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THE K-REGION DIHYDRODIOL OF BENZO[A]PYRENE INDUCES DNA DAMAGE AND MORPHOLOGICAL CELL TRANSFORMATION IN C3H10T1/2CL8 MOUSE EMBRYO CELLS WITHOUT THE FORMATION OF DETECTABLE STABLE COVALENT DNA ADDUCTS
Citation:
Nesnow, S, C. R. Davis, G B. Nelson, G. Lambert, W. Padgett, M Pimentel, A H. Tennant, A D. Kligerman, AND J A. Ross. THE K-REGION DIHYDRODIOL OF BENZO[A]PYRENE INDUCES DNA DAMAGE AND MORPHOLOGICAL CELL TRANSFORMATION IN C3H10T1/2CL8 MOUSE EMBRYO CELLS WITHOUT THE FORMATION OF DETECTABLE STABLE COVALENT DNA ADDUCTS. Presented at AACR 2002, San Francisco, CA, April 6-10, 2002.
Description:
The K -region dihydrodiol ofbenzo[ a ]pyrene induces DNA damage and morphological cell transformation in C3HlOTY2CL8 mouse embryo cells without the formation of detectable stable covalent DNA adducts
Benzo[ a ]pyrene (B[ a ]P) is the most thoroughly studied polycyclic aromatic hydrocarbon (P AH) with regard to its occurrence, metabolism, toxicological and carcinogenic activities. Many mechanisms have been suggested to explain its carcinogenic activity, yet many questions still remain. K-region diols of PAHs are common metabolic intermediates and have been thought to e detoxification products. Here, we present evidence that the K-region diol, of B[a] , trans-B[a]P-4,5-diol, induced morphological cell transfonnation (MCT) in C3HlOTY2CL8 mouse embryo fibroblasts (C3H10TY2 cells). This diol also induced DNA damage in these cells, but did not form stable covalent DNA adducts. tran~.-B[a]P-4,5-diol and B[a]P induced MCT in C3H10TY2 cells by producing significant numbers of Type II and Type ill foci over concentration ranges of 1.8-10.5 J.lM, for tran.S"-B[a]P-4,5-diol, and 2.1-8.1 J.lM for B[a]P. The dose response curves for trans-B[a]P-4,5-diol and B[a]P were indistinguishable. Using experimental conditions and concentrations similar to those employed in the MCT studies, both trans- B[a]P-4,5-diol (8 and 10 J.lM) and B[a]P (1,4,8,10 J.lM) exhibited significant DNA
damaging activity (determined as comet tail content) compared to the control after 1 hr of treatment without significant concurrent cytotoxicity. Furthermore, the distributions of comet tail contents were altered in the trans-B[a]P-4,5-diol and B[a]P treatment groups compared to the controls. DNA adduct patterns in C3H10TY2 cells were examined after P AH treatment using 32p-postlabeling techniques and TLC elution systems designed to separate polar adducts. While B[ a ]P treatment produced one major DNA adduct identified as anti-trans-B[a]P- 7 ,8-diol-9,1 O-epoxide-dGuo, no stable covalent DNA adducts were detected in the DNA oftrans-B[a]P-4,5-diol-treated cells. In summary, this study provides evidence for the DNA damaging and morphological cell transforming activities of the K -region dihydrodiol of B[ a ]P , in the absence of covalent stable DNA adducts. In concert with the morphological cell transformation activities of other K- region dihydrodiols of PAHs, these data suggest a new mechanism/pathway for the bioactivation of PAHs. This abstract does not reflect EPA policy.