Inflammatory response of mouse skin exposed to the very potent carcinogen dibenzo[a,l]pyrene: a model for tumor promotion.
The potent carcinogenicity of dibenzo[a,l]pyrene in mouse skin is associated with an inflammation unique among polycyclic aromatic hydrocarbons and expressed as erythema. The time course of erythema and the associated histological events in the skin of female SENCAR mice were determined after a single application of 6.25-200 nmol dibenzo[a,l]pyrene or selected metabolites. Dibenzo[a,l]pyrene and dibenzo[a,l]pyrene-11,12-dihydrodiol, precursor to the bay-region diol epoxide, induced an erythema first present 5-6 days after treatment. Dibenzo[a,l]pyrene-8,9-dihydrodiol and other dibenzo[a, l]pyrene metabolites, however, did not induce erythema. These findings suggest a central role for the bay-region diol epoxide in the induction of the observed inflammation. The intensity and duration of erythema were dose-dependent, whereas the delayed appearance of erythema was constant and dose-independent. These results suggest induction of an immune hypersensitivity by dibenzo[a, l]pyrene and its 11,12-dihydrodiol. Histological changes in the skin were consistent with a contact hypersensitivity reaction and included, in association with erythema, epidermal hyperplasia and the presence of mononuclear leukocytes in the dermis. Animals were tested for dibenzo[a,l]pyrene-induced contact hypersensitivity. Female SENCAR mice were treated with a single dermal application of dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene. Five days later, the animals were challenged with a single application of dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene to the ear pinna. Ear swelling exhibited features of a contact hypersensitivity reaction, including (1) delayed appearance after challenge, (2) noninducibility in animals not previously exposed to chemical sensitizer, and (3) chemical specificity. The results suggest that dibenzo[a,l]pyrene induces, via its bay-region diol epoxide, a contact hypersensitivity reaction that may promote tumor development and thereby enhance carcinogenic potency.
Casale
G P
GP
Eppley Institute for Research in Cancer, Department of Pathology and Microbiology, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska 68198-6805, USA.
Higginbotham
S
S
Johansson
S L
SL
Rogan
E G
EG
Cavalieri
E L
EL
D000279:Administration, Cutaneous; D000818:Animals; D001580:Benzopyrenes / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D003877:Dermatitis, Contact / Q000209:etiology* / Q000473:pathology; D004101:Dihydroxydihydrobenzopyrenes / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004431:Ear, External / Q000187:drug effects / Q000276:immunology; D004487:Edema / Q000139:chemically induced / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D018632:Mice, Inbred SENCAR; D012680:Sensitivity and Specificity; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D001580:Benzopyrenes; D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; C071371:dibenzo(a,l)pyrene 11,12-dihydrodiol; C041517:dibenzo(a,l)pyrene