title: In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung of gpt delta transgenic mice.
abstract: 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.
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Akiko H
authors.initials: AH
authors.lastname: Hashimoto
authors.forename: Kimiko
authors.initials: K
authors.lastname: Amanuma
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hiyoshi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Takano
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Masumura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D020029:Base Pairing; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007041:Hypoxanthine Phosphoribosyltransferase / Q000096:biosynthesis / Q000235:genetics*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013866:Thioguanine
chemical_list: D000393:Air Pollutants; D009153:Mutagens; D001564:Benzo(a)pyrene; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine