Glucuronidated Metabolites of Bisphenols A and S Alter the Properties of Normal Urothelial and Bladder Cancer Cells.

Bisphenol A (BPA) and bisphenol S (BPS) are synthetic chemicals used to produce plastics which can be released in food and water. Once ingested, BPA and BPS are metabolized by the liver, mainly as glucuronidated metabolites, and are excreted through urine. Since urine can be stored for many hours, the bladder is chronically exposed to BP metabolites, and studies have shown that these metabolites can remain active in the organism. Therefore, the effect of physiological concentrations of glucuronidated BPs was evaluated on the bioenergetics (glycolysis and mitochondrial respiration), migration and proliferation of normal urothelial cells, and non-invasive and invasive bladder cancer cells. The results demonstrated that an exposure of 72 h to glucuronidated BPA or BPS decreased the bioenergetics and activity of normal urothelial cells, while increasing these parameters for bladder cancer cells. These findings suggest that BP metabolites are not as inactive as initially believed, and their ubiquitous presence in the urine could promote bladder cancer progression.

Bisphenols A and S Alter the Bioenergetics and Behaviours of Normal Urothelial and Bladder Cancer Cells.

Bisphenol A (BPA) and bisphenol S (BPS) are used in the production of plastics. These endocrine disruptors can be released into the environment and food, resulting in the continuous exposure of humans to bisphenols (BPs). The bladder urothelium is chronically exposed to BPA and BPS due to their presence in human urine samples. BPA and BPS exposure has been linked to cancer progression, especially for hormone-dependent cancers. However, the bladder is not recognized as a hormone-dependent tissue. Still, the presence of hormone receptors on the urothelium and their role in bladder cancer initiation and progression suggest that BPs could impact bladder cancer development. The effects of chronic exposure to BPA and BPS for 72 h on the bioenergetics (glycolysis and mitochondrial respiration), proliferation and migration of normal urothelial cells and non-invasive and invasive bladder cancer cells were evaluated. The results demonstrate that chronic exposure to BPs decreased urothelial cells' energy metabolism and properties while increasing them for bladder cancer cells. These findings suggest that exposure to BPA and BPS could promote bladder cancer development with a potential clinical impact on bladder cancer progression. Further studies using 3D models would help to understand the clinical consequences of this exposure.

Bladder cancer cell lines adapt their aggressiveness profile to oxygen tension.

During the process of tumor growth, cancer cells will be subjected to intermittent hypoxia. This results from the delay in the development of the vascular network in relation to the proliferation of cancer cells. The hypoxic nature of a tumor has been demonstrated as a negative factor for patient survival. To evaluate the impact of hypoxia on the survival and migration properties of low and high-grade bladder cancer cell lines, two low-grade (MGHU-3 and SW-780) and two high-grade (SW-1710 and T24) bladder cancer cell lines were cultured in normoxic (20% O2) or hypoxic atmospheric conditions (2% O2). The response of bladder cancer cell lines to hypoxic atmospheric cell culture conditions was examined under several parameters, including epithelial-mesenchymal transition, doubling time and metabolic activities, thrombospondin-1 expression, whole Matrix Metallo-Proteinase activity, migration and resistance to oxidative stress. The low-grade cell line response to hypoxia was heterogeneous even if it tended to adopt a more aggressive profile. Hypoxia enhanced migration and pro-survival properties of MGHU-3 cells, whereas these features were reduced for the SW-780 cell line cultured under low oxygen tension. The responses of tested high-grade cell lines were more homogeneous and tended to adopt a less aggressive profile. Hypoxia drastically changed some of the bladder cancer cell line properties, for example matrix metalloproteinases expression for all cancer cells but also switch in glycolytic metabolism of low grade cancer cells. Overall, studying bladder cancer cells in hypoxic environments are relevant for the translation from in vitro findings to in vivo context.

Heat-Inactivation of Fetal and Newborn Sera Did Not Impair the Expansion and Scaffold Engineering Potentials of Fibroblasts.

Heat inactivation of bovine sera is routinely performed in cell culture laboratories. Nevertheless, it remains debatable whether it is still necessary due to the improvement of the production process of bovine sera. Do the benefits balance the loss of many proteins, such as hormones and growth factors, that are very useful for cell culture? This is even truer in the case of tissue engineering, the processes of which is often very demanding. This balance is examined here, from nine populations of fibroblasts originating from three different organs, by comparing the capacity of adhesion and proliferation of cells, their metabolism, and the capacity to produce the stroma; their histological appearance, thickness, and mechanical properties were also evaluated. Overall, serum inactivation does not appear to provide a significant benefit.

Bisphenol A Alters the Energy Metabolism of Stromal Cells and Could Promote Bladder Cancer Progression.

Bisphenol A (BPA) is an endocrine-disrupting molecule used in plastics. Through its release in food and the environment, BPA can be found in humans and is mostly excreted in urine. The bladder is therefore continuously exposed to this compound. BPA can bind to multiple cell receptors involved in proliferation, migration and invasion pathways, and exposure to BPA is associated with cancer progression. Considering the physiological concentrations of BPA in urine, we tested the effect of nanomolar concentrations of BPA on the metabolism of bladder fibroblasts and cancer-associated fibroblasts (CAFs). Our results show that BPA led to a decreased metabolism in fibroblasts, which could alter the extracellular matrix. Furthermore, CAF induction triggered a metabolic switch, similar to the Warburg effect described in cancer cells. Additionally, we demonstrated that nanomolar concentrations of BPA could exacerbate this metabolic switch observed in CAFs via an increased glycolytic metabolism, leading to greater acidification of the extracellular environment. These findings suggest that chronic exposure to BPA could promote cancer progression through an alteration of the metabolism of stromal cells.

Endocrine-disrupting effects of bisphenols on urological cancers.

Bisphenols are endocrine-disrupting chemicals found in a broad range of products that can modulate hormonal signalling pathways and various other biological functions. These compounds can bind steroid receptors, e.g. estrogen and androgen receptors, expressed by numerous cells and tissues, including the prostate and the bladder, with the potential to alter their homeostasis and normal physiological functions. In the past years, exposure to bisphenols was linked to cancer progression and metastasis. As such, recent pieces of evidence suggest that endocrine-disrupting chemicals can lead to the development of prostate cancer. Moreover, bisphenols are found in the urine of the wide majority of the population. They could potentially affect the bladder's normal physiology and cancer development, even if the bladder is not recognized as a hormone-sensitive tissue. This review will focus on prostate and bladder malignancies, two urological cancers that share standard carcinogenic processes. The description of the underlying mechanisms involved in cell toxicity, and the possible roles of bisphenols in the development of prostate and bladder cancer, could help establish the putative roles of bisphenols on public health.

Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing.

Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human patients. Innovative models became essential to develop more accurate knowledge. Tissue engineering provides some of those models, but it mostly relies on the use of prefabricated scaffolds on which cells are seeded. The self-assembly protocol has recently produced organ-specific human-derived three-dimensional models without the need for exogenous material. This strategy will help to achieve the 3R principles.

Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases.

Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1ß, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer-induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1-knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate-induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti-IL-1 therapies for pain management in patients with chronic inflammatory diseases.

Double anticholinergic therapy for refractory neurogenic and nonneurogenic detrusor overactivity in children: Long-term results of a prospective open-label study.

INTRODUCTION: In this study, we optimize pharmacotherapy in children who failed anticholinergic monotherapy by simultaneous administration of 2 anticholinergics (oxybutynin and/or tolterodine and/or solifenacin). METHODS: This report is an update of our previously published study on double anticholinergic regimen in children with refractory incontinence due to neurogenic (NDO) and non-neurogenic (DO) detrusor overactivity. Patients with an insufficient response (clinically/urodynamically) to an optimized dose of a single anticholinergic (oxybutynin or tolterodine) received a second anticholinergic (tolterodine or solifenacin), in addition to the pre-existing medication. The primary end-point was efficacy (continence) and the secondary end-points were tolerability and safety. The Patient Perception of Bladder Condition (PPBC) scale was used to rate subjective improvement of patients. RESULTS: In total, 56 patients with DO (n = 31) or NDO (n = 25) were enrolled at a mean age of 11.4 ± 3.5 years and were followed for a minimum of 3 months. The duration of double treatment was 36 ± 23 months. Our results found that 23 patients became dry, 18 improved significantly and 15 improved moderately. Urodynamic capacity improved from 158 ± 87 mL to 359 ± 148 mL and maximal pressure of contractions decreased from 76 ± 24 to 22 ± 22 cmH2O (p < 0.0001). The overall success rate was 82%, since 10 patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 28 patients, mild side effects by 20, moderate side effects by 8; 2 patients withdrew from the study due to their side effects. Of the 35 patients who voided spontaneously, 8 developed post-void residuals (>20%). CONCLUSIONS: With a larger cohort and prospective follow-up, we reiterated that double anticholinergic regimen in children with DO or NDO refractory to anticholinergic monotherapy is a feasible and efficient approach.

Long-term use of solifenacin in pediatric patients with overactive bladder: Extension of a prospective open-label study.

INTRODUCTION: We evaluate the efficacy and safety of solifenacin to treat incontinence in children with non-neurogenic (DO) or neurogenic detrusor overactivity (NDO) refractory to oxybutinin or tolterodine. METHODS: We updated and extended our previously published non-randomized uncontrolled study on open-label use of adjusted-dose regimens of solifenacin (1.25-10 mg) in children with refractory incontinence. The follow-up included voiding diaries, post-void residuals, urine cultures, ultrasounds and urodynamic studies. Clinical data were updated as of September 2012. Subjective improvement was assessed with the Patient Perception of Bladder Condition (PPBC) scale. The primary end point was efficacy toward continence and secondary end points were tolerability and safety. RESULTS: Overall, 244 patients (112 girls, 132 boys) were enrolled; 53 with NDO and 191 with DO. Minimal follow-up was 5 months, the mean duration of treatment was 21.0 months and the mean age at initiation was 9.2 years. Urodynamic capacity improved from 145 ± 76 mL to 339 ± 152 mL and the amplitude of uninhibited contractions decreased from 66 ± 26 to 20 ± 20 cmH2O (p < 0.0001). The overall success rate is 91%, and more specifically 94% for non-neurogenic and 79% for neurogenic, which is significantly different (p = 0.013). Twenty-three patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 175 patients, mild by 46, moderate by 9, and 14 withdrew due to their side effects. Ten patients developed post-void residuals of ≥20 mL. CONCLUSION: Although higher in the non-neurogenic group, high subjective and objective success rates were maintained over a longer follow-up with an adjusted-dose regimen of solifenacin to treat pediatric NDO or DO refractory to oxybutynin or tolterodine. Moreover, we found acceptable tolerability and safety profiles.