Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, SC 29634, USA.
Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634, USA.
Toxicol Appl Pharmacol. 2021 Jul 1;422:115561. doi: 10.1016/j.taap.2021.115561. Epub 2021 May 3.
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 (As) 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 β-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.
砷是一种全球性的健康问题，通过摄入受污染的水和食物会引起毒性。体外研究表明，砷会减少干细胞和祖细胞的分化。因此，本研究旨在确定砷是否会破坏肠道干细胞（ISC）的分化，从而改变肠道上皮细胞的数量、位置和/或功能。成年雄性 C57BL/6 小鼠通过饮用水暴露于 0 或 100 ppb 亚砷酸钠（As）5 周。收集十二指肠切片以评估形态、增殖和细胞类型的变化。qPCR 分析显示，砷暴露组小鼠的 Lgr5 转录物减少了 40%，Lgr5 是一种 ISC 标志物，而 Olfm4 的蛋白表达没有变化。潘氏（Defa1）、杯状（Tff3）和分泌过渡扩增（Math1）细胞的特异性转录标志物分别减少了 51%、44%和 30%，表明对 Wnt 依赖性分化途径有显著影响。此外，砷暴露组小鼠的磷酸化 β-连环蛋白蛋白水平降低，增加了 Wnt 依赖性转录物 CD44 和 c-myc 的表达。PCA 分析后，MANOVA 和回归分析显示，Lgr5 与过渡扩增（TA）细胞标志物 Math1 和 Hes1 之间存在显著变化和相关性，这些标志物与分泌细胞途径有关。Math1 与 Defa1 之间的类似比较表明，砷暴露组小鼠的潘氏细胞终末分化也减少。数据表明，ISC 在砷暴露后并未丢失，而是小肠中特定的 Wnt 依赖性祖细胞形成和终末分化减少。
