interferon-γ (IFN-γ), which is correlated with the robust T. gondii infection. In conclusion, our study provides new insights regarding the harmful effects of T. gondii infection on male reproductive system.


Asunto(s)
Células Intersticiales del Testículo/parasitología , Testosterona/biosíntesis , Toxoplasmosis/metabolismo , Animales , Quimiocina CCL2/biosíntesis , Interferón gamma/biosíntesis , Masculino , Ratones Endogámicos BALB C , Factores de Tiempo , Toxoplasma
20.
Front Endocrinol (Lausanne) ; 12: 665874, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33897623

RESUMEN

The testis expresses many long noncoding RNAs (lncRNAs), but their functions and overview of lncRNA variety are not well understood. The mouse Prss/Tessp locus contains six serine protease genes and two lncRNAs that have been suggested to play important roles in spermatogenesis. Here, we found a novel testis-specific lncRNA, Start (Steroidogenesis activating lncRNA in testis), in this locus. Start is 1822 nucleotides in length and was found to be localized mostly in the cytosol of germ cells and Leydig cells, although nuclear localization was also observed. Start-knockout (KO) mice generated by the CRISPR/Cas9 system were fertile and showed no morphological abnormality in adults. However, in adult Start-KO testes, RNA-seq and qRT-PCR analyses revealed an increase in the expression of steroidogenic genes such as Star and Hsd3b1, while ELISA analysis revealed that the testosterone levels in serum and testis were significantly low. Interestingly, at 8 days postpartum, both steroidogenic gene expression and testosterone level were decreased in Start-KO mice. Since overexpression of Start in two Leydig-derived cell lines resulted in elevation of the expression of steroidogenic genes including Star and Hsd3b1, Start is likely to be involved in their upregulation. The increase in expression of steroidogenic genes in adult Start-KO testes might be caused by a secondary effect via the androgen receptor autocrine pathway or the hypothalamus-pituitary-gonadal axis. Additionally, we observed a reduced number of Leydig cells at 8 days postpartum. Collectively, our results strongly suggest that Start is a regulator of steroidogenesis in Leydig cells. The current study provides an insight into the overall picture of the function of testis lncRNAs.


Asunto(s)
Células Intersticiales del Testículo/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Complejos Multienzimáticos/metabolismo , Progesterona Reductasa/metabolismo , ARN Largo no Codificante/genética , Espermatogénesis , Esteroide Isomerasas/metabolismo , Testículo/metabolismo , Testosterona/biosíntesis , Animales , Regulación de la Expresión Génica , Masculino , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Complejos Multienzimáticos/genética , Progesterona Reductasa/genética , Esteroide Isomerasas/genética
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