Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci

Abstract

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.

Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring

“…lesions, similar to the tumor promoting effect of folic acid supplementation on established (pre)neoplastic colonic lesions (11)(12)(13)(14). Another potential explanation for the contradictory finding between these studies is that terminal end bud density at puberty may not be a consistent predictor of mammary tumor risk in rodents as suggested by recent studies (40,41).…”

“…Amino acid-defined diets containing different levels of folic acid constitute a standard method of providing supplemental dietary folate in rodents and have been extensively used in previous studies of dietary folate and cancer in rodents (10)(11)(12)(13)(14) including mammary tumors (25,26). The control diet containing 2 mg of folic acid/kg diet is the basal dietary requirement (BDR) for rats (27) and was selected to represent the recommended dietary allowance for humans (0.4 mg/d of dietary folate equivalents).…”

“…Combined analyses of two Norwegian cardiovascular secondary prevention trials reported that folic acid (0.8 mg/d) and vitamin B12 significantly increased cancer incidence, cancer mortality, and all-cause mortality (9). Furthermore, animal studies have shown that folic acid supplementation prevents the development of cancer in normal tissues but promotes the progression of established (pre)neoplastic lesions (10)(11)(12)(13)(14). Animal studies have also suggested that supraphysiologic supplemental doses of folic acid may promote, rather than prevent, the cancer development (11).…”

Modulation of One-Carbon Metabolism by B Vitamins: Implications for Transformation and Progression of Prostate Cancer

“…However, studies thus far have been inconsistent and not confirmed this assumption save for a possible benefit in stroke prevention (Chen, J (J), Xu, X (X), et al, 2010;Wang et al, 2007;Robinson et al, 1998) and thrombophilia. Alarmingly, there are now laboratory animal (Lindzon et al, 2009;Ly et al, 2011) and epidemiological reports pointing to excessive malignancy, including prostate (Figueiredo et al, 2009), breast ({Campbell 2002Chen et al, 2005;Ericson et al, 2009;Stevens et al, 2010) colorectal and other cancers (Kim, 2005) associated with both hyper and hypo-sufficiency of folate and folate enzyme polymorphisms, reviewed by Young-In Kim and others Kim, 2008;Kim, 2005;Smith et al, 2008) …”

Quantification of Total Folate, Folate Species and Polyglutamyl Folate Distribution in Winged Beans (<i>Psophocarus tetragonolobus</i> (L) DC) from Different Cultivars and Growth Stages by Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry

“…In addition, polyglutamyl folate shows bioavailability equal to or higher than that of monoglutamyl folate (10)(11)(12). Pteroylmonoglutamyl folate has shown some adverse effects on human health (13,14). Therefore, many countries in EU ban the fortification of food with pteroylmonoglutamyl folate and recommend that people consume food with high native folate.…”