Arsenic exposure impairs intestinal stromal cells.

Arsenic is a toxicant commonly found in drinking water. Even though its main route of exposure is oral, little is known of the impact of in vivo arsenic exposure on small intestine. In vitro studies have shown that arsenic decreases differentiation of stem and progenitor cells in several different tissues. Thus, small intestinal organoids were used to assess if arsenic exposure would also impair intestinal stem cell differentiation. Unexpectedly, no changes in markers of differentiated epithelial cells were seen. However, exposing mice to 100 ppb arsenic in drinking water for 5 weeks impaired distinct populations of intestinal stromal cells. Arsenic reduced the width of the pericryptal lamina propria by 1.6-fold, and reduced Pdgfra mRNA expression, which is expressed in intestinal telocytes and trophocytes, by 4.2-fold. The height or extension of Pdgfra+ telopodes into the villus tip was also significantly reduced. Transcript expression of several other stromal cell markers, such as Grem1, Gli, CD81, were reduced by 1.9-, 2.3-, and 1.4-fold, respectively. Further, significant correlations exist between levels of Pdgfra and Gli1, Grem1, and Bmp4. Our results suggest arsenic impairs intestinal trophocytes and telocytes, leading to alterations in the Bmp signaling pathway.

Arsenic exposure in drinking water reduces Lgr5 and secretory cell marker gene expression in mouse intestines.

Arsenic is a global health concern that causes toxicity through ingestion of contaminated water and food. In vitro studies suggest that arsenic reduces stem and progenitor cell differentiation. Thus, this study determined if arsenic disrupted intestinal stem cell (ISC) differentiation, thereby altering the number, location, and/or function of intestinal epithelial cells. Adult male C57BL/6 mice were exposed to 0 or 100 ppb sodium arsenite (AsIII) through drinking water for 5 weeks. Duodenal sections were collected to assess changes in morphology, proliferation, and cell types. qPCR analysis revealed a 40% reduction in Lgr5 transcripts, an ISC marker, in the arsenic-exposed mice, although there were no changes in the protein expression of Olfm4. Secretory cell-specific transcript markers of Paneth (Defa1), Goblet (Tff3), and secretory transit amplifying (Math1) cells were reduced by 51%, 44%, and 30% respectively, in the arsenic-exposed mice, indicating significant impacts on the Wnt-dependent differentiation pathway. Further, protein levels of phosphorylated ß-catenin were reduced in the arsenic-exposed mice, which increased the expression of Wnt-dependent transcripts CD44 and c-myc. PCA analysis, followed by MANOVA and regression analyses, revealed significant changes and correlations between Lgr5 and the transit amplifying (TA) cell markers Math1 and Hes1, which are in the secretory cell pathway. Similar comparisons between Math1 and Defa1 show that terminal differentiation into Paneth cells is also reduced in the arsenic-exposed mice. The data suggests that ISCs are not lost following arsenic exposure, but rather, specific Wnt-dependent progenitor cell formation and terminal differentiation in the small intestine is reduced.