Carcinogenesis, Vol. 20, No. 10, 1933-1938,
October 1999
© 1999 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
Preferential induction of guanine deletion at 5'-GGGA-3' in rat mammary glands by 2-amino- 1-methyl-6-phenylimidazo[4,5-b]pyridine
Carcinogenesis Division, National Cancer Center Research Institute,1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045,
1 Low Dose Radiation Risk and Carcinogenesis Research Group, National Institute of Radiological Sciences, Anakawa 4-9-1, Inage-ku, Chiba 263-8555 and
2 First Department of Pathology, Nagoya City University Medical School, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is known to induce a characteristic mutation, G deletion at the 5'-GGGA-3' site, preferentially in the lacI transgene of the colonic mucosa of Big Blue® rats (BBR) and mice and specifically in the Apc gene of rat colon tumors. In this study, lacI mutations of the mammary glands in PhIP-treated rats were investigated. Six-week-old female (BBRxSprague–Dawley)F1 rats were administered 10 gavages of 65 mg/kg/day PhIP. Mammary ducts were collected from the macroscopically normal mammary tissue of PhIP-treated and untreated rats at 56–69 weeks of age by collagenase treatment. The mutant frequencies were 25 ± 2.1x10–6 in control rats and 323 ± 44x10–6 in the PhIP-treated rats. By sequencing 40 and 177 mutants in the control and PhIP-treated groups, respectively, 34 and 149 mutations were considered independent mutations. In the control group, G:C
A:T transitions at CpG sites dominated and no G:C deletions were detected. In the PhIP-treated group, G:CT:A transversions were most frequent (43%), followed by single base pair deletions of G:C (21%). A total of nine deletions were at 5'-GGGA-3' sites, accounting for 29% of the G:C deletions and 6% of the 149 total mutations. Clusters of more than three mutations at one nucleotide position were observed at 12 positions and two were G deletions at 5'-GGGA-3' sites. Comparison of the PhIP-induced mutations in the mammary glands with those previously reported in the colon revealed that G:CT:A transversions occurred at a significantly higher frequency in the mammary glands and that G:C deletions occurred at a significantly lower frequency. However, the signature mutation, G deletion at the 5'-GGGA-3' site, was commonly observed in both tissues.
Abbreviations: BBM, Big Blue® mouse; BBR, Big Blue® rat; DMEM, Dulbecco's modified Eagle's medium; F344, Fischer 344; MF, mutant frequency; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; SD, Sprague–Dawley; SSCP, single-strand conformation polymorphism.
3 To whom correspondence should be addressed Email: tushijim{at}ncc.go.jp
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