The effect of fluoride on the structure, function, and proteome of intestinal epithelia

• Published in: Environmental toxicology Vol. 33; no. 1; pp. 63 - 71
• Main Authors: Amadeu de Oliveira, Flávia, MacVinish, Lesley J., Amin, Simran, Herath, Duleni, Jeggle, Pia, Mela, Ioanna, Pieri, Maria, Sharma, Chetanya, Jarvis, Gavin E., Levy, Flávia M., Santesso, Mariana R., Khan, Zohaib N., Leite, Aline L., Oliveira, Rodrigo C., Buzalaf, Marília A. R., Edwardson, J. Michael
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2018
• Subjects: Abnormalities; Animals; atomic force microscopy; Caco-2 Cells; Cell adhesion; Cell Adhesion - drug effects; cell stiffness; Chlorides; Chlorides - metabolism; Drinking water; Elastic Modulus - drug effects; Electron microscopy; epithelial ion transport; Epithelium; Exposure; fluoride; Fluorides; Fluorides - pharmacology; Forskolin; gastrointestinal epithelia; Humans; Imaging techniques; Immunofluorescence; Intestinal Mucosa - drug effects; Intestinal Mucosa - physiology; Intestine; Ion transport; Large intestine; Malformations; Mechanical properties; Mice; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Modulus of elasticity; Monolayers; Monomolecular films; Patch-Clamp Techniques; Proteins; Proteome - drug effects; Proteome - metabolism; proteomics; Rats; Scanning electron microscopy; Secretion; Small intestine; Structure-function relationships; fluoride; cell stiffness; proteomics; atomic force microscopy; epithelial ion transport; gastrointestinal epithelia
• ISSN: 1520-4081; 1522-7278
• DOI: 10.1002/tox.22495

Fluoride exposure is widespread, with drinking water commonly containing natural and artificially added sources of the ion. Ingested fluoride undergoes absorption across the gastric and intestinal epithelia. Previous studies have reported adverse gastrointestinal effects with high levels of fluoride exposure. Here, we examined the effects of fluoride on the transepithelial ion transport and resistance of three intestinal epithelia. We used the Caco‐2 cell line as a model of human intestinal epithelium, and rat and mouse colonic epithelia for purposes of comparison. Fluoride caused a concentration‐dependent decline in forskolin‐induced Cl– secretion and transepithelial resistance of Caco‐2 cell monolayers, with an IC50 for fluoride of about 3 mM for both parameters. In the presence of 5 mM fluoride, transepithelial resistance fell exponentially with time, with a t1/2 of about 7 hours. Subsequent imaging by immunofluorescence and scanning electron microscopy showed structural abnormalities in Caco‐2 cell monolayers exposed to fluoride. The Young's modulus of the epithelium was not affected by fluoride, although proteomic analysis revealed changes in expression of a number of proteins, particularly those involved in cell–cell adhesion. In line with its effects on Caco‐2 cell monolayers, fluoride, at 5 mM, also had profound effects on Cl– secretion and transepithelial resistance of both rat and mouse colonic epithelia. Our results show that treatment with fluoride has major effects on the structure, function, and proteome of intestinal epithelia, but only at concentrations considerably higher than those likely to be encountered in vivo, when much lower fluoride doses are normally ingested on a chronic basis.