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Toxicology and applied pharmacology
07 01, 2021;422 115561.

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

Jordan T Jatko, Caitlin L Darling, Michael P Kellett, Lisa J Bain
Author Information
  1. Jordan T Jatko: Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, SC 29634, USA.
  2. Caitlin L Darling: Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634, USA.
  3. Michael P Kellett: Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634, USA.
  4. Lisa J Bain: 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. Electronic address: lbain@clemson.edu.
PMID: 33957193 DOI: 10.1016/j.taap.2021.115561

Abstract

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 ��-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.

Keywords

Arsenic Intestinal stem cell Intestine Lgr5 Wnt signaling

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Grants

  1. R15 ES031766/NIEHS NIH HHS

MeSH Term

Animals
Arsenites
Basic Helix-Loop-Helix Transcription Factors
Cell Differentiation
Down-Regulation
Duodenum
Male
Mice, Inbred C57BL
Paneth Cells
Receptors, G-Protein-Coupled
Sodium Compounds
Stem Cells
Trefoil Factor-3
Wnt Signaling Pathway
alpha-Defensins
Mice

Chemicals

Arsenites
Atoh1 protein, mouse
Basic Helix-Loop-Helix Transcription Factors
Lgr5 protein, mouse
Receptors, G-Protein-Coupled
Sodium Compounds
Tff3 protein, mouse
Trefoil Factor-3
alpha-Defensins
sodium arsenite
Journal Article Research Support, Non-U.S. Gov't

Word Cloud

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