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Effects of Dietary Folate on Intestinal Tumorigenesis in the Apc^Min Mouse¹

Departments of Medicine [Y-I. K.], Nutritional Sciences [J. S., Y-I. K.], Pathology [A. M.], and Surgery [S. G.], University of Toronto, Toronto, Ontario, M5S 1A8 Canada; Division of Gastroenterology, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, M5B 1W8 Canada [Y-I. K.]; Samuel Lunenfeld Research Institute Center for Cancer Genetics, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada [S. G.]; Vitamin Metabolism Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, and Divisions of Gastroenterology and Clinical Nutrition, Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111 [J. B. M.]

Dietary folate appears to be inversely related to colorectal cancer risk. This study investigated the effects of dietary intervention with folate on the 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 accurately reflected dietary folate levels (P < 0.001). At 3 months, no significant difference in the average number of total small intestinal polyps was observed among the four groups. However, increasing dietary folate levels significantly 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 ileal polyps compared with the other three diets (P < 0.007). The number of ileal polyps was inversely correlated with serum folate concentrations (P = 0.03). At 3 months, increasing dietary folate levels significantly decreased the number of colonic ACF in a dose-dependent manner (P = 0.05); the control and two folate supplemented diets significantly reduced the number of colonic ACF 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 differences in the average number of total small intestinal, duodenal, and jejunal polyps, colonic adenomas, and colonic ACF were observed among the four groups. However, the folate-deficient diet had a 62–76% lower number of ileal polyps compared with the control and two folate-supplemented diets (P < 0.003). Serum folate concentrations, but not dietary folate levels, were directly correlated with the number of ileal polyps (P = 0.006). These data suggest that dietary folate supplementation suppresses the development of ileal polyps and colonic ACF in this model. However, at later time points, folate supplementation appears to have an opposite effect on ileal polyps. These data generally support the role of folate in intestinal tumorigenesis suggested in epidemiological studies and chemical carcinogen animal models. Notwithstanding the limitations associated with this model, these data suggest that the optimal timing and dose of folate intervention need to be determined for safe and effective folate chemoprevention.

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