Carcinogenesis, Vol 18, 783-789, Copyright © 1997 by Oxford University Press
HL Hong, TR Devereux, RL Melnick, SR Eldridge, A Greenwell, J Haseman, GA Boorman and RC Sills
Isoprene is the 2-methyl analog of 1,3-butadiene, a genotoxic and
carcinogenic compound in rats and mice. Male B6C3F1 mice were exposed to 0,
2200 or 7000 ppm isoprene by inhalation (6 h/day; 5 days/week) for 26
weeks. Following a 26-week recovery period, an increased incidence of
Harderian gland (HG) neoplasms was observed at both concentrations. The
present study was designed to characterize genetic alterations in the K-ras
and H-ras protooncogenes in HG neoplasms. Mutations in K-ras and H-ras were
identified by single-strand conformational analysis and direct sequencing
of polymerase chain reaction (PCR) amplified DNA, isolated from
paraffin-embedded sections of HG neoplasms. A higher frequency of ras
mutations, in particular K- ras mutations, was detected in isoprene-induced
neoplasms than in 1,3- butadiene-induced or control HG neoplasms. All of
the isoprene-induced HG neoplasms exhibited activated K-ras (60%) or H-ras
(40%) mutations. In contrast, ras mutations were detected in 69% of HG
neoplasms from 1,3-butadiene exposed mice (14% K-ras and 55% H-ras) and in
56% of HG neoplasms obtained from control B6C3F1 mice (8% K-ras and 48%
H-ras). The predominant mutations in isoprene-induced HG neoplasms, but not
in previously or newly analysed 1,3-butadiene-induced HG neoplasms,
consisted of A-->T transversions (CAA-->CTA) at K-ras codon 61
(15/30) and C-->A transversions (CAA-->AAA) at H-ras codon 61 (8/30).
Two- thirds of the K-ras CTA mutations were detected in HG neoplasms from
the 2200 ppm exposure group while one-third was present in the 7000 ppm
group. Isoprene-induced HG neoplasms with K-ras or H-ras mutations had an
elevated proliferating cell nuclear antigen (PCNA) index, compared to
spontaneous HG neoplasms without ras mutations. The high frequency and
specificity of the ras mutation profile suggest that ras protooncogene
activation contributes to isoprene-induced HG tumorigenesis.
ARTICLES
Both K-ras and H-ras protooncogene mutations are associated with Harderian gland tumorigenesis in B6C3F1 mice exposed to isoprene for 26 weeks
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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