Role of estrogen receptor beta in polychlorinated biphenyls impacts on bladder function - PROJECT SUMMARY Lower urinary tract symptoms (LUTS) pose a significant healthcare and quality of life burden. Therapeutic strategies mainly target symptom improvement, primarily because underlying cause(s) are not well understood. The complex etiology of LUTS may include exposure to environmental chemicals such as polychlorinated biphenyls (PCBs), persistent organic pollutants that are ubiquitous in the environment and still unintentionally produced despite worldwide bans. Since PCBs consist of different structural variants in varying proportions in the environment and in people, we use a human-relevant PCB mixture known as MARBLES PCBs which mirrors the most abundant PCB congeners and their relative concentrations as measured from the blood serum of pregnant women in the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) cohort. PCBs can be endocrine disruptors, including directly binding to estrogen receptors and inducing estrogen receptor mediated gene transcription, but if and how PCBs influence bladder function is understudied. We previously demonstrated that MARBLES PCBs exposure in mice causes augmented urinary voiding physiology and bladder contractility. Study of PCBs’ mechanism(s) of action to perturb urinary voiding function is still ongoing, but preliminary data suggests that increased big potassium (BK) channel expression in the detrusor smooth muscle cells contributes to the observed voiding changes. Therefore, since literature supports the individual actions that PCBs can bind to and activate ERβ, ERβ agonism can increase BK channel expression, and increased BK channel expression in urinary bladder smooth muscle can impact urinary voiding physiology, I hypothesize that in utero and lactational exposure to human-relevant PCBs directly act upon ERβ which alters urinary voiding function via increased big potassium (BK) channel expression in mice at 6 weeks of age. We will address the hypothesis by characterizing MARBLES PCB’s ability to induced gene transcription of estrogen receptor beta in vitro. Then, in vivo utilizing control genotype and ERβ knockout mice, we will developmentally expose mice to vehicle control or the MARBLES PCB mixture. We will test developmental MARBLES PCB exposure’s effects on BK channel expression, bladder contractility, and urinary voiding physiology, and also elucidate ERβ’s role in affecting PCB adverse outcomes. Our studies will have far-reaching effects on elucidating the molecular mechanism of how human-relevant PCBs impact bladder function and disrupt steroid hormone action. It is of great importance for human health to understand the etiology of these complex pathologies and identify targets for pharmacological interventions. And more broadly, this proposal highlights how the intersection on toxicology, urology, and endocrinology can result in basic research that has wide outcomes for human health benefits.
