Heavy Metal-Laden Particulate Dust Alters Transcriptional Regulation in Human Colonoids

Abstract

Chronic heavy metals exposure in the southwestern United States co-occurs with greater incidences of metabolic and digestive diseases, particularly in the Indigenous and Hispanic populations. There is a need to understand how particulate heavy metals drive this dysbiotic state and propose a molecular explanation as a result of these exposures. Previously, our group demonstrated human colonoids to be a relevant model for investigating the physiological impact of environmental toxicants on the intestinal tract. The objective of this study is to elucidate the mechanism behind the transcriptional and cellular changes present in the intestinal epithelia upon acute exposure to non fissile uranium particulate dust. We hypothesize that non-fissile uranium exposure biases the differentiation of progenitor cells in the crypt to secretory roles through miRNA regulation. Colonoids were exposed (18 hours) to non-fissile uranium dust obtained from the Jackpile uranium mine, one of the largest open pit uranium mines, located on the Laguna Pueblo in New Mexico. Control and dust-exposed colonoids (n=3 unique donors) were digested into single cells and processed for droplet-based single cell sequencing (scRNAseq). Upon exposure, enteroendocrine cells (EEC) expanded >4 fold, along with increases in serotonin and PYY, as well as goblet cells (>3 fold) which indicates changes to the secretory lineage. Downstream pathway analysis found microRNAs miR-625-3p, miR-320a, miR-29b-3p to be differentially expressed. These results suggest that acute uranium dust exposure induces changes in differentiation pathways which are modulated by regulatory miRNAs. We would like to expand these findings by performing miRNA sequencing and comparing miRNA expression profiles between UBD exposed and control samples. Our results also provide an improved understanding of uranium dust’s impact on the gastrointestinal system, which may inform other physiological studies on the health of individuals exposed to heavy metals. This study was funded by K01DK106323, R56ES034400, P42ES025589, P20GM121176, P20GM130422, and AGA SURF. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.