There is accumulating evidence that high levels of
dietary iron may play a role in colon
carcinogenesis. We used a mouse model to investigate the impact of elevated
dietary iron on incidence of
aberrant crypt foci (ACF; a preneoplastic lesion) on
tumor formation and on induction of oxidative stress. A/J mice were injected intraperitoneally, once a week for 6 weeks, with the colonotropic
carcinogen,
azoxymethane (AOM) or saline (vehicle controls). Following AOM or saline treatments, mice were placed on diets of high (3,000 ppm) and low (30 ppm)
iron. Mice in each treatment group were sacrificed at 6 and 10 weeks following the final injection with AOM or saline. Colons were removed for subsequent histopathological analysis, which revealed average increases of 4.6 +- 1.3 vs. 10.4 +- 2.5 total
tumors at 6 weeks and 30.75 +- 2.7 vs. 41.5 +- 4.4 total
tumors at 10 weeks per AOM-treated mouse on low- and high-
iron diets, respectively. There were no significant differences in incidence of ACF attributable to
iron, although there was a trend toward greater crypt multiplicity per focus in mice on high-
iron diets. Notably, no
tumors were observed in mice receiving vehicle control
injections in place of
carcinogen, regardless of the level of
dietary iron. These data suggest that
iron exerts its effect at the stage of
tumor promotion, but is not sufficient to initiate
tumor formation. To learn more about mechanisms by which
iron promotes
tumor growth, colons were assayed for several
biomarkers of oxidative stress [BOS; total
F2-isoprostanes (F2-IsoPs), 15-F2t-isoprostanes (8-IsoPGF2s), Isofurans (IsoFs), and 8-hydroxyguanosines (8-
OH[d]Gs)], as well as
iron absorption, programmed cell death, and cellular proliferation. Elevated
PCNA and TUNEL staining of the colon epithelium revealed hyperproliferative and apoptotic responses to
iron, while no significant differences between
iron groups were observed in each of the BOS that were assayed. Our results suggest that, following
carcinogen exposure, elevated
dietary iron promotes the growth of
tumors with altered cellular homeostasis through a mechanism that is independent of oxidative stress.