DNA adduct formation and persistence in rat tissues following exposure to the mammary carcinogen dibenzo[a,l]pyrene.
Dibenzo[a,l]pyrene (DBP), an environmentally significant polycyclic aromatic hydrocarbon (PAH), is one of the most potent carcinogens with greater carcinogenicity in rodent mammary glands and skin than 7,12-dimethylbenz[a]anthracene or benzo[a]pyrene, respectively. In this study, we have examined the formation and persistence of stable DNA adducts in rats administered a carcinogenic intramammillary (i.m.) dose of DBP (0.25 micromol/gland). 32P-post-labeling analysis of mammary epithelial DNA 6 h, and 2, 5 and 14 days post-treatment produced one major (approximately 30%) and at least six minor adducts. Non-target tissue DNA (lung, heart, bladder and pancreas) also showed essentially the same adduct pattern as did mammary DNA, except liver which resulted in four additional adduct spots. The mammary DNA was most adducted (2640 +/- 532 adducts/10(9) nucleotides) on day 5 while the other tissue DNAs had 10- to 65-fold lower adduct levels (lung > liver > heart > bladder > pancreas). Adduct levels continued to increase at all time points examined for all tissues, except mammary tissue which showed a decline ( approximately 40%) on day 14. Chromatographic comparison with adducts formed in vitro by reaction of syn- and anti-DBP-11, 12-diol-13,14-epoxides (DBPDEs) with DNA and individual nucleotides indicated that the in vivo adducts were deoxyadenosine- and deoxyguanosine-derived, formed by interaction with both the anti- and syn-isomers; the adenine-derived adducts comprised 60-75% of the total adducts. However, the liver-specific DNA adducts (nos 8-11) were not derived from any of the DBPDE isomers. Our data show: (i) significantly higher DBP-DNA adduction in mammary tissue as compared with non-target tissues, which is consistent with its mammary carcinogenicity; (ii) adenine is highly reactive towards DBP metabolites as has been observed for many other PAHs; and (iii) the peak binding of DBP with DNA was shifted beyond 14 days for the non-target tissues by i.m. route of exposure.
Arif
J M
JM
Department of Preventive Medicine and Environmental Health and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536, USA.
Smith
W A
WA
Gupta
R C
RC
D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley
D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D019363:Cytochrome P-450 CYP1A1; C041517:dibenzo(a,l)pyrene