Contribution of obesity-environment interaction in bladder dysfunction

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Lower urinary tract symptoms (LUTS) such as urgency and frequent urination (overactive bladder) impose a significant healthcare burden and reduce quality of life. Factors which contribute to onset and severity of symptoms are not completely understood but are likely multifactorial, therefore we propose to lead new efforts in understanding interactions which may contribute to LUTS. In other organs, developmental exposures to environmental toxicants alone or in combination with a second stressor can influence disease progression later in life. Obesity is also a risk factor for many diseases including overactive bladder. Whether an obesity-environmental interaction paradigm exists for LUTS is unknown but could be a new risk factor for urinary disease. Here we propose to test the hypothesis that developmental exposure to polychlorinated biphenyls (PCBs) exacerbates urinary dysfunction when mice are later challenged with a common second stressor, diet induced obesity. Our preliminary data indicate that developmental exposure to environmental toxicants, polychlorinated biphenyls (PCBs), in mice, leads to small, more frequent voids as young adults. Other studies have shown that obesity is linked to bladder dysfunction, with high fat diets linked to small more frequent voids in rodents. Preliminary data indicate that developmental exposure to PCBs or a high fat diet alone increase F4/80+ macrophages in female bladder. Our expected results are that combined exposure to PCBs and high fat diet together will exacerbate increased voiding frequency. We also hypothesize that bladder inflammation, specifically increased macrophages, are a convergent target for both hits thus expected results are that combined exposure will lead to increased number of macrophages in bladder compared to either hit alone. Whether macrophages are the major inflammatory mediator and whether elevated macrophage numbers result from bladder resident macrophages or infiltrating monocytes which differentiate into macrophages is unknown but of potential clinical relevance since therapeutic approaches to block infiltrating monocytes could be employed. We will test our hypothesis in three aims. The first testing whether developmental PCB exposure combined with a high fat diet in adulthood increases voiding frequency and decreases voided urine volume in mice compared to either stressor alone. The second testing whether developmental PCB exposure combined with a high fat diet exacerbates bladder inflammation by increasing the abundance of infiltrating monocytes which differentiate into macrophages. The third testing whether infiltrating monocytes contribute to PCB or high fat diet induced voiding dysfunction.