2,3,7,8-Tetrachlorodibenzo-p-dioxin and ethinylestradiol as co-mitogens in cultured rat hepatocytes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts as a potent liver tumor promoter in female but not in male rats. As a basis for studying mechanisms of growth control by liver tumor promoters, the effects of TCDD, of two congeners and ethinylestradiol have been examined in primary cultures of hepatocytes. The agents alone were relatively ineffective but acted as co-mitogens when DNA synthesis was stimulated by epidermal growth factor (EGF). The co-mitogenic effect of TCDD was only observed in adult animals, which are less sensitive to EGF than juvenile animals. Similar effects were seen with two TCDD congeners (1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and octachlorodibenzo-p-dioxin) in the rank order of their affinity to the Ah receptor. The concentration maximum required for their co-mitogenic action (3 x 10(-12) M for TCDD) was lower than that required for enzyme induction. TCDD was not able to overcome the inhibitory action of TGF-beta (1 ng/ml). Ethinylestradiol additively or even synergistically increased the effect of TCDD. The results suggest: (i) co-mitogenic actions of TCDD and congeners are mediated by the Ah receptor. They are elicited at lower concentrations than those required for the induction of drug-metabolizing enzymes. (ii) Estrogens enhance the co-mitogenic actions of dioxins.