Carcinogenesis, Vol. 20, No. 4, 657-662,
April 1999
© 1999 Oxford University Press
High frequency of codon 61 K-ras A
T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2-chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene
Environmental Toxicology Program and
1 Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Chloroprene is the 2-chloro analog of 1,3-butadiene, a potent carcinogen in laboratory animals. Following 2 years of inhalation exposure to 12.8, 32 or 80 p.p.m. chloroprene, increased incidences of lung and Harderian gland (HG) neoplasms were observed in B6C3F1 mice at all exposure concentrations. The present study was designed to characterize genetic alterations in the K- and H-ras protooncogenes in chloroprene-induced lung and HG neoplasms. K-ras mutations were detected in 80% of chloroprene-induced lung neoplasms (37/46) compared with only 30% in spontaneous lung neoplasms (25/82). Both K- and H-ras codon 61 A
T transversions were identified in 100% of HG neoplasms (27/27) compared with a frequency of 56% (15/27) in spontaneous HG neoplasms. The predominant mutation in chloroprene-induced lung and HG neoplasms was an AT transversion at K-ras codon 61. This mutation has not been detected in spontaneous lung tumors of B6C3F1 mice and was identified in only 7% of spontaneous HG neoplasms. In lung neoplasms, greater percentages (80 and 71%) of AT transversions were observed at the lower exposures (12.8 and 32 p.p.m.), respectively, compared with 18% at the high exposure. In HG neoplasms, the percentage of AT transversions was the same at all exposure concentrations. The chloroprene-induced ras mutation spectra was similar to that seen with isoprene, where the predominant base change was an AT transversion at K-ras codon 61. This differed from 1,3-butadiene, where K-ras codon 13 GC transitions and H-ras codon 61 AG transitions were the predominant mutations. The major finding of K-ras AT transversions in lung and Harderian gland neoplasms suggests that this mutation may be important for tumor induction by this class of carcinogens.
Abbreviations: H & E, hematoxylin and eosin; HG, Harderian gland; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SSCP, single-stranded conformational polymorphism analysis.
2 To whom correspondence should be addressed Email: sills{at}niehs.nih.gov
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