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1.
Chemosphere ; 241: 125036, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31606569

RESUMO

Dimethoate is an organophosphate pesticide. It is widely used in agriculture. However, whether it blocks pubertal development of Leydig cells remains unknown. In the current study, we exposed male Sprague Dawley rats with 7.5 and 15 mg kg-1 dimethoate from postnatal day 35-56. We also exposed Leydig cells isolated from 35-day-old rats for 3 h. Dimethoate reduced serum testosterone levels at 7.5 and 15 mg kg-1 but increased serum luteinizing hormone and follicle stimulating hormone levels at 15 mg kg-1. Dimethoate did not influence Leydig cell number but reduced Leydig cell size and down-regulated Star, Cyp11a1, and Hsd3b1 in Leydig cells as well as their protein expression. Dimethoate inhibited basal androgen output in a dose-dependent manner with the inhibition starting at 0.05 µM. It significantly inhibited luteinizing hormone and 8Br-cAMP stimulated androgen outputs at 50 µM. It significantly inhibited 22R-hydroxycholesterol and progesterone-mediated androgen outputs at 50 µM. Further study demonstrated that dimethoate also down-regulated the expression of Star, Cyp11a1, and Hsd3b1 at 5 or 50 µM in vitro. Dimethoate did not directly inhibit rat testicular steroidogenic enzyme activities at 50 µM. In conclusion, dimethoate targets Star, Cyp11a1, and Hsd3b1 transcription, thus blocking Leydig cell differentiation during puberty.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Dimetoato/farmacologia , Células Intersticiais do Testículo/citologia , Puberdade , Androgênios/metabolismo , Animais , Inseticidas/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Complexos Multienzimáticos/genética , Fosfoproteínas/genética , Progesterona Redutase/genética , Ratos , Ratos Sprague-Dawley , Esteroide Isomerases/genética , Testosterona/sangue , Transcrição Genética
3.
Nat Med ; 25(12): 1894-1904, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792459

RESUMO

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.


Assuntos
Androgênios/metabolismo , Oócitos/metabolismo , Síndrome do Ovário Policístico/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Estudos de Coortes , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Núcleo Familiar , /metabolismo , Oócitos/imunologia , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Análise de Célula Única
4.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581661

RESUMO

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-ß), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-ß signaling, including the androgen/TGF-ß inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/metabolismo , Androgênios/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos
5.
Endocrinology ; 160(12): 2981-2989, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617897

RESUMO

Testicular germ cell cancer (TGCC) is the most frequent cancer of the young male, with an increasing incidence worldwide. The pathogenesis and reasons for this increase remain unknown. However, epidemiological and experimental data have suggested that, similar to genital malformations and sperm impairment, it could result from the interaction of genetic and environmental factors including fetal exposure to endocrine-disrupting chemicals (EDCs) with estrogenic effects. In this review, we analyze the expression of classic and nonclassic estrogen receptors by TGCC cells, the way they may influence germ cell proliferation induced by EDCs, and discuss how this estrogen dependency supports the developmental and environmental hypothesis.


Assuntos
Disruptores Endócrinos/efeitos adversos , Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/etiologia , Receptores Estrogênicos/metabolismo , Neoplasias Testiculares/etiologia , Androgênios/metabolismo , Animais , Epigênese Genética , Humanos
6.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533357

RESUMO

The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Androgênios/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Alelos , Biomarcadores , Regulação Enzimológica da Expressão Gênica , Testes Genéticos , Humanos , Padrões de Herança , Redes e Vias Metabólicas , Fenótipo , Esteroides/metabolismo
7.
Elife ; 82019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478829

RESUMO

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Androgênios/metabolismo , Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/biossíntese , Transcrição Genética , Células Cultivadas , Humanos , Masculino , Proteínas de Ligação a RNA/genética , Receptores Androgênicos/metabolismo
8.
Chem Biol Interact ; 312: 108817, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499053

RESUMO

Aconitine might have reproductive toxicity and the effects of aconitine on androgen synthesis in Leydig cells remain unclear. Here, we explore how aconitine affects androgen synthesis and metabolism in rat immature Leydig cells in vitro. Immature Leydig cells were isolated from 35-day-old male Sprague Dawley rats and cultured with 0-50 µM aconitine for 3 h in combination with LH, 8Br-cAMP, 22R-hydroxycholesterol, pregnenolone, progesterone, androstenedione, testosterone, and dihydrotestosterone, respectively. Medium androgens were measured. The levels of Leydig cell mRNAs, Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14, were measured by qPCR. ROS and apoptosis were determined after 24-h aconitine treatment. Aconitine inhibited basal androgen production in Leydig cells at 0.05 µM and the higher concentrations. Aconitine blocked pregnenolone, progesterone, and androstenedione mediated androgen outputs without affecting 22R-hydroxycholesterol-mediated androgen production at 5 µM. Aconitine also inhibited LH and 8Br-cAMP stimulated androgen outputs at 5 µM. Further investigation showed that aconitine blocked androgen synthesis via down-regulating the expression of Scarb1, Hsd3b1, Cyp17a1, and Hsd17b3. At 50 µM, aconitine also induced ROS generation and increased apoptotic rate of Leydig cells. Aconitine lowered serum testosterone levels at 1.5 mg/kg after 7 days of oral exposure from postnatal day 35. In conclusion, aconitine inhibits androgen synthesis.


Assuntos
Aconitina/farmacologia , Androgênios/metabolismo , Regulação para Baixo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Testosterona/sangue , Testosterona/farmacologia
9.
J Toxicol Sci ; 44(9): 575-584, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474739

RESUMO

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Androgênios/sangue , Androgênios/metabolismo , Cromatografia Líquida/métodos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Cetoconazol/toxicidade , Metirapona/toxicidade , Espectrometria de Massas em Tandem/métodos , Animais , Ritmo Circadiano , Desoxicorticosterona/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores
10.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395805

RESUMO

Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5-p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Neoplasias da Próstata/patologia , Androgênios/análise , Androgênios/metabolismo , Animais , Apoptose , Carcinogênese/metabolismo , Carcinogênese/patologia , Quinase 5 Dependente de Ciclina/análise , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Receptores Androgênicos/análise , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT3/análise , Fator de Transcrição STAT3/metabolismo
11.
Nat Commun ; 10(1): 3562, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395886

RESUMO

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.


Assuntos
Androgênios/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Receptores Androgênicos/metabolismo , Animais , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Camundongos Transgênicos , Ressonância Magnética Nuclear Biomolecular , Agregados Proteicos , Domínios Proteicos , Multimerização Proteica , Receptores Androgênicos/química , Receptores Androgênicos/genética , Solubilidade
12.
Gen Comp Endocrinol ; 283: 113235, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369730

RESUMO

Deer antlers offer a unique model to study organ regeneration in mammals. Antler regeneration relies on the pedicle periosteum (PP) cells and is triggered by a decrease in circulating testosterone (T). The molecular mechanism for antler regeneration is however, unclear. Label-free liquid chromatography-mass spectrometry (LC-MS/MS) was used to identify differentially-expressed proteins (DEPs) in the regeneration-potentiated PP (under low T environment) over the non-regeneration-potentiated PP (under high T environment). Out of total 273 DEPs, 189 were significantly up-regulated and 84 were down-regulated from these comparisons: after castration vs before castration, natural T vs before castration, and exogenous T vs before castration. We focused on the analysis only of those DEPs that were present in fully permissive environment to antler regeneration (low T). Nine transduction pathways were identified through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, including the estrogen signaling pathway. A total of 639 gene ontology terms were found to be significantly enriched in regeneration-potentiated PP (low T) from the DEPs. Reliability of the label free LC-MS/MS was determined by qRT-PCR to estimate the expression level of selected genes. The results suggest that up-regulated heat shock proteins (HSP90AB1, HSP90B1), peptidyl-prolyl cis-trans isomerase 4 (FKBP4), mitogen-activated protein kinase 3 (MAPK3) and calreticulin (CALR) and down-regulated SHC-transforming protein 1 (SHC1), heat shock protein family A member 1A (HSPA1A) and proto-oncogene tyrosine-protein kinase (SRC) may be associated directly or indirectly with antler regeneration. Further studies are required to investigate the roles of these proteins in regeneration using appropriate in vivo models.


Assuntos
Androgênios/metabolismo , Chifres de Veado/fisiologia , Cervos/metabolismo , Proteômica , Regeneração/fisiologia , Androgênios/sangue , Animais , Cromatografia Líquida , Regulação da Expressão Gênica , Ontologia Genética , Mapas de Interação de Proteínas , Proteoma/genética , Proteoma/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Espectrometria de Massas em Tandem , Testosterona/sangue
13.
Chemosphere ; 237: 124371, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31369902

RESUMO

Public concerns about potential ecological risks of androgens discharged to the environment through wastewater treatment plants (WWTPs) has resulted in an increased interest regarding the occurrence and fate of androgens in WWTPs. In this study, the occurrence and removal of eight androgens from 12 municipal WWTPs distributed in eleven cities in China were investigated. The composition profiles of eight androgens in influent, effluent, and excess sludge were studied. Multiple factor analyses were performed to reveal the factors affecting the distribution of androgens in WWTP influent. Results showed similar composition profiles of androgens in the studied WWTPs, with androsterone and dehydroepiandrosterone confirmed as the dominant androgens. The distributions of androgens in WWTP influent were related to the chemical oxygen demand in influent and the gross domestic product (GDP) of WWTP-associated cities. The target androgens have high aqueous removal rates, with a mean removal rate of >90%. Additionally, the behaviors of androgens were evaluated by mass balance along anaerobic-anoxic-oxic (AAO) processes in a WWTP, in which many of the androgens were eliminated mainly in the anaerobic tank. Further, 15 biotransformation products of testosterone were identified under anaerobic, anoxic, and aerobic sludge, respectively. Based on these metabolites, a general biotransformation pathway of testosterone under anaerobic, anoxic, and aerobic sludge is presented.


Assuntos
Androgênios/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise , Androgênios/metabolismo , Androsterona/análise , China , Cidades , Esgotos/química , Testosterona/metabolismo , Instalações de Eliminação de Resíduos , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/metabolismo , Purificação da Água
14.
Mol Carcinog ; 58(11): 2077-2090, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31411358

RESUMO

The plasma membrane (PM) is considered as a major druggable site. More than 50% of the existing drugs target PM proteins. In the wake of emerging data indicating a key role of estrogens in prostate cancer (PCa) pathogenesis, the study was undertaken to explore whether the estrogen binding sites exist on the PM and if such sites are functionally relevant in PCa. Estradiol (E2) binding to the PM was detected in androgen-dependent (LNCaP), androgen-independent (PC3, DU145) PCa cell lines, nontumorigenic (RWPE1) prostate epithelial cell line, and rat prostate cells. Conventional estrogen receptors (nuclear estrogen receptors), known for their nuclear localization, were detected in the PM enriched extracts. This was indirectly confirmed by reduced localization of ERs on the PM of cells, silenced for the expression of their cognate genes. Further, unlike cell-permeable E2, stimulation with cell-impermeable estradiol (E2-BSA) did not induce proliferation in LNCaP cells. However, stimulation with E2-BSA led to alterations in the phosphorylation status of several kinases including GSK3 and AKT, along with the hyperphosphorylation of cytoskeletal proteins such as ß-actin and cytokeratin 8 in LNCaP. This was accompanied by epithelial-to-mesenchymal (EMT) features such as increased migration and invasion; higher vimentin expression, and a concomitant decrease in the E-cadherin expression. These effects were not observed in RWPE1 cells. Interestingly, cell-permeable E2 failed to induce EMT in PCa cells. This in vitro study is the first to suggest that the PM-initiated estrogen signaling contributes to higher invasiveness in PCa cells. Plasma membrane ERs may act as novel targets for PCa therapeutics.


Assuntos
Androgênios/metabolismo , Membrana Celular/genética , Estrogênios/metabolismo , Neoplasias da Próstata/genética , Animais , Caderinas/genética , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Transição Epitelial-Mesenquimal/genética , Estradiol/farmacologia , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/genética , Humanos , Queratina-8/genética , Masculino , Camundongos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Ratos , Transdução de Sinais
15.
An Bras Dermatol ; 94(3): 327-330, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365662

RESUMO

BACKGROUND: Seborrheic dermatitis is a common disease characterized by the erythematous plaques with oily-yellow desquamation. Increased sebaceous gland activity by androgenic hormones has played a role in the etiology of the disease. The second-to-fourth digit (2D:4D) ratio is thought to be a marker of prenatal androgen exposure. OBJECTIVES: To investigate the association between 2D:4D ratios and seborrheic dermatitis in a male population. METHODS: Healthy male controls and patients with seborrheic dermatitis were included in this study. One hundred seborrheic dermatitis patients and 120 healthy controls, aged 17-59, were enrolled. A digital Vernier caliper was used to measure the finger lengths. Seborrheic dermatitis severity was assessed using the Seborrheic Dermatitis Area and Severity Index (SDASI). RESULTS: The 2D:4D ratios of the patients (x = 0.977) were significantly lower than those of the controls (x = 1.050) for right hands (t = 6.948; p = 0.000; > 0.05). No similar relationship was found between the 2D:4D ratio for left hands (t = 0.901; p = 0.368; > 0.05). Seborrheic dermatitis severity was negatively correlated with 2D:4D ratios of right hands (r = -0.391; p = 0.000-0.05). STUDY LIMITATIONS: One of the main limitations of this study was the small sample, which got a head of us from acquiring certain findings about the 2D:4D ratio and seborrheic dermatitis. The other limitation is that the patient selection did not reflect the general population, as a single clinic was studied. CONCLUSION: To the authors' knowledge, this is the first study examining the relationship between 2D:4D ratios and seborrheic dermatitis. The result of this study may indicate a line of investigation and can support the theory of prenatal androgen exposure.


Assuntos
Dermatite Seborreica/diagnóstico , Dedos/anatomia & histologia , Adolescente , Adulto , Androgênios/metabolismo , Antropometria , Biomarcadores , Estudos de Casos e Controles , Feminino , Mãos/anatomia & histologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Índice de Gravidade de Doença , Adulto Jovem
16.
J Steroid Biochem Mol Biol ; 193: 105420, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31283987

RESUMO

Mutations in the X-linked androgen receptor (AR) gene cause complete androgen insensitivity syndrome (CAIS). CAIS may cause congenital sexual development disorder, which frequently develops into testicular tumors. Here, we describe a novel splice-site intron 1 mutation in AR leading to improper splicing and AR protein absence in CAIS gonads. We characterized a patient's postpubertal gonadal steroidogenic enzyme expression profile. Localization of both CYP11A1 and CYP17A1 enzymes was restricted to both Leydig tumor cells and adjacent to tumor gonadal tissues. Sertoli cells of the CAIS gonad showed abundant HSD17B3 protein, which is an adult Leydig cell marker that enables the conversion of androstenedione to testosterone. Such HSD17B3 expression is typical for fetal-type Sertoli cells in rodents. The postpubertal CAIS gonad of our patient was completely devoid of androgen signaling pathway activity. Plausibly, the postpubertal Leydig cells consisted of two distinct cell populations: postpubertal fetal-type Leydig cells that persisted as androgen-independent cells and immature adult Leydig cells that failed to differentiate. Taken together, in this CAIS postpubertal testis, both Leydig and fetal-type Sertoli cells participated in testosterone production. Our results indicate the importance of molecular analysis as well as the characterization of steroidogenic enzyme profiling in the CAIS patient's gonad.


Assuntos
Síndrome de Resistência a Andrógenos/genética , Receptores Androgênicos/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , Síndrome de Resistência a Andrógenos/metabolismo , Androgênios/metabolismo , Feminino , Feto/metabolismo , Gônadas/metabolismo , Hormônios/sangue , Humanos , Íntrons , Masculino , Mutação , Receptores Androgênicos/metabolismo
17.
Ecotoxicol Environ Saf ; 182: 109405, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31276886

RESUMO

The effect of glyphosate, both pure and formulated (Roundup Ultramax®), was evaluated on males of the estuarine crab Neohelice granulata, by means of both in vivo and in vitro assays. The in vivo assays comprised the exposure for 30 d to 1 mg/L of the herbicide, until finally assessing weight gain, levels of energy reserves, sperm number per spermatophore, proportion of abnormal spermatophores, and sperm viability. At the end of this assay, significant (p < 0.05) decrease in weight gain and muscle protein levels was detected by effect of both pure and formulated glyphosate. In spermatophores from the vas deferens, a significant (p < 0.05) decrease of the sperm count was observed by effect of Roundup, while a significant incidence (p < 0.05) of abnormal spermatophores was observed either with glyphosate or with Roundup treatment. No changes were seen in the spermatophore area or in vas deferens secretions. Since no sperm mortality was induced by the formulated herbicide, we propose a probable inhibiting effect on spermatogenesis might explain the observed sperm count decrease. In this sense, an in vitro assay was designed by incubating testes and vasa deferentia with Roundup, in order to corroborate the possible interference of glyphosate with the secretion of the androgenic gland hormone that controls the spermatogenesis, in the presence or absence of the androgenic gland. Although the herbicide per se was able to reduce the sperm count to some extent, the increase in the number of spermatozoa/spermatophore produced by the co-incubation with the androgenic gland was completely reverted by the addition of Roundup (1 mg/L of glyphosate a.e.), suggesting that an inhibition on the secretion and/or transduction of the androgenic gland hormone could be taking place.


Assuntos
Braquiúros/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Androgênios/metabolismo , Animais , Estuários , Glicina/toxicidade , Masculino , Contagem de Espermatozoides , Espermatogênese/efeitos dos fármacos
18.
Prostate ; 79(12): 1386-1398, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31334877

RESUMO

BACKGROUND: Despite the overall success of radiotherapy, a significant number of patients develop radioresistance, which leads to local regional recurrence and distant metastasis. We studied whether repeated radiation treatment promotes androgen-independent survival of prostate cancer (PCa) cells and their metastatic potential. We also studied whether glucocorticoid receptor (GR) increase in radioresistant cells is associated with acquisition of these aggressive characteristics. METHODS: Radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) PCa sublines were developed by repeated radiation treatments of parental cells. Levels and activations of androgen receptor (AR) and GR in radioresistant PCa cells and respective parental cells were investigated in quantitative real-time polymerase chain reaction/Western blot analyses and immunofluorescence staining. Androgen-independent survival of radioresistant cells was tested in in vitro cell growth assays and the castration-resistant survival of these cell-derived tumors were investigated in mouse xenografts. RESULTS: Higher GR levels, but lower AR levels were detected in radioresistant cells than in parental cells. Radiation-induced GR upregulation was associated with increased intracellular cyclic adenosine monophosphate. As a consequence of GR activation, LNCaPR18 cells survived well in an androgen-depleted culture condition while parental cells could not. Results of in vivo mouse studies showed survival of LNCaPR18 cell-derived tumors in castrated mice while parental cell-derived tumors regressed. The growth of LNCaPR18 cell-derived tumors in castrated mice was impaired when treated with the anti-GR agent mifepristone. In experiments with C4-2/C4-2R26 cell sets, GR activation in C4-2R26 cells increased their metastatic potential. CONCLUSION: GR activation in radioresistant cells mediates androgen independence and facilitates PCa progression.


Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Tolerância a Radiação/efeitos da radiação , Radioterapia/efeitos adversos , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta à Radiação , Humanos , Masculino , Camundongos , Neoplasias da Próstata/química , Receptores Androgênicos/análise , Receptores de Glucocorticoides/análise , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
20.
PLoS One ; 14(7): e0217986, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269032

RESUMO

There is limited physiological information on onset of puberty in male lions. The aim of this study was to use longitudinal non-invasive monitoring to: 1) assess changes in steroid metabolite excretory patterns as a function of age and body weight; 2) determine correlations between fecal androgen (FAM) and glucocorticoid (FGM) metabolite concentrations; and 3) confirm spermiogenesis non-invasively through urinalysis. Specifically, FAM and FGM metabolites were analyzed in samples collected twice weekly from 21 male lions at 17 institutions (0.9-16 years of age) for 3.8 months- 2.5 years to assess longitudinal hormone patterns. In addition, body weights were obtained approximately monthly from 10 individuals at five zoos (0.0-3.0 years), and urine was collected from six males at two facilities (1.2-6.3 years) and evaluated for the presence of spermatozoa. An increase in overall mean FAM occurred at 2.0 years of age, at which point concentrations remained similar throughout adulthood. The onset of puberty occurred earlier in captive-born males (<1.2 years of age) compared to wild-born counterparts (<2.5 years of age). Additionally, males in captivity gained an average of 7.3 kg/month compared to 3.9 kg/month for wild males over the first 2-2.5 years of age. Sperm (spermaturia) was observed in males as young as 1.2 years in captivity compared to 2.5 years in the wild (ejaculates). There was no difference in FAM or FGM concentrations with regards to age or season. Overall, this study demonstrates that: 1) captive male lions attain puberty at an earlier age than wild counterparts; 2) onset of puberty is influenced by body weight (growth rate); and 3) spermiogenesis can be confirmed via urinalysis. Knowledge about the linkage between body weight and onset of puberty could facilitate improved reproductive management of ex situ populations via mitigating the risk of unintended breedings in young animals.


Assuntos
Androgênios/metabolismo , Peso Corporal/fisiologia , Glucocorticoides/metabolismo , Leões/fisiologia , Maturidade Sexual/fisiologia , Espermatozoides/metabolismo , Animais , Fezes , Masculino , Espermatozoides/citologia
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