The aryl hydrocarbon receptor agonist ITE reduces inflammation and urinary dysfunction in a mouse model of autoimmune prostatitis.

OBJECTIVES: Prostate inflammation is linked to lower urinary tract dysfunction and is a key factor in chronic prostatitis/chronic pelvic pain syndrome. Autoimmunity was recently identified as a driver of prostate inflammation. Agonists of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, have been used to suppress autoimmunity in mouse models of colitis, rhinitis, and dermatitis, but whether AHR agonists suppress prostate autoimmunity has not been examined. Here, we test whether ITE (2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester), an AHR agonist, suppresses inflammation, allodynia, and urinary dysfunction in a mouse model of experimental autoimmune prostatitis (EAP). METHODS: C57BL/6J adult male mice were immunized with rat prostate antigen to induce EAP or TiterMax Gold® adjuvant (uninflamed control). Mice were also treated with ITE (10 mg/kg/day IP) or DMSO (vehicle, 5 mg/kg/day IP) for 6 days. Using the Nanostring nCounter Inflammation Panel, we evaluated the impact of EAP and ITE on prostatic RNA abundance. We validated EAP and ITE-mediated changes in a subset of RNAs by RT-PCR and RNAScope in situ RNA detection. RESULTS: EAP appeared to heighten histological inflammation in the dorsal prostate, induced tactile allodynia, and appeared to increase the frequency of non-voiding bladder contractions. ITE mitigated some actions of EAP. EAP changed abundance of 40 inflammation-related RNAs, while ITE changed abundance of 28 inflammation-related RNAs. We identified a cluster of RNAs for which ITE protected against EAP-induced changes in the abundance of H2-Ab1, S100a8, and S100a9. ITE also increased the abundance of the AHR-responsive Cyp1a1 RNA. CONCLUSIONS: These findings support the hypothesis that ITE activates the AHR in the prostate and reduces autoimmune-mediated prostatitis in mice.

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research.

Lower urinary tract dysfunction (LUTD) is nearly ubiquitous in men of advancing age and exerts substantial physical, mental, social, and financial costs to society. While a large body of research is focused on the molecular, genetic, and epigenetic underpinnings of the disease, little research has been dedicated to the influence of environmental chemicals on disease initiation, progression, or severity. Despite a few recent studies indicating a potential developmental origin of male LUTD linked to chemical exposures in the womb, it remains a grossly understudied endpoint in toxicology research. Therefore, we direct this review to toxicologists who are considering male LUTD as a new aspect of chemical toxicity studies. We focus on the LUTD disease process in men, as well as in the male mouse as a leading research model. To introduce the disease process, we describe the physiology of the male lower urinary tract and the cellular composition of lower urinary tract tissues. We discuss known and suspected mechanisms of male LUTD and examples of environmental chemicals acting through these mechanisms to contribute to LUTD. We also describe mouse models of LUTD and endpoints to diagnose, characterize, and quantify LUTD in men and mice.

An immunohistochemical prostate cell identification key indicates that aging shifts procollagen 1A1 production from myofibroblasts to fibroblasts in dogs prone to prostate-related urinary dysfunction.

BACKGROUND: The identity and spatial distribution of prostatic cell types has been determined in humans but not in dogs, even though aging- and prostate-related voiding disorders are common in both species and mechanistic factors, such as prostatic collagen accumulation, appear to be shared between species. In this publication we characterize the regional distribution of prostatic cell types in the young intact dog to enable comparisons with human and mice and we examine how the cellular source of procollagen 1A1 changes with age in intact male dogs. METHODS: A multichotomous decision tree involving sequential immunohistochemical stains was validated for use in dog and used to identify specific prostatic cell types and determine their distribution in the capsule, peripheral, periurethral and urethral regions of the young intact canine prostate. Prostatic cells identified using this technique include perivascular smooth muscle cells, pericytes, endothelial cells, luminal, intermediate, and basal epithelial cells, neuroendocrine cells, myofibroblasts, fibroblasts, fibrocytes, and other hematolymphoid cells. To enhance rigor and transparency, all high resolution images (representative images shown in the figures and biological replicates) are available through the GUDMAP database at https://doi.org/10.25548/16-WMM4. RESULTS: The prostatic peripheral region harbors the largest proportion of epithelial cells. Aging does not change the density of hematolymphoid cells, fibroblasts, and myofibroblasts in the peripheral region or in the fibromuscular capsule, regions where we previously observed aging- and androgen-mediated increases in prostatic collagen abundance Instead, we observed aging-related changes the procollagen 1A1 positive prostatic cell identity from a myofibroblast to a fibroblast. CONCLUSIONS: Hematolymphoid cells and myofibroblasts are often identified as sources of collagen in tissues prone to aging-related fibrosis. We show that these are not the likely sources of pathological collagen synthesis in older intact male dogs. Instead, we identify an aging-related shift in the prostatic cell type producing procollagen 1A1 that will help direct development of cell type and prostate appropriate therapeutics for collagen accumulation.