2,3,7,8-Tetrachlorodibenzo-p-dioxin enhancement of N-methyl-N'-nitro-N-nitrosoguanidine-induced transformation of rat tracheal epithelial cells in culture.
The abilities of various dioxins to induce toxicity or transformation of rat tracheal epithelial cells in culture were examined. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was not cytotoxic and did not induce transformation as measured by the induction of growth-altered, preneoplastic cells (termed enhanced growth variants). However, TCDD enhanced the transformation of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated rat tracheal epithelial cells. Other dioxin congeners with 0 to 3 chloro substitutions were inactive in enhancing MNNG transformation. TCDD was most effective at a concentration of 0.3 nM and when treatment was administered immediately after MNNG exposure. The dose-response curves for enhancement of MNNG-induced transformation and induction of aryl hydrocarbon hydroxylase activity by TCDD were similar. These results are consistent with the hypothesis that the enhancement of cell transformation by TCDD is mediated through the TCDD receptor. TCDD also enhanced transformation when the cells were treated before MNNG treatment. The ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) to enhance MNNG-induced rat tracheal epithelial transformation was also examined. In contrast to the findings with TCDD, the number of transformed colonies was increased only by pretreatment with TPA followed by MNNG. TPA-pretreatment enhanced equally the number of normal cells forming colonies and the total number of transformed colonies after selection; therefore, the transformation frequency (transformants per total surviving colonies) was unchanged by TPA. In contrast, TCDD treatment enhanced the transformation frequency in MNNG-exposed cultures since the number of transformed colonies increased while the number of total colonies remained constant. Thus, TCDD appears to act by a different mechanism than TPA. TCDD enhancement of MNNG-induced transformation may be attributed to a promotional effect, a comutagenic action, or a modulation of cell proliferation and/or differentiation mediated through the TCDD receptor.
Tanaka
N
N
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Nettesheim
P
P
Gray
T
T
Nelson
K
K
Barrett
J C
JC
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D008297:Male; D008769:Methylnitronitrosoguanidine; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013755:Tetradecanoylphorbol Acetate; D014132:Trachea / Q000187:drug effects* / Q000473:pathology
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D008769:Methylnitronitrosoguanidine; D013755:Tetradecanoylphorbol Acetate