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1.
Gen Comp Endocrinol ; 246: 258-269, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28041790

ABSTRACT

Experimental data demonstrated the negative impact of maternal protein malnutrition (MPM) on rat prostate development, but the mechanism behind the impairment of prostate growth has not been well understood. Male Sprague Dawley rats, borned to dams fed a normal protein diet (CTR group, 17% protein diet), were compared with those borned from dams fed a low protein diet (6% protein diet) during gestation (GLP group) or gestation and lactation (GLLP). The ventral prostate lobes (VP) were removed at post-natal day (PND) 10 and 21, and analyzed via different methods. The main findings were low birth weight, a reduction in ano-genital distance (AGD, a testosterone-dependent parameter), and an impairment of prostate development. A delay in prostate morphogenesis was associated with a reduced testosterone levels and angiogenic process through downregulation of aquaporin-1 (AQP-1), insulin/IGF-1 axis and VEGF signaling pathway. Depletion of the microvascular network, which occurs in parallel to the impairment of proliferation and differentiation of the epithelial cells, affects the bidirectional flux between blood vessels impacting prostatic development. In conclusion, our data support the hypothesis that a reduction in microvascular angiogenesis, especially in the subepithelial compartment, is associated to the impairment of prostate morphogenesis in the offspring of MPM dams.


Subject(s)
Fetal Development , Fetal Nutrition Disorders/pathology , Microvessels/embryology , Neovascularization, Pathologic/pathology , Prostate/pathology , Protein-Energy Malnutrition/physiopathology , Animals , Animals, Newborn , Blotting, Western , Female , Insulin/blood , Insulin-Like Growth Factor I/metabolism , Lactation/physiology , Male , Pregnancy , Prostate/blood supply , Prostate/metabolism , Rats , Rats, Sprague-Dawley , Testosterone/blood , Vascular Endothelial Growth Factor A/metabolism
2.
Biochem Biophys Res Commun ; 457(4): 538-41, 2015 Feb 20.
Article in English | MEDLINE | ID: mdl-25600809

ABSTRACT

Matrix metalloproteinases (MMPs) are zinc (Zn(2+)) and calcium (Ca(2+)) dependant endopeptidases, capable of degradation of numerous components of the extracellular matrix. Cadmium (Cd(2+)) is a well known environmental contaminant which could impair the activity of MMPs. In this sense, this study was conducted to evaluate if Cd(2+) intake inhibits these endopeptidases activities at the rat prostate and testicles and if it directly inhibits the activity of MMP2 and MMP9 at gelatinolytic assays when present in the incubation buffer. To investigate this hypothesis, Wistar rats (5 weeks old), were given tap water (untreated, n = 9), or 15 ppm CdCl2 diluted in drinking water, during 10 weeks (n = 9) and 20 weeks (n = 9). The animals were euthanized and their ventral prostate, dorsal prostate, and testicles were removed. These tissue samples were processed for protein extraction and subjected to gelatin zymography evaluation. Additionally, we performed an experiment of gelatin zymography in which 5 µM or 2 mM cadmium chloride (CdCl2) was directly dissolved at the incubation buffer, using the prostatic tissue samples from untreated animals that exhibited the highest MMP2 and MMP9 activities in the previous experiment. We have found that CdCl2 intake in the drinking water led to the inhibition of 35% and 30% of MMP2 and MMP9 (p < 0.05) at the ventral prostate and testis, respectively, in Cd(2+) treated animals when compared to controls. Moreover, the activities of the referred enzymes were 80% and 100% inhibited by 5 µM and 2 mM of CdCl2, respectively, even in the presence of 10 mM of CaCl2 within the incubation buffer solution. These important findings demonstrate that environmental cadmium contamination may deregulate the natural balance in the extracellular matrix turnover, through MMPs downregulation, which could contribute to the toxic effects observed in prostatic and testicular tissue after its exposure.


Subject(s)
Cadmium/toxicity , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/toxicity , Prostate/enzymology , Testis/enzymology , Water Pollutants, Chemical/toxicity , Animals , Male , Prostate/drug effects , Rats, Wistar , Testis/drug effects
3.
Exp Cell Res ; 326(1): 103-11, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24929113

ABSTRACT

Clinical experience for peripheral arterial disease treatment shows poor results when synthetic grafts are used to approach infrapopliteal arterial segments. However, tissue engineering may be an option to yield surrogate biocompatible neovessels. Thus, biological decellularized scaffolds could provide natural tissue architecture to use in tissue engineering, when the absence of ideal autologous veins reduces surgical options. The goal of this study was to evaluate different chemical induced decellularization protocols of the inferior vena cava of rabbits. They were decellularized with Triton X100 (TX100), sodium dodecyl sulfate (SDS) or sodium deoxycholate (DS). Afterwards, we assessed the remaining extracellular matrix (ECM) integrity, residual toxicity and the biomechanical resistance of the scaffolds. Our results showed that TX100 was not effective to remove the cells, while protocols using SDS 1% for 2h and DS 2% for 1h, efficiently removed the cells and were better characterized. These scaffolds preserved the original organization of ECM. In addition, the residual toxicity assessment did not reveal statistically significant changes while decellularized scaffolds retained the equivalent biomechanical properties when compared with the control. Our results concluded that protocols using SDS and DS were effective at obtaining decellularized scaffolds, which may be useful for blood vessel tissue engineering.


Subject(s)
Surface-Active Agents/pharmacology , Tissue Engineering , Tissue Scaffolds , Tissue Transplantation , Vena Cava, Inferior/cytology , Vena Cava, Inferior/physiology , Adipose Tissue/cytology , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Biomechanical Phenomena , Cell Differentiation , Cells, Cultured , Extracellular Matrix/chemistry , Female , Immunoenzyme Techniques , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Rabbits , Vena Cava, Inferior/drug effects
4.
Reprod Fertil Dev ; 26(7): 967-73, 2014 Aug.
Article in English | MEDLINE | ID: mdl-23920146

ABSTRACT

Maternal malnutrition due to a low-protein diet is associated with functional disorders in adulthood, which may be related to embryonic development failures. The effects of gestational protein restriction on prostate morphogenesis in male offspring were investigated. Pregnant rat dams were divided into normoprotein (NP; fed a normal diet containing 17% protein) and hypoprotein (LP; fed a diet containing 6% protein) groups. On the day of birth (PND1), anogenital distance and bodyweight were measured in male pups. Seven males per experimental group (one male per litter) were killed, and the pelvic urethra was evaluated. LP offspring showed a significant reduction in bodyweight and anogenital distance on PND1. On three-dimensional reconstruction of the prostate, the number of prostatic buds was lower in LP than in NP males. Mesenchymal cells surrounding the buds were androgen-receptor positive, and the quantity and intensity of nucleus immunoreactivity was decreased in LP. The proliferation index was lower in LP than in NP prostatic buds. Immunoreactivity for α-actin in mesenchymal cells and that for epidermal growth factor receptor in epithelial cells was higher in NP than in LP. Our findings demonstrate that maternal protein restriction delays prostatic morphogenesis, probably because of considerable disruption in the epithelium-mesenchyme interaction.


Subject(s)
Organogenesis/physiology , Pregnancy Complications , Prostate/embryology , Protein Deficiency/complications , Animals , Animals, Newborn , Apoptosis , Cell Proliferation , Diet, Protein-Restricted , Epithelial Cells/cytology , Female , Male , Mesoderm/chemistry , Mesoderm/embryology , Pregnancy , Pregnancy Complications/etiology , Prostate/cytology , Rats , Rats, Wistar , Receptors, Androgen/analysis
5.
Gen Comp Endocrinol ; 206: 60-71, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-24983773

ABSTRACT

Clinical and experimental studies have shown that exposure to adverse conditions during the critical stages of embryonic, fetal or neonatal development lead to a significantly increased risk of later disease. Diabetes during pregnancy has been linked to increased risk of obesity and diabetes in offspring. Here, we investigated whether mild gestational diabetes mellitus (GDM) followed or not by maternal insulin replacement affects the ventral prostate (VP) structure and function in male offspring at puberty and adulthood. Pregnant rats were divided into the following 3 groups: control (CT); streptozotocin (STZ)-induced diabetes (D); and D plus insulin replacement during lactation (GDI). The male offspring from different groups were euthanized at postnatal day (PND) 60 and 120. Biometrical parameters, hormonal levels and prostates were evaluated. Mild-GDM promoted reduction in the glandular parenchyma and increased collagen deposition. Insulin replacement during lactation restored the VP morphology. Most importantly, mild-GDM decreased the androgen-induced secretory function as determined by prostatein expression, and insulin replacement reversed this effect. Our results demonstrated that mild GDM impairs VP parenchyma maturation, which is associated with an increase in the fibromuscular stroma compartment. Functionally, the reduction in the VP parenchyma decreases the glandular secretory activity as demonstrated by low expression of prostatein, a potent immunosuppressor factor that protects sperm from immunologic damage into the feminine reproductive tract. This change could lead to impairment of reproductive function in male offspring from diabetic mothers. Maternal insulin replacement during the weaning period apparently restores the prostate function in male offspring.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Diabetes, Gestational/physiopathology , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Lactation/drug effects , Prostate/metabolism , Sexual Maturation/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Cell Proliferation/drug effects , Female , Humans , Hypoglycemic Agents/pharmacology , Immunoenzyme Techniques , Insulin/pharmacology , Male , Pregnancy , Rats , Rats, Wistar
6.
Int J Exp Pathol ; 93(6): 429-37, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23136995

ABSTRACT

Coffee intake has been associated with a low risk of developing cancer, including prostate cancer, which is one of the most commonly diagnosed cancer in men. However, few studies have evaluated the chronic effects of caffeine, which is the most abundant methylxanthine in coffee, on prostate morphology and physiology. In the present study, we investigated the effects of chronic, low-dose caffeine intake on rat prostate morphology from puberty to adulthood. Five-week-old male Wistar rats were randomized into two experimental groups: caffeine-treated (20 ppm in drinking water, n = 12) and control (n = 12). The ventral and dorsolateral prostates were dissected, weighted and submitted to morphological, morphometrical and immunohistochemical analysis of cellular proliferation, apoptosis and androgen receptor (AR) tissue expression. The testosterone (T) and dihydrotestosterone (DHT) concentrations were measured in the plasma. Our results show that caffeine intake increased the concentrations of T and DHT, organ weight, epithelial cell proliferation and AR tissue expression in the ventral prostatic lobe. All the ventral prostates from the caffeine-treated animals presented various degrees of epithelial and stromal hyperplasia. Our results suggest that chronic caffeine intake from puberty increases androgenic signalling and cell proliferation in the rat prostate gland and can be related to the development of benign prostatic hyperplasia.


Subject(s)
Caffeine/toxicity , Central Nervous System Stimulants/toxicity , Prostate/drug effects , Prostatic Hyperplasia/chemically induced , Administration, Oral , Androgens/metabolism , Animals , Apoptosis/drug effects , Cell Proliferation , Chronic Disease , Dihydrotestosterone/blood , Dose-Response Relationship, Drug , Male , Prostate/metabolism , Prostate/pathology , Prostatic Hyperplasia/pathology , Rats , Rats, Wistar , Receptors, Androgen/metabolism , Signal Transduction , Testosterone/blood , Water Supply
7.
J Gerontol A Biol Sci Med Sci ; 74(6): 751-759, 2019 05 16.
Article in English | MEDLINE | ID: mdl-29762647

ABSTRACT

Carcinogenesis is frequently linked to genetic background, however, exposure to environmental risk factors has gained attention as the etiologic agent for several types of cancer, including prostate. The intrauterine microenvironment has been described as a preponderant factor for offspring health; and maternal exposure to insult has been linked to chronic disease in older offspring. Using a model of maternal exposure to low-protein diet (LPD; 6% protein), we demonstrated that impairment of offspring rat prostatic growth on postnatal day (PND) 21 was associated with prostate carcinogenesis in older offspring (PND 540). One explanation is that maternal LPD consumption exposed offspring to an estrogenic intrauterine microenvironment, which potentially sensitized prostate cells early during glandular morphogenesis, increasing cellular response to estrogen in older rats. The onset of accelerated prostatic growth, observed on PND 21, associated with an unbalanced estrogen/testosterone ratio and increased circulating IGF-1 in older offspring appears to contribute to the development of prostate carcinoma in groups on gestational low protein and gestational and lactational low protein diets (33 and 50%, respectively). Our study strongly indicated maternal exposure to LPD as a potential risk factor for induction of slow-growing prostate carcinogenesis in rat offspring later in life.


Subject(s)
Carcinogenesis , Diet, Protein-Restricted , Prostate/growth & development , Prostatic Neoplasms/pathology , Age Factors , Animals , Animals, Newborn , Biomarkers/metabolism , Female , Hormones/metabolism , Male , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, Sprague-Dawley
8.
Endocrinology ; 160(11): 2692-2708, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31433456

ABSTRACT

Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERß and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERß to the cell membrane with caveolin-1 interactions. Exposure to 17ß-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2-dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERß in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERß selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERß, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERß membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.


Subject(s)
Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Neoplastic Stem Cells/metabolism , Prostate/metabolism , Caveolin 1/metabolism , Cells, Cultured , Histone Methyltransferases/metabolism , Humans , MAP Kinase Signaling System , Male , Phosphorylation , Phosphotransferases/metabolism , Prostate/cytology
9.
Anat Rec (Hoboken) ; 300(2): 291-299, 2017 02.
Article in English | MEDLINE | ID: mdl-27788294

ABSTRACT

Gestational diabetes mellitus (GDM) has increased in recent years. Although the cellular and molecular mechanisms involved in GDM-increased risk factors to offspring remained poorly understood, some studies suggested an association between an increase in oxidative stress induced by maternal hyperglycemia and complications for both mothers and newborns. Here, we investigated the impact of maternal hyperglycemia followed by maternal insulin replacement during lactation on the expression of antioxidant enzymes and mast cell number in offspring ventral prostate (VP) at puberty. Pregnant rats were divided into three groups: control (CT); streptozotocin-induced maternal hyperglycemia (MH); and MH plus maternal insulin replacement during lactation (MHI). Male offspring were euthanized at postnatal day (PND) 60 and the VP was removed and processed for histology and Western blotting analyses. Maternal hyperglycemia delayed prostate maturation, and increased mast cell number catalase (CAT), superoxide dismutase (SOD), glutatione-s-transferase (GST-pi), and cyclooxygenase-2 (Cox-2) expression in the offspring of hyperglycemic dams. Maternal insulin replacement restored VP structure, mast cell number and antioxidant protein expression, except for Cox-2, which remained higher in the MHI group. Thus, an increase in oxidative stress induced by intrauterine hyperglycemia impacts prostate development and maturation, which persists until puberty. The overall improvement of maternal metabolism after insulin administration contributes to the restoration of prostate antioxidant enzymes and secretory function. Taken together, our results highlighted that imbalanced physiological maternal-fetal interaction contributes to the impairment of reproductive performance of the offspring from diabetic mothers. Anat Rec, 300:291-299, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes, Gestational/metabolism , Mast Cells/metabolism , Prenatal Exposure Delayed Effects/metabolism , Prostate/metabolism , Animals , Blood Glucose/metabolism , Cell Count , Cyclooxygenase 2/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Experimental/pathology , Diabetes, Gestational/drug therapy , Diabetes, Gestational/enzymology , Diabetes, Gestational/pathology , Female , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/pharmacology , Insulin/therapeutic use , Male , Mast Cells/drug effects , Mast Cells/pathology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Pregnancy , Prenatal Exposure Delayed Effects/enzymology , Prenatal Exposure Delayed Effects/pathology , Prostate/drug effects , Prostate/enzymology , Prostate/pathology , Rats , Rats, Wistar
10.
Life Sci ; 92(13): 763-74, 2013 Apr 19.
Article in English | MEDLINE | ID: mdl-23439325

ABSTRACT

AIMS: Maternal malnutrition by low protein diet is associated with an increased incidence of metabolic disorders and decreased male fertility in adult life. This study aimed to assess the impact of maternal protein malnutrition (MPM) on prostate growth, tissue organization and lesion incidence with aging. MAIN METHODS: Wistar rat dams were distributed into two groups, which were control (NP; fed a normal diet containing 17% protein) or a restricted protein diet (RP, fed a diet containing 6% protein) during gestation. After delivery all mothers and offspring received a normal diet. Biometrical parameters, hormonal levels and prostates were harvested at post-natal days (PND) 30, 120 and 360. KEY FINDINGS: MPM promoted low birth weight, decreased ano-genital distance (AGD) and reduced androgen plasma levels of male pups. Prostatic lobes from RP groups presented reduced glandular weight, epithelial cell height and alveolar diameter. The epithelial cell proliferation and collagen deposition were increased in RP group. Incidences of epithelial dysplasia and prostatitis were higher in the RP offspring than in the NP offspring at PND360. SIGNIFICANCE: Our findings show that MPM delays prostate development, growth and maturation until adulthood, probably as a result of low testosterone stimuli. The higher incidence of cellular dysplasia and prostatitis suggests that MPM increases prostate susceptibility to diseases with aging.


Subject(s)
Diet, Protein-Restricted/adverse effects , Fetal Nutrition Disorders/pathology , Prostate/growth & development , Prostate/pathology , Prostatitis/etiology , Prostatitis/pathology , Aging , Animals , Animals, Newborn , Apoptosis , Body Weight , Collagen/analysis , Eating , Female , Fetal Nutrition Disorders/blood , Fetal Nutrition Disorders/physiopathology , Male , Pregnancy , Prostatitis/blood , Prostatitis/physiopathology , Rats , Rats, Wistar , Receptors, Androgen/analysis , Testosterone/blood
11.
Reprod Toxicol ; 35: 137-43, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23099337

ABSTRACT

The aim of this study was to investigate the effects of caffeine (20 mg/L) intake on cadmium (15 mg/L) accumulation in the rat blood, testes, epididymis and prostate as well as cadmium-induced changes to the antioxidant defense system of the epididymis. Caffeine reduced the cadmium concentration in all tissues analyzed. Meanwhile, cadmium reduced catalase activity and increased superoxide dismutase (SOD) activity in the epididymis. Caffeine increased SOD activity, catalase and glutathione tissue expression and sustains the cadmium's effect on catalase and GSP-Px activity. No differences in the expression of metallothionein and lipid peroxidation were observed among the different treatments in the epididymis. In conclusion, low doses of cadmium alter the antioxidant enzymatic profile of the epididymis, but not induced oxidative lipid damage. Caffeine intake reduces overall cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis, thus exerting a protective effect against this metal.


Subject(s)
Cadmium/toxicity , Caffeine/pharmacology , Environmental Pollutants/toxicity , Epididymis/drug effects , Protective Agents/pharmacology , Animals , Catalase/metabolism , Epididymis/metabolism , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Lipid Peroxides/metabolism , Male , Oxidative Stress , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Tissue Distribution
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