Carcinogenesis, Vol 19, 1209-1215, Copyright © 1998 by Oxford University Press
EG Snyderwine, CD Davis, HA Schut and SJ Roberts-Thomson
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic
amine derived from cooked meat that is a mammary gland carcinogen in rats.
A carcinogenic dose-regimen of PhIP (75 mg/kg, p.o., 10 doses, once per
day) was administered to 43-day old female Sprague-Dawley rats, and the
rats were then placed on a defined high fat (23.5% corn oil) or low fat (5%
corn oil) diet for up to 6 weeks. At various times after carcinogen and
diet, and prior to carcinogenesis, we examined the percentage of
proliferating cells in terminal end bud (TEB) epithelial structures of the
rat mammary gland by proliferating cell nuclear antigen staining, mammary
gland architecture by whole mounting, and PhIP-DNA adduct levels in mammary
epithelial cells by the 32P-post-labeling assay. Immediately after dosing,
the percentage of proliferating epithelial cells in TEBs was significantly
higher in PhIP-treated rats than in control rats receiving vehicle only
[7.5 +/- 0.9% (n = 99) versus 4.2 +/- 0.6% (n = 127), respectively]. The
mammary glands of PhIP-treated rats showed a significantly lower density of
alveolar buds (ABs) and a higher density of TEBs than control rats, which
suggests that PhIP exposure partially inhibited the normal glandular
differentiation of TEBs to ABs. After 6 weeks on the diet, proliferation in
TEBs was statistically higher in rats given PhIP plus a high fat diet than
in rats given vehicle plus a low fat diet. The mammary glands from rats on
a high fat diet also showed a statistically higher density of TEBs when
compared with rats on a low fat diet [2.08 +/- 0.34% versus 1.04 +/- 0.20%,
respectively (n = 6)]. PhIP-DNA adduct levels were relatively high in
mammary epithelial cells of treated rats. At 3 h after the last dose of
PhIP, DNA adduct levels [relative adduct labeling (RAL) x 10(7), mean +/-
SE] were 10.5 +/- 1.7 (n = 8) and 0.9 +/- 0.2 (n = 7) in epithelial cells
isolated from mammary gland and in the liver, respectively. DNA adduct
removal rates from the mammary gland were not different between rats on the
high fat and low fat diets. Adducts were still detected after 6 weeks on
either diet. Thus, events that occurred prior to neoplasia in the mammary
glands of PhIP-treated rats include formation of PhIP-DNA adducts at
relatively high levels, and enhanced proliferation in TEBs (putative sites
of origin of mammary gland carcinomas) and partial inhibition of TEB
differentiation. The high fat diet, a promoter of PhIP-induced mammary
gland carcinogenesis, appeared to sustain the proliferative effect of PhIP
in mammary gland TEBs at a time when PhIP- DNA adducts are still
detectable. These early events may contribute to the targeting and
carcinogenicity of PhIP to the mammary gland of rats.
ARTICLES
Proliferation, development and DNA adduct levels in the mammary gland of rats given 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and a high fat diet
Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
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