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Mutagenicity, Stable DNA Adducts, and Abasic Sites Induced in Salmonella by Phananthro[3,4-b]- and Phenanthro[4,3-b]thiophenes, Sulfur Analogs of Benzo[c]phenanthrene
SWARTZ, C., L. C. KING, S. NESNOW, D. M. UMBACH, H. C. SIKKA, S. KUMAR, AND D. M. DEMARINI. Mutagenicity, Stable DNA Adducts, and Abasic Sites Induced in Salmonella by Phananthro[3,4-b]- and Phenanthro[4,3-b]thiophenes, Sulfur Analogs of Benzo[c]phenanthrene. MUTATION RESEARCH. Elsevier Science Ltd, New York, NY, (661):47-56, (2009).
Sulfur-containing polycyclic compounds have been identified in cigarette smoke, diesel exhaust, and air pollution. However, they have not been studied extensively. This study evaluated 9 structurally related sulfur-phenanthrene compounds for mutagenicity and DNA adducts in Salmonella, and we found that the sulfone structure was the most mutagenic (more mutagenic than benzo[a]pyrene), but it did not induce stable DNA adducts. Instead, it induced unstable DNA adducts, resulting in abasic sites. Our data also indicated that these compounds induce mutations at guanine and/or adenine sites in DNA, depending on the structure of the compound. This study showed that sulfur-PAHs can be highly mutagenic and that their mechanism of action may involve the formation of unstable DNA adducts, resulting in abasic sites within DNA. The finding that the sulfone strucuture was even more mutagenic than benzo[a]pyrene, which is a commonly measured PAH in air pollution, indicates that the presence of such sulfur-PAHs may account for some of the measured mutagenic activity of urban air
Sulfur-containing polycyclic aromatic hydrocarbons (thia-PAHs or thiaarenes) are common constituents of air pollution and cigarette smoke, yet little is known of the biological significance of exposure to these compounds. Some are mutagenic and carcinogenic, but only a few have been studied. We evaluated the mutagenicity in Salmonella TA98, TA100, and TA104 of two sulfur-containing derivatives of benzo[c]phenanthrene, phenanthro[3,4-b]thiophene (P[3,4-b]T), and phenanthro[4,3-b]thiophene (P[4,3-b]T) as well as their dihydrodiol and sulfone derivatives. In addition, we assessed levels of stable DNA adducts (by 32P-postlabeling) as well as abasic sites (by an aldehydic-site assay) produced by six of these compounds in Salmonella TA100. P[3,4-b]T and its 6,7- and 8,9-diols, P[3,4-b]T sulfone, P[4,3-b]T, and its 8,9-diol were mutagenic in TA100. P[3,4-b]T sulfone, the most potent mutagen, was approximately twice as potent as benzo[a]pyrene in both TA98 and TA100. Benzo-ring dihydrodiols were much more potent than K-region dihydrodiols, which had little or no mutagenic activity in any strain. P[3,4-b]T sulfone produced only abasic sites and not stable DNA adducts; the other five compounds examined, B[c]P, B[c]P 3,4-diol, P[3,4-b]T, P[3,4-b]T 8,9-diol, and P[4,3-b]T 8,9-diol, produced only stable DNA adducts. Interestingly, P[3,4-b]T sulfone was the only compound that produced significant levels of frameshift mutations (TA98) and induced mutations primarily at GC sites, i.e., it was more mutagenic in TA100 than in TA104. In contrast, B[c]P, its 3,4-diol, and the 8,9 diols of the phenanthrothiophenes were more mutagenic in TA104 than in TA100, suggesting that they induced mutations primarily at AT sites. P[3,4-b]T was not mutagenic in TA104, whereas P[3,4-b]T sulfone was. These data, combined with prior metabolism data, suggest that the two isomeric forms (P[3,4-b]T and P[4,3-b]T) are activated differently, with the former not involving a diol pathway and the latter involving a diol epoxide pathway. This study is the first to illustrate the potential importance of abasic sites in the mutagenesis of thia-PAHs.
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Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
MOLECULAR TOXICOLOGY BRANCH