Lung-specific mutagenicity and mutational spectrum in B6C3F1 lacI transgenic mice following inhalation exposure to 1,2-epoxybutene

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.