Fortification of grains has resulted in a positive public health outcome vis-a-vis reduced incidence of neural tube defects. Whether folate has a correspondingly beneficial effect on other disease outcomes is less clear. A role for dietary folate in the prevention of colorectal cancer has been established through epidemiological data. Experimental data aiming to further elucidate this relationship has been somewhat equivocal. Studies report that folate depletion increases DNA damage, mutagenesis, and chromosomal instability, all suggesting inhibited DNA repair. While these data connecting folate depletion and inhibition of DNA repair are convincing, we also present data demonstrating that genetic inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. The purpose of this paper is to (1) give an overview of the data demonstrating a DNA repair defect in response to folate depletion, and (2) critically compare and contrast the experimental designs utilized in folate/colorectal cancer research and the corresponding impact on tissue folate status and critical colorectal cancer endpoints. Our analysis suggests that there is still an important need for a comprehensive evaluation of the impact of differential dietary prescriptions on blood and tissue folate status. 1. Introduction Folate deficiency has been linked to a variety of pathologic conditions and cancers. Perhaps most notably, folate is required during pregnancy for normal development of the neural tube closure. Once the connection between reduced dietary folate consumption and neural tube defects (NTDs) was well established, the FDA mandated fortification of grain-based foods with folic acid. This mandate resulted in a >25% decrease in incidence of NTDs in the United States [1]. This fortification resulted in a slight bump in average serum folate levels in the United States from approximately 12？ng/mL to approximately 19？ng/mL [2]. Normal range for serum folate concentration in humans is 2.7–17？ng/mL [3]. Thus, folate fortification has resulted in a positive public health outcome for its intended population, women of childbearing age, through moderate increases in serum folate levels and significant reduction in NTD incidence. However, folate is also strongly connected through epidemiological data to an increased risk to develop colorectal cancer. Unlike prevention of NTDs which targets young, healthy populations, colorectal cancer is primarily a disease of aging. Concern for whether folate fortification may be
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