Journal Article

DNA adduct and tumor formations in rats after intratracheal administration of the urban air pollutant 3-nitrobenzanthrone

Eszter Nagy, Magnus Zeisig, Ken Kawamura, Yoshiharu Hisamatsu, Akiko Sugeta, Shuichi Adachi and Lennart Möller

in Carcinogenesis

Volume 26, issue 10, pages 1821-1828
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI:
DNA adduct and tumor formations in rats after intratracheal administration of the urban air pollutant 3-nitrobenzanthrone

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3-Nitrobenzanthrone (3-NBA) has been isolated from diesel exhaust and airborne particles and identified as a potent direct-acting mutagen in vitro and genotoxic agent in vivo. In order to evaluate the in vivo toxicity and carcinogenicity of 3-NBA in a situation corresponding to inhalation, a combined short-term and lifetime study with intratracheal (i.t.) instillation in female F344 rats was performed. DNA adduct formation, as a marker for the primary effect and analyzed by 32P-HPLC after single instillation, showed a few major DNA adducts and a rapid increase with a peak after 2 days, followed by a decline. No DNA adducts above the background level were observed after 16 days. The highest DNA adduct formation was observed in lung [∼250 DNA adducts/108 normal nucleotides (NN)] closely followed by kidney (∼200 DNA adducts/108 NN), whereas liver contained only 12% (∼30 DNA adducts/108 NN) of the levels of DNA adducts found in lung. In the tumor study, squamous cell carcinomas were found after 7–9 months in the high-dose group (total dose of 2.5 mg 3-NBA) and after 10–12 months in the low-dose group (total dose of 1.5 mg 3-NBA). The fraction of squamous cell carcinoma out of the total amount of tumors observed at the end of experiment at 18 months, corresponded to 3/16 and 11/16 in the low- and high-dose group, respectively. A single case of adenocarcinoma was also observed in each group. In the control group, no tumors were observed during the entire study of 18 months. In addition, a few cases of squamous metaplasia were also observed in the lung in both dose groups but not in the controls. In conclusion, 3-NBA forms DNA adducts in the lung immediately after i.t. administration but almost all DNA adducts were eliminated after 16 days. Tumor formation in two dose groups was observed in a dose-dependent manner with squamous cell carcinomas as the predominant tumor type at high exposure.

Keywords: 3-ABA, 3-aminobenzanthrone; AUC, area under curve; B[a]f, benzo[a]pyrene; dG-C8-C2-ABA, 8-(3-amino-7H-benz[de]anthracen-7-one-2-yl)-2′-deoxyguanosine; dG-C8-N-ABA, 8-(3-amino-7H-benz[de]anthracen-7-one-N-yl)-2′-deoxyguanosine; dG-N2-C2-ABA, N2-(3-amino-7H-benz[de]anthracen-7-one-2-yl)-2′-deoxyguanosie; i.p., intraperitoneal; i.t., intratracheal; NATs, N,O-acetyltransferases; 3-NBA, 3-nitrobenzanthrone; NuP1 Nuclease P1; SULTs, sulfotransferases; TBA, tetrabutyl ammonium chloride; XMEs, xenobiotic metabolizing enzymes

Journal Article.  5310 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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