Comparative dose-response study on the pulmonary carcinogenicity of 1, 6-dinitropyrene and benzo[<i>a</i>]pyrene in F344 rats

Iwagawa, Masanori; Maeda, Toshiharu; Izumi, Kiyotaka; Otsuka, Hisashi; Nishifuji, Keiko; Ohnishi, Yoshinari; Aoki, Shigenobu

doi:10.1093/carcin/10.7.1285

Cited by 32 publications

(22 citation statements)

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“…An exception to this high level of binding was aflatoxin BI and, interestingly, both this carcinogen and 1,6-dinitropyrene induce tumors at very low concentrations. In our study, we also detected DNA adducts at dose levels (e.g., 3 pg of 1,6-dinitropyrene) where Iwagawa et al (11) did not detect lung tumors.…”

Section: Discussionsupporting

confidence: 75%

“…Iwagawa et al (11) would have had to treat considerably more rats than the 30 animals they used to detect such a difference. F344 rats exposed to 2.2 to 7.1 mg/mi3 diesel emissions for 24 to 30 months develop an increased incidence of lung tumors (2).…”

Section: Discussionmentioning

confidence: 99%

“…[4,5,9,1 0-3H] 1,6-Dinitropyrene (0, 0.3, 1, 3, 10, 30, 100, or 150 pg; 1257 mCi/mmole) in 50 pl of beeswax and tricaprylin (1:1) was then administered using the lung implantation method of Stanton et al (26) as described by Iwagawa and co-workers (11). Seven days after treatment, the animals were exposed to carbon dioxide, decapitated, and the lungs, livers, and spleens were quickly excised.…”

Section: Dna Adduct Analysesmentioning

confidence: 99%

“…Although nitro PAHs are found at much lower levels than PAHs, certain members of this class are powerful mutagens and carcinogens. 1,6-Dinitropyrene, for instance, is one of the most mutagenic compounds tested in the Ames Salmonella reversion assay and it induces tumors at a number of sites in a variety of experimental animals (7)(8)(9)(10)(11)(12). Because nitro PAHs are interrelated through metabolism to aromatic amines (13), a class of carcinogens known to cause bladder cancer in humans (3,14), they may contribute to the increased incidence of both lung and bladder tumors in individuals exposed to diesel exhaust.…”

Section: Introductionmentioning

confidence: 99%

“…Two markers that have received much attention are DNA (16,17) and protein (18) adducts, and a number of reports have appeared documenting correlations between carcinogen exposure and adduct concentrations (16)(17)(18)(19)(20)(21). While We recently reported (23,24) the formation of DNA adducts and T-lymphocyte mutations after the administration of either 30 or 100 pg of 1,6-dinitropyrene directly to the lungs of F344 rats according to a protocol known to induce lung tumors (10,11). In lung and spleen lymphocytes, one major adduct, N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, was detected.…”

Section: Introductionmentioning

confidence: 99%

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Formation of DNA Adducts and Induction of Mutations in Rats Treated with Tumorigenic Doses of 1,6-Dinitropyrene

Beland¹,

Fullerton²,

Smith³

et al. 1994

Environmental Health Perspectives

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1,6-Dinitropyrene, a component of diesel exhaust, is a lung carcinogen in male F344 rats following a single intrapulmonary administration. In this study, rats were treated with tumorigenic doses of 1,6-dinitropyrene to establish dose-response relationships for the formation of DNA adducts in target (lung) and nontarget (liver) tissues and for the induction of 6-thioguanine-resistant mutations in spleen T-lymphocytes. One week after treatment with 0.3, 1, 3, 10, 30, 100, or 150 pg of 1 ,6-dinitropyrene, dose-responsive DNA binding was measured in lung and liver with binding in the lung being 10-fold higher than in the liver. In the lung, a 2-fold increase in dose resulted in a 1.8-fold increase in DNA binding at treatments up to 30 pg of 1,6-dinitropyrene, while in the liver, a 2-fold increase in 1,6-dinitropyrene produced a 2-fold increase in DNA binding at doses up to the 10 pg treatment. Higher doses of 1,6-dinitropyrene resulted in proportionally smaller increases in adduct formation in the two tissues. When measured 21 weeks after treatment, mutations in T-lymphocytes increased with doses up to 100 pg of 1,6-dinitropyrene, but the response was nonlinear throughout the dose range. These findings indicate that concentrations of 1,6-dinitropyrene that produce a dose-dependent induction of lung tumors also result in a dose-dependent formation of DNA adducts and induction of lymphocyte mutations but that the dose-response curves for DNA binding and mutations are different. -Environ Health Perspect 102(Suppl 6): 185-189 (1994)

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Dna Adduct Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Formation of DNA Adducts and Induction of Mutations in Rats Treated with Tumorigenic Doses of 1,6-Dinitropyrene

Beland¹,

Fullerton²,

Smith³

et al. 1994

Environmental Health Perspectives

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In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung ofgpt delta transgenic mice

Hashimoto

Amanuma

Hiyoshi

et al. 2005

Environ. Mol. Mutagen.

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Benzo[a]pyrene (B[a]P) is a ubiquitous airborne pollutant whose mutagenicity has been evaluated previously by oral and intraperitoneal administration to experimental animals. In this study, mutagenesis in the lungs, the target organ of air pollutants, was examined after a single intratracheal instillation of 0-2 mg B[a]P into gpt delta transgenic mice. Intratracheal injection of B[a]P resulted in a statistically significant and dose-dependent increase in gpt mutant frequency as measured by 6-thioguanine selection. The mutant frequencies at B[a]P doses of 0.5, 1, and 2 mg were 2.8, 4.2, and 6.8 times higher than the frequency seen in nontreated mice (0.60 +/- 0.13 x 10(-5)). The most frequent mutations induced by B[a]P treatment were G:C-->T:A transversions, which are characteristic of B[a]P mutagenesis in other models, and single-base deletions of G:C base pairs. To characterize the hotspots of B[a]P-induced mutations in the gpt gene, we analyzed sequences adjacent to the mutated G:C base pairs. Guanine bases centered in the nucleotide sequences CGT, CGA, and CGG were the most frequent targets of B[a]P. Our results indicate that intratracheal instillation of B[a]P into gpt delta mice causes a dose-dependent increase in gpt mutant frequency in the lung, and that the predominant mutation induced is G:C-->T:A transversion.

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In vivo mutagenesis in the lungs of gpt‐delta transgenic mice treated intratracheally with 1,6‐dinitropyrene

Hashimoto

Amanuma

Hiyoshi

et al. 2006

Environ and Mol Mutagen

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1,6-Dinitropyrene (1,6-DNP) is a ubiquitous airborne pollutant found in diesel exhaust. In this study, mutagenesis was examined in the lungs of gpt-delta transgenic mice after intratracheal instillation of 0-0.1 mg 1,6-DNP. In addition, the 1,6-DNP-induced gpt mutation spectrum was compared with that of control mice. A single intratracheal injection of 0-0.05 mg 1,6-DNP resulted in significant dose-dependent increases in mutant frequency; the induced mutant frequency declined at the 0.1 mg dose. The average lung mutant frequencies at doses of 0.025, 0.05, and 0.1 mg 1,6-DNP were 2.9-, 4.1-, and 1.9-times higher than for control mice ((0.50+/-0.16)x10(-5)). The major mutations induced by 1,6-DNP included G:C-->A:T transitions, G:C-->T:A transversions, and 1-base deletions. Among the G:C-->A:T transitions isolated from 1,6-DNP-treated mice, five (at nucleotide positions 64, 110, 115, 116, and 418) were observed in four or more animals. These positions therefore are potential hotspots for 1,6-DNP mutation. The predominant frameshift mutations following 1,6-DNP treatment included single base pair deletions at G:C (9/13=69%). The results of this study indicate that 1,6-DNP is mutagenic for the lungs of mice.

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Comparative dose-response study on the pulmonary carcinogenicity of 1, 6-dinitropyrene and benzo[a]pyrene in F344 rats

Cited by 32 publications

References 0 publications

Formation of DNA Adducts and Induction of Mutations in Rats Treated with Tumorigenic Doses of 1,6-Dinitropyrene

Formation of DNA Adducts and Induction of Mutations in Rats Treated with Tumorigenic Doses of 1,6-Dinitropyrene

In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung ofgpt delta transgenic mice

In vivo mutagenesis in the lungs of gpt‐delta transgenic mice treated intratracheally with 1,6‐dinitropyrene

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