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, S. Goto, Kenichi Masumura, Takehiko Nohmi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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
Volume37
Issue number1
DOIs
Publication statusPublished - 2015

Fingerprint

Hypoxanthine Phosphoribosyltransferase
Benzo(a)pyrene
mutagenicity
pyrene
mutation
Lung
Mutation
fold
Cytidine
Deamination
genomics
harbor
Mutagens
DNA
Transgenic Mice
Spectrum Analysis
gene
air
Air

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Environmental Science (miscellaneous)
  • Social Psychology

Cite this

Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages. / Aoki, Yasunobu; Hashimoto, Akiko H.; Sugawara, Yoshiki; Hiyoshi-Arai, Kyoko; Goto, S.; Masumura, Kenichi; Nohmi, Takehiko.

In: Genes and Environment, Vol. 37, No. 1, 7, 2015.

Research output: Contribution to journalArticle

Aoki, Yasunobu ; Hashimoto, Akiko H. ; Sugawara, Yoshiki ; Hiyoshi-Arai, Kyoko ; Goto, S. ; Masumura, Kenichi ; Nohmi, Takehiko. / Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages. In: Genes and Environment. 2015 ; Vol. 37, No. 1.
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abstract = "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.",
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T1 - Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages

AU - Aoki, Yasunobu

AU - Hashimoto, Akiko H.

AU - Sugawara, Yoshiki

AU - Hiyoshi-Arai, Kyoko

AU - Goto, S.

AU - Masumura, Kenichi

AU - Nohmi, Takehiko

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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KW - Air pollutant

KW - In vivo mutation

KW - Oxidative stress

KW - Transgenic rodent assay

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