Time-dependent Inhibition by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of Skin Tumorigenesis with Polycyclic Hydrocarbons1

The effects of treating female mice with single topical doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at various times before and after 7,12-dimethylbenz(a)anthracene (DMBA), benzo(a)pyrene, 3-methylcholanthrene (MCA), and (±)-trans7/S,8«-dihydroxy-9a,10a-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene were studied. TCDD, at doses of 1 /ig/mouse, was applied topically 3 days prior to, 5 min prior to, or 1 day after the initiator. The application of TCDD 5 min prior to or 1 day after initiation with DMBA, benzo(a)pyrene, or MCA had little or no effect on papilloma formation. In contrast, when TCDD was applied 3 days prior to initiation with these hydrocarbons, a marked reduction in papilloma formation was observed. TCDD, applied 3 days prior to, 5 min prior to, or 1 day after initiation with (±)-frans-7/?,8«-dihydroxy-9a,10a-epoxy7,8,9,10-tetrahydrobenzo(a)pyrene produced 81, 50, and 39% inhibition of papilloma formation after 20 weeks of pro motion. Similar effects were observed when higher initiating doses of DMBA and the diol-epoxide were utilized. In addition, single i.p. doses of TCDD (1 /xg/mouse) 3 days prior to initiation with DMBA or MCA were highly effective at inhibiting papilloma formation. Several congeners of TCDD, lacking, possessing similar, or possessing different inducing properties, were tested for their effects on tumor initiation by DMBA. 3,4,3',4'-Tetrachlorobiphenyl effectively inhibited tumor initiation by DMBA, whereas 2,7-dichlorodibenzo-p-dioxin and 2,4,5,2',4',5'-hexachlorobiphenyl had little or no effect on the tumor response. Topical application of TCDD at the doses utilized in the tumor experiments markedly induced epidermal aryl hydrocarbon hydroxylase (21-fold) 3 days after treatment. In addition, epi dermal uridine diphosphoglucuronyltransferase activities were stimulated 2to 3-fold 3 days following TCDD treatment. TCDD treatment had little or no effect on epidermal epoxide hydrase or glutathione-S-transferase activities. The time course for induction of epidermal aryl hydrocarbon hydroxylase and uri dine diphosphoglucuronyltransferase correlated with the time course for the inhibitory effects of TCDD on tumor initiation with DMBA, benzo(a)pyrene, and MCA.