Development and distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced aberrant crypt foci in the rat large intestine

Aberrant crypt foci (ACF) are generally considered to be preneoplastic lesi ons for colon ranter, To assess their induction by 2-amino-1-methyl-6-pheny limidazo[4,5-b]pyridine (PhIP), a colon carcinogen, we performed a sequenti al study of ACF morphology and localization, F344 male rats were given PhIP , and methylene blue-stained colon epithelium and isolated crypts were anal yzed at weeks 12, 25, 50, and 75, Each crypt was classified into 2 groups, "single" with round bottoms and "bifurcating" displaying V-shaped clefts (i ndicating proliferation). In combination with the number of crypts in an AC F, this classification was a good indicator for the generation of ACI: in l ine with the fission mechanism of growth. Increasing numbers of crypts in A CF: through weeks 12 to 75 and decreased percentages of ACF with bifurcatin g crypts at the late time points indicated that proliferation of crypts occ urs predominantly during the early stages, The distribution pattern showed a significant shift (P<0.000005) from the distal to the proximal part of th e large intestine between weeks 25 and 50, Adenocarcinomas were first found to develop at week 50 in the ascending colon and cecum where bifurcating c rypts were generally lacking at weeks 12 and 25, These data suggest the exi stence of (1) proliferating ACF which contains bifurcating crypt(s) and (2) quiescent or senescent ACF which consists of only single crypts.