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MORPHOLOGICAL CELL TRANSFORMATION OF C3H10T1/2CL8 MOUSE EMBRYO CELLS BY THE K-REGION DIHYDRODIOL OF BENZO[A]PYRENE OCCURS IN COINCIDENCE WITH DNA DAMAGE, BUT 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. MORPHOLOGICAL CELL TRANSFORMATION OF C3H10T1/2CL8 MOUSE EMBRYO CELLS BY THE K-REGION DIHYDRODIOL OF BENZO[A]PYRENE OCCURS IN COINCIDENCE WITH DNA DAMAGE, BUT WITHOUT THE FORMATION OF DETECTABLE STABLE COVALENT DNA ADDUCTS. Presented at Society of Toxicology 41st annual meeting, Nashville, TN, 03/17-21/2002.
Description:
Abstract:
Benzo[a]pyrene (B[a]P) has been the most thoroughly studied polycyclic aromatic hydrocarbon (PAH). 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 be detoxification products. Here, we present evidence that the K-region diol of B[a]P, B[a]P-4,5-diol, induced morphological cell transformation (MCT) in C3H10T1/8C18 mouse embryo fibroblasts (C3H10T1/8 cells). This diol also induced DNA damage in these cells but did not form stable covalent DNA adducts. B[a]P-4,5-diol and B[a]P induced MCT in C3H10T1/8 cells by producing significant numbers of Type II and Type III foci over a concentration range of 1.8-10.5 uM for B[ a ]P-4,5-diol, and 2.1-8.1 uM for B [a]P. The dose-response curves for B[a]P-4,5-diol and B[a]P were indistinguishable. Both B[a]P-4,5-diol (8 and 10 uM) and B[a]P (1,4,8,10 uM) exhibited significant DNA damaging activity as determined by the comet assay after 1 hr of treatment without significant concurrent cytotoxicity. Furthermore, the distributions of comet tail contents were altered in the B[a]P- 4,5-diol and B[a]P treatment groups compared to the controls. DNA adduct patterns in C3Hl OT1/8 cells were examined after P AH treatment using 32p- postlabeling techniques and TLC elution systems designed for polar adducts. While B[a]P treatment produced one major DNA adduct identified as B[a]P- DE-dGuo, no stable covalent DNA adducts were detected in the DNA ofB[a] P-4,5-diol-treated cells. In summary, this study provides evidence for the DNA damaging and MCT activities of the K-region diol ofB[a]P in the absence of covalent stable DNA adducts. In concert with the reported MCT activities of K-region diols of other PARs, these data suggest a new mechanism/pathway for the bioactivation of PAHs.
This abstract does not necessarily reflect EPA policy.
Abstract: Benzo[a]pyrene (B[a]P) has been the most thoroughly studied polycyclic aromatic hydrocarbon (P AH). Many mechanisms have been suggested to
explain its carcinogenic activity, yet many questions still remain. K-region
diols of P AHs are common metabolic intermediates and have been thought to
be detoxification products. Here, we present evidence that the K-region diol of B[a]P, B[a]P-4,5-diol, induced morphological cell transformation (MCT) in C3H10T~C18 mouse embryo fibroblasts (C3H10T~ cells). This diol also
induced DNA damage in these cells but did not form stable covalent DNA adducts. B[a]P-4,5-diol and B[a]P induced MCT in C3H10T~ cells by producing significant numbers of Type II and Type III foci over a
concentration range of 1.8-10.5 ~M for B[ a ]P-4,5-diol, and 2.1-8.1 ~M for B [a]P. The dose-response curves for B[a]P-4,5-diol and B[a]P were indistinguishable. Both B[a]P-4,5-diol (8 and 10 ~M) and B[a]P (1,4,8,10 ~M) exhibited significant DNA damaging activity as determined by the comet assay after 1 hr of treatment without significant concurrent cytotoxicity.
Furthermore, the distributions of comet tail contents were altered in the B[a]P- 4,5-diol and B[a]P treatment groups compared to the controls. DNA adduct patterns in C3Hl OT~ cells were examined after P AH treatment using 32p- postlabeling techniques and TLC elution systems designed for polar adducts. While B[a]P treatment produced one major DNA adduct identified as B[a]P- DE-dGuo, no stable covalent DNA adducts were detected in the DNA ofB[a] P-4,5-diol-treated cells. In summary, this study provides evidence for the DNA damaging and MCT activities of the K-region diol ofB[a]P in the absence of covalent stable DNA adducts. In concert with the reported MCT activities of K-region diols of other PARs, these data suggest a new mechanism/pathway for the bioactivation of PAHs.
This abstract does not necessarily reflect EPA policy.