Objective Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however, the outcome appears to be dependent on timing. This study sought to determine the effect of altering folate (and related B vitamin) availability during in-utero development and the suckling period on intestinal tumorigenesis.
Design Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B2, B6, B12 and folate for 4 weeks before mating to Apc1638N males. Females remained on their diet throughout pregnancy and until weaning. After weaning, all Apc1638N offspring were maintained on replete diets for 29 weeks.
Results At 8 months of age tumour incidence was markedly lower among offspring of supplemented mothers (21%) compared with those of replete (59%) and deficient (55%) mothers (p=0.03). Furthermore, tumours in pups born to deficient dams were most likely to be invasive (p=0.03). The expression of Apc, Sfrp1, Wif1 and Wnt5a—all of which are negative regulatory elements of the Wnt signalling cascade—in the normal small intestinal mucosa of pups decreased with decreasing maternal B vitamin intake, and for Sfrp1 this was inversely related to promoter methylation. β-Catenin protein was elevated in offspring of deficient dams.
Conclusions These changes indicate a de-repression of the Wnt pathway in pups of deficient dams and form a plausible mechanism by which maternal B vitamin intake modulates tumorigenesis in offspring. These data indicate that maternal B vitamin supplementation suppresses, while deficiency promotes, intestinal tumorigenesis in Apc1638N offspring.
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Funding This work was supported by grants from the NIH; 2-T32-DK062032-18 (EDC) and 5-K05- CA100048-05 (JBM) and Prevent Cancer Foundation (ZL). This material is based upon work supported by the US Department of Agriculture, under agreement no 58-1950-7-707. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the US Department of Agriculture.
Ethics approval All animal procedures were approved by the institutional review board of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.
Provenance and peer review Not commissioned; externally peer reviewed.
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