Cj. Saranko et al., Lung-specific mutagenicity and mutational spectrum in B6C3F1 lacI transgenic mice following inhalation exposure to 1,2-epoxybutene, MUT RES-F M, 473(1), 2001, pp. 37-49
Citations number
48
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
1,3-Butadiene (BD) is carcinogenic and mutagenic in B6C3F1 mice. BD inhalat
ion induces an increased frequency of specific base substitution mutations
in the bone marrow and spleen of B6C3F1 lacI transgenic mice. BD is bioacti
vated to at least three mutagenic metabolites: 1,2-epoxybutene (EB), 1,2-ep
oxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB), however, the con
tribution of these individual metabolites to the in vivo mutational spectru
m of BD is uncertain. In the present study, lacI transgenic mice were expos
ed by inhalation (6 h per day, 5 days per week for 2 weeks) to 0 or 29.9 pp
m of the ED metabolite, EB to assess its contribution to the in vivo mutati
onal spectrum of BD. No increase in lacI mutant frequency was observed in t
he bone marrow or spleen of EB-exposed mice. The lack of mutagenicity in th
e bone marrow or spleen likely relate to insufficient levels of EB reaching
these tissues. The lacI mutant frequency was increased 2.7-fold in the lun
gs of EB-exposed mice (mean +/- S.D., 9.9 +/- 3.0 x 10(-5)) compared to air
control mice (3,6 +/- 0.7 x 10(-5)). DNA sequence analysis of 65 and 66 mu
tants from the lungs of air control and EB-exposed mice, respectively, reve
aled an increase in the frequency of two categories of base substitution mu
tation and deletions. Like mice exposed to BD, EB-exposed mice had an incre
ased frequency of A:T --> T:A transversions. However, in contrast to the BD
mutational spectra, G:C --> A:T transitions at 5'-CpG-3' sequences, occurr
ed with increased frequency in the EB-exposed mice. The increased frequency
of deletions as well as the induction of two tandem mutations and a tandem
deletion in the lungs of EB-exposed mice are also inconsistent with previo
us mutational spectra from BD-exposed mice or EB-exposed cells in culture.
We hypothesize that the direct in vivo mutagenicity and further in situ met
abolism of EB in the lungs of EB-exposed mice played a prominent role in th
e generation of the current mutational spectrum. (C) 2001 Elsevier Science
B.V, All rights reserved.