Age at exposure and Apc status influence the levels of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in mouse intestine and liver.
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.
Steffensen
Inger-Lise
IL
Department of Food Toxicology, Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, NO-0403 Oslo, Norway. inger-lise.steffensen@fhi.no
Schut
Herman A J
HA
Alexander
Jan
J
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D018736:DNA Adducts; D005786:Gene Expression Regulation; D017491:Genes, APC; D007093:Imidazoles / Q000633:toxicity*; D007422:Intestines / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D051760:Xeroderma Pigmentosum Group A Protein / Q000096:biosynthesis
D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D051760:Xeroderma Pigmentosum Group A Protein; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine