Effect of chronic exposure to inorganic arsenic on intestinal cells

J Appl Toxicol. 2019 Jun;39(6):899-907. doi: 10.1002/jat.3778. Epub 2019 Feb 12.

Abstract

Chronic exposure to inorganic arsenic (As)-As(III) + As(V)-is associated with type 2 diabetes, vascular diseases and various types of cancer. Although the oral route is the main way of exposure to inorganic As, the adverse gastrointestinal effects produced by chronic exposure are not well documented. The aim of the present study is to evaluate the effect of chronic exposure to As(III) on the intestinal epithelium. For this purpose, NCM460 cells, non-transformed epithelial cells from the human colon, were exposed to As(III) (0.01-0.2 mg/L) for 6 months and monitored for acquisition of a tumor-like phenotype. Secretion of matrix metalloproteinases, histone modifications (H3 acetylation), hyperproliferation capacity, formation of floating spheres, anchorage-independent growth, release of cytokine interleukin-8 and expression of relevant genes in colon tumorigenesis were assessed. The results show a maintained proinflammatory response from the beginning, with an increase in interleukin-8 secretion (≤570%). Downregulation of CDX1 and CDX2 was also observed. After 14 weeks of exposure, cells presented marked increases in matrix metalloproteinase-2 secretion and histone modifications. As(III)-treated cells were hyperproliferative, grew in low-serum media and were able to form free-floating spheres. Overall, these data suggest that exposure of human colon epithelial cells to As(III) facilitates acquisition of transformed cell characteristics.

Keywords: arsenite; cellular transformation; inflammation; inorganic arsenic; intestinal epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / genetics
  • Arsenic / toxicity*
  • CDX2 Transcription Factor / genetics
  • Cell Line
  • Cell Proliferation / drug effects
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Humans
  • Interleukin-8 / metabolism
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Matrix Metalloproteinase 2 / analysis

Substances

  • AC133 Antigen
  • CDX1 protein, human
  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Histones
  • Homeodomain Proteins
  • Interleukin-8
  • PROM1 protein, human
  • Matrix Metalloproteinase 2
  • Arsenic