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Issue 6, 2015
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Cadmium interference with ERK1/2 and AhR signaling without evidence for cross-talk

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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 that Cd may induce a concentration and time-dependent increase in MTT (3-[4,5-dimethyl-2-thiazol-2-yl]-2,5-diphenyltetrazolium bromide assay) activity in differentiated cultures exclusively. This effect was insensitive to estrogen antagonist, and it was not related to cell proliferation but to enhanced protein synthesis that involves ERK1/2 activation. Because some studies have suggested cross-talk between AhR and ERK signaling pathways we have hypothesized that Cd may indirectly lead to AhR activation. Western blot analysis and immunofluorescence data show that: (i) contrary to Cd and insulin, dioxin (TCDD) or benzo[a]pyrene did not increase ERK phosphorylation; (ii) TCDD and Cd both increased the nuclear translocation of AhR; (iii) TCDD but not Cd or insulin increased CYP450 1A1/2 expression; (iv) there was no correlation between phospho-ERK and AhR activation. In conclusion, the Cd-induced hormesis-like effect on MTT activity in the Caco-2 cells is a differentiation stage-specific phenomenon that is not observed with xenobiotics acting as AhR ligands. ERK phosphorylation is not a prerequisite to AhR activation and it does not necessarily lead to AhR activation. Cd does not stimulate the transcriptional activity of AhR but it favors its nuclear translocation which may have an impact on cell's sensitivity to AhR activators.

Graphical abstract: Cadmium interference with ERK1/2 and AhR signaling without evidence for cross-talk

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Publication details

The article was received on 12 Aug 2015, accepted on 03 Sep 2015 and first published on 07 Sep 2015

Article type: Paper
DOI: 10.1039/C5TX00284B
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Citation: Toxicol. Res., 2015,4, 1488-1497

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    Cadmium interference with ERK1/2 and AhR signaling without evidence for cross-talk

    C. Gebraël and C. Jumarie, Toxicol. Res., 2015, 4, 1488
    DOI: 10.1039/C5TX00284B

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