Superfund Research Program
Mechanisms of Modulation of Gut Immunity by Ingested Uranium and Mixed Metal Exposures
- Project Summary
Project Summary (2022-2027)
This project 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 environmental and biologic projects in Metals Exposure and Toxicity Assessment on Tribal Lands in the Southwest, including BP Lung and BP Comm. BP Gut relies on the work of the Community Engagement Core (CEC) and the Data Management and Analysis Core (DMAC). An overall theme of the studies is understanding how exposures to metals present in or near mine sites in New Mexico might affect community members and lead to immunotoxicity. The researchers focus on soluble and particulate forms of uranium (U) and vanadium (V), given via oral routes of exposure, because multiple exposures to these types of mixed metals has been observed in their community partners. The project has 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.
Aim 1 is using mouse studies for 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 are being explored alone and in combination with other metals, including arsenic. Environmentally derived mine samples rich in carnotite are also being studied in mice. This project is screening 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 researchers are performing microbiome metagenomic analyses on the feces obtained from these mice and are screening the feces using a large metabolomic panel to determine possible pathways responsible for immune modulation.
For Aim 2, the toxicity of these same metals and mixtures is being examined on human colonic organoids obtained from normal human donors. Researchers are assessing the metabolic changes in these tissues following in vitro exposures, as well as 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 are being studied to understand mechanisms of barrier disruption.
For Aim 3, the team is working with the CEC and Biomarkers and Mechanisms of Metal and Mixed Metal Exposures to examine the stool samples from study participants in the community for metal exposure, changes in inflammatory biomarkers, microbiome metagenomics, and metabolomic profiles examined in Aims 1 and 2. These studies rely on statistical and mixed metal analyses developed by DMAC. The 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 is informing communities through the CEC on how to avoid exposures and also informing environmental projects (Transport and Bioavailability of U and Co-Occurring Metals in Nanoparticulate Matter on Tribal Lands Affected by Mining Legacy and Bioremediation by Integrating Plant-Fungi Symbiosis and Natural Minerals for Uptake of Metal Mixtures) on potential remediation of these sites.