The blood-testis barrier (BTB) is responsible for providing a protected environment and coordinating the spermatogenesis. Endocrine disruptors (EDs) might lead to infertility, interfering in the BTB structure and modulation. This study aimed to correlate the actions of two EDs, monobutyl phthalate (MBP) and bisphenol A (BPA) in different periods of exposure, in a low toxicity dose to the human Sertoli cells (HSeC) and its effects on the proteins of the BTB and regulatory proteins involved in its modulation. HSeC cells were exposed to MBP (10μM) and BPA (20μM) for 6 and 48h. Western Blot assay indicated that MBP was able to reduce the expression of occludin, ZO-1, N-cadherin and Androgen Receptor (AR), while BPA leads to a reduction of occludin, ZO-1, β-catenin and AR. TGF-β2 and F-actin were not modified. Phalloidin and Hematoxylin and Eosin assay revealed phenotically disruption in Sertoli cells adhesion, without changes in F-actin expression or localization. Our data suggested both EDs present potential for disrupting the structure and maintenance of the human BTB by AR dependent pathway.

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.

Throughout the last decades, increasing exposure to environmental Endocrine Disruptors Chemicals (EDCs) has been associated with the occurrence of male reproductive disorders, such as impairment of prostate development and function, increase of susceptibility to oncogenesis, Epithelial-Mesenchymal Transition and the metastatic invasive potential. Nevertheless, few studies address the mechanisms involved in these alterations, especially those related to cell junctions, which are hormonally regulated and, therefore, possible EDCs targets. The cellular mechanisms discussed in this review are addressed to EDCs actions on tight, gap and adherent junctions and its related genes and proteins, such as claudin-1, -3, -4 and -8, connexin-32 and -43, E-cadherin and β-catenin, respectively. The impairment of cell junction function, mainly due EDCs exposure during the prostate's critical window of development, can corroborate to acquire a mesenchymal phenotype by epithelial cells and the prostate microenvironment becomes susceptible to development of lesions in the latter stages of life.

Objectives This study evaluated raloxifene (ral) effects on LNCaP prostate tumour cells modulating the activity of GPER1/GPR30 receptors. Methods LNCaP cells were submitted for 40/120 min and 12 h to the following treatments: C: RPMI + DMSO; R: RPMI + Ral; G: RPMI + Ral + G15 (GPER1 antagonist). Trypan blue staining measured cell viability. Migratory potential (12 h) was measured by transwell migration test in translucent inserts, which were then stained with DAPI and analysed under a fluorescence microscope for quantification. Cells from 40-and 120-min treatments were subjected to protein extraction to the study of AKT, pAKT, ERK, pERK, ERb and SIRT1. Key findings There is a reduction in cellular viability in R compared to C at all evaluated times, and an increased cell viability in G when compared to R; cell viability was similar in C and G in all times studied. The migration assay demonstrated a significant decrease in migration potential of tumour cells in R compared to C and G. Ral treatment reduced pERK expression and increased pAKT in the treated groups after 40 min, pointing out to an antiproliferative and apoptotic effect in the GPER1-controlled rapid-effect pathways. Conclusions Raloxifene was able to modulate GPER1 in LNCaP prostate tumour cells, decreasing cell viability and their migratory potential.

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This study evaluated the protective effects of resveratrol on the prostate development of rats exposed to TCDD. Pregnant rats received TCDD (1 μg/kg) at GD15 and/or RES (20 mg/kg/day) from GD10 to PND21. Newborn and adult males from Control, TCDD, TCDD + RES and RES groups were euthanized and the prostate was excised. On PND1, there was a reduction in the number of prostatic buds, AR-positive mesenchymal cells and proliferation index in epithelial and mesenchymal cells in TCDD group, but restored by RES. AhR immunoreactivity was greater in TCDD group than the other groups. On PND90, there was higher frequency of functional hyperplasia in the distal area of the prostate acini in TCDD group, but restored by RES. AhRR expression was higher in the TCDD while NRF2 was higher in the TCDD + RES compared to the other groups. Resveratrol was able to reduce the adverse effects of TCDD on prostate development and its long-term repercussions.

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.

Testosterone is often recommended in the treatment of several aging-related conditions. However, there are still questions about the consequences of this therapy in terms of hormonal and inflammatory parameters that are crucial for prostate homeostasis. Thus, we investigate if the testosterone therapy (TT) modulates the hormone receptors and inflammatory cytokines in the ventral prostate of adult rats. Wistar rats aging 150 days were divided into two experimental groups (n = 10/group): T: received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks; and C: received corn oil as vehicle. Animals were euthanized at 180 days old by decapitation. Blood was collected to obtain hormone and cytokines concentrations. The ventral prostate was dissected and processed for light microscope and molecular analyses. Relative ventral prostate weight and epithelial compartment were increased after TT. The number of intact and degranulated mast cells was reduced in the T group. Plasma testosterone, DHT and intraprostatic testosterone concentrations were higher in the T group. TT leads to an increase in cell proliferation and up-regulation of AR, ERβ, PAR-4, and NRF2. Importantly, plasma concentration and tissue expression of IL-10 and TNF-α were higher after TT. In summary, these results indicate that TT can regulate inflammatory response, with impacts in cytokines and mast cell population, and modulates steroids receptors, important parameters for prostatic homeostasis.