Inhibition of gap junctional intercellular communication by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat hepatocytes.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent rodent hepatic tumor promoter. Unlike observations with the majority of tumor promoting chemicals studied to date, most investigations have failed to demonstrate down-regulation of gap junctional intercellular communication (GJIC) in cultured cells by TCDD. The present study examined the effect of TCDD on GJIC in rat hepatocytes in primary culture. At non-cytolethal doses TCDD inhibited GJIC in a time- (1, 4, 24 and 48 h) and concentration (1 x 10(-8) - 1 x 10(-14) M)-dependent manner. This inhibition occurred within 4 h of treatment at doses of 1 x 10(-8) - 1 x 10(-12) M TCDD and persisted for up to 48 h, despite removal of TCDD. Treatment of rat hepatocytes with TCDD resulted in a decrease in hepatocyte connexin 32 mRNA, but had no apparent effect on connexin 26 mRNA. Co-incubation of rat hepatocytes with TCDD and alpha-napthoflavone abolished down-regulation of GJIC by TCDD. Similarly, co-treatment with a cAMP analog (8-bromoadenosine 3',5'-cyclic monophosphate) prevented down-regulation of GJIC by TCDD. The results of this investigation demonstrated, for the first time, that TCDD inhibits GJIC in the in vivo target of its tumor promoting effect and that this effect may, in part, be mediated through the Ah receptor. In addition, this study showed that inhibition of GJIC by TCDD may be due to transcriptional down-regulation or stability of the connexin 32 gap junction mRNA.
Baker
T K
TK
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202-5196, USA.
Kwiatkowski
A P
AP
Madhukar
B V
BV
Klaunig
J E
JE
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017630:Connexins / Q000096:biosynthesis; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D000097002:Gap Junction beta-1 Protein
D015124:8-Bromo Cyclic Adenosine Monophosphate; D002273:Carcinogens; D017630:Connexins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D000097002:Gap Junction beta-1 Protein