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.
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 proto-oncogenes 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 A-->T 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 A-->T 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 A-->T 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 A-->T transversion at K-ras codon 61. This differed from 1,3-butadiene, where K-ras codon 13 G-->C transitions and H-ras codon 61 A-->G transitions were the predominant mutations. The major finding of K-ras A-->T transversions in lung and Harderian gland neoplasms suggests that this mutation may be important for tumor induction by this class of carcinogens.
Sills
R C
RC
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. sills@niehs.nih.gov
Hong
H L
HL
Melnick
R L
RL
Boorman
G A
GA
Devereux
T R
TR
D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics; D000280:Administration, Inhalation; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced* / Q000235:genetics; D002737:Chloroprene / Q000008:administration & dosage / Q000633:toxicity*; D003062:Codon / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D011905:Genes, ras; D006243:Harderian Gland / Q000737:chemistry / Q000187:drug effects*; D045782:Hemiterpenes; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010420:Pentanes; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012626:Sebaceous Gland Neoplasms / Q000139:chemically induced* / Q000235:genetics; D013329:Structure-Activity Relationship
D002070:Butadienes; D002273:Carcinogens; D003062:Codon; D004273:DNA, Neoplasm; D045782:Hemiterpenes; D010420:Pentanes; C005059:isoprene; D002737:Chloroprene; C031763:1,3-butadiene