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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.

Diesel exhaust (DE) is a major airborne pollutant of urban areas. It contains various polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs. In this study, gpt delta mice were treated with inhalation of 1 or 3 mg m(-3) DE, or a single intratracheal instillation of diesel exhaust particles (DEP) or DEP extract. In the lungs of mice treated with inhalation of 3 mg m(-3) DE for 12 weeks, the mutant frequency (MF) was 3.2-fold higher than that of the control group (1.90 x 10(-5) and 0.59 x 10(-5), respectively). An instillation of DEP and DEP extract resulted in a significant dose-dependent linear increase in MF. In mice treated with 0.5 mg DEP and 0.2 mg DEP extract, the MFs were 3.0- and 2.7-fold higher than that of the control group, respectively. The mutagenic potency (MF mg(-1)) of DEP extract (5.6 x 10(-5)) was double that of DEP (2.7 x 10(-5)), suggesting that the mutagenicity of the latter is derived primarily from compounds in the extract, which itself is responsible for ca. 50% of the weight of DEP. G:C-->A:T transitions were the predominant gpt mutation induced by all three treatments and G:C-->T:A transversions were induced by DEP and DEP extract. Guanine bases centered in nucleotide sequences such as GGA, TGA, CGG, and CGT were the major mutation targets of all three treatments. Thus, our results suggest that the mutagens contained in DEP such as PAH and nitrated PAHs induce mutations and may be responsible for carcinogenesis caused by inhalation of DE., ((c) 2007 Wiley-Liss, Inc.)

The proton transfer to solvent in the excited state of protonated diaminonaphthalenes, 1,5-diaminonaphthalene (1,5-DAN) and 1,8-diaminonaphthalene (1,8-DAN), in aqueous solution, has been investigated by picosecond time-resolved fluorescence measurements. The deprotonation rate constants of the dications of 1,8-DAN and 1,5-DAN in the excited state to produce the corresponding monocations are determined to be 1.3 x 10(10) and 5.6 x 10(9) s(-1), respectively, from dynamic analyses of their fluorescence time profiles. The much larger proton-dissociation rates compared with that of 1-aminonaphthalene (0.6 x 10(9) s(-1)) can be attributed to an electron-withdrawing effect due to the ammonium group at the 5- or 8-position in the naphthalene ring. The remarkably large proton-dissociation rate in 1,8-DAN can be ascribed to its larger reaction exergonicity which results from the electrostatic repulsion between the two ammonium groups in the reactant (the dication state) and the stabilization of the monocation state due to hydrogen bonding interactions between the NH3+ and NH2 moieties. The difference in their acidities in the excited state is discussed in terms of the reaction free energy and the proton affinities are evaluated from ab initio MO calculations.