Basic—Alimentary TractFolate Deficiency Induces Genomic Uracil Misincorporation and Hypomethylation But Does Not Increase DNA Point Mutations
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Experimental Mice and Diet Schedule
Big Blue Mice with the CII transgene (C57BL/6J background) were purchased from Stratagene (La Jolla, CA) and crossed with Ung−/− mice (129 background) that were previously generated in our lab.25 Ung+/− intercrosses with one parent Big Blue+/− generated the 2 experimental genotypes Big Blue+/−, Ung+/+ and Big Blue+/−, Ung−/−. The genetic background of all mice was 50% C57BL/6J and 50% 129. To control for genetic background effects, we evenly distributed littermates of the same genotype between
Folate Deficiency Causes Increased Plasma Homocysteine But Does Not Increase Tumor Numbers
To verify that the experimental diet was successful in achieving folate deficiency, we analyzed plasma folate levels at 3 months and 8 months of dietary intervention (Figure 1). Severe reduction of folate levels was seen after 3 months and persisted until the end of the experiment (88% decrease, P < .001). Parallel to the observed decrease in plasma folate, we detected an increase in plasma homocysteine (60% increase at 8 months, P < .001). Folate deficiency caused a moderate but not
Discussion
The primary goal of our study was to evaluate the genetic and epigenetic consequences of folate deficiency to help clarify the role of this nutrient in tumor development. Also, we wanted to investigate whether lack of the DNA repair enzyme Ung can increase point mutations during folate deficiency. We improved on previous studies by using a long-term dietary intervention (8 months) and by focusing on tissues with a high cell turnover rate, which is important for detecting passive loss of DNA
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The authors disclose the following: H.G.L. is supported by a postdoctoral fellowship from the Fritz-Thyssen Stiftung. This work was supported by Philip Morris International and National Institutes of Health grant NIH RO1-CA087869 to R.J., and by the US Department of Agriculture, Agricultural Research Service (agreement No. 58-1950-7-707). Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture.