NF-kB Mediated Inflammatory Changes inthe Gut and Microbiome by PCB 153

项目摘要/摘要 多氯联苯(PCbs)是一种普遍存在的持久性有机污染物，对人类健康造成不利影响 健康。尽管多氯联苯的工业生产已经停止，但它们仍然是一个紧迫的环境问题。 问题是它们的生物降解速度慢，亲油性高。这些特性使多氯联苯能够生物积累 在食物链中，导致生物体中的高组织水平，对人类消费至关重要。一旦进入身体， 多氯联苯在不同的器官中积聚，导致转录因子NF-кB的炎症和激活。 核因子-кB是炎症的驱动力，并与多种疾病有关，如炎症性肠病 疾病、癌症和糖尿病。尽管饮食暴露是接触多氯联苯的主要途径，但人类 在研究多氯联苯的促炎作用时，胃肠道一直被广泛忽视。这是一个 由于肠上皮细胞(IECS)同时暴露于 炎症影响肠道微生物区系，后者也受到多氯联苯的影响。的功能后果 多氯联苯对微生物群的影响也有待研究。这是非常重要的信息 微生物群的影响。拟议的研究将询问多氯联苯、IECS和 微生物区系，特别关注PCB153(最普遍的 环境)发挥其作用。已有研究表明，接触PCB153会导致肠道疾病增加 通透性以及大肠炎症的迹象和微生物组的变化。我假设 PCB153通过基因毒性激活PCB153引起肠道炎症和增加肠道通透性 核因子-кB和创建促炎肠道微生物群。为了询问这一点，《特定目标1》将查看 PCB153在体外和体内对IECS的特异性作用。肠上皮细胞系与灵知生素 小鼠，完全缺乏微生物组的小鼠，将被用来确定NF-кB的激活程度和机制 在没有微生物组的情况下由PCB153产生。拟议机制的专用性将通过以下方式确定 一种核因子-кB的化学抑制剂。特异靶2将确定PCB153‘S效应对 微生物群。暴露在多氯联苯中的微生物将被移植到灵知菌小鼠体内，然后用 一种促炎剂。他们的炎症水平将与移植的小鼠进行比较 多氯联苯-幼稚的微生物群揭示了多氯联苯暴露的微生物群对 主持人。这些研究将确定核因子-кB在炎症和通透性改变中的重要性 我的PCB153在肠子里。重要的是，他们将能够就联合国的不同角色得出明确的结论。 微生物区系和IECS。这些知识将为人类描绘新的研究路线和潜在的治疗方法 以及其他暴露在有机污染物中的生物。

Project Summary/Abstract Polychlorinated biphenyls (PCBs) are ubiquitous and persistent organic pollutants that adversely affect human health. Although industrial production of PCBs has been discontinued, they remain a pressing environmental problem due to their slow biodegradation and high lipophilicity. These properties enable PCBs to bio-accumulate in food chains leading to high tissue levels in organism important for human consumption. Once in the body, PCBs accumulates in various organs leading to inflammation and activation of the transcription factor NF-кB. NF-кB is a driver of inflammation and has been linked to a multitude of diseases such as inflammatory bowel disease, cancer and diabetes. Despite dietary exposure being the main route of exposure to PCBs, the human gastrointestinal tract has been widely ignored when studying the pro-inflammatory effects of PCBs. This is a significant oversight given that the intestinal epithelial cells (IECs) are simultaneously exposed to the inflammatory effects the gut microbiota, which are also affected by the PCBs. The functional consequences of PCBs effects on the microbiome have also yet to be studied. This is vital information given the widespread influence of the microbiome. The proposed studies will interrogate interaction between PCBs, IECs, and the microbiota with particular focus on the mechanism by which PCB153 (the most prevalent PCB in the environment) exerts its effects. Exposure to PCB153 has been shown to lead to an increased intestinal permeability along with signs of gross intestinal inflammation and changes in the microbiome. I hypothesize that PCB153 causes intestinal inflammation and increases gut permeability via genotoxic activation of NF-кB and the creation of a pro-inflammatory gut microbiome. To interrogate this, specific aim 1 will look at the effects of PCB153 specifically on the IECs, both in vitro and in vivo. Intestinal cell lines along with gnotobiotic mice, mice entirely lacking a microbiome, will be used to determine the extent and mechanism of NF-кB activation by PCB153 in the absence of the microbiome. Specificity to the proposed mechanism will be established using a chemical inhibitor of NF-кB. Specific aim 2 will determine the functional consequences of PCB153's effect on the microbiome. PCB-exposed microbiomes will be transplanted into gnotobiotic mice and then challenged with a pro-inflammatory agent. Their levels of inflammation will be compared with those of mice transplanted with PCB-naïve microbiomes shedding light on the pro-inflammatory effects of the PCB-exposed microbiome on the host. These studies will establish the importance of NF-кB in the inflammatory and permeability changes caused my PCB153 in the gut. Importantly, they will be able to draw clear conclusions about the distinct roles of the microbiota and IECs. This knowledge, will depict new routes of investigation and potential therapies for humans and other organisms exposed to organic pollutants.