Impact of developmental polychlorinated biphenyls on bladder contractility

Lower urinary tract symptoms (LUTS) impose a significant healthcare burden and reduce quality of life. This is especially true in individuals with Autism Spectrum Disorder (ASD) who experience LUTS as a comorbidity. Existing therapies largely just treat symptoms because LUTS etiology is not fully understood and likely multifactorial. Developmental exposure to environmental toxicants

alone or in combination with genetic susceptibilities can influence disease progression in other organs; whether this paradigm is true for LUTS is unknown. Our goal is to fill this gap by examining how environmental factors negatively impact Ca2+ dependent bladder contractility pathways. Polychlorinated biphenyls (PCBs), can disrupt Ca2+ signaling pathways in brain and we have

shown that developmental PCB exposure leads to an overactive bladder phenotype in young adult mice. Here we propose to test the hypothesis that developmental exposure to PCBs increases bladder contractility leading to overactive voiding symptoms in part by upregulating BK channel regulatory subunits. BK channels (large conductance calcium- and voltage-activated K+

channel, KCNM) are important for dampening bladder contractions but their efficiency can be altered by regulatory subunits. Our central hypothesis is supported by key pieces of preliminary data. Bladders from adult mice developmentally exposed to PCBs are more sensitive to contractile stimuli, and have increased expression of two BK channel regulatory subunits that can

slow BK channel activity. Mutations in BK channels have been linked to ASD, and mice completely lacking BK channels display bladder overactivity phenotypes. Whether PCBs converge on these channels to confer heightened LUTS risk alone or in relation to ASD is unknown. The following aims are designed to examine this gene x environment interaction and further expand

understanding of mechanisms by which PCBs alter bladder contractility. We will test our hypothesis in three aims. The first testing whether in utero and lactational PCB exposure leads to changes in bladder contractility via pre-junctional and post-junctional mechanisms. The second testing whether BK channel regulatory subunits mediate PCB effects on contractility and that a

pharmacological BK channel opener can ameliorate abnormal voiding phenotypes. The third testing whether gene x environment interactions relevant to ASD and LUTS may converge on BK channel activity. For these aims we will use genetic mouse models as well as in vivo and ex vivo tissue bath applications to determine voiding function/bladder contractility which will allow us to

understand the mechanisms driving PCB induced changes in contractility and whether pharmacological intervention to open BK channels mitigates PCB effects on contractility.