DIBENZO(A,1)PYRENE--TUMOR INITIATION AND PROMOTION

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Dibenzo(a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons (pAH). Its very high carcinogenic activity in mouse skin is accompanied by an erythema unique among PAH. The time course of erythema is constant and dose-independent, although the intensity is dose-dependent, suggesting an immune induction. We propose that an adaptive immune response to specific DB[a,l]P diol epoxide-protein adducts produces delayed erythema and contributes significantly to epidermal hyperplasia. DB[a,l]P represents a unique model for studying (1) the mechanism of tumor initiation by determining the structure of DB[a,l]P-DNA adducts and their significance in tumor initiation, and (2) DB(a,l]P-induced inflammation as a critical factor in the process of tumor promotion. This will be achieved by accomplishing the following specific aims: (1) Complete the identification and quantitation of stable DNA adducts formed by DB[a,l]P in vitro by horseradish peroxidase (HRP) and 3- methylcholanthrene (MC)induced rat liver microsomes; (2) Identify and quantify the stable and depurinating DNA adducts formed by DB[a,l]P in vivo in mouse skin and rat mammary gland; (3) Identify and quantify the DB[a,l]P-DNA depurinating adducts excreted in the urine of rats treated with DB[a,l]P by intramammillary injection and mice treated topically with DB[a,l]P; (4) Determine whether the histological changes in skin observed on days 5-7 after treatment with DB[a,l]P are also observed on days 5-7 after treatment with DMBA, BP or 11-methylBP in a dose-response study; (5) Assess the contribution of DB[a,l]P-induced inflammation to the development of DB[a,l]P-induced tumors in mouse skin by determining the effects of dexamethasone treatment on inflammation and tumor production; and (6) Determine the contribution of serum complement and CD4+ T cells to the promotional activity of DB[a,l]P. Determination of the structure of DB[a,l]P-DNA adducts formed in vivo will indicate the DNA lesions involved in tumor initiation. The proposed studies of tumor promotion will take advantage of the constant and relatively short time course of histological events induced by a single dermal application of DB[a,l]P that are generally considered central to tumor promotion. These studies will determine (l) the degree to which other PAH carcinogens may induce the same histological changes, (2) the contribution of DB[a,l]P-induced inflammation to the carcinogenic potency of this PAH, (3) the relationship of observed histological events to tumor production and (4) the importance of two adaptive immune pathways leading to inflammation and epidermal hyperplasia to DB[a,l]P-induced tumor promotion.