RESUMO
In brief: Maternal obesity plus high-fat diet in breastfeeding induces stromal hyperplasia and diffuse acinar atrophy in the rat prostate at aging, related to dyslipidemia and testosterone reduction. The high-lipid nutritional environment from intrauterine and throughout life favors the development of prostatic intraepithelial neoplasia and aggravated degenerative alterations in the gland. Abstract: Maternal obesity and high-fat diet (HFD) affect permanently prostate histophysiology in adulthood, but the consequences during aging are unknown. Here, we evaluated the prostate alterations in middle-aged rats subjected to a high-lipid nutritional environment (HLE) in different ontogenetic periods. Wistar rats (56 weeks of age) were assigned into groups exposed to standard nutrition (C) or HLE during gestation (G), gestation and lactation (GL), from lactation onward (L), from weaning onward (W) and from gestation onward (AL). HLE in the periods after weaning consisted of HFD (20% fat), and during gestation and lactation it also included previous maternal obesity induced by the HFD. HLE increased total cholesterol and triglyceride levels in all groups and led to insulin resistance in GL and AL and obesity in L. Serum testosterone levels decreased ~67% in GL, ~146% in L and W, and ~233% in AL. Histological and stereological analysis revealed an increment of the stromal compartment and collagen fibers in the prostates of all HLE groups, as well as degenerative lesions, such as cell vacuolation and prostate concretions. HLE aggravated acinar atrophy in G, GL, and L, and in AL it reached more than 50% of the prostate area for most animals. The foci of prostatic intraepithelial neoplasia increased in AL. Tissue expression of androgen receptor did not vary among groups, except for a higher stromal expression for G and GL. Even when restricted to gestation and lactation, HLE induces diffuse acinar atrophy in the aging prostate and worsens degenerative and premalignant lesions when it continues throughout life.
Assuntos
Doenças Metabólicas , Obesidade Materna , Neoplasia Prostática Intraepitelial , Neoplasias da Próstata , Masculino , Ratos , Feminino , Gravidez , Animais , Humanos , Próstata/metabolismo , Ratos Wistar , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/patologia , Dieta Hiperlipídica/efeitos adversos , Lactação , Testosterona , Envelhecimento , Neoplasias da Próstata/patologia , Atrofia/metabolismo , Atrofia/patologia , Lipídeos , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
Prostate cancer is the most common cancer in American men, aside from skin cancer. As an alternative cancer treatment, photodynamic laser therapy (PDT) can be used to induce cell death. We evaluated the PDT effect, using methylene blue as a photosensitizer, in human prostate tumor cells (PC3). PC3 were subjected to four different conditions: DMEM (control); laser treatment (L-660 nm, 100 mW, 100 J.cm-2); methylene blue treatment (MB-25 µM, 30 min), and MB treatment followed by low-level red laser irradiation (MB-PDT). Groups were evaluated after 24 h. MB-PDT treatment reduced cell viability and migration. However, because MB-PDT did not significantly increase the levels of active caspase-3 and BCL-2, apoptosis was not the primary mode of cell death. MB-PDT, on the other hand, increased the acid compartment by 100% and the LC3 immunofluorescence (an autophagy marker) by 254%. Active MLKL level, a necroptosis marker, was higher in PC3 cells after MB-PDT treatment. Furthermore, MB-PDT resulted in oxidative stress due to a decrease in total antioxidant potential, catalase levels, and increased lipid peroxidation. According to these findings, MB-PDT therapy is effective at inducing oxidative stress and reducing PC3 cell viability. In such therapy, necroptosis is also an important mechanism of cell death triggered by autophagy.
Assuntos
Fotoquimioterapia , Neoplasias da Próstata , Masculino , Humanos , Fotoquimioterapia/métodos , Sobrevivência Celular , Azul de Metileno/farmacologia , Necroptose , Fármacos Fotossensibilizantes/farmacologia , Neoplasias da Próstata/tratamento farmacológicoRESUMO
BACKGROUND: Experimental data indicate that high-fat diet (HFD) may alter proliferative activity and prostate health. However, the consequences of HFD exposure during different periods of ontogenetic development on prostate histophysiology remain to be elucidated. Herein, we compare the influence of obesogenic environment (OE) due to maternal obesity and HFD at different periods of life on proliferative activity and nuclear receptors frequency in the rat ventral prostate and a possible relationship with metabolic and hormonal alterations. METHODS: Male Wistar rats (19 weeks old), treated with balanced chow (Control group-C; 3% high-fat, 3.5 Kcal/g), were compared with those exposed to HFD (20% high-fat, 4.9 kcal/g) during gestation (G-maternal obesity), gestation and lactation (GL), from post-weaning to adulthood (WA), from lactation to adulthood (LA) and from gestation to adulthood (GA). After the experimental period, the ventral prostate lobes were removed and analyzed with different methods. RESULTS: Metabolic data indicated that G and GL rats became insulin resistant and WA, LA, and GA became insulin resistant and obese. There was a strong inverse correlation between serum testosterone (â¼133% lower) and leptin levels (â¼467% higher) in WA, LA, and GA groups. Estrogen serum levels increased in GA, and insulin levels increased in all groups, especially in WA (64.8×). OE-groups exhibited prostatic hypertrophy, since prostate weight increased â¼40% in G, GL, LA, and GA and 31% in WA. As indicated by immunohistochemistry, all HFD-groups except G exhibited an increase in epithelial cell proliferation (PCNA-positive) and a decrease in frequency of AR- and ERß-positive epithelial cells; there was also an increment of ERα-positive stromal cells in comparison with control. Cells containing PPARγ increased in both epithelium and stroma of all OE groups and those expressing LXRα decreased, particularly in groups OE-exposed during gestation (G, GL and GA). CONCLUSIONS: OE leads to prostate hypertrophy regardless of the period of development and, except when restricted to gestation, leads to a hyperproliferative status which was correlated to downregulation of AR and LXRα and upregulation of ERα and PPARγ signaling.
Assuntos
Dieta Hiperlipídica , Obesidade/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/patologia , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Proliferação de Células , Regulação para Baixo , Estrogênios/sangue , Feminino , Resistência à Insulina/fisiologia , Leptina/sangue , Receptores X do Fígado , Masculino , Obesidade/metabolismo , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Próstata/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Testosterona/sangue , Regulação para CimaRESUMO
BACKGROUND: TNF-α is a key cytokine involved in prostate carcinogenesis and is mediated by the TNF-α receptor type 1 (TNFR-1). This receptor triggers two opposite pathways: cell death or cell survival and presents a protective or stimulator role in cancer. Thus, the purpose of this study was to evaluate the role of TNF signaling in chemically induced prostate carcinogenesis in mice. METHODS: C57bl/6 wild type (WT) and p55 TNFR-1 knockout mice (KO) were treated with mineral oil (control) or N-methyl N-nitrosurea (MNU) in association with testosterone (MNU+T, single injection of 40 mg/kg and weekly injection 2 mg/kg, respectively) over the course of 6 months. After this induction period, prostate samples were processed for histological and biochemical analysis. RESULTS: MNU+T treatment led to the development of prostate intraepithelial neoplasia (PIN) and adenocarcinoma (PCa) in both WT and KO animals; however, the incidence of PCa was lower in KO group than in WT. Cell proliferation analysis showed that PCNA levels were significantly lower in the KO group, even after carcinogenesis induction. Furthermore, the prostate of KO animals had lower levels of p65 and p-mTOR after treatment with MNU+T than WT. There was also a decrease in prostate androgen receptor levels after induction of carcinogenesis in both KO and WT mice. Regarding the extracellular matrix in the prostate, KO mice had higher levels of fibronectin and lower levels of matrix metalloproteinase 2 (MMP2) after carcinogenesis. Finally, there was a similar increase in apoptosis in both groups after carcinogenesis, indicating that the TNAFr1 pathway in prostate carcinogenesis presented proliferative, and not apoptotic, stimuli. CONCLUSIONS: TNF-α, through its receptor TNFR-1, promoted cell proliferation and cell survival in prostate by activation of the AKT/mTOR and NFKB pathway, which stimulated prostate carcinogenesis in chemically induced mice. Prostate 76: 917-926, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Carcinogênese , Neoplasias da Próstata , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Adenocarcinoma/patologia , Animais , Apoptose , Carcinogênese/patologia , Proliferação de Células , Sobrevivência Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Antígeno Nuclear de Célula em Proliferação/análise , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Androgênicos/análise , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Serina-Treonina Quinases TOR/análise , Serina-Treonina Quinases TOR/metabolismo , Fator de Transcrição RelA/análiseRESUMO
This study evaluated the impact of a high-fat diet (HFD) during different stages of rat life, associated or not with maternal obesity, on the content of sex steroid hormones and morphophysiology of Leydig cells. The following periods of development were examined: gestation (O1), gestation and lactation (O2), from weaning to adulthood (O3), from lactation to adulthood (O4), gestation to adulthood (O5), and after sexual maturation (O6). The HFD contained 20% unsaturated fat, whereas the control diet had 4% fat. Maternal obesity was induced by feeding HFD 15 weeks before mating. All HFD groups presented increased body weight, hyperinsulinemia and reduced insulin sensitivity. Except for O1, all HFD groups exhibited a higher adiposity index, hyperleptinemia, reduced testosterone and estradiol testicular levels, and decreased testicular 17ß-HSD enzyme . Morphometrical analyses indicated atrophy of Leydig cells in the O2 group. Myelin vesicles were observed in the mitochondrial matrix of Leydig cells in O3, O4, O5 and O6, and autophagosomes containing mitochondria were found in O5 and O6. In conclusion, HFD feeding, before or after sexual maturation, reduces the functional capacity of rat Leydig cells. Maternal obesity associated with HFD during pregnancy/lactation prejudices Leydig cell steroidogenesis and induces its atrophy in adulthood, even if it is replaced by a conventional diet at later stages of life. Regardless of the life period of exposure to HFD, deregulation of leptin is the main factor related to steroidogenic impairment of Leydig cells, and, in groups exposed for longer periods (O3, O4, O5 and O6), this is worsened by structural damage and mitochondrial degeneration of these cells.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hormônios Esteroides Gonadais/biossíntese , Resistência à Insulina , Células Intersticiais do Testículo/patologia , Obesidade/patologia , Adiposidade , Animais , Feminino , Células Intersticiais do Testículo/metabolismo , Masculino , Obesidade/metabolismo , Gravidez , Ratos , Ratos Wistar , Aumento de PesoRESUMO
This study determined the phases of sexual development of the male Mongolian gerbil (Meriones unguiculatus) based on an integrative analysis of testicular morphology, hormonal data and sperm parameters. Male gerbils were analysed at 1, 7, 14, 21, 28, 35, 42, 50, 60, 70, 90, 100 and 120 days of age. Body, testicular and epididymal weights increased up to Day 70, 60 and 90, respectively. The impuberal phase, characterised by the presence of gonocytes, extended until Day 14. The prepubertal period lasted until Day 42, when puberty was achieved and a drastic increase in serum testosterone levels, mature adult Leydig cells and elongated spermatids was observed. Gerbils at 60 days of age showed a remarkable number of spermatozoa in the testis, epididymidis caput/corpus and cauda, and at Day 70 the maximum daily sperm production was reached. However, the gerbil may be considered sexually mature only from Day 90 onward, when sperm reserves become stable. The total transit time of spermatozoa along the epididymis of sexually mature gerbils was 11 days, with 1 day in the caput/corpus and 10 days in the cauda. These data cover a lacuna regarding the reproductive parameters of this rodent and provide foundations for its use in testicular toxicology studies.
Assuntos
Animais de Laboratório/crescimento & desenvolvimento , Epididimo/crescimento & desenvolvimento , Gerbillinae/crescimento & desenvolvimento , Maturidade Sexual , Espermatogênese , Testículo/crescimento & desenvolvimento , Fatores Etários , Animais , Animais de Laboratório/sangue , Animais de Laboratório/fisiologia , Epididimo/citologia , Estrogênios/sangue , Gerbillinae/sangue , Gerbillinae/fisiologia , Células Intersticiais do Testículo/citologia , Masculino , Tamanho do Órgão , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermátides/citologia , Espermátides/crescimento & desenvolvimento , Espermatogônias/citologia , Espermatogônias/crescimento & desenvolvimento , Espermatozoides/citologia , Espermatozoides/crescimento & desenvolvimento , Testículo/citologia , Testículo/metabolismo , Testosterona/sangueRESUMO
Recent studies have shown a positive association of cancer and obesity, but the morphological and molecular mechanisms involved in this relationship are still unknown. This study analysed the impact of long-term obesity on rat prostate, focusing on stromal changes. Male adult Wistar rats were treated with high-fat diet to induce obesity, while the control group received a balanced diet. After 30 weeks of feeding, the ventral prostate was analysed by immunohistochemistry for cell proliferation, smooth muscle α-actin, vimentin, chondroitin sulphate and metalloproteinases (MMP-2 and 9). The content of androgen receptor (AR), oestrogen receptors (ERs) and vascular endothelial growth factor (VEGF) was measured by Western blotting, and activity of catalase and Glutathione-S-Transferase (GST) were quantified by enzymatic assay. Long-term obesity decreased testosterone plasma levels by 70% and resulted in stromal prostate hyperplasia, as evidenced by increased collagen fibres. Such stromal hyperplasia was associated with increased number of blood vessels and raised VEGF content, and increased expression of chondroitin sulphate, vimentin, α-actin and MMP-9. In spite of the high cell density in prostate, the proliferative activity was lower in the prostates of obese rats, indicating that hyperplasia was established during the early phases in this obesity model. AR levels increased significantly, whereas the ERα decreased in this group. Moreover, the levels of catalase and GST were changed considerably. These findings indicate that long-term obesity, besides disturbing the antioxidant control, causes intense stromal remodelling and release of factors that create an environment that can promote proliferative disorders in the gland, culminating with diffuse hyperplasia.
Assuntos
Matriz Extracelular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Obesidade/complicações , Próstata/enzimologia , Hiperplasia Prostática/etiologia , Células Estromais/enzimologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Catalase/metabolismo , Proliferação de Células , Microambiente Celular , Modelos Animais de Doenças , Glutationa Transferase/metabolismo , Insulina/sangue , Masculino , Malondialdeído/metabolismo , Oxirredução , Próstata/patologia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Ratos Wistar , Receptores Androgênicos/metabolismo , Fatores de Risco , Células Estromais/patologia , Testosterona/sangue , Fatores de Tempo , Regulação para CimaRESUMO
This study compares the impact of obesogenic environment (OE) in six different periods of development on sperm parameters and the testicular structure of adult rats and their correlations with sex steroid and metabolic scenario. Wistar rats were exposed to OE during gestation (O1), during gestation/lactation (O2), from weaning to adulthood (O3), from lactation to adulthood (O4), from gestation to sexual maturity (O5), and after sexual maturation (O6). OE was induced by a 20% fat diet, and control groups were fed a balanced diet (4% fat). Serum leptin levels and adiposity index indicate that all groups were obese, except for O1. Three progressive levels of impaired metabolic status were observed: O1 presented insulin resistance, O2 were insulin resistant and obese, and groups O3, O4, and O5 were insulin resistant, obese, and diabetic. These three levels of metabolic damage were proportional to the increase of leptin and decreased circulating testosterone. The impairment in the daily sperm production (DSP) paralleled these three levels of metabolic and hormonal damage being marginal in O1, increasing in O2, and being higher in groups O3, O4, O5, and O6. None of the OE periods affected the sperm transit time in the epididymis, and the lower sperm reserves were caused mainly by impaired DSP. In conclusion, OE during sexual maturation markedly reduces the DSP at adulthood in the rat. A severe reduction in the DSP also occurs in OE exposure during gestation/lactation but not in gestation, indicating that breast-feeding is a critical period for spermatogenic impairment under obesogenic conditions.
Assuntos
Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Crescimento e Desenvolvimento/efeitos dos fármacos , Obesidade , Oligospermia/etiologia , Oligospermia/metabolismo , Maturidade Sexual/efeitos dos fármacos , Animais , Dieta Hiperlipídica/efeitos adversos , Meio Ambiente , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Espermatogênese/efeitos dos fármacosRESUMO
In this study, we evaluated whether maternal obesity (MO) affects testis development and gonocyte differentiation in the rat from 0.5 to 14.5 postnatal days. Male Wistar rats were used at 0.5, 4.5, 7.5, and 14.5 days post partum (dpp). These rats were born from obese mothers, previously fed with a high-fat diet (20% saturated fat), for 15 weeks, or normal mothers that had received a balanced murine diet (4% lipids). MO did not affect testis weight or histology at birth but changed the migratory behavior of gonocytes. The density of relocated cells was higher in MO pups at 0.5 dpp, decreased at 4.5 dpp, and differed from those of control pups, where density increased exponentially from 0.5 to 7.5 dpp. The numerical density of gonocytes within seminiferous cords did not vary in MO, in relation to control neonates, for any age considered, but the testis weight was 50% lower at 4.5 dpp. A wide variation in plasmatic testosterone and estrogen levels was observed among the groups during the first week of age and MO pups exhibited higher steroid concentrations at 4.5 dpp, in comparison with controls. At this age, higher estrogen levels of MO pups impaired the gonocyte proliferation. At 7.5 dpp, the testicular size and other parameters of gonocyte development are retrieved. In conclusion, MO and saturated lipid diets disturb gonocyte development and sexual steroid levels during the first days of life, with recovery at prepubertal age.
Assuntos
Diferenciação Celular , Células Germinativas/fisiologia , Obesidade , Complicações na Gravidez , Maturidade Sexual , Testículo/crescimento & desenvolvimento , Testículo/ultraestrutura , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Dieta Hiperlipídica/efeitos adversos , Feminino , Células Germinativas/efeitos dos fármacos , Masculino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Testículo/efeitos dos fármacosRESUMO
This study evaluated the consequences of gestational exposure to di-n-butyl phthalate (DBP) for testicular steroidogenesis and sperm parameters of the adult gerbil and the interference of corn oil (co), a vehicle widely used for administration of liposoluble agents, on DBP effects. Pregnant gerbils received no treatment or were treated from gestational day 8 to 23 via gavage with 0.1 mL/day of co only or containing DBP (100 mg/kg/day). Maternal co intake enhanced serum estradiol levels and testicular content of ERα, and reduced sperm reserve of adult offspring. Gestational DBP exposure caused dyslipidemia, increased serum and intratesticular estradiol levels and reduced sperm reserve and motility. Thus, maternal co supplementation alters circulating estradiol and impairs sperm quantity and quality of offspring. Gestational DBP exposure alters lipid metabolism and testicular steroidogenesis and worsens the negative effects of co on the sperm reserve and motility of gerbil. Therefore, co interferes with the reproductive response to DBP.
Assuntos
Óleo de Milho/administração & dosagem , Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Estradiol/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Espermatozoides/efeitos dos fármacos , Animais , Feminino , Gerbillinae , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Gravidez , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testículo/efeitos dos fármacos , Testículo/metabolismoRESUMO
Both high-fat diet and exposure to endocrine-disrupting chemicals have been implicated in susceptibility to pathological prostate lesions, but the consequences of combining the two have not yet been examined. We evaluated the effects of gestational and postnatal exposure to a high-fat diet (20% fat) and low doses of di-n-butyl phthalate (DBP; 5mg/kg/day), individually or in combination, on the tissue response and incidence of pathological lesions in the ventral prostate of adult gerbils. Continuous intake of a high-fat diet caused dyslipidemia, hypertrophy, and promoted the development of inflammatory, premalignant and malignant prostate lesions, even in the absence of obesity. Life-time DBP exposure was obesogenic and dyslipidemic and increased the incidence of premalignant prostate lesions. Combined exposure to DBP and a high-fat diet also caused prostate hypertrophy, but the effects were less severe than those of individual treatments; combined exposure neither induced an inflammatory response nor altered serum lipid content.