Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction

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PROJECT SUMMARY Clinical management of urinary disorders costs Americans over four billion dollars annually, demanding a better understanding of risk factors that underlie or contribute to these disorders. We provide compelling evidence for a new paradigm that a man's fetal andneonatal environment determines his risk of developing urinary complications of benign prostatic disease in adulthood. The proposed studies offer needed insight into disease pathogenesis, incidence, and why some men develop urinary complications of benign prostate hyperplasia (BPH) at a younger age or with more severe symptoms than others. Our preliminary results show in utero and lactational (IUL) exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) causes severe urinary dysfunction in mice susceptible to BPH. TCDD is a widespread contaminant, ubiquitous in serum of American men, and a selective activator of the aryl hydrocarbon receptor (AHR), a receptor that can be activated by many persistent organic pollutants. We isolated two potential mechanisms by which IUL TCDD exposure impairs urinary function: by increasing sensory nerve fibers during lower urinary tract development and by enhancing estrogen receptor signaling. We also discovered that age of mice at the time of TCDD exposure determines the impact on mouse urinary function. Adult TCDD exposure has the opposite effect of IUL exposure - it protects against urinary dysfunction in mice susceptible to urinary complications of BPH. These findings create a remarkable opportunity to test whether AHR activation in the prostate and lower urinary tract of adult males is therapeutic for urinary dysfunction. We synthesized novel selective AHR modulators (SAHRMs), verified their potency in vitro, and will perform pre-clinical testing in vivo. This proposal's three specific aims will test the following hypotheses: (1) IUL TCDD exposure increases the number of sensory nerve fibers in the prostate and prostatic urethra, having a lasting effect on urinary function, (2) IUL TCDD exposure impairs urinary function through a mechanism requiring stromal estrogen receptor-alpha (ERα), and (3) the impact of TCDD exposure on urinary function differs depending on when exposure occurs, perinatal period versus adulthood. As part of aim 3, we will also test the hypothesis that adult exposure to SAHRMs, which lack TCDD-like toxicity, offers therapeutic benefit by reducing urinary dysfunction in BPH susceptible mice. By establishing a mechanistic connection between TCDD exposure and urinary function, the proposed studies launch original lines of research into a disease process never before linked to developmental origins or AHR signaling. We also expect to reveal the AHR as a new therapeutic target for treating urinary complications of BPH, a disease against which current drugs are only marginally effective.