Keil Stietz Kimberly P, Kennedy Conner L, Sethi Sunjay, Valenzuela Anthony, Nunez Alexandra, Wang Kathy, Wang Zunyi, Wang Peiqing, Spiegelhoff Audrey, Puschner Birgit, Bjorling Dale E, Lein Pamela J
Department of Molecular Biosciences, University of California-Davis, School of Veterinary Medicine, Davis, CA, USA.
Department of Comparative Biosciences, University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI, USA.
Curr Res Toxicol. 2021;2:1-18. doi: 10.1016/j.crtox.2021.01.002. Epub 2021 Jan 12.
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 βIII-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.
膀胱功能障碍，包括尿失禁、膀胱排空困难或尿急，是一个普遍存在的健康和生活质量问题。然而，导致这些症状的风险因素尚未完全明确，而且环境化学物质暴露，尤其是在发育过程中的暴露，对膀胱形成和功能的影响研究较少。已知多氯联苯（PCBs）等环境污染物会对发育中的大脑构成风险；然而，它们对膀胱等外周靶器官发育的影响尚不清楚。为了填补这一数据空白，从交配前两周开始，至妊娠和哺乳期，将C57Bl/6J小鼠母鼠每天暴露于0、0.1、1或6mg/kg与环境相关的多氯联苯混合物中。在出生后第28 - 31天收集子代小鼠的膀胱。在膀胱中检测到的多氯联苯浓度呈剂量依赖性。多氯联苯对膀胱的影响具有性别和剂量依赖性。总体而言，在雄性而非雌性膀胱中观察到了多氯联苯的影响。与溶剂对照组相比，多氯联苯增加了膀胱体积和膀胱上皮下βIII - 微管蛋白阳性神经密度。与最低多氯联苯剂量组相比，暴露于最高多氯联苯剂量的小鼠中，降钙素基因相关蛋白（CGRP）阳性神经纤维增加，表明这些神经中的一部分是感觉肽能轴突。多氯联苯诱导的神经密度增加也与膀胱中肥大细胞数量呈正相关，提示可能涉及炎症。如裂解的半胱天冬酶3的表达所示，上皮组成或凋亡没有可检测到的变化，表明多氯联苯不会引起明显的毒性。膀胱体积变化并未伴随膀胱质量或上皮厚度的变化，表明不太可能涉及梗阻。总之，这些结果首次表明，发育暴露后，多氯联苯可分布至膀胱并改变雄性小鼠的神经解剖发育和膀胱体积。
