RESUMO
Paradoxical sleep deprivation (PSD) presents different effects on metabolism and neurological functions. In addition, over long duration, sleep restriction (SR) can promote permanent changes. The prostate is an endocrine-dependent organ with homeostatic regulation directly related to hormone levels. Our study proposed to demonstrate the experimental prostatic effects of PSD (96 h), PSD with recovery (PSR - 96/96 h), and sleep restriction (SR - 30 PSD cycles/recovery). PSD and SR promoted decrease in serum testosterone and significant increase in serum and intraprostatic corticosterone. In agreement, androgen receptors (AR) were less expressed and glucocorticoid receptors (GR) were enhanced in PSR and SR. Thus, the prostate, especially under SR, demonstrates a castration-like effect due to loss of responsiveness and sensitization by androgens. SR triggered an important inflammatory response through enhancement of serum and intraprostatic pro- (IL-1α, IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines. Furthermore, the respective receptors of anti-inflammatory cytokines (IL-1RI and TNF-R) were highly expressed in the prostatic epithelium and stroma. PSR can partially restore prostate homeostasis, as it restores testosterone and the prostate proliferation index, in addition to promoting balance in the inflammatory response that is considered protective. PSD and SR are key factors in the endocrine axis that coordinate prostatic homeostasis, and significant changes in these factors have consequences on prostate functionality.
Assuntos
Gerbillinae , Próstata , Receptores Androgênicos , Privação do Sono , Testosterona , Animais , Masculino , Privação do Sono/metabolismo , Privação do Sono/patologia , Próstata/metabolismo , Próstata/patologia , Testosterona/sangue , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Corticosterona/sangue , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Castração , Androgênios/metabolismoRESUMO
The prostate undergoes normal or pathological morphological changes throughout life. An understanding of these changes is fundamental for the comprehension of aging-related pathological processes such as benign prostatic hyperplasia (BPH) and cancer. In the present study, we show some of these morphological changes, as well as histochemical techniques like Weigert's resorcin-fuchsin method, Picrosirius Red, and Gömöri's reticulin for use as tools in the study of prostate tissue under light microscopy. For this purpose, prostates of the Mongolian gerbil (n = 9), an experimental model that develops BPH spontaneously, were analyzed at three life stages: young (1 month old), adult (3 months old), and old (15 months old). The results showed that fibrillar components such as collagen, and reticular and elastic fibers, change throughout life. In young animals, the prostate has cuboidal epithelium surrounded by thin layers of smooth muscle, continuous collagen fibers, winding reticular fibers, and sporadic elastic fibers. With adulthood, the epithelium becomes columnar, encircled by compacted muscle cells among slender collagen fibers, elongated reticular fibers, and linear elastic fibers. In aging individuals, the prostate's epithelium stratifies, surrounded by thick muscle layers among dense collagen fibers, disordered reticular fibers, and elastic fibers in different planes. We also identified a few accumulations of lipid droplets and lipofuscin granules in adult animals and high accumulation in old animals evidenced by Oil red O and Gömöri-Halmi techniques, respectively. The histochemical techniques presented here have been demonstrated to be useful and accessible tools in prostate studies. RESEARCH HIGHLIGHTS: Cytochemical techniques to study prostate morphology. The prostate changes with age.
Assuntos
Próstata , Hiperplasia Prostática , Masculino , Animais , Humanos , Adulto , Lactente , Próstata/patologia , Reticulina , Hiperplasia Prostática/patologia , Colágeno , Envelhecimento , Histocitoquímica , GerbillinaeRESUMO
The female prostate is associated with the urogenital system and presents homology in morphological terms with the male prostate. Due to its responsiveness to endogenous hormones, this gland is under a constant risk of developing prostatic pathologies and neoplasia when exposed to certain exogenous compounds. Bisphenol A (BPA) is an endocrine disruptor found in different plastic and resin products. Studies have emphasized the effects of perinatal exposure to this compound on different hormone-responsive organs. However, there have been few studies highlighting the influence on female prostate morphology of perinatal exposure to BPA. The objective of this study was to describe the histopathological alterations caused by perinatal exposure to BPA (50 µg/kg) and 17-ß estradiol (E2) (35 µg/kg) in the prostate of adult female gerbils. The results showed that E2 and BPA induced proliferative lesions in the female prostate and acted along similar pathways by modulating steroid receptors in the epithelium. BPA was also found to be a pro-inflammatory and pro-angiogenic agent. The impacts of both agents were marked in the prostatic stroma. An increase in the thickness of the smooth muscle layer and a decrease in AR expression were observed, but no alterations in the expression of ERα and ERß, leading to estrogenic sensitivity of the prostate. However, a peculiar response of the female prostate was to diminish the collagen frequency under BPA exposure correlated to smooth muscle layer. These data therefore indicate the development of features related to estrogenic and non-estrogenic tissue repercussions by BPA perinatally exposure in gerbil female prostate.
Assuntos
Disruptores Endócrinos , Próstata , Animais , Gravidez , Masculino , Feminino , Gerbillinae , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/metabolismoRESUMO
Ultimately, the Mongolian gerbils (Meriones unguiculatus) have acquired a relevant role in biological and biomedical experiments alongside other rodents. The use of gerbils in research has been mainly oriented to physiological and pharmacological studies, with special attention to nervous, digestive, and auditory systems as well as microbiology and parasitology. Ultimately, gerbils have also been applied for studying carcinogenesis in different organs and systems, since these animals show a natural propensity to develop spontaneous proliferative lesions, especially in steroid-responsive organs. This characteristic shed light on the reproductive aspects of this rodent model regarding morphological features in male and female individuals. This review of literature summarizes the significance of this model as an alternative to the use of inbred mice and rats in reproductive experimental research, highlighting recent findings. Gerbils have contributed to the expansion of knowledge in prostate biology in male and female individuals, providing studies related to prostatic morphogenesis and neoplasia. In the testes, spermiogenesis occurs in 15 steps, differently from other experimental models. Also, the complete maturation of the testis-epididymal complex occurs between the second and third months. Mammary gland alterations related to the estrous cycle and pregnancy were described, as well as its modulation under endogenous and exogenous estrogenic compounds. The ovaries frequently present ovarian cysts. Furthermore, this organ shows predominantly interstitial steroidogenic glands in the stroma, especially at aging. Adrenal gland shows a large size compared to other animals, presenting three distinct zones with a remarkable role in steroidogenesis.
Assuntos
Estrogênios , Reprodução , Gravidez , Masculino , Feminino , Ratos , Camundongos , Animais , Gerbillinae/fisiologia , Estrogênios/fisiologia , Próstata/fisiologia , BiologiaRESUMO
BACKGROUND: The aim of this study was to evaluate modifications in proteoglycan morphology and composition in the prostatic stroma of 18-month-old gerbils after surgical castration, in association or not with an androgenic blockade. METHODS: The animals (n = 5) were sorted into groups subjected or not to antiandrogen treatment (flutamide 10 mg/kg/day) administered for the total postsurgery period and euthanized at 7- or 30-day postcastration; the control group consisted of intact animals. Tissue analysis included immunohistochemical assessment (perlecan and chondroitin sulfate) and proteoglycan morphology was analyzed by transmission electron microscopy. RESULTS: Chondroitin sulfate frequency was increased 7 days postcastration with an androgenic blockade. The presence of these carbohydrates was rare after 30 days of androgenic blockade treatment. There was a significant increase in the amount of perlecan in the prostate stroma from groups subjected to castration plus flutamide for 7 or 30 days. Ultrastructural analysis showed that the incidence of areas occupied by proteoglycans and basement membrane was altered by treatment. In addition, androgenic blockade results in changes in the amount, thickness, and morphology of these structures. At 30 days postcastration, with or without flutamide treatment, larger proteoglycans were common. CONCLUSIONS: In this study, in particular, the decrease in chondroitin sulfate after the longer period might be understood as a prostatic response to androgenic deprivation, while the high frequency and permanence of perlecan led to the assumption that its modulation could be androgen-independent. Length and form alterations in proteoglycans as well as associations among them and with the basement membrane were dynamic events in the prostate microenvironment.
Assuntos
Flutamida , Próstata , Masculino , Animais , Flutamida/farmacologia , Gerbillinae , Androgênios/farmacologia , Sulfatos de Condroitina/farmacologia , OrquiectomiaRESUMO
Bisphenol A (BPA) is a chemical agent which can exert detrimental effects on the male reproductive system, especially the prostate gland. In this study we described the efficacy of the dietary agent curcumin, alone or combined with piperine, to suppress the impact of BPA on the prostate. Adult gerbils were divided into nine experimental groups (n = 7 each group), regarding control (water and oil), exposed to BPA (50 µg/kg/day in water) or curcumin (100 mg/kg) and/or piperine (20 mg/kg). To evaluate the effects of the phytotherapic agents, the other groups received oral doses every two days, BPA plus curcumin (BCm), piperine (BP), and curcumin + piperine (BCmP). BPA promoted prostatic inflammation and morphological lesions in ventral and dorsolateral prostate lobes, associated with an increase in androgen receptor-positive cells and nuclear atypia, mainly in the ventral lobe. Curcumin and piperine helped to minimize these effects. BPA plus piperine or curcumin showed a reduction in nuclear atypical phenotype, indicating a beneficial effect of phytochemicals. Thus, these phytochemicals minimize the deleterious action of BPA in prostatic lobes, especially when administered in association. The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis.
Assuntos
Alcaloides/farmacologia , Compostos Benzidrílicos/toxicidade , Benzodioxóis/farmacologia , Curcumina/farmacologia , Fenóis/toxicidade , Compostos Fitoquímicos/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Neoplasias da Próstata , Animais , Carcinogênese/induzido quimicamente , Disruptores Endócrinos/toxicidade , Gerbillinae , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/patologia , Substâncias ProtetorasRESUMO
The mammary gland (MG) and female prostate are plastic reproductive organs which are highly responsive to hormones. Thus, endocrine disruptors, such as bisphenol A (BPA) and exogenous estrogens, negatively affect glandular homeostasis. In addition to previously described alterations, changes in inflammatory markers expression also trigger the development of a microenvironment that contributes to tumor progression. The current work aimed to evaluate the inflammatory responses of the MG and prostate gland to BPA (50 µg/kg) and 17-ß estradiol (35 µg/kg) exposure during the perinatal window of susceptibility. The results showed that at 6 months of age there was an increase in the number of phospho-STAT3 (P-STAT3) positive cells in the female prostate from animals perinatally exposed to 50 µg/kg BPA daily. In addition, the number of macrophages increased in these animals in comparison with nonexposed animals, as shown by the F4/80 marker. Despite an increase in the incidence of lobuloalveolar and intraductal hyperplasia, the MG did not show any difference in the expression of the four inflammatory markers evaluated: tumor necrosis factor-α, COX-2, P-STAT3, and F4/80. Analysis of both glands from the same animal led to the conclusion that exposure to endocrine disruptors during the perinatal window of susceptibility leads to different inflammatory responses in different reproductive organs. As the prostate is more susceptible to these inflammatory mechanisms, it is reasonable to affirm that possible neoplastic alterations in this organ are related to changes in the inflammatory pattern of the stroma, a characteristic that is not evident in the MG.
Assuntos
Disruptores Endócrinos/farmacologia , Glândulas Endócrinas/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Compostos Benzidrílicos/farmacologia , Disruptores Endócrinos/metabolismo , Glândulas Endócrinas/metabolismo , Estradiol/farmacologia , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/metabolismo , Gerbillinae , Humanos , Inflamação/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Fenóis/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Esteroides/farmacologiaRESUMO
Resumo Tratou-se de um estudo correlacional com 108 líderes e 176 liderados de quatro empresas públicas ou de economia mista em que se testou o efeito da percepção de raiva e de poder do líder no desempenho do liderado, moderado por dois traços pessoais dos liderados (conscienciosidade e agradabilidade). A base teórica foi o modelo EASI (Emotion as Social Information). Os liderados responderam três instrumentos: a) traços pessoais de agradabilidade e conscienciosidade; b) Medida de Poder Social Global do líder; e c) Escala de Percepção da Expressão Emocional de raiva do líder. Os líderes responderam à Medida de Desempenho de Tarefa de seus liderados. Os resultados indicaram que apenas a conscienciosidade moderou a relação entre a percepção de raiva do líder e o desempenho do liderado.
Abstract It was a correlational study with 108 leaders and 176 subordinates from four public and mixed-economy companies, in which the effect of anger perception and leader's power on subordinate´s performance has been tested, moderated by two subordinates' personal traits (conscientiousness and agreeableness). The theoretical basis was the EASI (Emotion as Social Information) model. The subordinates answered three instruments: a) personal traits of agreeableness and conscientiousness; b) Leader's Global Social Power Measure; and c) Leader's Emotional Expression Perception Scale. Leaders responded to the subordinates Task Performance Measure. The results indicated that only conscientiousness moderated the relationship between the leader anger perception and the subordinate´s performance.
RESUMO
The endocrine disruptive effects caused by bisphenol A (BPA) are well known. Despite this, to date, evaluation of its long term effects is limited, meaning that there is still much to be unveiled in terms of alterations caused by perinatal exposure to BPA. Our aim was to determine if perinatal exposure to two different doses of BPA causes long term morphological and molecular alteration effects in the mammary gland (MG). We evaluated MG from Mongolian gerbil offspring exposed perinatally (during gestation and lactation) to 50 or 5000 µg/kg/day BPA. At 90 days of age the animals were subjected to a single dose of N-nitroso-N-methylurea in order to mimic a carcinogenic environment. At 6 months of age, animals in estrous were euthanized for morphological evaluation of the MGs. The MG architecture presented considerable changes in terms of detached epithelial cells, inflammation, glandular hyperplasia, and collagen fiber deposition. Furthermore, a higher index of epithelial cell proliferation was detected in comparison to the intact control group. In addition, we verified a higher molecular expression of EZH2 in the vehicle treated group, indicating that corn oil applied alone can alter the expression of this epigenetic biomarker. In conclusion, BPA perinatal exposure promotes significant changes in glandular cytoarchitecture and increases glandular epithelium proliferation rate, leading to the retention of stem-like properties. This event could compromise the fate and differentiation potential of mammary epithelium.
Assuntos
Envelhecimento/patologia , Compostos Benzidrílicos/toxicidade , Glândulas Mamárias Animais/patologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Actinas/metabolismo , Animais , Proliferação de Células , Colágeno/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Gerbillinae , Histonas/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , GravidezRESUMO
Hormonal regulation controls mammary gland (MG) development. Therefore some hormone-related factors can disrupt the early phases of MGs development, making the gland more susceptible to long term modifications in its response to circulating hormones. Endocrine disruptors, such as bisphenol A (BPA), are able to cause alterations in hormone receptor expression, leading to changes in the cell proliferation index, which may expose the tissue to neoplastic alterations. Thus, we evaluated the variations in hormone receptor expression in the MG of 6-month old Mongolian gerbils exposed to BPA and 17ß estradiol during the perinatal period. Receptors for estrogen alpha (ERα), beta (ERß), progesterone (PGR), prolactin (PRL-R), and co-localization of connexin 43 (Cx43) and ERα in gerbils were analyzed, and serum concentrations of estradiol and progesterone were assessed. No alterations in body, liver, and ovary-uterus complex weights were observed. However, there was an increase in epithelial ERα expression in the 17ß estradiol (E2) group and in PGR in the BPA group. Although immunohistochemistry did not show alterations in ERß expression, western blotting revealed a decrease in this protein in the BPA group. PRL-R was more present in epithelial cells in the vehicle control (VC), E2, and BPA groups in comparison to the intact control group. Cx43 was more frequent in E2 and BPA groups, suggesting a protective response from the gland against possible malignancy. Serum concentration of estradiol reduced in VC, E2, and BPA groups, confirming that alterations also impacts steroid levels. Consequently, perinatal exposure to BPA and the reference endogenous estrogen, 17ß estradiol, are able to increase the tendency of endocrine disruption in MG in a long term manner, since repercussions are observed even 6 months after exposure.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Glândulas Mamárias Animais/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Gerbillinae , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
The aim of the present study was to evaluate the histological, histochemical, and stereological changes caused by mycophenolate mofetil (MMF) on the tunica albuginea of rat penises submitted to an injection of transforming growth factor beta (TGF-ß) for the induction of Peyronie's disease (PD). Twenty adult male Wistar rats were divided into four groups: Control group; TGF-ß group (TGF-ß injection); MMF-7d group (treated with MMF 7 days after induction with TGF-ß); and MMF-30d group (treated with MMF 30 days after induction with TGF-ß). The steorological evaluation included the relative volume of different types of connective fibres of the tunica albuginea. The histochemical analysis revealed the fragmentation and degradation of elastin in the tunica albuginea. This process was partially reversed in the MMF-7d group and a situation very close to normality was observed in the MMF-30d group. In the collagen III/collagen I ratio it was observed increase in this ratio in the TGF-ß (59.4 ± 5.53) and MMF-7d (49 ± 18.2) groups and a decrease in the MMF-30d group (28.7 ± 4), approaching normality. The injection of TGF-ß promoted fibrotic alterations in the penile tunica albuginea in Wistar rats corresponding to PD. In this model, MMF acts as a regenerating anti-fibrotic agent.
Assuntos
Ácido Micofenólico/farmacologia , Ereção Peniana , Induração Peniana/tratamento farmacológico , Pênis/patologia , Animais , Modelos Animais de Doenças , Fibrose , Masculino , Induração Peniana/induzido quimicamente , Induração Peniana/patologia , Pênis/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Crescimento Transformador betaRESUMO
Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.
Assuntos
Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Androgênios/metabolismo , Animais , Carcinogênese , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Masculino , Inibidores de Fosfoinositídeo-3 Quinase , Ratos , Ratos Endogâmicos F344 , Transdução de Sinais , Células Tumorais CultivadasRESUMO
BACKGROUND: Studies have shown that exposure to environmental chemicals known as endocrine disruptors can cause permanent changes in genital organs, such as the prostate. Among these environmental chemicals stands out bisphenol A (BPA). Another factor associated with prostate changes is the consumption of a high-fat diet. Although the relationship between the consumption of a high-fat diet and an increased risk of prostate cancer is well established, the mechanisms that lead to the establishment of this disease are not completely understood, nor the simultaneous action of BPA and high-fat diet. METHODS: Adult gerbils (100 days old) were divided in four groups (n = 6 per group): Control (C): animals that received a control diet and filtered water; Diet (D): animals that received a high-fat diet and filtered water; BPA: animals that received a control diet and BPA - 50 µg kg-1 day-1 in drinking water; BPA + Diet (BPA + D): animals that received a high-fat diet + BPA - 50 µg kg-1 day-1 in drinking water. After the experimental period (6 months), the dorsolateral and ventral prostate lobes were removed, and analyzed by several methods. RESULTS: Histological analysis indicated premalignant and malignant lesions in both prostatic lobes. However, animals of the D, BPA, and BPA + D groups showed a higher incidence and larger number of prostatic lesions; inflammatory foci were also common. Markers to assess prostate lesions, such as increased activation of the DNA repair system (PCNA-positive cells), androgen receptor (AR), and number of basal cells, confirmed the histology. However, serum levels of testosterone did not change under the experimental conditions. CONCLUSIONS: The results indicated that the methodology used was effective in generating metabolic changes, which directly compromised prostatic homeostasis. Diet and BPA appear to modulate the activation of the AR pathway and thereby optimize tumor establishment in the gerbil prostate.
Assuntos
Compostos Benzidrílicos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Fenóis/efeitos adversos , Próstata , Neoplasias da Próstata , Administração Oral , Animais , Compostos Benzidrílicos/administração & dosagem , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Modelos Animais de Doenças , Disruptores Endócrinos , Estrogênios não Esteroides/administração & dosagem , Estrogênios não Esteroides/efeitos adversos , Gerbillinae , Masculino , Fenóis/administração & dosagem , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , TempoRESUMO
Chronic hyperglycemia increases production of reactive oxygen species, which favors carcinogenesis. The association between diabetes and prostate cancer is controversial. Melatonin has antioxidant, anti-inflammatory, and antiproliferative properties. We investigated whether low doses of melatonin prevent the tissue alterations caused by diabetes and alter prostate histology of healthy rats. We also investigated whether experimental diabetes promoted the development of pathological lesions in the ventral prostate of rats. Melatonin was provided in drinking water (10 µg/kg/day) from age 5 weeks until the end of experiment. Diabetes was induced at 13 weeks by administration of streptozotocin (40 mg/kg, ip). Rats were euthanized at 14 or 21 weeks. Histological and stereological analyses were carried out and the incidence and density of malignant and pre-malignant lesions were assessed. Immunohistochemical assays of α-actin, cell proliferation (PCNA), Bcl-2, glutathione S-transferase (GSTPI), and DNA methylation (5-methylcytidine) were performed. Melatonin did not elicit conspicuous changes in the prostate of healthy animals; in diabetic animals there was a higher incidence of atrophy (93%), microinvasive carcinoma (10%), proliferative inflammatory atrophy, PIA (13%), prostatitis (26%), and prostate intraepithelial neoplasia, PIN (20%) associated with an increase of 40% in global DNA methylation. Melatonin attenuated epithelial and smooth muscle cell (smc) atrophy, especially at short-term diabetes-and normalized incidence of PIN (11%), inflammatory cells infiltrates, prostatitis (0%) and PIA (0%) at long-term diabetes. MLT was effective in preventing inflammatory disorders and PIN under diabetic condition. Although MLT has antioxidant action, it did not influence DNA methylation and not avoid carcinogenesis at low doses.
Assuntos
Metilação de DNA/efeitos dos fármacos , Complicações do Diabetes/genética , Diabetes Mellitus Experimental/genética , Melatonina/farmacologia , Próstata/efeitos dos fármacos , Neoplasias da Próstata/patologia , Animais , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Complicações do Diabetes/induzido quimicamente , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Masculino , Próstata/metabolismo , Próstata/patologia , Prostatite , RatosRESUMO
BACKGROUND: Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms. METHODS: We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues. RESULTS: Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns. CONCLUSIONS: Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time.
Assuntos
Androgênios , Estradiol , Próstata , Neoplasias da Próstata , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinógenos/farmacologia , Dano ao DNA/efeitos dos fármacos , Progressão da Doença , Células Epiteliais/patologia , Estradiol/metabolismo , Estradiol/farmacologia , Masculino , Metilnitrosoureia/farmacologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Neoplasias da Próstata/prevenção & controle , Fatores de Proteção , RatosRESUMO
Developmental toxicity caused by environmental exposure to heavy metals during the perinatal period has raised questions about offspring health. Cadmium (Cd) is an endocrine-disrupting chemical with the potential to interfere with morphogenesis and susceptibility to diseases in reproductive organs. Taking into account that in the rat prostate morphogenesis occurs during the perinatal period, and that pregnant females absorb and retain more dietary Cd than their non-pregnant counterparts, it is important to understand the effects of perinatal Cd exposure on the adult rat prostate. Therefore this study investigated the effects of gestational and lactational Cd exposure on adult offspring rat prostate histopathology. Pregnant rats (n = 20) were divided into two groups: Control (treated with aqueous solution of sodium acetate 10 mg/l) and treated (treated with aqueous solution of cadmium acetate 10 mg/l) administered in the drinking water. After weaning, male offspring from different litters (n = 10) received food and water 'ad libitum'. The animals were euthanized at postnatal day 90 (PND90), the ventral prostates (VPs) were removed, weighed and examined histopathologically. Blood was collected for the measurement of testosterone (T) levels. Immunohistochemistry for androgen receptor (AR) and Ki67, and a TUNEL assay were performed. There were no differences in T levels, cell proliferation and apoptosis indexes, or AR immunostaining between the experimental groups. Stromal inflammatory foci and multifocal inflammation increased significantly in the treated group. These changes were associated with inflammatory reactive epithelial atypia and stromal fibrillar rearrangement. In conclusion, VP was permanently affected by perinatal Cd exposition, with increased incidence of inflammatory disorders with ageing.
Assuntos
Acetatos/toxicidade , Cádmio/toxicidade , Disruptores Endócrinos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Próstata/efeitos dos fármacos , Animais , Feminino , Lactação , Masculino , Troca Materno-Fetal , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/embriologia , Próstata/metabolismo , Próstata/patologia , Ratos Wistar , Receptores Androgênicos/metabolismo , Testosterona/sangueRESUMO
In the present study, it was evaluated the susceptibility of prostatic lesions in male adult rats exposed to Di-N-butyl-phthalate during fetal and lactational periods and submitted to MNU plus testosterone carcinogenesis protocol. Pregnant females were distributed into four experimental groups: CN (negative control); CMNU (MNU control); TDBP100 (100 mg/kg of DBP); TDBP500 (500 mg/kg of DBP). Females from the TDBP groups received DBP, by gavage, from gestation day 15 (GD15) to postnatal day 21 (DPN21), while C animals received the vehicle (corn oil). CMNU, TDBP100, and TDBP500 groups received a single intraperitoneal injection of MNU (50 mg/kg) on the sixth postnatal week. After that, testosterone cypionate was administered subcutaneously two times a week (2 mg/kg) for 24 weeks. The animals were euthanized on PND220. Distal segment fragments of the ventral (VP) and dorsolateral prostate (DLP) were fixed and processed for histopathological analysis. Protein extracts from ventral prostate were obtained, and western blotting was performed to AR, ERα, MAPK (ERK1/2), and pan-AKT. Stereological analysis showed an increase in the epithelial compartment in TDBP100 and TDBP500 compared to CN. In general, there was increase in the incidence of inflammation and metaplasia/dysplasia in the DBP-treated groups, mainly in DLP, compared to CN and CMNU. Proliferation index was significant higher in TDBP500 and PIN (prostatic intraepithelial neoplasia) was more frequent in this group compared to CMNU. Western blot assays showed an increase in the expressions of AR and MAPK (ERK1/2) in the TDBP100 compared to CN, and ERα and AKT expressions were higher in the TDBP500 group compared do CN. These results showed that different doses of DBP during prostate organogenesis in Wistar rats could increase the incidence of premalignant lesions in initiated rats inducing distinct biological responses in the adulthood. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1185-1195, 2016.
Assuntos
Dibutilftalato/toxicidade , Metilnitrosoureia/toxicidade , Próstata/efeitos dos fármacos , Testosterona/análogos & derivados , Animais , Western Blotting , Receptor alfa de Estrogênio/metabolismo , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Lactação , Masculino , Exposição Materna , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Gravidez , Próstata/metabolismo , Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/metabolismo , Testosterona/sangue , Testosterona/toxicidade , Regulação para Cima/efeitos dos fármacosRESUMO
Recurrent gene fusions between the genes TMPRSS2 and ERG have been described in prostate cancer (PCa) and are found in 27% to 79% of radical prostatectomy. This fusion transcription results in ERG overexpression, which can be detected by immunohistochemistry (IHC) and provide a potential diagnostic marker for PCa. Three tissue microarrays (TMAs) containing samples from 98 patients with PCa and one TMA of 27 samples from individuals without PCa were tested for ERG immunostaining, and the presence of TMPRSS2:ERG transcripts was confirmed by quantitative real time PCR (qRT-PCR). The results showed that 46.9% of tumors tested positive for ERG immunostaining, and this finding was consistent with the results of qRT-PCR testing (k = 0.694, p < 0.001). IHC had a specificity of 83.3% and a sensitivity of 81% in detecting TMPRSS2:ERG fusion. Patients with PSA < 4.0 ng/mL showed positive immunoreactivity for ERG (p = 0.031). Kaplan-Meier analysis suggested that ERG expression did not influence the time of biochemical recurrence. This study demonstrates that both IHC and qRT-PCR are useful tools in detecting TMPRSS2:ERG fusions. A correlation between ERG expression and clinical and pathological parameters was not found, but the frequency, specificity and recurrence of ERG in PCa suggests that it may be a potential adjunct diagnostic tool.
Assuntos
Fusão Gênica/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Serina Endopeptidases/genética , Transativadores/genética , Biomarcadores Tumorais/genética , Brasil , Estudos de Casos e Controles , Humanos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/genética , Sensibilidade e Especificidade , Transcrição Gênica/genética , Regulador Transcricional ERGRESUMO
BACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes. We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes. METHODS: Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment. Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes. RESULTS: Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency. However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups. Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration. Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining. Moreover, VL lesions emerged throughout the entire lobe. MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining. CONCLUSIONS: There are distinct pathways involved in tumor progression in gerbil prostate lobes. This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes.
Assuntos
Alquilantes/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Metilnitrosoureia/toxicidade , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/patologia , Testosterona/toxicidade , Animais , Gerbillinae , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Fatores de TempoRESUMO
MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.