Effects of dietary folate on intestinal tumorigenesis in the Apc(Min) mouse

Dietary folate appears to be inversely related to colorectal cancer risk, T his study investigated the effects of dietary intervention with folate on t he development of intestinal polyps in Min (Apc+/-) mice. Weanling Min mice were fed diets containing 0, 2 (basal requirement), 8, or 20 mg folate/kg diet, At 3 and 6 months of dietary intervention, 50% of the mice From each group were sacrificed, and the small intestine and colon were analyzed for polyps and aberrant crypt foci (ACF), Serum folate concentrations accuratel y reflected dietary folate levels (P < 0.001). At 3 months, no significant difference in the average number of total small intestinal polyps was obser ved among the four groups. However, increasing dietary folate levels signif icantly reduced the number of ileal, but not duodenal or jejunal, polyps in a dose-dependent manner (P-trend = 0.001); folate supplementation at 20 mg /kg diet was associated with a 68-78% reduction in the number of deal polyp s compared with the other three diets (P < 0.007). The number of ileal poly ps was inversely correlated with serum folate concentrations (P = 0.03). At 3 months, increasing dietary folate levels significantly decreased the num ber of colonic ACF in a dose-dependent manner (P = 0.05); the control and t wo folate supplemented diets significantly reduced the number of colonic AC F by 75-100% compared with the folate-deficient diet (P < 0.04). The number of colonic ACF was inversely correlated with serum folate concentrations ( P = 0.05). No significant difference in the number of colonic adenomas was observed among the four groups at 3 months. At 6 months, no significant dif ferences in the average number of total small intestinal, duodenal, and jej unal polyps, colonic adenomas, and colonic ACF were observed among the four groups. However, the folate-deficient diet had a 62-76% lower number of il eal polyps compared with the control and two Folate-supplemented diets (P < 0.003). Serum folate concentrations, but not dietary folate levels, were d irectly correlated with the number of ileal polyps (P = 0.006). These data suggest that dietary folate supplementation suppresses the development of i leal polyps and colonic ACF in this model. However, at later time points, f olate supplementation appears to have an opposite effect on heal polyps. Th ese data generally support the role of folate in intestinal tumorigenesis s uggested in epidemiological studies and chemical carcinogen animal models. Notwithstanding the limitations associated with this model, these data sugg est that the optimal timing and dose of folate intervention need to be dete rmined for safe and effective Folate chemoprevention.