963 Iron (III)-Sodium-EDTA As Used for Food Fortification Aggravates Intestinal Inflammation and Drives Tumorigenesis in Mouse Models of Colitis-Associated Cancer

Abstract

Background: Western lifestyle is associated with increasing prevalence of IBD, processed food and food fortification being a likely cause. Iron supplementation may increase gut inflammation and colitis-associated cancer (CAC). Novel Fe products which are chemically not Fe(II) salts and presumably better tolerated have become available. Methods: Here we compared various Fe compounds at 450mg elemental Fe/kg chow [Na-EDTA-Fe(III) (as used for food fortification), Fe(III) maltol (Iron Therapeutics Ltd), plant Fe (Biogena, Austria), and Fe(II)SO4)], in their potential to promote colitis and CAC in animal models of IBD (AOM/DSS and IL-10-/-). In addition, experiments were performed in vitro to evaluate their impact on ROS production (DCFD assay), DNA damage ( γH2AX) and activation of oncogenic pathways (in HT29, HCT116, Caco-2 and RKO, and the normal colonic cell line 1CT). Results: Unexpectedly, Na-EDTA-Fe(III)-treated mice developed the severest form of colitis and only the 1st and 4th DSS cycles were administered. Similarly, in IL-10-/mice, the NaEDTA-Fe(III) group was euthanized 4 months before all other groups due to severe weight loss and disease activity (DAI). The mean DAI in the Na-EDTA-Fe(III) AOM/DSS mice was higher (1.82 vs. 0.94 (control), 0.76 (Fe(II)SO4), 0.67 (Fe(III) maltol), 0.54 (plant Fe), 0.80 (ID); p<0.001 by ANOVA). The total tumor area per mouse was higher with Na-EDTAFe(III) (Figure; p=0.001 by ANOVA), and there were more invasive tumors. ROS production was not elevated but there was an increase in γH2AX with Na-EDTA-Fe(III) and phosphorylation of Akt and Erk. Conclusion: Na-EDTA-Fe(III), as it is commonly used for food fortification in flour products and cereals, exacerbates intestinal inflammation and drives tumorigenesis in mouse models of IBD. It is currently unclear whether this toxic effect is caused by EDTA itself (which also is added to food as Na-EDTA or Na-EDTA-Ca(II)) or only in