Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages

Yasunobu Aoki, Akiko H. Hashimoto, Yoshiki Sugawara, Kyoko Hiyoshi-Arai, Sataro Goto, Kenichi Masumura, Takehiko Nohmi

Research output: Contribution to journalArticle

3 Citations (Scopus)


Introduction: 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.

Original languageEnglish
Article number7
JournalGenes and Environment
Issue number1
Publication statusPublished - Jan 1 2015


  • Aging
  • Air pollutant
  • In vivo mutation
  • Oxidative stress
  • Transgenic rodent assay

ASJC Scopus subject areas

  • Social Psychology
  • Genetics
  • Environmental Science (miscellaneous)

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