2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (
PhIP) has been implicated as a major mutagenic heterocyclic
amine in the human diet and is carcinogenic in the rat prostate. To validate
PhIP-induced rat prostatic
neoplasia as a model of human
prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow progressive changes over time. We fed sixty-seven 5-week-old male Fischer F344 rats with
PhIP (400 ppm) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at the ages of 25, 45, and 65 weeks. Animals treated with
PhIP showed significantly more
inflammation (P = .002, > .001, and .016 for 25, 45, and 65 weeks, respectively) and
atrophy (P = .003, > .001, and .006 for 25, 45, and 65 weeks, respectively) in their prostate glands relative to controls.
Prostatic intraepithelial neoplasia (PIN) occurred only in
PhIP-treated rats. PIN lesions arose in areas of glandular
atrophy, most often in the ventral prostate. Atypical cells in areas of
atrophy show loss of
glutathione S-transferase pi immunostaining preceding the development of PIN. None of the animals in this study developed invasive
carcinomas, differing from those in previous reports. Overall, these findings suggest that the pathogenesis of prostatic
neoplasia in the
PhIP-treated rat prostate proceeds from
inflammation to postinflammatory proliferative
atrophy to PIN.