Effects of cadmium chloride on the paracellular barrier function of intestinal epithelial cell lines.
In the present study we characterized the functional and structural disruption of the paracellular barrier of intestinal epithelium in vitro in relation to cytotoxicity after apical Cd2+ exposure. For that purpose filter-grown Caco-2 and IEC-18 cells were apically exposed to 5 to 100 microM CdCl2 for 4 or 14 h. It was found that the effects of Cd2+ on the epithelial barrier were concentration- and time-dependent. The first detected effects of Cd2+ in Caco-2 cells after 4 h exposure were a decrease in transepithelial electrical resistance, increased permeabilities of mannitol and PEG-4000, and changes in intercellular localization of ZO-1, occludin, and e-cadherin. The effects were far more pronounced after prolonged exposure. The disruption of the paracellular barrier by 5 to 30 microM Cd2+ was detected without a significant loss of viability of the Caco-2 cells. In the IEC-18 cells, Cd2+ concentrations affecting the barrier (50 and 100 microM) also affected cell viability. In both cell lines the effects on the cell layers continued to develop after removal of extracellular Cd2+. This correlated with the cellular retention of Cd2+, which was high for the 12 h following 4 h accumulation. This study showed that the decreased epithelial barrier function of intestinal epithelial cells is accompanied by tight junction disruption. It is concluded that Cd2+ causes increased paracellular permeability by disruption of junctional function and structure. The initial junctional effects of Cd2+ suggest that Cd2+ increases its own bioavailability by causing disruption of the intestinal paracellular barrier.
Toxicology Division, TNO Nutrition and Food Research Institute, AJ Zeist, 3700, The Netherlands.
E
E
Duizer
A J
AJ
Gilde
C H
CH
Versantvoort
J P
JP
Groten
D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D019256:Cadmium Chloride / Q000493:pharmacokinetics / Q000633:toxicity*; D002106:Cadmium Radioisotopes; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007408:Intestinal Absorption / Q000187:drug effects*; D008353:Mannitol / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000493:pharmacokinetics; D062793:Occludin; D010750:Phosphoproteins / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects; D062826:Zonula Occludens-1 Protein
D015820:Cadherins; D002106:Cadmium Radioisotopes; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D008353:Mannitol; D011092:Polyethylene Glycols; D019256:Cadmium Chloride