Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix

Abstract

Objective-The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the USA is associated with changes in DNA methyltransferase (Dnmt) 1 expression in cells involved in cervical carcinogenesis.Methods-Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before and after mandatory folic acid fortification (2000-02) were used to examine the expression of Dnmt 1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the pre-fortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt 1, its assessment and data entry were blinded with regard to the fortification status.Results-Age-and race-adjusted mean percentage of cells positive for Dnmt 1 or the Dnmt 1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN or carcinoma in situ) detected in the postfortification period compared to pre-fortification period (P < 0.05, all comparisons). The degree of Dnmt 1 was significantly higher (P < 0.0001) in ≥ CIN 2 lesions compared to ≤ CIN 1 lesions, regardless of the fortification group. Conclusions-These results suggest that mandatory fortification with folic acid in the UnitedStates seem to have resulted in a change in the degree of expression of Dnmt 1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt 1, validating these results in other study populations and or with other techniques of assessing Dnmt 1 will increase the scientific credibility of these findings.

Serum Folate and Cancer Mortality Among U.S. Adults: Findings from the Third National Health and Nutritional Examination Survey Linked Mortality File

“…A recent study reported a temporal association of folic acid fortification with an increase in colorectal cancer incidence rates in the United States (29). Another study suggested that folic acid fortification resulted in a change in the degree of expression of DNA methyltransferase in cells involved in cervical carcinogenesis that was consistent with an increased risk for cancer (57). Our scenario 2 sensitivity analysis, which was restricted to individuals with a history of cancer at baseline, yielded HRs >1.0 for those in the higher quintiles of serum folate.…”

We are what we Eat: How Nutritional Compounds Such as Isoflavones Shape Our Epigenome

“…A recent study suggests a link between dietary folate levels and Dnmt1 expression. An increase in the expression of Dnmt1 was observed in cervical intraepithelial neoplasia samples compared with samples collected prior to mandatory fortification of grain products with folic acid in the United States (Piyathilake et al, 2008). Dnmt1 has also been shown to be reduced in the liver of rat offspring born to protein-restricted mothers (Lillycrop et al, 2007).…”

“…SAM is formed from methyl groups derived from choline, methionine, or methyl-tetrahydrofolate, and is the primary methyl donor for the various methyltransferase enzymes within an organism (Zeisel, 2009). The end product of SAM metabolism is S-adenosylhomocysteine (SAH), which forms a negative feedback loop via direct inhibition of these methylation reactions (Hirsch et al, 2008;Piyathilake et al, 2008). There is a correlation between the availability of methyl groups in the diet and levels in an organism.…”

Epigenetic Effects of Nutrients and the Promise for Refined Cardiovascular Disease Prevention

“…hypoacetylation and lysine 20 (H4K20) hypermethylation [6]. Second, arachidonic acid induced DNA hypermethylation in endothelial cells, suggesting that the organism's fatty acid pool may regulate vascular tissue homeostasis by imposing epigenetic changes [36].…”

“…D hypermethylation [46] pro vitamin A hypermethylation [36] folic acid hypermethylation [47] Antibiotics hypermethylation [45] Arsenic hypermethylation [48] The selected examples discussed above indicate that the human population is exposed to a cocktail of potential and proven epigenome modifiers, which may significantly affect human health and vascular disease risk in particular (Table 1). Arguably, the issue is a burning one especially in transition countries but does not spare any population group.…”