Carcinogenesis Advance Access originally published online on June 18, 2009
Carcinogenesis 2009 30(9):1536-1543; doi:10.1093/carcin/bgp152
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Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci
1 Department of Nutritional Sciences
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
3 Department of Pathology, Humber River Regional Hospital, Toronto, Ontario, Canada M9N 1N8
4 Department of Medicine
5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
6 Statistical Consultant, 300 Willow Avenue, Toronto, Ontario, Canada M4E 3K7
7 Division of Gastroenterology, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8
* To whom correspondence should be addressed. Department of Medicine and Nutritional Sciences, Room 7258, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8. Tel: +1 416 978 1183; Fax: +1 416 978 8765; Email: youngin.kim{at}utoronto.ca
Whether or not folic acid supplementation promotes the progression of colorectal preneoplastic lesions to cancer is an important public health issue, given mandatory fortification and widespread supplemental use of folic acid in North America. We investigated the effect of folic acid supplementation on the progression of aberrant crypt foci (ACF), the earliest precursor of colorectal cancer. Male Sprague-Dawley rats (n = 152) were placed on a control diet (2 mg folic acid/kg diet) at weaning and ACF were induced by azoxymethane. Six weeks post-ACF induction, rats were randomized to receive 0, 2, 5 or 8 mg folic acid/kg diet. At 34 weeks of age, rats were killed, and colorectal tumor parameters, plasma folate and homocysteine (a sensitive inverse indicator of tissue folate status) concentrations and rectal epithelial proliferation were determined. Although the number of ACF increased as dietary folic acid levels increased (P = 0.015), the incidence of colorectal tumors did not differ significantly among the four dietary groups. However, tumor multiplicity was positively correlated with dietary folic acid levels (r = 0.32; P = 0.002) and inversely with plasma homocysteine concentrations (r = –0.32; P = 0.005). Tumor burden was positively correlated with dietary folic acid levels (r = 0.35; P = 0.001) and plasma folate concentrations (r = 0.33; P = 0.008) and inversely with plasma homocysteine concentrations (r = –0.42; P < 0.001). Rectal epithelial proliferation was positively correlated with dietary folic acid levels (r = 0.39; P < 0.001) and plasma folate concentrations (r = 0.34; P < 0.001) and inversely with plasma homocysteine concentrations (r = –0.37; P < 0.001). Our data suggest that folic acid supplementation may promote the progression of ACF to colorectal tumors.
Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; BDR, basal dietary requirement; CI, confidence interval; RDA, recommended dietary allowance
Received March 31, 2009; revised June 1, 2009; accepted June 9, 2009.