The combination of benzo[a]pyrene and ultraviolet A causes an in vivo time-related accumulation of DNA damage in mouse skin.
Polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are ubiquitous environmental carcinogens. BaP is metabolized in vivo to reactive intermediates that become covalently bound to DNA and form BaP-DNA adducts, an initial event in carcinogenesis. Ultraviolet A (UVA) synergizes with BaP to significantly enhance genetic damage and accelerate carcinogenic processes. This study was initiated to investigate in vivo cellular changes related to carcinogenesis induced by repeated exposures to BaP plus UVA. Simulated chronic exposure to an environmental carcinogen and sunlight was conducted through biweekly topical application of BaP followed 2 h later by UVA exposure over a 10 week period. BaP diol epoxide (BPDE)-DNA adducts were measured in vivo by immunohistochemistry using an anti-BPDE-DNA monoclonal antibody. Oxidative DNA damage was measured by the detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation using high-performance liquid chromatography. Alterations in the cell cycle that were relevant to carcinogenesis were revealed by changes in p53, as identified in vivo using a polyclonal anti-p53 antibody. We found that cells containing BPDE-DNA adducts and nuclear p53 expression significantly increased between 2 and 10 weeks of BaP-UVA treatment, whereas neither BPDE-DNA adducts nor significant changes in p53 were observed in untreated skin. Using regression analysis, oxidative 8-OHdG damage also showed a parallel increase over 2-10 weeks (r = 0.80). These results indicate that genetic damage caused by exposures to BaP plus UVA accumulates with time and increases the potential for inductive events leading to carcinogenesis and tumor formation.
Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Rao
R
Saladi
Lisa
L
Austin
Dayuan
D
Gao
Yuhun
Y
Lu
Robert
R
Phelps
Mark
M
Lebwohl
Huachen
H
Wei
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D051379:Mice; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014466:Ultraviolet Rays
D001564:Benzo(a)pyrene