We have previously shown that C57BL/6J-Min/+ (multiple intestinal
neoplasia) mice, heterozygous for the Min mutation in the
adenomatous polyposis coli gene, were more susceptible to intestinal
tumorigenesis and had higher intestinal
PhIP-DNA adduct levels after exposure to the food
mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP) on day 12 than on day 36 after birth [I.-L. Steffensen, H.A.J. Schut, J.E. Paulsen, A. Andreassen, J. Alexander, Intestinal
tumorigenesis in multiple intestinal
neoplasia mice induced by the food
mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine: perinatal susceptibility, regional variation, and correlation with
DNA adducts,
Cancer Res. 61 (200l) 8689-8696]. In the present study, we have evaluated further whether this difference in susceptibility is related to adduct formation/removal, cell proliferation, apoptosis or expression of the nucleotide excision repair
protein Xeroderma pigmentosum group A (XPA) in the intestines. Min/+ and +/+ (wild-type) mice were given a
subcutaneous injection of 50 mg/kgbw
PhIP on day 12 or 36, and the levels of
PhIP-
DNA adducts after 8, 12, 24 h, 3 or 7 days were quantified by use of 32P-postlabelling. In Min/+ mice, adduct levels were significantly higher after exposure on day 12 than on day 36 in the middle (1.5- to 8.5-fold) and distal (1.3- to 6.5-fold) small intestine from 8h to 3 days after administration of
PhIP, but not in the colon and proximal small intestine. In the liver - a non-target organ for
PhIP - adduct levels were 2.0- to 7.5-fold higher after exposure on day 12 than on day 36 from 8 to 24h after exposure. Adduct levels were generally higher in the middle (1.1- to 1.8-fold) and distal (1.1- to 2.0-fold) small intestines of Min/+ compared with +/+ mice after
PhIP exposure on day 12, i.e. in the area of the intestines previously found also to have the highest number of
tumors in Min/+ mice.
PhIP increased cell proliferation and the number of apoptotic cells in the intestine and liver. However, the higher susceptibility to intestinal
tumorigenesis in Min/+ mice exposed to
PhIP at early age, or in Min/+ mice compared with +/+ mice, could not be explained by differences in cell proliferation, apoptosis or expression of the
XPA repair protein.