Abstract
Cadmium (Cd) is a toxic metal that enters the food chain. Following oral ingestion, the intestinal epithelium may in part protect against Cd toxicity but is also a target tissue. Using human enterocytic‐like Caco‐2 cells, we have previously shown differences in sensitivity to Cd according to the differentiation status. The present study focuses on Cd effects on differentiated cells. Concentration and time‐dependent increases in MTT (3‐[4,5‐dimethyl‐2‐thiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay) activity were observed in post‐confluent cultures exclusively, with a twofold maximal stimulation in 21‐day‐old cells exposed to 10 µM Cd for 24 h. No concomitant increase in [methyl‐^3^H] thymidine incorporation was noted and Cd did not modify cell distribution in the cell‐cycle phases. However, Cd‐induced increase in MTT activity was inhibited by cycloheximine as well as by inhibitors of ERK1/2 and p38, but not by that of JNK. Consistently, Cd increased the levels of ERK1/2 and p38 phosphorylation. Inhibition of Ras‐GTP or PI3K enhanced the stimulatory effect of Cd, whereas mTOR inhibition had no effect. Inhibition of G protein‐phospholipase and PKC decreased MTT stimulation. These results show a hormesis‐like stimulation of Cd on MTT activity in differentiated intestinal cells exclusively. This effect is not related to cell proliferation but more likely to increased protein synthesis which involves ERK1/2 and p38 cascades and possibly PLC‐β signaling pathways. Because growth‐related differentiation of intestinal cells is linked to the selective and sequential activation of MAPKs, the impacts that these Cd‐induced perturbations in signaling pathways may have on intestinal functions clearly deserve to be investigated. J. Cell. Physiol. 224:250–261, 2010 © 2010 Wiley‐Liss, Inc.