MODULATING EFFECTS OF 2,3,7,8- TETRACHLORODIBENZO-P-DIOXIN ON SKIN CARCINOGENESIS INITIATED BY THE WEAK INDUCER 7,12-DIMETHYLBENZ(A)ANTHRACENE

Abstract

The effects of topical pretreatment of CF1-Swiss mice with TCDD on the carcinogenesis induced by DMBA were studied. We also determined the intrinsic features of DMBA as an aryl hydrocarbon hydroxylase (AHH) inducer through either its binding ability to Ah receptor or its inducing effects on benzo(a)pyrene (BP) hydroxylase or DMBA hydroxylase. DMBA is a poor ligand of the Ah receptor (26-fold and 4.3-fold weaker than 3-methylcholanthrene and BP respectively) and a very weak AHH inducer (ten million-fold weaker than TCDD). Nevertheless, DMBA induces a specific isozyme of cytochrome P-450 1A1 since, for an equal dose administered to C57BL/6 mice (200 mg/kg body weight), the DMBA-hydroxylase activity was 1.72-fold increased by DMBA while it remained unchanged after BP treatment. In contrast, the BP-hydroxylase activity was 1.91-fold increased by BP and only 1.47-fold by DMBA. A dose-dependent relationship exists between the increasing dose of TCDD (from 0.001 to 1 microg per mouse) applied to mouse skin and the induction of AHH activity of skin microsomes (from 1 to 60-fold increase). For carcinogenesis experiments, mice were either untreated or pretreated with single different doses of TCDD and, after 24h, DMBA (10 or 25 microg per mouse) was applied to the skin. The average number of papillomas per mouse was dependent on 1) the dose of DMBA and 2) the metabolic capacity of the skin. For 10 microg DMBA, the TCDD only exerts an anticarcinogenic effect (from 5.5 to 0.6 tumor per mouse) whereas for 25 microg DMBA, TCDD exerts a dual effect: first, a cocarcinogenic effect (from 6.2 to 9 and 11.5 tumors per mouse for 0.001 and 0.01 microg TCDD respectively) then an anticarcinogenic effect (2.3 and 1.5 tumors per mouse for 0.1 and 1 microg TCDD respectively). The discussion underlines the decisive importance of two factors: 1) the effective dose of the ultimate carcinogen in contact with cellular targets during a sensitive step of the cell cycle and 2) the time-persistence of a high steady state level of the carcinogen.