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1.
Endocrinology ; 160(10): 2471-2484, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398247

RESUMO

Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifest oligo-/anovulation, hyperandrogenism, and polyfollicular ovary. The polyfollicular ovarian morphology, a result of persistence of antral follicles, arises, in part, by transcriptional changes in key mediators of follicular development that, in turn, are driven by epigenetic mechanisms. We hypothesized that prenatal T excess induces, in a cell-specific manner, transcriptional changes in key mediators of follicular development associated with relevant changes in epigenetic machinery. Expression levels of key mediators of follicular development, DNA methyltransferases (DNMTs), and histone de-/methylases and de-/acetylases were determined in laser-capture microdissection-isolated antral follicular granulosa and theca and ovarian stromal cells from 21 months of age control and prenatal T-treated sheep (100 mg IM twice weekly from gestational day 30 to 90; term: 147 days). Changes in histone methylation were determined by immunofluorescence. Prenatal T treatment induced the following: (i) cell-specific changes in gene expression of key mediators of follicular development and steroidogenesis; (ii) granulosa, theca, and stromal cell-specific changes in DNMTs and histone de-/methylases and deacetylases, and (iii) increases in histone 3 trimethylation at lysine 9 in granulosa and histone 3 dimethylation at lysine 4 in theca cells. The pattern of histone methylation was consistent with the expression profile of histone de-/methylases in the respective cells. These findings suggest that changes in expression of key genes involved in the development of the polyfollicular phenotype in prenatal T-treated sheep are mediated, at least in part, by cell-specific changes in epigenetic-modifying enzymes.


Assuntos
Epigênese Genética/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Síndrome do Ovário Policístico/veterinária , Doenças dos Ovinos/induzido quimicamente , Propionato de Testosterona/toxicidade , Animais , Feminino , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ovinos , Doenças dos Ovinos/metabolismo
2.
Biol Pharm Bull ; 42(1): 1-9, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30381617

RESUMO

Veratrum maackii (VM), a perennial plant in the Melanthiaceae family, has anti-hypertensive, anti-cholinergic, anti-asthmatic, anti-tussive, anti-fungal, anti-melanogenesis, and anti-tumor activities. Here, we investigated the therapeutic effect of VM on benign prostatic hyperplasia (BPH) in human normal prostate cell line (WPMY-1) and a testosterone propionate-induced BPH animal model. WPMY-1 cells were treated with VM (1-10 µg/mL) and testosterone propionate (100 nM). BPH in rats was generated via daily subcutaneous injections of testosterone propionate (3 mg/kg) dissolved in corn oil, for 4 weeks. VM (150 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the testosterone propionate. All rats were sacrificed and the prostates were dissected, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Immunoblotting experiments indicated that WPMY-1 cells treated testosterone propionate had increased expression of prostate specific antigen (PSA) and androgen receptor (AR), and treatment with VM or finasteride blocked this effect. In rat model, VM significantly reduced prostate weight, prostatic hyperplasia, prostatic levels of dihydrotestosterone (DHT), and expression of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1, but increased the expression of pro-apoptotic Bcl-2-associated X protein (Bax) and the cleavage of caspase-3. VM administration also suppressed the testosterone propionate-induced activation of nuclear factor-kappaB (NF-κB). Our results indicate that VM effectively represses the development of testosterone propionate-induced BPH, suggesting it may be a useful treatment agent for BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Propionato de Testosterona/toxicidade , Veratrum , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
3.
Biomed Pharmacother ; 107: 1641-1647, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257382

RESUMO

Gestational androgen excess has been implicated in the development of cardiac dysfunction with poor mechanistic delineation. The role of sodium acetate on cardiac uric acid (UA) production and glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense in pregnancy is not known. The study therefore sought to test the hypothesis that rats exposed to elevated testosterone in late pregnancy would have increased cardiac UA production and defective G6PD-dependent antioxidant defense. We also hypothesized that sodium acetate (SAc) or androgen receptor blocker, flutamide (Flu) would ameliorate these effects through endoglin inhibition. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; po) or Flu (7.5 mg/kg; po) in the late gestation between gestational day 14 and 19. The results showed that in the late gestation, testosterone exposure led to increased plasma and cardiac endoglin. In the heart of rats exposed to gestational testosterone there were elevated lactate dehydrogenase, adenosine deaminase, xanthine oxidase, uric acid (UA), cardiac injury markers and decreased G6PD-dependent antioxidant defense. However, either SAc or Flu comparably ameliorated these testosterone-induced effects. The data from the present study revealed that testosterone exposure in the late gestation causes elevated cardiac Eng that is accompanied by increased UA production and defective G6PD-dependent anti-oxidant defenses. Besides, the findings also suggest that the inhibitory effect of SAc or Flu on endoglin attenuates UA production and enhances the G6PD-dependent anti-oxidant barrier, thereby implying that endoglin may be a potentially novel therapeutic intervention for cardiac dysfunction particularly in pregnancy.


Assuntos
Endoglina/antagonistas & inibidores , Flutamida/farmacologia , Acetato de Sódio/farmacologia , Propionato de Testosterona/administração & dosagem , Antagonistas de Androgênios/farmacologia , Animais , Antioxidantes/metabolismo , Feminino , Glucosefosfato Desidrogenase/metabolismo , Coração/efeitos dos fármacos , Exposição Materna/efeitos adversos , Gravidez , Ratos , Ratos Wistar , Propionato de Testosterona/toxicidade , Ácido Úrico/metabolismo
4.
Endocr Metab Immune Disord Drug Targets ; 17(4): 317-323, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-28901866

RESUMO

OBJECTIVE: To investigate potential reproductive effects of Pterocarpus marsupium methanolic extract on testosterone propionate induced Polycystic Ovarian Syndrome (PCOS) in female albino rats. METHODOLOGY: PCOS was induced in female albino rats by daily injecting testosterone propionate for 15 days intraperitoneally. Animals are divided into five groups with six rats per group. Group 1: Control group received olive oil, Group 2: Testosterone propionate+natural recovery, Group 3: Testosterone propionate + a dose of clomiphene citrate (standard), Group 4 and 5: Testosterone propionate + low dose (200mg/kg) and high dose (400mg/kg) b.w respectively for 15 days. Various biochemical and histopathological investigations were assessed. RESULTS: Methanol extract of Pterocarpus marsupium was able to exert its protective effect successfully by restoring all the parameters to normal and diminishing the cysts found in ovaries. CONCLUSION: Pterocarpus marsupium showed potential reproductive effects on testosterone propionate induced PCOS female albino rats and could be used as an alternative therapy in the treatment of PCOS.


Assuntos
Extratos Vegetais/uso terapêutico , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Pterocarpus , Reprodução/efeitos dos fármacos , Propionato de Testosterona/toxicidade , Animais , Feminino , Metanol/farmacologia , Metanol/uso terapêutico , Extratos Vegetais/farmacologia , Síndrome do Ovário Policístico/patologia , Distribuição Aleatória , Ratos , Reprodução/fisiologia , Resultado do Tratamento
5.
Biol Pharm Bull ; 40(12): 2125-2133, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28943529

RESUMO

Quisqualis indica (QI) has been used for treating disorders such as stomach pain, constipation, and digestion problem. This study was aimed to evaluate the therapeutic efficacy of QI extract on treating benign prostatic hyperplasia (BPH) in LNCaP human prostate cancer cell line and a testosterone-induced BPH rat model. LNCaP cells were treated with QI plus testosterone propionate (TP), and androgen receptor (AR) and prostate specific antigen (PSA) expression levels were assessed by Western blotting. To induce BPH, the rats were subjected to a daily subcutaneous injection of TP (3 mg/kg) for 4 weeks. The rats in treatment group were orally gavaged with QI (150 mg/kg) together with the TP injection. In-vitro studies showed that TP-induced increases in AR and PSA expression in LNCaP cells were reduced by QI treatment. In BPH-model rats, the prostate weight, testosterone in serum, dihydrotestosterone (DHT) concentration and 5α-reductase type 2 mRNA expression in prostate tissue were significantly reduced following the treatment with QI. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 were significantly attenuated in QI-treated rats. In addition, QI induced apoptosis by up-regulating caspase-3 and -9 activity and decreasing the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio in prostate tissues of BPH rats. Further investigation showed that TP-induced activation of AKT and glycogen synthase kinase 3ß (GSK3ß) was reduced by QI administration. Therefore, our findings suggest that QI attenuates the BPH state in rats through anti-proliferative and pro-apoptotic activities and might be useful in the clinical treatment of BPH.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Combretaceae/química , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Animais , Di-Hidrotestosterona/sangue , Humanos , Masculino , Extratos Vegetais/uso terapêutico , Antígeno Nuclear de Célula em Proliferação , Próstata/citologia , Próstata/patologia , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Sementes/química , Testosterona/sangue , Testosterona/metabolismo , Propionato de Testosterona/toxicidade
7.
J Steroid Biochem Mol Biol ; 171: 34-42, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28179209

RESUMO

Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg-1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), ßMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of ßMHC and ßMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.


Assuntos
Envelhecimento , Anabolizantes/toxicidade , Androgênios/toxicidade , Cardiomegalia/induzido quimicamente , Vasos Coronários/efeitos dos fármacos , Coração/efeitos dos fármacos , Isquemia Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Anabolizantes/administração & dosagem , Androgênios/administração & dosagem , Animais , Cardiomegalia/fisiopatologia , Catalase/antagonistas & inibidores , Catalase/genética , Catalase/metabolismo , Vasos Coronários/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/fisiopatologia , Injeções Intramusculares , Masculino , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Miocárdio/patologia , Cadeias Pesadas de Miosina/química , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Distribuição Aleatória , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Propionato de Testosterona/administração & dosagem , Propionato de Testosterona/toxicidade , Fatores de Tempo
8.
Horm Mol Biol Clin Investig ; 29(2): 71-77, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27802175

RESUMO

BACKGROUND: Polycystic ovarian syndrome (PCOS), one of the leading causes of infertility seen in women, is characterized by anovulation and hyperandrogenism, resulting in ovarian dysfunction. In addition, associations of several metabolic complications like insulin resistance, obesity, dyslipidemia and psychological co-morbidities are well known in PCOS. One of the major factors influencing mood and the emotional state of mind is neurotransmitters. Also, these neurotransmitters are very crucial for GnRH release. Hence, the current study investigates the status of neurotransmitters in PCOS. MATERIALS AND METHODS: A PCOS rat model was developed using testosterone. Twenty-one-day-old rats were subcutaneously injected with 10 mg/kg body weight of testosterone propionate (TP) for 35 days. The animals were validated for PCOS characteristics by monitoring estrus cyclicity, serum testosterone and estradiol levels and by histological examination of ovarian sections. Neurotransmitter estimation was carried out using fluorometric and spectrophotometric methods. RESULTS: TP-treated animals demonstrated increased serum testosterone levels with unaltered estradiol content, disturbed estrus cyclicity and many peripheral cysts in the ovary compared to control rats mimicking human PCOS. Norepinephrine (NE), dopamine, serotonin, γ-amino butyric acid (GABA) and epinephrine levels were significantly low in TP-induced PCOS rats compared to control ones, whereas the activity of acetylcholinesterase in the PCOS brain was markedly elevated. CONCLUSION: Neurotransmitter alteration could be one of the reasons for disturbed gonadotropin-releasing hormone (GnRH) release, consequently directing the ovarian dysfunction in PCOS. Also, decrease in neurotransmitters, mainly NE, serotonin and dopamine (DA) attributes to mood disorders like depression and anxiety in PCOS.


Assuntos
Modelos Animais de Doenças , Neurotransmissores/metabolismo , Síndrome do Ovário Policístico/metabolismo , Propionato de Testosterona/toxicidade , Animais , Dopamina/metabolismo , Epinefrina/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Norepinefrina/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos , Serotonina/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/metabolismo
9.
Environ Toxicol ; 31(11): 1460-1468, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26031391

RESUMO

Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E2 ) after weaning (0.4 mg/kg) and at adulthood (10 or 100 µg/day), when the pituitary response was also evaluated. At adulthood, control and 0.05 mg/kg groups presented a uterine weight increment when exposed to 100 µg/day of E2 , 0.1 mg/kg group only responded to 10 µg/day of E2 , and the 0.2 mg/kg group showed increased uterine weight at both doses. The pituitary weight was similarly increased after estradiol stimulation in all experimental groups. In conclusion, testosterone propionate exposure induced an abnormal stimulation of uterine tissue growth by estrogen stimulus without affecting pituitary response. More studies are needed to clarify whether these alterations are capable of impairing the reproductive capacity of the female tract. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1460-1468, 2016.


Assuntos
Estradiol/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Propionato de Testosterona/toxicidade , Útero/efeitos dos fármacos , Útero/patologia , Androgênios/toxicidade , Animais , Animais Recém-Nascidos , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Reprodução/efeitos dos fármacos , Fatores de Tempo , Útero/metabolismo
10.
Biol Reprod ; 94(1): 5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26586841

RESUMO

Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels.


Assuntos
Intolerância à Glucose/etiologia , Hiperinsulinismo/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Propionato de Testosterona/toxicidade , Animais , Glicemia/metabolismo , Peso Corporal , Peptídeo C/metabolismo , Feminino , Intolerância à Glucose/patologia , Hiperandrogenismo/etiologia , Hiperinsulinismo/patologia , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Masculino , Músculo Esquelético/patologia , Orquiectomia , Pâncreas/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/metabolismo , Testosterona/sangue
11.
J Toxicol Environ Health A ; 77(7): 375-89, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24617542

RESUMO

Environmental contaminants known as endocrine-disrupting chemicals (EDC) have been associated with adverse effects on reproductive processes. These chemicals may mimic or antagonize endogenous hormones, disrupting reproductive functions. Although preliminary studies focused on environmental estrogens, the presence of compounds with androgenic activity has also been described. This study examines exposure of female pregnant and lactating rats to low doses of androgens and assesses potential effects on female offspring. Pregnant Wistar rats were exposed to testosterone propionate (TP) at doses of 0.05, 0.1, or 0.2 mg/kg or corn oil (vehicle), subcutaneously, to determine influence on reproductive health of female offspring. There were two exposure groups: (1) rats treated from gestational day (GD) 12 until GD 20; and (2) animals treated from GD 12 until the end of lactation. Perinatal exposure to TP produced increased anogenital distance after birth and diminished height of uterine glandular epithelium at puberty in animals exposed to 0.2 mg/kg. However, these alterations were not sufficient to impair sexual differentiation and normal physiology of the female rat reproductive tract.


Assuntos
Androgênios/toxicidade , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Lactação , Efeitos Tardios da Exposição Pré-Natal , Desenvolvimento Sexual/efeitos dos fármacos , Anormalidades Urogenitais/induzido quimicamente , Androgênios/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Endométrio/anormalidades , Endométrio/efeitos dos fármacos , Poluentes Ambientais/administração & dosagem , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Injeções Subcutâneas , Exposição Materna/efeitos adversos , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Teratogênios/toxicidade , Propionato de Testosterona/administração & dosagem , Propionato de Testosterona/toxicidade
12.
Reprod Toxicol ; 40: 1-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23669243

RESUMO

Exposure to environmental chemicals may contribute to reproductive disorders, especially when it occurs in critical periods of development. The female reproductive system can be a target for androgens derived from environmental contaminants or pathological conditions. The purpose of this study was to assess the long-term effects of androgens on uterine tissue after maternal exposure limited to the time of gestation and lactation. Pregnant Wistar rats were treated with testosterone propionate (TP) at 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg or corn oil (vehicle), s.c., from gestational day 12 until the end of lactation. The results show changes in the pattern of expression of receptors for estrogen, progesterone, and androgen at all doses tested, and decreases in both apoptosis and cell proliferation indices at 0.1 and 0.2 mg/kg. We conclude that early TP exposure, under these experimental conditions, causes changes in cellular and molecular parameters that are essential for normal uterine function in the adult.


Assuntos
Androgênios/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Receptores de Esteroides/metabolismo , Propionato de Testosterona/toxicidade , Útero/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Troca Materno-Fetal , Gravidez , Ratos , Ratos Wistar , Útero/citologia , Útero/metabolismo
13.
Mol Med Rep ; 7(3): 848-54, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23314795

RESUMO

The aim of this study was to evaluate the therapeutic efficacy of Qianliening capsule (QC) against benign prostatic hyperplasia (BPH) in vivo in a BPH rat model, as well as to investigate the effects of QC on prostatic cell apoptosis and the possible molecular mechanisms mediating its anti-BPH activity. Fifty male Sprague­Dawley (SD) rats were randomly classified into five groups. The rats of the four groups were castrated and subcutaneously injected with testosterone propionate to generate BPH. One week after model establishment, BPH rats were orally administrated with various doses of QC daily for 28 days. The prostatic tissues from BPH rats were collected to evaluate prostatic index (PI). The histological changes of prostate were observed by hematoxylin and eosin staining. TUNEL analysis was performed to examine cell apoptosis. The mRNA expression of Bcl-2 and Bax in prostatic tissues was determined by reverse transcription­polymerase chain reaction (RT-PCR). The protein expression of Bcl-2, Bax and cleaved caspase 3 were examined by immunohistochemistry. Administration with QC significantly decreased PI in a dose-dependent manner (P<0.05 or P<0.01) and improved prostatic hyperplasia in BPH rats. Additionally, QC treatment induced prostatic cell apoptosis in a dose-dependent manner. Moreover, QC promoted the cleavage of caspase 3, an indicator of apoptosis, in a dose-dependent manner. Furthermore, following QC treatment, the expression ratio of pro­apoptotic Bax to anti­apoptotic Bcl-2 in prostatic tissues was increased in a dose-dependent manner. As a result, QC was effective in the treatment of BPH in rats. Promoting apoptosis of prostatic cells may therefore be one of the mechanisms by which QC treats BPH.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Animais , Caspase 3/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Imuno-Histoquímica , Masculino , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Propionato de Testosterona/toxicidade , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
Circ Res ; 110(11): e73-85, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22539767

RESUMO

RATIONALE: Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown. OBJECTIVE: To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs. METHODS AND RESULTS: One-day-old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells. CONCLUSIONS: These data reveal an unrecognized role of transient sex hormone exposures during neonatal development as long-lasting mediators of regional aortic AT1aR expression and sexual dimorphism of AAAs.


Assuntos
Angiotensina II/toxicidade , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Receptor Tipo 1 de Angiotensina/metabolismo , Propionato de Testosterona/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Células Cultivadas , Feminino , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/deficiência , Receptor Tipo 1 de Angiotensina/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fatores de Risco , Caracteres Sexuais , Fatores Sexuais , Propionato de Testosterona/administração & dosagem , Regulação para Cima
15.
PLoS One ; 6(9): e24877, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21935484

RESUMO

Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.


Assuntos
Fígado/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Glucosiltransferases/metabolismo , Fígado/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (ATP) , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/metabolismo , Gravidez , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Ovinos , Propionato de Testosterona/toxicidade
16.
Reproduction ; 142(1): 167-73, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21493716

RESUMO

Androgens play important roles during the first trimester of intrauterine life, coinciding with genital tract differentiation, during virilization and maintenance of secondary male characteristics, and during initiation of spermatogenesis. Little is known about the impact of inappropriate exposure to excess androgens during fetal development on male sexual maturation and reproduction. The objectives of this study were to determine the effects of prenatal 5α-dihydrotestosterone (DHT) and testosterone treatment during ovine sexual differentiation on post-pubertal testicular formation and subsequent potential for fertility as assessed by epididymal sperm characteristics. Rams prenatally treated with testosterone exhibited increased testicular weight relative to age-matched controls and prenatal DHT-treated rams (P<0.05), as well as elevated total and free testosterone concentrations compared with DHT-treated rams (P=0.07 and P<0.05 respectively). The percentage of progressively motile sperm from the epididymis was significantly reduced in prenatal DHT-treated but not testosterone-treated rams compared with control rams (P<0.05). The testosterone-treated rams had a greater number of germ cell layers than DHT-treated rams, but comparable to the controls. Prenatal testosterone-treated rams had significantly larger seminiferous tubule diameter and lumen diameter compared with prenatal DHT-treated (P<0.05). Significantly, more prenatal DHT- and testosterone-treated rams (P<0.05) had occluded tubule lumen than control rams. Findings from this study demonstrate that exposure to excess testosterone/DHT during male fetal sexual differentiation have differential effects on post-pubertal testicular size, seminiferous tubule size and function, sperm motility, and testosterone concentrations.


Assuntos
Di-Hidrotestosterona/metabolismo , Infertilidade Masculina/etiologia , Efeitos Tardios da Exposição Pré-Natal , Diferenciação Sexual , Testosterona/metabolismo , Androgênios/toxicidade , Animais , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/toxicidade , Epididimo/efeitos dos fármacos , Epididimo/patologia , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Infertilidade Masculina/sangue , Infertilidade Masculina/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Diferenciação Sexual/efeitos dos fármacos , Carneiro Doméstico , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue , Propionato de Testosterona/toxicidade
17.
Poult Sci ; 90(1): 168-74, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21177456

RESUMO

The aim of the current study was to examine whether analysis of the appearance of specific lectin-positive substances in the quail embryonic cloacal gland would be useful for evaluating the androgenic and antiandrogenic effects of chemicals. Fertilized Japanese quail eggs were injected with 0 to 75 µg of cyproterone acetate (CA), an antiandrogenic compound, on d 12 of incubation (d 12), followed by injection of 0 to 300 µg of testosterone propionate (TP) on d 13. Experimental groups consisted of a control group (corn oil injections on d 12 and 13), a TP-L group [corn oil and a low dose (L; 30 µg) of TP], a TP-H group [corn oil and a high dose (H; 300 µg) of TP], a CA-L + TP-H group [a low dose (L;7.5 µg) of CA + TP-H], and a CA-H + TP-H group [a high dose (H; 75 µg) of CA + TP-H]. The cloacal tissues were collected on d 16, processed into paraffin sections, and stained using 14 different biotinylated lectins. The Vicia villosa (VVA) lectin most strongly stained the developing cloacal glandular cells in TP-H. Western blotting analysis showed 1 VVA-positive band of approximately 75 kDa. The ratio of VVA-positive areas per unit square examined microscopically by image analysis was significantly greater in the TP-H group than in the control group in both males and females. The ratio was significantly decreased in the CA-L + TP-H and CA-H + TP-H groups compared with the TP-H group in both males and females. Furthermore, the ratio was smaller in females than in males within a TP-L or TP-H treatment group. These results suggest that lectin histochemistry on quail embryonic cloaca using VVA is useful for evaluating the androgenic and antiandrogenic effects of chemical compounds.


Assuntos
Coturnix , Acetato de Ciproterona/toxicidade , Imuno-Histoquímica/veterinária , Lectinas/metabolismo , Propionato de Testosterona/toxicidade , Antagonistas de Androgênios/toxicidade , Androgênios/toxicidade , Animais , Coturnix/embriologia , Feminino , Masculino
18.
Biol Reprod ; 84(1): 87-96, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20739662

RESUMO

Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ~147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64-66, 87-90, and 139-140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.


Assuntos
Ovinos/embriologia , Propionato de Testosterona/toxicidade , Animais , Glicemia , Estrogênios/sangue , Estrogênios/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Propionato de Testosterona/sangue , Propionato de Testosterona/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue
19.
In Vivo ; 24(4): 463-70, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20668312

RESUMO

BACKGROUND: The aim of this study was to investigate the effect of fetal exposure to 4-n-octylphenol (OP) on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rats. MATERIALS AND METHODS: All rats which showed vaginal plugs or sperm by vaginal smear test after mating were fed a normal diet only, or a diet mixed with 10, 100, 1000 ppm OP throughout the pregnancy period and from day 13 of pregnancy to the end of the pregnancy. No abnormal pregnancy was seen in any of the rats. Pups were given 10 mg DMBA by gastric intubation 50 days after birth. RESULTS: Uterine weight decrease was observed in pups with fetal exposure to 1000 ppm OP throughout the pregnancy period. No endocrine disrupting conditions, such as persistent estrus, anovulatory ovaries or abnormal lactation in the mammary glands were seen in pups with fetal exposure to OP. However, fetal exposure to 100 and 1000 ppm OP throughout pregnancy period enhanced the early incidence and number of mammary carcinomas (MCs) while it did not enhance the incidence and number of benign proliferative lesions (PLs) which consisted of solid masses (fibroadenoma and lobular hyperplasia) and gross cysts. CONCLUSION: These results suggest that fetal exposure to the very weak estrogenicity of OP could enhance the induction of MCs but not affect the induction of PLs.


Assuntos
Neoplasias Mamárias Animais/induzido quimicamente , Fenóis/toxicidade , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/epidemiologia , Carcinógenos/toxicidade , Divisão Celular/efeitos dos fármacos , Dietilestilbestrol/toxicidade , Relação Dose-Resposta a Droga , Estradiol/toxicidade , Estro/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Humanos , Neoplasias Mamárias Animais/patologia , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Propionato de Testosterona/toxicidade , Ganho de Peso/efeitos dos fármacos
20.
Am J Med Sci ; 338(3): 196-200, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19745610

RESUMO

BACKGROUND: (-)Doxazosin is one of the enantiomers of (+/-)doxazosin, and it was reported that (-)doxazosin possessed higher selectivity for lower urinary tract between the cardiovascular system and the urinary system in the animal experiments in comparison with that of (+/-)doxazosin and (+)doxazosin. Therefore, it is important to know whether (-)doxazosin has a therapeutic effect on the hyperplastic prostate. METHODS: (-)Doxazosin and (+/-)doxazosin were administered intragastrically to prostatic hyperplasia rats, induced by testosterone propionate for 4 weeks, and each experimental group contained 8 animals. The histomorphologic changes of the prostate were observed under light microscope, the quantitative analysis of the prostatic glandular cavity was performed using an image analysis system, and the cell apoptosis was detected by using flow cytometry. RESULTS: In comparison with model-control group, the volume index of the prostate in (-)doxazosin 3.0 mg/kg group became significantly smaller. The maximal diameter, perimeter, and area of the hyperplastic prostate glandular cavity, and the glandular epithelial cell height in (-)doxazosin (0.3, 1.0, and 3.0 mg/kg) groups and (+/-)doxazosin group were significantly reduced. (-)Doxazosin and (+/-)doxazosin did not significantly affect cell cycle distribution and cell proliferation index of the hyperplastic prostate. However, apoptotic rates of the prostatic cells in (-)doxazosin (0.3, 1.0, and 3.0 mg/kg) groups and (+/-)doxazosin group were significantly increased in comparison with those of model-control group. CONCLUSIONS: Both (-)doxazosin and (+/-)doxazosin inhibit the prostatic hyperplasia induced by testosterone propionate in castrated rats. The induction of prostate cell apoptosis might be one of the mechanisms underlying the therapeutic role of (-)doxazosin.


Assuntos
Apoptose/efeitos dos fármacos , Doxazossina/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Animais , Masculino , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Ratos , Ratos Wistar , Propionato de Testosterona/toxicidade
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