Preferential induction of guanine deletion at 5′-GGGA-3′ in rat mammary glands by 2-amino- 1-methyl-6-phenylimidazo[4,5-b]pyridine

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Abstract
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 (BBR×Sprague–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 ± 2.1×10–6 in control rats and 323 ± 44×10–6 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:C→T: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:C→T: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.

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