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1.
Chemosphere ; 264(Pt 1): 128468, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33032228

RESUMO

Azoles are used in agriculture and medicine to combat fungal infections. We have previously examined the endocrine disrupting properties of the agricultural azole fungicides triticonazole and flusilazole. Triticonazole displayed strong androgen receptor (AR) antagonism in vitro, whereas in utero exposure resulted in anti-androgenic effects in vivo evidenced by shorter anogenital distance (AGD) in fetal male rats. Flusilazole displayed strong AR antagonism, but less potent than triticonazole, and disrupted steroidogenesis in vitro, whereas in utero exposure disrupted fetal male plasma hormone levels. To elaborate on how these azole fungicides can disrupt male reproductive development by different mechanisms, and to investigate whether feminization effects such as short AGD in males can also be detected at the transcript level in fetal testes, we profiled fetal testis transcriptomes after in utero exposure to triticonazole and flusilazole by 3'Digital Gene Expression (3'DGE). The analysis revealed few transcriptional changes after exposure to either compound at gestation day 17 and 21. This suggests that the observed influence of flusilazole on hormone production may be by directly targeting steroidogenic enzyme activity in the testis at the protein level, whereas observations of shorter AGD by triticonazole may primarily be due to disturbed androgen signaling in androgen-sensitive tissues. Expression of Calb2 and Gsta2 was altered by flusilazole but not triticonazole and may pinpoint novel pathways of disrupted testicular steroid synthesis. Our findings have wider implication for how we integrate omics data in chemical testing frameworks, including selection of non-animal test methods and building of Adverse Outcome Pathways for regulatory purposes.


Assuntos
Fungicidas Industriais , Animais , Azóis/toxicidade , Ciclopentanos , Fungicidas Industriais/toxicidade , Perfilação da Expressão Gênica , Humanos , Masculino , Ratos , Silanos , Testículo , Testosterona/farmacologia , Triazóis
2.
Life Sci ; 263: 118584, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058919

RESUMO

AIMS: The non-genomic (prompt) actions of sex steroids on pregnant uterine contractility are not fully explored yet, the aim of our study was to clarify such effects of 17-ß estradiol (E2), progesterone (P4) and testosterone (T) on late (22-day) pregnant uterine contractions together with the signaling pathways in rats in vitro. METHODS: The uterine effects of sex steroids on KCl-stimulated contractions were examined in the presence of genomic pathway blocker actinomycin D and cycloheximide, sex hormone receptor antagonists (flutamide, fulvestrant, mifepristone) and also after removing the endometrium. The modifications in uterine G-protein activation and cAMP levels were also detected. RESULTS: T and E2 both relaxed the uterine contractions in the concentration range of 10-8-10-3 M with an increase in the activated G-protein and cAMP levels of the uterus, while P4 was ineffective. Cycloheximide, actinomycin D, antagonist for T and E2 were not able to modify the responses along with the endothelium removal. Mifepristone blocked the relaxing effects of T and E2 and reduced the activation of G-protein and the formation of cAMP. SIGNIFICANCE: T and E2 can inhibit KCl-stimulated contractions in the late pregnant uterus in high concentrations and in a non-genomic manner. Their actions are mediated by a G-protein coupled receptor that can be blocked by mifepristone. A single and high dose of T or E2 might be considered in premature contractions, however, further preclinical and clinical studies are required for the approval of such a therapeutic intervention.


Assuntos
Estradiol/farmacologia , Progesterona/farmacologia , Testosterona/farmacologia , Contração Uterina/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Feminino , Flutamida/farmacologia , Fulvestranto/farmacologia , Mifepristona/farmacologia , Contração Muscular/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Gravidez , Progesterona/administração & dosagem , Ratos , Ratos Sprague-Dawley , Testosterona/administração & dosagem
3.
Am J Physiol Lung Cell Mol Physiol ; 319(5): L843-L847, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32996784

RESUMO

The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.


Assuntos
Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/metabolismo , Sistema Respiratório/metabolismo , Adulto , Idoso , Células Cultivadas , Infecções por Coronavirus/enzimologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Sistema Respiratório/citologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/enzimologia , Fatores Sexuais , Testosterona/metabolismo , Testosterona/farmacologia
4.
Am J Physiol Endocrinol Metab ; 319(4): E678-E688, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32776828

RESUMO

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants (n = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM (P < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA (P < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Modificação Traducional de Proteínas/efeitos dos fármacos , Receptores Androgênicos/biossíntese , Testosterona/farmacologia , Adolescente , Adulto , Composição Corporal , Dieta , Exercício Físico , Hormônios/sangue , Humanos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Receptores de Interleucina-6/metabolismo , Receptor de TWEAK/metabolismo , Regulação para Cima , Adulto Jovem
5.
Life Sci ; 261: 118342, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32853655

RESUMO

AIMS: The increased incidence of heart failure with reduced ejection fraction in men compared with women suggests that male sex hormones significantly impact myocardial contractile activation. This study aims to examine associations among molecular alterations, cellular modulations and in vivo cardiac contractile function upon deprivation of testicular hormones. MAIN METHODS: Myocardial structure and functions were compared among sham-operated control and twelve-week orchidectomized (ORX) male rats with and without testosterone supplementation. KEY FINDINGS: Echocardiography and pressure-volume relationships demonstrated a decreased left ventricular ejection fraction compared with sham-operated controls. The percentage of contractility reduction was generally similar to the decrease in tension development detected in both right ventricular trabeculae and skinned isolated left ventricular cardiomyocytes of ORX rats. Reductions in tension cost and the rate constant of tension redevelopment (ktr) in ORX samples suggested a decrease in the rate of cross-bridge formation, reflecting a reduced number of cross-bridges. Slow cross-bridge detachment in ORX rat hearts could result from a shift of myosin heavy chain isoforms towards a slower ATPase activity ß-isoform and reductions in the phosphorylation levels of cardiac troponin I and myosin binding protein-C. All the changes in the ORX rat heart, including ejection fractions and myofilament protein expression and phosphorylation, were completed attenuated by a physiological dose of testosterone. SIGNIFICANCE: Testosterone plays a critical role in regulating the mechanical and contractile dynamics of the heart. Deprivation of male sex hormones cause the loss of normal preserved cardiac contractile function leading to a high risk of severe cardiomyopathy progression.


Assuntos
Cardiomiopatias/fisiopatologia , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Testosterona/metabolismo , Animais , Progressão da Doença , Coração/fisiologia , Masculino , Cadeias Pesadas de Miosina/metabolismo , Orquiectomia , Ratos , Ratos Sprague-Dawley , Volume Sistólico/fisiologia , Testosterona/administração & dosagem , Testosterona/farmacologia , Função Ventricular Esquerda/fisiologia
6.
PLoS Pathog ; 16(7): e1008506, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645119

RESUMO

Circulating androgens can modulate immune cell activity, but the impact of androgens on viral pathogenesis remains unclear. Previous data demonstrate that testosterone reduces the severity of influenza A virus (IAV) infection in male mice by mitigating pulmonary inflammation rather than by affecting viral replication. To examine the immune responses mediated by testosterone to mitigate IAV-induced inflammation, adult male mice remained gonadally intact or were gonadectomized and treated with either placebo or androgen-filled (i.e., testosterone or dihydrotestosterone) capsules prior to sublethal IAV infection. Like intact males, treatment of gonadectomized males with androgens improved the outcome of IAV infection, which was not mediated by changes in the control of virus replication or pulmonary cytokine activity. Instead, androgens accelerated pulmonary leukocyte contraction to limit inflammation. To identify which immune cells were contracting in response to androgens, the composition of pulmonary cellular infiltrates was analyzed and revealed that androgens specifically accelerated the contraction of total pulmonary inflammatory monocytes during peak disease, as well as CD8+ T cells, IAV-specific CD8+ T numbers, cytokine production and degranulation by IAV-specific CD8+ T cells, and the influx of eosinophils into the lungs following clearance of IAV. Neither depletion of eosinophils nor adoptive transfer of CD8+ T cells could reverse the ability of testosterone to protect males against IAV suggesting these were secondary immunologic effects. The effects of testosterone on the contraction of immune cell numbers and activity were blocked by co-administration of the androgen receptor antagonist flutamide and mimicked by treatment with dihydrotestosterone, which was also able to reduce the severity of IAV in female mice. These data suggest that androgen receptor signaling creates a local pulmonary environment that promotes downregulation of detrimental inflammatory immune responses to protect against prolonged influenza disease.


Assuntos
Vírus da Influenza A/imunologia , Pulmão/efeitos dos fármacos , Infecções por Orthomyxoviridae/imunologia , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Animais , Feminino , Inflamação/imunologia , Inflamação/virologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
7.
J Int Acad Periodontol ; 22(3): 146-155, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32655040

RESUMO

BACKGROUND: Skin-related disorders and periodontitis are distinct diseases that have been associated with altered levels of testosterone. Understanding the mechanisms through which testosterone mediates gingival enlargement in animals and humans is crucial for preventing or treating this condition. In this study, we investigated the impact of different doses of androgens, the role of aromatase inhibition, and the effects of testosterone association with sex hormone receptor antagonists or aromatase inhibitors on human gingival fibroblast proliferation and migration in vitro. METHODS: Fibroblasts were cultivated in Dulbecco's Modified Eagle's Medium in a humidified atmosphere and treated with different doses of testosterone or dihydrotestosterone, and testosterone in association with: aromatase inhibitor - anastrozole; antagonist of androgen receptors - flutamide; and antagonist of estrogen receptors - fulvestrant. RESULTS: Low (1nM) and high (1µM) doses of testosterone significantly increased cell migration, but the higher dose did not alter cell proliferation. Those effects were related to both androgen and estrogen receptors activation, as evidenced by the dihydrotestosterone and drug interaction groups. CONCLUSIONS: Testosterone association with sex hormone receptor antagonists flutamide and fulvestrant suggests that not only androgen receptors, but also estrogen receptors, may take part in fibroblast cell proliferation and migration in vitro.


Assuntos
Androgênios , Testosterona , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Animais , Proliferação de Células , Estradiol/farmacologia , Fibroblastos , Humanos , Receptores Estrogênicos , Testosterona/farmacologia
8.
Proc Biol Sci ; 287(1931): 20200976, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32673552

RESUMO

Several studies have implicated testosterone in the modulation of altruistic behaviours instrumental to advancing social status. Independent studies have also shown that people tend to behave more altruistically when being watched (i.e. audience effect). To date, little is known about whether testosterone could modulate the audience effect. In the current study, we tested the effect of testosterone on altruistic behaviour using a donation task, wherein participants were asked to either accept or reject a monetary transfer to a charity organization accompanying a personal cost either in the presence or absence of an observer. We administered testosterone gel or placebo to healthy young men (n = 140) in a double-blind, placebo-controlled, mixed design. Our results showed that participants were more likely to accept the monetary transfer to the charity when being observed compared to when they completed the task alone. More importantly, this audience effect was amplified among people receiving testosterone versus placebo. Our findings suggest that testosterone administration increases the audience effect and further buttress the social status hypothesis, according to which testosterone promotes status-seeking behaviour in a context-dependent manner.


Assuntos
Androgênios/farmacologia , Testosterona/farmacologia , Adolescente , Adulto , Humanos , Masculino , Comportamento Social , Meio Social , Adulto Jovem
9.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32514526

RESUMO

Restoration of spermatogenesis and fertility is a major issue to be solved in male mammals with hypogonadotropic hypogonadism. Kiss1 knockout (KO) male mice are postulated to be a suitable animal model to investigate if hormonal replacement rescues spermatogenesis in mammals with this severe reproductive hormone deficiency, because KO mice replicate the hypothalamic disorder causing hypogonadism. The present study investigated whether testosterone supplementation was able to restore spermatogenesis and in vitro fertilization ability in Kiss1 KO mice. To this end, spermatogenesis, in vitro fertilization ability of Kiss1 KO sperm, and preimplantation development of wild-type embryos inseminated with Kiss1 KO sperm, were examined. The newly generated Kiss1 KO male mice showed infertility with cryptorchidism. Subcutaneous testosterone supplementation for 6 weeks restored plasma and intratesticular testosterone levels, elicited testicular descent, and induced complete spermatogenesis from spermatocytes to elongated spermatids in the testis, resulting in an increase in epididymal sperm number in testosterone-supplemented Kiss1 KO male mice. Epididymal sperm derived from the testosterone-supplemented Kiss1 KO mice showed normal in vitro fertilization ability, and the fertilized eggs showed normal preimplantation development, while the males failed to impregnate females. These results suggest that the failure of spermatogenesis in Kiss1 KO mice is mainly due to a lack of testosterone production, and that Kiss1 KO sperm are capable of fertilizing eggs if the animals receive the appropriate testosterone supplementation without local kisspeptin signaling in the testis and epididymis. Thus, testosterone supplementation would restore spermatogenesis of male mammals showing hypogonadotropic hypogonadism with genetic inactivation of the KISS1/Kiss1 gene.


Assuntos
Fertilidade/efeitos dos fármacos , Kisspeptinas/genética , Espermatogênese/efeitos dos fármacos , Testosterona/farmacologia , Animais , Células Cultivadas , Feminino , Fertilidade/genética , Fertilização In Vitro , Hipogonadismo/tratamento farmacológico , Hipogonadismo/genética , Hipogonadismo/patologia , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Espermatogênese/genética , Testosterona/uso terapêutico
10.
Endocrinology ; 161(8)2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516392

RESUMO

Prenatal testosterone (T)-treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T-treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep. In controls, 3494 genes were differentially expressed between cell types with cell signaling, proliferation, extracellular matrix, immune, and tissue development genes enriched in theca; and mitochondrial, chromosomal, RNA, fatty acid, and cell cycle process genes enriched in granulosa cells. Prenatal T treatment 1) increased gene expression of transforming growth factor ß receptor 1 and exosome component 9, and decreased BCL6 corepressor like 1, BCL9 like, and MAPK interacting serine/threonine kinase 2 in both cells, 2) induced differential expression of 92 genes that included increased mitochondrial, ribosome biogenesis, ribonucleoprotein, and ubiquitin, and decreased cell development and extracellular matrix-related pathways in granulosa cells, and 3) induced differential expression of 56 genes that included increased noncoding RNA processing, ribosome biogenesis, and mitochondrial matrix, and decreased transcription factor pathways in theca cells. These data indicate that follicular function is affected by genes involved in transforming growth factor signaling, extracellular matrix, mitochondria, epigenetics, and apoptosis both in a common as well as a cell-specific manner and suggest possible mechanistic pathways for prenatal T treatment-induced PCO morphology in sheep.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Células da Granulosa/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Testosterona/farmacologia , Células Tecais/efeitos dos fármacos , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células da Granulosa/metabolismo , Hiperandrogenismo/genética , Hiperandrogenismo/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Ovário/efeitos dos fármacos , Ovário/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Ovinos , Células Tecais/metabolismo
11.
BMC Med ; 18(1): 122, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32493397

RESUMO

BACKGROUND: Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available. METHODS: We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly (p value < 5 × 10-8) predicted testosterone in a sex-specific manner were applied to 179,916 white British men (6016 CKD cases) and 212,079 white British women (5958 CKD cases) to obtain sex-specific associations with CKD, albuminuria, and estimated glomerular filtration rate (eGFR). We also used multivariable MR to control for sex hormone binding globulin (SHBG). For validation, we similarly examined their role in hemoglobin and high-density lipoprotein cholesterol (HDL-c). We also assessed the role of kidney function in serum testosterone, by applying eGFR-related SNPs to testosterone in the UK Biobank. RESULTS: Genetically predicted testosterone was associated with CKD in men (odds ratio (OR) for bioavailable testosterone 1.17 per standard deviation, 95% confidence interval (CI) 1.03 to 1.33) based on 125 SNPs but not in women (OR 1.02, 95% CI 0.92 to 1.14 for total testosterone) based on 254 SNPs. Multivariable MR allowing for SHBG showed consistent patterns. Genetically predicted bioavailable testosterone in men and women and genetically predicted total testosterone in women increased hemoglobin and lowered HDL-c, as seen in RCTs. Genetically predicted eGFR was not related to serum testosterone in men or in women. CONCLUSIONS: Genetically predicted testosterone was associated with CKD and worse kidney function in men, whilst not affected by kidney function. Identifying drivers of testosterone and the underlying pathways could provide new insights into CKD prevention and treatment.


Assuntos
Bancos de Espécimes Biológicos/normas , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/tratamento farmacológico , Testosterona/uso terapêutico , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Testosterona/farmacologia , Reino Unido
12.
Adv Gerontol ; 33(2): 385-390, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593257

RESUMO

There are changes in the metabolism, reproductive and nervous systems with ageing, which have a systemic and interrelated nature. The purpose of this work was to demonstrate the effectiveness of audiovisual correction and therapy with testosterone drugs in addition to the standard therapy in patients with polymorbid pathology. 89 men aged 35-55 years old with diabetes mellitus, polymorbid cardiovascular disease, obesity, anxiety and depressive disorders were examined. They were divided into 3 groups depending on the treatment: the 1st - standard therapy and escitalopram / tofisopam; the 2nd - standard therapy + audiovisual correction; the 3rd - standard therapy + audiovisual correction + testosterone undecanoate. Laboratory examination was carried out in all patients before the start of treatment and 9 months after the treatment. The severity of androgen deficiency was determined using IIEF-5 questionnaire and the AMS male aging scale. In was shown a decrease in testosterone levels, signs of erectile dysfunction and symptoms of moderate to severe androgen deficiency, increased proatherogenic and decreased antiatherogenic lipoproteins, increased glucose, glycated hemoglobin, insulin, HOMA index in our study. In group of audiovisual correction we saw a more significant improvement in the lipid profile after treatment. Audiovisual correction and androgen therapy contributed to the improvement of erectile function indices and a decrease in the severity of the symptoms of ageing in men.


Assuntos
Senilidade Prematura/prevenção & controle , Androgênios/uso terapêutico , Recursos Audiovisuais , Terapia de Reposição Hormonal , Idoso , Androgênios/deficiência , Androgênios/farmacologia , Disfunção Erétil/terapia , Humanos , Masculino , Ereção Peniana/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/farmacologia , Testosterona/uso terapêutico
13.
Exp Mol Pathol ; 115: 104473, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32454105

RESUMO

The aim of this study was to evaluate the impact of prenatal testosterone exposure on prostate development in male and female neonatal gerbils. Pregnant females were exposed to subcutaneous injections of testosterone cypionate (500 µg/animal) at gestational days 20 and 22. Male and female pups were then euthanized at postnatal day 1. Morphological analysis showed that females were severely affected by androgen exposure. We also observed that male and female urogenital sinus (UGS) responded differentially to testosterone treatment, demonstrating heterogeneous immunostaining for the androgen receptor (AR), estrogen receptor alpha (ERα), and proliferating cell nuclear antigen (PCNA). Smooth muscle α-actin (α-SMA) analysis showed that testosterone delays the myodifferentiation, allowing buds to reach the ectopic mesenchymes of the female UGS. Our data showed that abnormal testosterone exposure disrupted prostate organogenesis, altered the expression patterns of important markers, and demonstrated that female UGS was particularly influenced by androgen exposure during a critical window in the developmental period.


Assuntos
Organogênese/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Testosterona/farmacologia , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Gerbillinae , Imageamento Tridimensional , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/anatomia & histologia , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Testosterona/sangue
14.
PLoS One ; 15(5): e0232120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407351

RESUMO

Decades of work indicate that female birds can control their offspring sex ratios in response to environmental and social cues. In laying hens, hormones administered immediately prior to sex chromosome segregation can exert sex ratio skews, indicating that these hormones may act directly on the germinal disc to influence which sex chromosome is retained in the oocyte and which is discarded into an unfertilizable polar body. We aimed to uncover the gene pathways involved in this process by testing whether treatments with testosterone or corticosterone that were previously shown to influence sex ratios elicit changes in the expression of genes and/or gene pathways involved in the process of meiotic segregation. We injected laying hens with testosterone, corticosterone, or control oil 5h prior to ovulation and collected germinal discs from the F1 preovulatory follicle in each hen 1.5h after injection. We used RNA-sequencing (RNA-seq) followed by DESeq2 and gene set enrichment analyses to identify genes and gene pathways that were differentially expressed between germinal discs of control and hormone-treated hens. Corticosterone treatment triggered downregulation of 13 individual genes, as well as enrichment of gene sets related to meiotic spindle organization and chromosome segregation, and additional gene sets that function in ion transport. Testosterone treatment triggered upregulation of one gene, and enrichment of one gene set that functions in nuclear chromosome segregation. This work indicates that corticosterone can be a potent regulator of meiotic processes and provides potential gene targets on which corticosterone and/or testosterone may act to influence offspring sex ratios in birds.


Assuntos
Corticosterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Meiose/efeitos dos fármacos , Meiose/genética , Folículo Ovariano/citologia , Ovulação , Testosterona/farmacologia , Animais , Galinhas , Feminino , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia
15.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G989-G999, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363890

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2-/- mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover, immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.


Assuntos
Estradiol/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Testosterona/farmacologia , Aminoácidos , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Cromo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Estradiol/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Cirrose Hepática , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Knockout , Ácidos Nicotínicos , Hepatopatia Gordurosa não Alcoólica/patologia , Orquiectomia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Testosterona/administração & dosagem , Testosterona/deficiência , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
16.
J Fish Biol ; 97(2): 374-382, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32388872

RESUMO

The in vivo effect of 11-ketotestosterone (11KT) on transcript levels of the gonadotropin receptors (fshr and lhr) and sex differentiation-related genes (dmrt1 and foxl2) was examined in the ovaries of immature female beluga. For this purpose, six fish were treated with implants containing 2.5 mg 11KT and a placebo group of six females of the same age and gametogenic stage were given a blank implant. The implants were intraperitoneally inserted into 4-year-old females at the previtellogenic stage (mean body weight 5580 ± 165 g) and maintained under culture conditions for 8 weeks. Ovary samples for gene expression analysis of lhr, fshr, dmrt1 and foxl2 were collected by biopsy at 3 and 8 weeks post implantation. Diameters of oocytes increased in response to 11KT treatment, both at 3 and at 8 weeks post implantation, but no obvious changes were evident in cytology. Three weeks of 11KT treatment did not affect target gene expression, but a tendency for a time-dependent decrease of lhr and dmrt1 mRNA levels was observed in both treatment and placebo groups. By 8 weeks of treatment, however, 11KT implants provoked the upregulation of fshr and foxl2 transcript levels. Furthermore, lhr and dmrt1 transcript abundances recovered by 8 weeks of exposure in both blank- and 11KT-implanted beluga. These results suggest that 11KT, either directly or indirectly, may affect gametogenesis and regulate some key components of the reproductive axis in female beluga.


Assuntos
Peixes/genética , Proteína Forkhead Box L2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Receptores da Gonadotropina/genética , Testosterona/análogos & derivados , Fatores de Transcrição/genética , Animais , Implantes de Medicamento , Feminino , Oócitos/efeitos dos fármacos , Receptores do FSH/genética , Diferenciação Sexual/genética , Testosterona/farmacologia
18.
Life Sci ; 251: 117628, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247620

RESUMO

AIM: Investigation whether androgen/androgen receptor (AR) might regulate megalin expression and/or functionality and thus affecting Gentamicin-induced nephrotoxicity (GIN). MAIN METHODS: Male Wistar rats were treated with gentamicin with/out AR ligands (testosterone as agonist and flutamide as antagonist). Megalin expression in the kidney tissues was determined by real-time RT-PCR and western blot. Besides, megalin functionality was assessed using immunofluorescence imaging of fluorescein isothiocyanate (FITC) conjugated bovine serum albumin (BSA) (FITC-BSA). The effects of different treatments on the kidney were assessed at the structural level by histopathological evaluation and the biochemical level by colorimetric assay of blood urea nitrogen (BUN), serum creatinine (SCr) and urinary albumin/creatinine (A/C) ratio, besides, kidney expression of neutrophil gelatinase-associated lipocalin (NGAL) by immunoblotting. KEY FINDINGS: Our results revealed that treatment with testosterone either alone or combined with gentamicin increased megalin expression at mRNA and protein levels as well as at the functional level. These effects were paralleled by increased GIN as manifested by increased SCr, BUN, A/C ratio, renal expression of NGAL or histopathological changes. On the other hand, treatment with flutamide ameliorated GIN and megalin expression and functionality. Computational analysis of megalin promotor revealed the presence of multiple response elements that mediate androgen response. SIGNIFICANCE: Androgen/AR regulates megalin expression at the transcriptional level and consequently GIN. This may explain the sexual dimorphism in GIN and might represent a druggable target for treatment or prevention of GIN.


Assuntos
Androgênios/metabolismo , Antibacterianos/toxicidade , Gentamicinas/toxicidade , Nefropatias/induzido quimicamente , Receptores Androgênicos/metabolismo , Animais , Flutamida/farmacologia , Nefropatias/fisiopatologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Ratos , Ratos Wistar , Testosterona/farmacologia
19.
Int J Mol Sci ; 21(7)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283828

RESUMO

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.


Assuntos
Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Progesterona/farmacologia , Progestinas/farmacologia , Testosterona/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Progesterona/química , Progestinas/química , Testosterona/química
20.
Gen Comp Endocrinol ; 294: 113472, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32243956

RESUMO

Kisspeptin (Kiss) is considered an upstream regulator of gonadotropin-releasing hormone in mammals but its role in non-mammalian vertebrates is not unequivocally established. In the catfish Heteropneustes fossilis, a 605 bp long cDNA was identified from the brain by cloning as well as by retrieving from the catfish transcriptome database. The open reading frame (ORF, 93-405 bp) codes for a 113 amino acids long precursor protein. Homology and phylogenetic analyses showed that the predicted protein belongs to the vertebrate Kiss2 type with a high degree of conservation in the Kiss2-10 region (FNFNPFGLRF). The kiss2 transcripts were expressed highly in the brain and gonads in a dimorphic manner with a female bias. In the brain, kiss2 transcripts showed regional differences with higher expression in the medulla oblongata and forebrain regions. The kiss2 transcripts showed significant seasonal variations with the highest expression in the brain in spawning phase and in the gonads in prespawning phase. The kiss2 transcripts were localized in the brain (nucleus preopticus, habenular nucleus, nucleus recessus posterioris, nucleus recessus lateralis) and stratum periventriculare (radial glial cells) of optic tectum, pituitary and ovary (follicular layer and germinal vesicle). Ovariectomy (1, 2, 3 and 4 weeks) decreased brain kiss2 mRNA levels and a single injection of estradiol-17ß (E2; 0.5 µg/g body weight) in 3- week ovariectomized (OVX) and sham operated fish resulted in an increase in the transcript levels after 24 h. The E2 receptor antagonist Tamoxifen (TMX) produced biphasic effects on the kiss2 expression in the dose- response study. TMX inhibited the expression in the OVX fish, but elicited a stimulatory effect in the OVX + E2-treated fish. Testosterone (T) decreased, and progesterone (P4) inhibited (resting phase) or stimulated (prespawning phase) the transcript level in 3-week OVX fish. In the 3-week sham groups, E2 increased, and TMX, T and P4 inhibited the kiss2 transcript levels. The results suggest that Kiss2 is an important regulator of the brain- pituitary- gonadal- endocrine axis, and in habenular and optic tectum functions.


Assuntos
Peixes-Gato/genética , DNA Complementar/genética , Perfilação da Expressão Gênica , Kisspeptinas/genética , Esteroides/metabolismo , Sequência de Aminoácidos , Animais , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica , Humanos , Kisspeptinas/química , Kisspeptinas/metabolismo , Ovariectomia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Filogenia , Progesterona/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estações do Ano , Tamoxifeno/farmacologia , Testosterona/farmacologia
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