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

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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.

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