Determination of mutagenicity in tissues of transgenic mice following exposure to 1,3-butadiene and N-ethyl-N-nitrosourea.
1,3-Butadiene (BD) is carcinogenic in the B6C3F1 mouse in multiple organs, including lung and liver. We conducted a study to measure the frequency of BD mutations in mouse tissues using a transgenic mouse (Muta mouse; MM). MM is a BALB/c x DBA/2 (CD2F1) mouse that has a bacteriophage lambda shuttle vector with the target gene lacZ integrated into the mouse genome. Mice were exposed by inhalation to 625 ppm BD (6 hr/day) for 5 days and the lacZ- mutant frequency (mf) was determined in lung, bone marrow, and liver. The lacZ- mf in lung increased twofold above air-exposed control animals, but the bone marrow and liver samples did not exhibit an increase above background. N-ethyl-N-nitrosourea (250 mg/kg ip) was mutagenic in all three tissues examined. Studies on the biotransformation of BD using MM liver microsomes showed that the ratio between the rates of BD bioactivation to BD monoepoxide (BMO) and hydrolysis of BMO by epoxide hydrolases was approximately 40% less than this ratio using B6C3F1 mouse liver microsomes. Quantitation of adducts of BMO to N-terminal valine in hemoglobin (Hb) in the MM revealed an adduct level of 3.7 pmol/mg globin. Using this value, the predicted Hb adduct level in MM would be approximately one-half of that measured in the B6C3F1 mouse following similar exposures. These results indicate that BD induces mutations in vivo in a known murine target tissue, but strain differences in the biotransformation of BD should be considered in comparing the susceptibility of transgenic mouse strains to mutation.
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Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Osterman-Golkar
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Csanády
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Turner
M J
MJ
Myhr
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Moss
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Bond
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JA
D000818:Animals; D001711:Biotransformation; D002070:Butadienes / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D004852:Epoxy Compounds / Q000378:metabolism; D005038:Ethylnitrosourea / Q000633:toxicity*; D005798:Genes, Bacterial / Q000187:drug effects* / Q000235:genetics; D006454:Hemoglobins / Q000378:metabolism; D007763:Lac Operon / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009152:Mutagenicity Tests; D014633:Valine / Q000378:metabolism
D002070:Butadienes; D004852:Epoxy Compounds; D006454:Hemoglobins; D014633:Valine; C031763:1,3-butadiene; D005038:Ethylnitrosourea