Exposure to asphalt fumes activates activator protein-1 through the phosphatidylinositol 3-Kinase/Akt signaling pathway in mouse epidermal cells.
Ma-C; Wang-J; Luo-J
J Biol Chem 2003 Nov; 278(45):44265-44272
Occupational exposure to asphalt fumes may pose a health risk. Experimental studies using animal and in vitro models indicate that condensates from asphalt fumes are genotoxic and can promote skin tumorigenesis. Enhanced activity of activator protein-1 (AP-1) is frequently associated with the promotion of skin tumorigenesis. The current study investigated the effect of exposure to asphalt fumes on AP-1 activation in mouse JB6 P+ epidermal cells and the skin of transgenic mice expressing the AP-1 luciferase reporter gene. Asphalt fumes were generated from a dynamic generation system that simulated road-paving conditions. Exposure to asphalt fumes significantly increased AP-1 activity in JB6 P+ cells as well as in cultured keratinocytes isolated from transgenic mice expressing AP-1 reporter. In addition, topical application of asphalt fumes by painting the tail skin of mice increased AP-1 activity by 14-fold. Exposure to asphalt fumes promoted basal as well as epidermal growth factor-stimulated anchorage-independent growth of JB6 P+ cells in soft agar. It activated phosphatidylinositol 3-kinase and induced phosphorylation of Akt at Ser-473/Thr-308, and concurrently activated downstream p70 S6 kinase as well as glycogen synthase kinase-3. Asphalt fumes transiently activated c-Jun NH2-terminal kinases without affecting extracellular signal-regulated kinases and p38 mitogen-activated protein kinases. Further study indicated that blockage of phosphatidylinositol 3-kinase activation eliminated asphalt fume-stimulated AP-1 activation and formation of anchorage-independent colonies in soft agar. This is the first report showing that exposure to asphalt fumes can activate AP-1 and intracellular signaling that may promote skin tumorigenesis, thus providing important evidence on the potential involvement of exposure to asphalt fumes in skin carcinogenesis.
Laboratory-animals; Animal-studies; Animals; Asphalt-fumes; Cell-function; Cellular-reactions; Genes; Proteins; Exposure-assessment; Exposure-methods; Skin-disorders; Skin-exposure; Skin-tumors; Polycyclic-aromatic-hydrocarbons; Carcinogenesis; Tumorigenesis
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Science Center, Morgantown, WV 26506
75-09-2; 110-54-3; 120-12-7
Journal of Biological Chemistry