@article{saranko_meyer_pluta_henderson_recio_2001, title={Lung-specific mutagenicity and mutational spectrum in B6C3F1 lacI transgenic mice following inhalation exposure to 1,2-epoxybutene}, volume={473}, ISSN={["1873-135X"]}, DOI={10.1016/S0027-5107(00)00122-6}, abstractNote={1,3-Butadiene (BD) is carcinogenic and mutagenic in B6C3F1 mice. BD inhalation induces an increased frequency of specific base substitution mutations in the bone marrow and spleen of B6C3F1 lacI transgenic mice. BD is bioactivated to at least three mutagenic metabolites: 1,2-epoxybutene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB), however, the contribution of these individual metabolites to the in vivo mutational spectrum of BD is uncertain. In the present study, lacI transgenic mice were exposed by inhalation (6h per day, 5 days per week for 2 weeks) to 0 or 29.9ppm of the BD metabolite, EB to assess its contribution to the in vivo mutational spectrum of BD. No increase in lacI mutant frequency was observed in the bone marrow or spleen of EB-exposed mice. The lack of mutagenicity in the 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 lungs of EB-exposed mice (mean+/-S.D., 9.9+/-3.0x10(-5)) compared to air control mice (3.6+/-0.7x10(-5)). DNA sequence analysis of 65 and 66 mutants from the lungs of air control and EB-exposed mice, respectively, revealed an increase in the frequency of two categories of base substitution mutation and deletions. Like mice exposed to BD, EB-exposed mice had an increased 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, occurred 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 previous mutational spectra from BD-exposed mice or EB-exposed cells in culture. We hypothesize that the direct in vivo mutagenicity and further in situ metabolism of EB in the lungs of EB-exposed mice played a prominent role in the generation of the current mutational spectrum.}, number={1}, journal={MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS}, author={Saranko, CJ and Meyer, KG and Pluta, LJ and Henderson, RF and Recio, L}, year={2001}, month={Jan}, pages={37–49} }
 @article{healy_pluta_recio_1999, title={Expression and distribution of cytochrome P450 2E1 in B6C3F1 mouse liver and testes}, volume={121}, ISSN={["1872-7786"]}, DOI={10.1016/S0009-2797(99)00082-4}, abstractNote={Cytochrome P450 2E1 (CYP2E1) is believed to have a significant role in the bioactivation of 1,3-butadiene (BD) to DNA reactive epoxide metabolites that induce somatic and germ cell genotoxicity in mice. To assess the potential role of in situ bioactivation of BD by mouse testes for inducing germ cell genotoxicity, the presence of CYP2E1 in testes has been demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoprecipitation-Western blotting methods (IP-Western) and immunohistochemistry of tissue sections. Detection of CYP2E1 in the testes was limited to interstitial cells. In liver a known site of BD bioactivation and a positive control tissue used for these studies, a discrete, zonal staining pattern of liver CYP2E1 expression detected by immunohistochemical staining was shown. These results suggest that in situ bioactivation of BD in testes by CYP2E1 may contribute to BD-induced germ cell genotoxicity.}, number={2}, journal={CHEMICO-BIOLOGICAL INTERACTIONS}, author={Healy, LN and Pluta, LJ and Recio, L}, year={1999}, month={Jul}, pages={199–207} }
 @article{saranko_recio_1998, title={Butadiene metabolite, 1,2:3,4-diepoxybutane, induces micronuclei but is only weekly mutagenic at lacI in the Big Blue(R) Rat2 lacI transgenic cell line}, volume={31}, number={1}, journal={Environmental and Molecular Mutagenesis}, author={Saranko, C. J. and Recio, L.}, year={1998}, pages={32–40} }
 @article{saranko_pluta_recio_1998, title={Molecular analysis of lacI mutants from transgenic fibroblasts exposed to 1,2-epoxybutene}, volume={19}, ISSN={["1460-2180"]}, DOI={10.1093/carcin/19.11.1879}, abstractNote={1,3-Butadiene (BD) is a genotoxic carcinogen that is bioactivated to at least two mutagenic metabolites: 1,2-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB). We reported previously that lacI transgenic mice exposed to BD had an increased frequency of specific base substitution mutations in the bone marrow and spleen relative to unexposed controls. In the experiments described here, we determined the mutagenicity and mutational spectrum of EB in Rat2 lacI transgenic fibroblasts as a means of assessing the contribution of this metabolite to the lacI mutational spectrum of BD. Rat2 cells were exposed to 0, 0.4, 0.6, 0.8 or 1.0 mM EB for 24 h, resulting in a range of cell survival from 100 to 15%, respectively. Mutagenicity was assessed at 0, 0.6 and 1.0 mM EB. Unexposed controls had a background mutant frequency of 6 +/- 1 +/- 10(-5), while the mutant frequency in cells exposed to 0.6 and 1.0 mM EB was increased 2- and 3-fold, respectively. DNA sequence analysis of 154 lacI mutants recovered in these experiments revealed an increase in the frequency of specific base substitution mutations in cells exposed to 1.0 mM EB compared with controls. These included G:C-->A:T transitions at non-CpG sites, G:C-->T:A transversions and A:T-->T:A transversions, which have all been observed in lacI mutants isolated from transgenic mice exposed to BD. These results suggest that EB causes mutation primarily by base substitution and that the spectrum of these mutations closely resembles that of BD. These data, along with previous findings from our laboratory, suggest that EB is more likely than DEB to be primarily responsible for the lacI mutational spectrum observed in lacI transgenic mice exposed to BD.}, number={11}, journal={CARCINOGENESIS}, author={Saranko, CJ and Pluta, LJ and Recio, L}, year={1998}, month={Nov}, pages={1879–1887} }