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

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 commu nication (IC) were determined in order to investigate the in vitro tum or promoting potency of these compounds. 2,3,7,8-TCDD and the two copl anar 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 depend ent 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 c omparison of the IC inhibitory effects of 2,3,7,8-TCDD and PCBs with a well-known aryl hydrocarbon receptor (AhR)-mediated response, the ind uction of ethoxyresorufin O-deethylase (EROD) activity, in the same ce lls 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, re spectively. The time course of IC inhibition was paralleled by EROD in duction, 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 inhibitio n in AhR-defective Hepa1c1c7 cells. Transient inhibition of IC was obs erved in the mutant cells only at early time points (within 2 hr of ex posure). These results and the observation that alpha-naphtoflavone (a n 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 t hat the mouse Hepa1c1c7 cells may be a good model in which to study in vitro tumor promoting capacity of dioxins, PCBs, and related compound s. (C) 1994 Academic Press, Inc.