Mutagenesis vol. 19 no. 3 pp. 215-222,
May 2004
© 2004 UK Environmental Mutagen Society/Oxford University Press
In vivo mutagenicity and mutation spectrum in the bone marrow and testes of B6C3F1 lacI transgenic mice following inhalation exposure to ethylene oxide
CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, NC 27709, USA 1Present address: Genetic and Cellular Toxicology, Merck Research Laboratories WP45-324, West Point, PA 19486, USA 2Present address: E.I. du Pont de Nemours and Co., Duport Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road, Newark, DE 19711, USA 3Present address: AstraZeneca R&D Sodertalje, S-151 85 Sodertalje, Sweden 4Present address: Director, Environmental Carcinogenesis Division, US Environmental Protection Agency NHEERL, MD-68 Research Triangle Park, NC 27711, USA
The lacI mutant frequency and mutation spectrum were determined in the bone marrow and testes of B6C3F1 lacI transgenic mice exposed by inhalation to ethylene oxide (EO). Groups of male transgenic lacI B6C3F1 mice were exposed to 0, 25, 50, 100 or 200 p.p.m. EO for up to 48 weeks (6 h/day, 5 days/week) and were killed at 12, 24 or 48 weeks of EO exposure for determination of lacI mutant frequency. In the bone marrow, the lacI mutant frequency was significantly increased at the two highest exposure levels (100 and 200 p.p.m.) and at the 48 week exposure time point. The shape of the exposure–response curve for lacI mutant frequency in the bone marrow was non-linear. DNA sequence analysis of the bone marrow mutation spectrum revealed that only AT
TA transversions occurred at an increased frequency in EO-exposed mice: 25.4% in EO-exposed mice for 48 weeks (200 p.p.m.) compared with 1.4% in air controls. In testes, the lacI mutant frequency was increased at a single exposure level of 200 p.p.m. for 24 weeks. At 48 weeks, the lacI mutant frequency in testes was significantly increased to an equal degree at 25, 50 and 100 p.p.m. EO but not at 200 p.p.m. Analysis of the testes mutation spectrum in air control mice and in mice exposed to 200 p.p.m. EO for 48 weeks revealed that no single mutational type occurred at an increased frequency. In the testes, there was a small increase across all mutational types that was sufficient to increase the overall lacI mutation frequency although not significant individually. The mutation spectrum in testes of EO-exposed mice also revealed that the increased lacI mutant frequency observed at 25 or 50 p.p.m. EO was not due to an increase in mutant siblings (clonality). These data demonstrate that inhalation exposure to EO for up to 48 weeks produces distinct mutagenic responses in bone marrow and testes.
5To whom correspondence should be addressed. Tel: +1 215 652 5006; Fax: +1 215 652 3888; Email: leslie_recio{at}merck.com
Received on October 13, 2003; revised on January 5, 2004; accepted on January 9, 2004
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