title: Assessment of the in vivo mutagenicity of ethylene oxide in the tissues of B6C3F1 lacI transgenic mice following inhalation exposure.
abstract: In the present study, the lacI mutant frequency was determined in the tissues of B6C3F1 lacI transgenic mice exposed by inhalation to ethylene oxide (EO). Groups of 15 male transgenic lacI B6C3F1 mice were exposed to either 0, 50, 100, or 200 ppm EO for 4 weeks (6 h/day, 5 days/week) and were sacrificed at 0, 2, or 8 weeks after the last EO exposure. The lacI transgene was recovered from lung, bone marrow, spleen, and germ cells for determination of the lacI mutant frequency. The tissues selected for analysis were tumor target site tissues in chronic bioassays (lung tumors and lymphomas) and germ cells. The lacI mutant frequency in lung was significantly increased at 8 weeks post exposure to 200 ppm EO (6.2 +/- 2.2 vs. 9.1 +/- 1.5. p = 0.046). In contrast, the lacI mutant frequency in spleen and bone marrow at 2 and 8 weeks was not significantly increased in mice exposed to 200 ppm EO. The lacI mutant frequencies in male germ cells for 200 ppm EO-exposed mice were not increased compared to air controls at 2 and 8 weeks post-exposure. In a spleen cell fraction two of three EO-exposed mice at the 200 ppm exposure level demonstrated an elevated lacI mutant frequency. The increased lacI mutant frequency in these animals was likely due to mutant siblings that contained background G:C --> A:T transitions at CpG sites. These results demonstrate that a 4-week inhalation exposure to EO is mutagenic in lung. However, EO did not increase the frequency of mutations recovered at the lacI transgene in other tissues examined under the conditions used in the present studies. Since the mutational spectrum for EO in other systems consists of an increased proportion of large deletions, the lack of a mutagenic response in the tissues examined is likely due to the lack of recovery of large deletions in lambda-based shuttle vector systems. These data indicate that a primary mechanism of EO-induced mutagenicity in vivo is likely through the induction of deletions, not specific point mutations.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Sisk
authors.forename: L J
authors.initials: LJ
authors.lastname: Pluta
authors.forename: K G
authors.initials: KG
authors.lastname: Meyer
authors.forename: B C
authors.initials: BC
authors.lastname: Wong
authors.forename: L
authors.initials: L
authors.lastname: Recio
mesh_terms: D000280:Administration, Inhalation; D000388:Air; D000818:Animals; D001426:Bacterial Proteins / Q000187:drug effects / Q000235:genetics*; D001853:Bone Marrow / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins; D005027:Ethylene Oxide / Q000008:administration & dosage* / Q000633:toxicity*; D005854:Germ Cells / Q000187:drug effects; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D056968:Lac Repressors; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests / Q000379:methods; D009154:Mutation; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics*; D012671:Seminiferous Tubules / Q000187:drug effects; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins; D007041:Hypoxanthine Phosphoribosyltransferase; D005027:Ethylene Oxide