Polychlorinated biphenyl (PCB) exposure in adult female mice can influence bladder contractility.

Lower urinary tract symptoms (LUTS) greatly reduce quality of life. While LUTS etiology is not completely understood, it is plausible that environmental contaminants could play a role. Polychlorinated biphenyls (PCBs), are a group of persistent environmental toxicants frequently documented in animal and human tissues. PCBs are capable of influencing voiding function in mouse offspring exposed developmentally, however whether PCB exposure during adulthood can also influence voiding dynamics is unknown. Therefore, the purpose of this study was to determine whether PCB exposure in adult female mice can impact voiding function. As part of a larger study to generate developmentally exposed offspring, adult female C57Bl/6J mice were dosed orally with the MARBLES PCB mixture (0.1, 1, or 6 mg/kg/day) or vehicle control beginning two weeks before mating and throughout gestation and lactation (9 weeks). Adult dosed female dams then underwent void spot assay, uroflowmetry, and anesthetized cystometry to assess voiding function. Bladder contractility was assessed in ex vivo bladder bath assays, and bladders were collected for morphology and histology assessments. While voiding behavior endpoints were minimally impacted, alterations to bladder contractility dynamics were more pronounced. Adult female mice dosed with 1 mg/kg/d PCB showed an increase in urine spots 2-3 cm2 in size, increased bladder contractility in response to electrical field stimulation, and decreased bladder wall thickness compared to vehicle control. PCBs also altered contractile response to cholinergic agonist in a dose-dependent manner. Overall, these results indicate that exposure to PCBs in adult female mice is sufficient to produce changes in bladder physiology. These results also highlight the critical role of timing of exposure in influencing voiding function.

Polychlorinated Biphenyls (PCBs) Impact Prostatic Collagen Density and Bladder Volume in Young Adult Mice Exposed during in Utero and Lactational Development.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants linked to deleterious health outcomes, including voiding dysfunction in developmentally exposed mice. Changes in prostate volume and/or extracellular matrix composition are associated with voiding dysfunction in men and animal models. Whether PCB-induced changes in voiding function in male mice occur in part via alterations to the prostate or an alternate mechanism is unclear. Therefore, we tested whether developmental exposure to the MARBLES PCB mixture altered prostate morphology in young adult offspring. C57Bl/6J female mice were dosed daily with the MARBLES PCB mixture at 0, 0.1, 1 or 6 mg/kg/d for two weeks prior to mating and through gestation and lactation, offspring were collected at 6 weeks of age. Ventral prostate mass was decreased in the 1 mg/kg/d PCB group compared to other PCB groups. There were no PCB-induced changes in prostate smooth muscle thickness, apoptosis, proliferation, or testes mass. PCBs impacted the prostate extracellular matrix; anterior prostate collagen density was decreased in the 1 mg/kg/d PCB group compared to all other groups. Normalized bladder volume was increased in male and female offspring in the 6 mg/kg/d PCB group compared to control. No change in water consumption, bladder mass or bladder smooth muscle thickness accompanied changes in bladder volume. Urine and serum creatinine concentrations were elevated but only in male mice. Together, these results suggest that developmental exposure to PCBs can influence prostate wet weight and prostate/bladder morphology, but PCBs do not promote prostate enlargement. Whether these changes persist throughout adult life and how they contribute to voiding function in animal models and humans is of future interest.

Developmental polychlorinated biphenyl (PCB) exposure alters voiding physiology in young adult male and female mice.

The impact of developmental exposure to environmental chemicals on lower urinary tract function is not well understood, despite the fact that these chemicals could contribute to etiologically complex lower urinary tract symptoms (LUTS). Polychlorinated biphenyls (PCBs) are environmental toxicants known to be detrimental to the central nervous system, but their impact on voiding function in mouse models is not known. Therefore, we test whether developmental exposure to PCBs is capable of altering voiding physiology in young adult mice. C57Bl/6J female mice received a daily oral dose of the MARBLES PCB mixture for two weeks prior to mating and through gestation and lactation. The mixture mimics the profile of PCBs found in a contemporary population of pregnant women. Voiding function was then tested in young adult offspring using void spot assay, uroflowmetry and anesthetized cystometry. PCB effects were sex and dose dependent. Overall, PCBs led to increases in small size urine spots in both sexes with males producing more drop-like voids and greater peak pressure during a voiding cycle while females displayed decreases in void duration and intervoid interval. Together, these results indicate that developmental exposure to PCBs are capable of altering voiding physiology in young adult mice. Further work to identify the underlying mechanisms driving these changes may help develop more effective preventative or therapeutic strategies for LUTS.

In utero and lactational PCB exposure drives anatomic changes in the juvenile mouse bladder.

Bladder dysfunction, including incontinence, difficulty emptying the bladder, or urgency to urinate is a pervasive health and quality of life concern. However, risk factors for developing these symptoms are not completely understood, and the influence of exposure to environmental chemicals, especially during development, on the formation and function of the bladder is understudied. Environmental contaminants such as polychlorinated biphenyls (PCBs) are known to pose a risk to the developing brain; however, their influence on the development of peripheral target organs, such as bladder, are unknown. To address this data gap, C57Bl/6J mouse dams were exposed to an environmentally-relevant PCB mixture at 0, 0.1, 1 or 6 mg/kg daily beginning two weeks prior to mating and continuing through gestation and lactation. Bladders were collected from offspring at postnatal days (P) 28-31. PCB concentrations were detected in bladders in a dose-dependent manner. PCB effects on the bladder were sex- and dose-dependent. Overall, PCB effects were observed in male, but not female, bladders. PCBs increased bladder volume and suburothelial ßIII-tubulin-positive nerve density compared to vehicle control. A subset of these nerves were sensory peptidergic axons indicated by increased calcitonin gene-related protein (CGRP) positive nerve fibers in mice exposed to the highest PCB dose compared to the lowest PCB dose. PCB-induced increased nerve density was also positively correlated with the number of mast cells in the bladder, suggesting inflammation may be involved. There were no detectable changes in epithelial composition or apoptosis as indicated by expression of cleaved caspase 3, suggesting PCBs do not cause overt toxicity. Bladder volume changes were not accompanied by changes in bladder mass or epithelial thickness, indicating that obstruction was not likely involved. Together, these results are the first to suggest that following developmental exposure, PCBs can distribute to the bladder and alter neuroanatomic development and bladder volume in male mice.

The Bladder Is a Novel Target of Developmental Polychlorinated Biphenyl Exposure Linked to Increased Inflammatory Cells in the Bladder of Young Mice.

Bladder inflammation is associated with several lower urinary tract symptoms that greatly reduce quality of life, yet contributing factors are not completely understood. Environmental chemicals are plausible mediators of inflammatory reactions within the bladder. Here, we examine whether developmental exposure to polychlorinated biphenyls (PCBs) leads to changes in immune cells within the bladder of young mice. Female mice were exposed to an environmentally relevant mixture of PCBs through gestation and lactation, and bladders were collected from offspring at postnatal day (P) 28-31. We identify several dose- and sex-dependent PCB effects in the bladder. The lowest concentration of PCB (0.1 mg/kg/d) increased CD45+ hematolymphoid immune cells in both sexes. While PCBs had no effect on CD79b+ B cells or CD3+ T cells, PCBs (0.1 mg/kg/d) did increase F4/80+ macrophages particularly in female bladder. Collagen density was also examined to determine whether inflammatory events coincide with changes in the stromal extracellular matrix. PCBs (0.1 mg/kg/d) decreased collagen density in female bladder compared to control. PCBs also increased the number of cells undergoing cell division predominantly in male bladder. These results implicate perturbations to the immune system in relation to PCB effects on the bladder. Future study to define the underlying mechanisms could help understand how environmental factors can be risk factors for lower urinary tract symptoms.