Mechanisms of Modulation of Gut Immunity by Ingested Uranium and Mixed Metal Exposures

生物项目-肠道(BP GURT)主要研究金属在胃肠道中诱导免疫毒性的机制 (Git)在使用小鼠和人类细胞和组织的一系列研究中。BP的肠子高度 与所有SRP金属环境和生物项目相结合，包括英国石油公司和英国石油公司。BP GUT依赖于CEC和DMAC的工作。这些研究的一个总主题是理解如何 新墨西哥州矿场内或附近存在的金属可能会使社区成员接触到导致 免疫毒性。我们主要关注通过口服途径给出的可溶的和颗粒状的铀(U)和钒(V) 暴露的可能性，因为在我们的社区中已经观察到多次接触这些类型的混合金属 合伙人。我们之前已经在阶段1中表明，小鼠口服(45d)饮用水暴露于U铅 到高暴露于Git导致小鼠和大鼠的淋巴组织和上皮细胞发生显著变化 肠子。在SA1中，小鼠研究将探索暴露于铀酰后的体内、体外和体外研究 醋酸盐(UA，可溶)和柠檬酸铀(UCit，不溶纳米材料)，原钒酸钠(Na3VO4， V2O4(不溶)和V2O4(不溶)。这些金属将单独勘探，并与 其他金属，包括砷。富含角闪石的环境衍生矿样也将在#年进行研究。 老鼠。我们将筛选小肠和大肠片段中的mRNA变化，重点是细胞因子、氧化 应激和芳香烃受体(AhR)途径。这些研究的另一个新方面是 我们将对这些小鼠的粪便进行微生物组元基因组分析，并进行筛选 排泄物使用大的代谢组来确定可能的免疫途径 调制。在SA2中，我们将检测这些相同的金属和混合物对人类结肠的毒性 从正常的人类捐献者身上获得的有机化合物。我们将评估这些组织在以下方面的代谢变化 体外暴露，我们将评估使用有机物和人类的上皮屏障功能的变化 结肠细胞系。血管内皮细胞跨上皮电阻、mRNA和蛋白表达的变化 将研究膜紧密连接分子，以了解屏障破坏的机制。在SA3中， 我们将与CEC和BP Comm合作，检查来自社区研究参与者的粪便样本 对于金属暴露，炎性生物标志物、微生物组元基因组学和代谢组学的变化 已在SA1和SA2中进行检查。这些研究将依靠由开发的统计和混合金属分析 德马克。这些研究的最终目标是解决社区对接触混合污染物的关注。 来自废弃铀矿和其他硬金属矿的金属导致潜在的免疫变化 和疾病。这些研究的数据将通过CEC向社区提供如何避免暴露和 向环境项目(ESE PM、ESE Remed)通报这些场地的潜在补救措施。

BioProject- Gut (BP Gut) focuses on mechanisms of metal-induced immunotoxicity in the gastrointestinal tract (GIT) of mice and humans in a series of studies using mouse and human cells and tissues. BP Gut is highly integrated with all SRP METALS environmental and biologic projects, including BP Lung and BP Comm. BP Gut relies on the work of the CEC and the DMAC. An overall theme of the studies is the understanding of how metals present in or near mine sites in New Mexico might expose community members leading to immunotoxicity. We focus on soluble and particulate forms uranium (U), and vanadium (V) given via oral routes of exposure, because multiple exposures to these types of mixed metals has been observed in our community partners. We have previously shown during Phase 1 that oral (45d) drinking water exposure of mice to U leads to high exposures of GIT leading to significant changes in lymphoid and epithelial cells in the small and large intestines. In SA1, mouse studies will explore in vivo, ex vivo, and in vitro studies following exposures to uranyl acetate (UA, soluble) and uranium citrate (UCit, insoluble nanomaterial), sodium orthovanadate (Na3VO4, soluble) and vanadium oxide (V2O4, insoluble). These metals will be explored alone and in combination with other metals, including arsenic. Environmentally derived mine samples rich in carnotite will also be studied in mice. We will screen for mRNA changes in small and large intestinal snips focusing on cytokines, oxidative stress, and aromatic hydrocarbon receptor (AhR) pathways. An additional novel aspect of these studies is that we will perform microbiome metagenomic analyses on the feces obtained from these mice, and we will screen the feces using a large metabolomic panel to determine possible pathways responsible for immune modulation. In SA2, we will examine the toxicity of these same metals and mixtures on human colonic organoids obtained from normal human donors. We will assess metabolic changes in these tissues following in vitro exposures and we will assess changes in epithelial barrier function using both organoids and human colonic cell lines. Changes in transepithelial electrical resistances, mRNA and protein expression for membrane tight junction molecules will be studied to understand mechanisms of barrier disruption. In SA3, working with the CEC and BP Comm, we will examine stool samples from study participants in the community for metal exposure, changes in inflammatory biomarkers, microbiome metagenomics, and metabolomic profiles examined in SA1 and SA2. These studies will rely on statistical and mixed metal analyses developed by DMAC. The ultimate goal of these studies is to address community concerns regarding exposure to mixed metals from abandoned uranium mines and other hard metal mines leading to potential immunologic changes and diseases. Data from these studies will inform communities through CEC on how to avoid exposures and inform environmental projects (ESE PM, ESE Remed) on potential remediation of these sites.