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.

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 alpha-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.

• Authors: L H De Haan, J W Simons, A T Bos, J M Aarts, M S Denison, A Brouwer
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 129 Issue 2 Pg. 283-93 (Dec 1994) ISSN: 0041-008X [Print] United States
• PMID: 7992318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon
• Cytochrome P-450 Enzyme System
• Polychlorinated Biphenyls
• Oxidoreductases
• Cytochrome P-450 CYP1A1
• 3,4,5,3',4',5'-hexachlorobiphenyl
• 3,4,3',4'-tetrachlorobiphenyl

Topics

• Animals
• Carcinogens (toxicity)
• Cell Communication (drug effects)
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 Enzyme System (metabolism)
• Dose-Response Relationship, Drug
• Liver Neoplasms, Experimental (metabolism, physiopathology)
• Mice
• Mice, Inbred C57BL
• Oxidoreductases (metabolism)
• Polychlorinated Biphenyls (toxicity)
• Polychlorinated Dibenzodioxins (toxicity)
• Receptors, Aryl Hydrocarbon (drug effects)
• Time Factors
• Tumor Cells, Cultured