Mutagenicity and mutational spectra of 1,3-butadiene in the bone marrow of B6C3F1 lacI transgenic mice

We are using B6C3F(1) lad transgenic mice to investigate the in vivo mutagenicity and mutational spectra of 1,3-butadiene (ED). Male B6C3F(1) lacl transgenic mice were exposed by inhalation to 0, 62.5, 625, or 1250 ppm BD for 4 weeks (6 h/day, 5 days/week). Tissues were collected 2 weeks after the final exposure for mutant frequency analysis. The lacl(-) mutant frequency in bone marrow from ED-exposed mice was increased 2- to 3.5-foId over air control mice. Analysis of the mutational spectrum of lacl mutants isolated from the bone marrow of lad mice exposed to 625 ppm ED indicated a shift in the mutational spectrum at A:T base pairs relative to air controls: 2/41 point mutations occurred at A:T base pairs in air controls versus 6/24 in ED-exposed animals: 10/40 mutations occurred at A:T base pairs in lacl mice exposed to 1250 ppm ED. A --> T transversions were found only in ED-exposed animals. Although there was a reduction in the proportion of GC --> AT transitions at 5'-CpG-3' sites recovered from the bone marrow of ED-exposed mice (25%) relative to air controls (50%), there was no difference in the contribution of GC --> AT transitions at 5'-CpG-3' sites to the mutation frequency in ED-exposed mice compared to air controls. Since the bioactivation of ED by B6C3F, mice produces at least two mutagenic metabolites epoxybutene (EB) and diepoxybutane (DEB), studies on the in vivo mutational spectra begin to provide the framework for the ultimate identification of the ED metabolite(s) responsible for the specific mutations observed.