Dose‐ and time‐dependent expression of transforming growth factor‐β1 mRNA and protein in mouse epidermis and papillomas after repeated topical application of benzo[a]pyrene

Abstract

Topical weekly application of 64 μg of benzo[a]pyrene (BAP) for 4 wk induced transforming growth factor (TGF)-β1 mRNA in the epidermis of Swiss (ICR) mice, with a maximum at 6–12 h after the last treatment. The increase in TGF-β1 mRNA concentration was accompanied by an increase in immunohistochemically detectable intracellularly localized TGF-β1 protein in the suprabasal epidermis and by the appearance of extracellularly localized TGF-β1 in the basal layers. A dose rate of 16 μg/wk for 4 wk was unable to induce the same response. In contrast, after 20 weekly topical applications of 16 or 64 μg of BAP, an increase in TGF-β1 mRNA concentration and the appearance of extracellularly localized protein in the epidermis were observed. These changes in TGF-β1 expression were paralleled by changes in epidermal morphology. A similar group of animals treated with 4 μg of BAP/wk for 20 wk did not respond differently from untreated controls. Papillomas resulting from treatment with 16 or 64 μg of BAP/wk for 28 wk stained for intracellularly localized TGF-β1 predominantly in the differentiating and nondividing layers. Papillomas stained for extracellularly localized TGF-β1 solely in the less differentiated and dividing cells. These results suggest that tumorigenesis by BAP involves the induction of cumulative changes in epidermal TGF-β1 mRNA and protein concentrations as well as alterations in skin morphology associated with a tumor-promotion process.