SYNERGISTIC CARCINOGENICTY OF UVA AND BENZO(A)PYRENE

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Sunlight exposure and polycyclic aromatic hydrocarbons (PAHs) have been implicated in human skin cancers. It is assumed that excess exposure to long wavelength ultraviolet A (UVA) combined with PAHs from cigarette smoking or environmental pollution may be associated with the alarmingly increased skin cancers. The central hypothesis of this proposal is that a wide-spread environmental pollutant benzo(a)pyrene (BaP) serves as a photosensitizer to generate reactive oxygen species (ROS) upon UVA inadiation. ROS preduced by BaP-UVA treatment induce oxidative DNA damage, enhance the BaP-DNA adduct fonnation (genetic effect) as well as activate the signal transduction cascades (epigenetic effects). Thus, combination of subcaminogenic BaP and UVA potentiates both initiating and promoting activities, and subsequently leads to synergistic carcinogenicity. To test the established hypothesis, four specific aims have been proposed. The initial aim is to determine if UVA and BaP synergistically enhance skin carcinogenesis. BaP will be topically applied to dorsal skin of hairless mice or orally administered, then followed by UVA irradiation. The latent period, tumor incidence and multiplicity will be recorded to evaluate the synergetic action. The second aim is to elucidate the mechanisms of synergistic action in vivo. We will determine if application of BaP potentiates the formation of oxidants, oxidized DNA bases and bulky DNA adducts, expression of protooncogenes, and mutation of ms oncogenes and p53 tumor suppressor genes in UVA-irradiated mouse skin and tumor tissues. The third aim is to characterize molecular mechanisms of synergetic action in vitro. Murine and human keratinocytes will be used to investigate the mechanisms by which BaP modulates UVA-induced oxidative DNA damage, phosphorylation of epidermal growth factor receptor and activation of tyrosine protein kinases and mitogen-activated protein kinases. Finally, we will examine if topical application of a SOD biomimetic inhibits oxidant generation, DNA oxidation as well as skin tumorigenicity by BaP-UVA. Intervention of BaP plus UVA-enhanced oxidative DNA damage and skin carcinogenesis will confirm the important role of ROS and help us elucidate the molecular mechanisms of synergetic action of long wavelength UV light and BaP.