# Impact of developmental polychlorinated biphenyls on bladder contractility

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $372,100

## Abstract

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.

## Key facts

- **NIH application ID:** 10802747
- **Project number:** 1R01ES035020-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Kimberly Preston Keil Stietz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,100
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802747

## Citation

> US National Institutes of Health, RePORTER application 10802747, Impact of developmental polychlorinated biphenyls on bladder contractility (1R01ES035020-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10802747. Licensed CC0.

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