Inhibition of Intercellular Communication by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like PCBs in Mouse Hepatoma Cells (Hepa1c1c7): Involvement of the Ah Receptor

L. H J Dehaan, J. W F A Simons, A. T. Bos, J. M M J G Aarts, M. S. Denison, A. Brouwer

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Abstract

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and the coplanar 3,3′,4,4′-tetrachlorobiphenyl (3,3′,4,4′-TCB) and 3,3′,4,4′,5,5′-hexachlorobiphenyl (3,3′,4,4′,5,5′-HCB) on intercellular communication (IC) were determined in order to investigate the in vitro tumor promoting potency of these compounds. 2,3,7,8-TCDD and the two coplanar PCBs tested caused a rapid (2 hr) and a sustained inhibition (48 hr) of IC in the mouse hepatoma cell line (Hepa1c1c7) to 20 and 50% of the unexposed control, respectively. Inhibition of IC was dose dependent with an EC50 range of about 50-100 pM for 2,3,7,8-TCDD, 2-5 nM for 3,3′,4,4′-TCB, and 10-15 nM for 3,3′,4,4′,5,5′-HCB, respectively. A comparison of the IC inhibitory effects of 2,3,7,8-TCDD and PCBs with a well-known aryl hydrocarbon receptor (AhR)-mediated response, the induction of ethoxyresorufin O-deethylase (EROD) activity, in the same cells revealed EROD induction by 2,3,7,8-TCDD, 3,3′,4,4′-TCB, and 3,3′,4,4′,5,5′-HCB with EC50 ranges of 100-200 pM, 20-70 nM, and 5-10 nM, respectively. The time course of IC inhibition was paralleled by EROD induction, although the time of onset of the response was earlier for IC (1 hr) than for EROD (2.5 hr). A role of the AhR in the inhibition of IC by 2,3,7,8-TCDD and PCBs was demonstrated by the lack of inhibition in AhR-defective Hepa1c1c7 cells. Transient inhibition of IC was observed in the mutant cells only at early time points (within 2 hr of exposure). These results and the observation that α-naphtoflavone (an AhR antagonist) greatly reduced the 2,3,7,8-TCDD-dependent sustained inhibition of IC strongly support a role of the AhR in the sustained inhibition of IC by these compounds. Furthermore, these data suggest that the mouse Hepa1c1c7 cells may be a good model in which to study in vitro tumor promoting capacity of dioxins, PCBs, and related compounds.

Original languageEnglish (US)
Pages (from-to)283-293
Number of pages11
JournalToxicology and Applied Pharmacology
Volume129
Issue number2
DOIs
StatePublished - Dec 1994

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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