title: Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages.
abstract: BACKGROUND
  To examine whether the mutagenic potential of lung exposure to air-borne environmental mutagens is age dependent, we administered 1 mg of benzo[a]pyrene intratracheally to 11- and 24-month old (middle-aged and old, respectively) gpt delta transgenic mice that harbor gpt (guanine phosphoribosyltransferase) genes integrated in the genomic DNA as a target for mutation detection, and then analyzed the benzo[a]pyrene-induced and spontaneous in vivo mutations and mutation spectrum in the lungs.
  
  
  RESULTS
  The mutant frequencies in the lungs of the 11- and 24-month-old control (vehicle-treated) gpt delta mice were 1.14 ± 0.22 × 10(-5) and 1.00 ± 0.20 × 10(-5), respectively, which are significantly higher than that observed for the control 3-month-old (young) mice (0.59 ± 0.13 × 10(-5)) in our previous studies, indicating that spontaneous mutation in the lung increases with age. The mutant frequencies in 11- and 24-month-old mice treated with benzo [a] pyrene were 1.5- and 2.3-fold, respectively, that of the age-matched control mice, and 4.3-fold that of the 3-month-old mice in our previous studies. Analysis of mutation spectra showed that both G:C to A:T transitions and G:C to T:A transversions were predominant in the lungs of control mice at all ages. In benzo [a] pyrene-treated mice in our previous studies, G:C to T:A transversions were the predominant type of mutation (55 %) at 3 months. Here we found that their frequency was dramatically reduced to 18 % by 24 months, and the G:C to A:T transitions became the predominant type of mutation in 24-month-old mice (41 % [16 % at CpG sites]).
  
  
  CONCLUSIONS
  Our findings suggest that susceptibility to benzo[a]pyrene is highest in young mice and is elevated again in old age. The elevation of G:C to A:T transitions was observed following benzo [a] pyrene administration in the lungs of aged mice, and accelerated cytidine deamination is speculated to contribute to this elevation.
authors.affiliation: National Institute for Environmental Studies, Center for Environmental Risk Research, 16-2 Onogawa, 305-8506 Tsukuba, Ibaraki Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: National Institute for Environmental Studies, Center for Environmental Risk Research, 16-2 Onogawa, 305-8506 Tsukuba, Ibaraki Japan.
authors.forename: Akiko H
authors.initials: AH
authors.lastname: Hashimoto
authors.affiliation: National Institute for Environmental Studies, Center for Environmental Risk Research, 16-2 Onogawa, 305-8506 Tsukuba, Ibaraki Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugawara
authors.affiliation: National Institute for Environmental Studies, Center for Environmental Risk Research, 16-2 Onogawa, 305-8506 Tsukuba, Ibaraki Japan ; Present address: University of Shizuoka, School of Nursing, 422-8526 Suruga-ku, Shizuoka Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hiyoshi-Arai
authors.affiliation: Juntendo University, Graduate School of Health and Sports Science, 270-1695 Inzai, Chiba Japan.
authors.forename: Sataro
authors.initials: S
authors.lastname: Goto
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 158-8501 Setagaya-ku, Tokyo Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Masumura
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 158-8501 Setagaya-ku, Tokyo Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
keywords: Aging; Air pollutant; In vivo mutation; Oxidative stress; Transgenic rodent assay