RESUMO
In the epididymis, lysosomal proteins of the epithelial cells are normally targeted from the Golgi apparatus to lysosomes for degradation, although their secretion into the epididymal lumen has been documented and associated with sperm maturation. In this study, cathepsin D (CatD) and prosaposin (PSAP) were examined in adult epididymis of control, and 2-day castrated rats without (Ct) and with testosterone replacement (Ct+T) to evaluate their expression and regulation within epididymal epithelial cells. By light microscope-immunocytochemistry, a quantitative increase in size of lysosomes in principal cells of Ct animals was noted from the distal initial segment to the proximal cauda. Androgen replacement did not restore the size of lysosomes to control levels. Western blot analysis revealed a significant increase in CatD expression in the epididymis of Ct animals, which suggested an upregulation of its expression in principal cells; androgens restored levels of CatD to that of controls. In contrast, PSAP expression in Ct animals was not altered from controls. Additionally, an increase in procathepsin D levels was noted from samples of the epididymal fluid of Ct compared to control animals, accompanied by an increased complex formation with PSAP. Moreover, an increased oligomerization of prosaposin was observed in the epididymal lumen of Ct rats, with changes reverted to controls in Ct+T animals. Taken together these data suggest castration causes an increased uptake of substrates that are acted upon by CatD in lysosomes of principal cells and in the lumen by procathepsin D. These substrates may be derived from apoptotic cells noted in the lumen of proximal regions and possibly by degenerating sperm in distal regions of the epididymis of Ct animals. Exploring the mechanisms by which lysosomal enzymes are synthesized and secreted by the epididymis may help resolve some of the issues originating from epididymal dysfunctions with relevance to sperm maturation.
Assuntos
Androgênios/genética , Catepsina D/genética , Precursores Enzimáticos/genética , Saposinas/genética , Androgênios/metabolismo , Animais , Castração/efeitos adversos , Epididimo/crescimento & desenvolvimento , Epididimo/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/genética , Lisossomos/genética , Lisossomos/fisiologia , Masculino , Ratos , Espermatozoides/metabolismo , Testosterona/genética , Testosterona/metabolismoRESUMO
Over the past decades, an increase has been described in exposure to environmental toxins; consequently, a series of studies has been carried out with the aim of identifying problems associated with health. One of the main risk factors is exposure to heavy metals. The adverse effects that these compounds exert on health are quite complex and difficult to elucidate, in that they act at different levels and there are various signaling pathways that are implicated in the mechanisms of damage. The Sertoli cells plays a role of vital importance during the process of spermatogenesis, and it has been identified as one of the principal targets of heavy metals. In the present review, cadmium, lead, and arsenic are broached as altering the physiology of the Sertoli cells, citing mechanisms that have been cited in the literature.
Assuntos
Arsênio/toxicidade , Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Células de Sertoli/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Humanos , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Masculino , Células de Sertoli/citologia , Células de Sertoli/metabolismo , Transdução de Sinais , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Testosterona/antagonistas & inibidores , Testosterona/genética , Testosterona/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Endocrine-disrupting chemicals (EDCs) generate reproductive dysfunctions affecting the biosynthesis of steroid hormones and genes of the steroidogenic pathway. EDCs effects are mainly reported as a result of exposure to single compounds. However, humans are environmentally exposed to a mixture of EDCs. Herein, we assess chronic exposure to single alkylphenols and phthalates versus a mixture in mouse testes histology and steroidogenesis. Pregnant mice were exposed through drinking water to: 0.3 mg/kg-body weight (BW)/d of each phthalate (bis (2-ethylhexyl) phthalate, dibutyl phthalate, benzyl butyl phthalate), 0.05 mg/kg-BW/d of each alkylphenol (4-nonylphenol, 4-tert-octylphenol), or their mixture, covering from 0.5 postcoital day to weaning, continuing in the male offspring each exposure until adulthood (60-days old). Body and relative testis weight were increased in mixture-exposed mice along with histological alterations. Intratesticular testosterone (T) changed only in mice exposed to DBP, whereas estradiol (E2) levels were altered in all groups (except benzyl butyl phthalate). mRNA levels of genes encoding hormones of the steroid pathway (Cyp11a1, Hsd3b1, Cyp17a1, and Cyp19a1), cholesterol transporters (Star), and transcriptional factors (Sp1) showed that mice exposed to single or mixed compounds had alterations in at least 2 transcripts. However, none of the different types of exposure induced changes in all transcripts. In addition, changes at the mRNA or protein levels with single compounds were not always the same as those with a mixture. In conclusion, the effects of a chronic exposure to a mixture of EDCs on the expression of genes and proteins of the steroidogenic pathway and hormonal status were different from those exposed to single EDC.
Assuntos
Disruptores Endócrinos/toxicidade , Estradiol/metabolismo , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Disruptores Endócrinos/química , Estradiol/genética , Células Germinativas/efeitos dos fármacos , Células Germinativas/patologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Testículo/metabolismo , Testículo/patologia , Testosterona/genéticaRESUMO
A case of male pseudo-hermaphrodite in a six-month-old Pinscher dog with mild signs of agression towards other dogs is reported. The animal presented fibrous mass in clitorial region, with structure similar to a diminutive penis. Testicles were found in the abdominal cavity, uterus had normal size and localization and hypertrophic clitoris was seen during exploratory laparotomy. The histopathological examination revealed testicular tissue, composed of hypotrophic seminipherous tubules and exuberant stroma and uterus with normal histological appearance. Moreover, the animal presented high levels of testosterone.(AU)
Assuntos
Animais , Cães , Cães/anormalidades , Transtornos do Desenvolvimento Sexual/veterinária , Testosterona/genética , Técnicas Histológicas/veterináriaRESUMO
In sheep embryos, steroidogenic activity has been reported as taking place during the period of sexual differentiation. In the case of mouse embryos, the sporadic detection or absence of steroidogenic enzymes suggests that the ovary is inactive. The purpose of this work was to establish if mouse undifferentiated gonads express steroidogenic enzymes in a similar way as in sheep embryos. To know this, we analyzed the mRNA expression pattern of 3ß-Hsd1 and P450arom as well as protein expression pattern of 3ß-HSD1 and Testosterone in normal undifferentiated and differentiated gonads from both male and female mice embryo. Our data indicate that there is expression of 3ß-Hsd1 in XX gonads during gonad differentiation period. Nevertheless the Testosterone which would indicate steroidogenic activity is not produced. Besides, the absence of P450arom indicates that the production of Estradiol as observed in the ovaries of sheep does not occur. The detection of 3ß-Hsd1 in the early stages of ovarian development, as well as the absence of Testosterone suggests that XX gonads are not steroidogenic and that 3ß-Hsd1 enzyme may play a different role than in the steroidogenesis process.
Assuntos
3-Hidroxiesteroide Desidrogenases/biossíntese , Aromatase/biossíntese , Ovário/enzimologia , Diferenciação Sexual/fisiologia , Testículo/enzimologia , 3-Hidroxiesteroide Desidrogenases/genética , Animais , Aromatase/genética , Estradiol/biossíntese , Estradiol/genética , Estradiol/metabolismo , Feminino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Masculino , Camundongos , Ovário/citologia , Ovário/crescimento & desenvolvimento , RNA Mensageiro/genética , Diferenciação Sexual/genética , Testículo/citologia , Testículo/crescimento & desenvolvimento , Testosterona/biossíntese , Testosterona/genética , Testosterona/metabolismoRESUMO
17ß-Estradiol (E2) and Testosterone (T) exert actions in most animal tissues, in addition to the reproductive system. Thus, both sex steroid hormones affect growth and different cell functions in several organs. Accordingly, the nuclear estrogen (ER) and androgen (AR) receptors are ubiquitously expressed. Moreover, ER and AR may have non-classical intracellular localizations, e.g. plasma membrane, mitochondria and endoplasmic reticulum, raising additional complexity to the functional roles of E2 and T. In addition to the modulation of gene transcription by direct interaction with their cognate nuclear receptors, the steroids can rapidly activate signaling pathways by a non-genomic mechanism mediated by receptors identical to or different from known steroid receptors. Among various functions, E2 and T can regulate apoptosis through those pathways. In mitochondria, the presence of ER and AR and actions of estrogen and androgen have been shown, in keeping with the organelle being a control point of apoptosis. The most recurrent action for each steroid hormone is the protection of mitochondria against different insults, resulting in antiapoptosis. This review summarizes the molecular basis of the modulation of programmed cell death by E2 and T in several tissues.
Assuntos
Apoptose/genética , Estradiol/metabolismo , Mitocôndrias/metabolismo , Testosterona/metabolismo , Animais , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Estradiol/genética , Humanos , Mitocôndrias/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Testosterona/genética , Transcrição GênicaRESUMO
Cancer cells, as with most mammalian cells, depend on a continuous supply of glucose; not only as a precursor of glycoproteins, triglycerides and glycogen, but also as an important source of energy. This review concentrates on GLUT transporter expression in both normal and cancerous classical sex-steroid hormone tissues (i.e. breast, uterus, ovary, testis and prostate, among others). Given the importance of estrogen, progesterone and androgens in carcinogenesis, as well as in survival and propagation of these cancers, this review also highlights the current literature on hormone regulation of glucose transporters and on the role of hypoxia in their expression. Given the recent explosion of information on the newer GLUT6-12 family members, a brief overview on their function and general expression has been included. Finally, an insight into the use of glucose transporters as markers of cancer progression and clinical outcome is also discussed.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Neoplasias Hormônio-Dependentes/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estrogênios/genética , Estrogênios/metabolismo , Feminino , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Masculinos/genética , Neoplasias dos Genitais Masculinos/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Hormônios Esteroides Gonadais/genética , Humanos , Masculino , Progesterona/genética , Progesterona/metabolismo , Testosterona/genética , Testosterona/metabolismoRESUMO
Este trabajo fue realizado con el objetivo de conocer los efectos a largo plazo del consumo de extractos acuosos de hojas de Stevia rebaudiana (Bertoni) sobre el número de crías, la micromorfología de los órganos genitales, niveles de testosterona y estrógeno totales, de ratones albinos. Se Trabajó con cuatro grupos de ratones, cada grupo estuvo conformado por seis macho y seis hembras. Un grupo control (C) y tres tratamientos, el primero consumió alimento y agua mientras que los grupos tratamientos consumieron el mismo alimento pero en vez del agua un extracto de S. rebaudiana a concentraciones de (g/Kg) 3,75 (I), 7,5 (II) y 15 (III), por 120 días. Las crías fueron contadas y pesadas después de cada nacimiento, la histología de los órganos genitales entre los grupos fue comparada, se midió los niveles séricos de testosterona y estrógeno total por inmunoquimio-luminiscencia, así mismo se observó el comportamiento sexual. Los niveles de testosterona total (ng/mL) fueron significativamente diferentes entre los grupos (C= 1,02±0,03; I= 1,12±0,01; II= 1,16±0,02; III= 1,21±0,01). Así mismo los niveles de estrógeno total (pg/mL) también mostraron diferencias significativas (C= 20,77±7,22; I= 30,58±2,07; II= 33,08±3,45; III= 43,58±10,3). Sin embargo no se observaron diferencias significativas entre los pesos (g) de los úteros, trompas y ovarios (C= 0,065±0,005; I= 0,058±0,007; II= 0,058±0,007; III= 0,056±0,005). El peso (g) de testículos mostró diferencias significativas solamente con el tratamiento III (C= 0,153±0,005; I= 0,155±0,005; II= 0,145±0,005; III= 0,110±0,008).
The objective of this work was to determine the long-term effects of consuming aqueous extracts of Stevia rebaudiana (Bertoni) leaves on the number of offspring, microscopic morphology of genitalia, and levels of testosterone and estrogens in albino mice. We studied four groups of mice, each consisting of 6 males and 6 females. One group was the control (C) and received food and plain water. Three groups received treatment of food and water with extract of S. rebaudiana at concentrations of (g/Kg) 3,75g (I), 7,5 (II) and 15 (III) for a period of 120 days. The offspring were counted and the histology of genitalia among the groups was compared. Serum levels of total testosterone and estrogens were measured by immunoassay and sexual behaviour was observed. Levels of total testosterone (ng/mL) were significantly different between groups (C= 1,02±0,03; I=1,12±0,01; II= 1,16±0,02; III= 1,21±0,01). Likewise were also significantly different the levels of total estrogens (pg/mL) (C= 20,77±7,22; I= 30,58±2,07; II= 33,08±3,45; III= 43,58±10,3). But no significant differences were observed between the weights (g) of the uterus, tubes and ovaries in group (C= 0,065±0,005; I= 0,058±0,007, II= 0,058±0,007; III= 0,056±0,005). The weight (g) of the testicles showed significant differences only with the treatment III (C= 0,153±0,005; I= 0,155±0,005, II= 0,145±0,005; III= 0,110±0,008).
Assuntos
Hormônios Esteroides Gonadais/genética , Hormônios Esteroides Gonadais/química , Stevia/química , Testosterona/genéticaRESUMO
Predictive quantitative structure-activity relationship (QSAR) models of anabolic and androgenic activities for the testosterone and dihydrotestosterone steroid analogues were obtained by means of multiple linear regression using quantum and physicochemical molecular descriptors (MD) as well as a genetic algorithm for the selection of the best subset of variables. Quantitative models found for describing the anabolic (androgenic) activity are significant from a statistical point of view: R(2) of 0.84 (0.72 and 0.70). A leave-one-out cross-validation procedure revealed that the regression models had a fairly good predictability [q(2) of 0.80 (0.60 and 0.59)]. In addition, other QSAR models were developed to predict anabolic/androgenic (A/A) ratios and the best regression equation explains 68% of the variance for the experimental values of AA ratio and has a rather adequate q(2) of 0.51. External validation, by using test sets, was also used in each experiment in order to evaluate the predictive power of the obtained models. The result shows that these QSARs have quite good predictive abilities (R(2) of 0.90, 0.72 (0.55), and 0.53) for anabolic activity, androgenic activity, and A/A ratios, respectively. Last, a Williams plot was used in order to define the domain of applicability of the models as a squared area within +/-2 band for residuals and a leverage threshold of h=0.16. No apparent outliers were detected and the models can be used with high accuracy in this applicability domain. MDs included in our QSAR models allow the structural interpretation of the biological process, evidencing the main role of the shape of molecules, hydrophobicity, and electronic properties. Attempts were made to include lipophilicity (octanol-water partition coefficient (logP)) and electronic (hardness (eta)) values of the whole molecules in the multivariate relations. It was found from the study that the logP of molecules has positive contribution to the anabolic and androgenic activities and high values of eta produce unfavorable effects. The found MDs can also be efficiently used in similarity studies based on cluster analysis. Our model for the anabolic/androgenic ratio (expressed by weight of levator ani muscle, LA, and seminal vesicle, SV, in mice) predicts that the 2-aminomethylene-17alpha-methyl-17beta-hydroxy-5alpha-androstan-3-one (43) compound is the most potent anabolic steroid, and the 17alpha-methyl-2beta,17beta-dihydroxy-5alpha-androstane (31) compound is the least potent one of this series. The approach described in this report is an alternative for the discovery and optimization of leading anabolic compounds among steroids and analogues. It also gives an important role to electron exchange terms of molecular interactions to this kind of steroid activity.