Dose- and time-dependent expression of transforming growth factor-beta 1 mRNA and protein in mouse epidermis and papillomas after repeated topical application of benzo[a]pyrene.
Topical weekly application of 64 micrograms of benzo[a]pyrene (BAP) for 4 wk induced transforming growth factor (TGF)-beta 1 mRNA in the epidermis of Swiss (ICR) mice, with a maximum at 6-12 h after the last treatment. The increase in TGF-beta 1 mRNA concentration was accompanied by an increase in immunohistochemically detectable intracellularly localized TGF-beta 1 protein in the suprabasal epidermis and by the appearance of extracellularly localized TGF-beta 1 in the basal layers. A dose rate of 16 micrograms/wk for 4 wk was unable to induce the same response. In contrast, after 20 weekly topical applications of 16 or 64 micrograms of BAP, an increase in TGF-beta 1 mRNA concentration and the appearance of extracellularly localized protein in the epidermis were observed. These changes in TGF-beta 1 expression were paralleled by changes in epidermal morphology. A similar group of animals treated with 4 micrograms of BAP/wk for 20 wk did not respond differently from untreated controls. Papillomas resulting from treatment with 16 or 64 micrograms of BAP/wk for 28 wk stained for intracellularly localized TGF-beta 1 predominantly in the differentiating and nondividing layers. Papillomas stained for extracellularly localized TGF-beta 1 solely in the less differentiated and dividing cells. These results suggest that tumorigenesis by BAP involves the induction of cumulative changes in epidermal TGF-beta 1 mRNA and protein concentrations as well as alterations in skin morphology associated with a tumor-promotion process.
Sherman
J H
JH
Department of Environmental Health, University of Cincinnatti College of Medicine, Ohio 45267-0056.
Miller
M L
ML
Albert
R E
RE
Baxter
C S
CS
D000287:Administration, Topical; D000818:Animals; D001564:Benzo(a)pyrene; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D008813:Mice, Inbred ICR; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010212:Papilloma / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D012879:Skin Physiological Phenomena; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001564:Benzo(a)pyrene