Submitted to: Gut
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2011
Publication Date: 12/1/2011
Citation: Crott, J., Ciappio, E., Liu, Z., Brooks, R., Mason, J., Bronson, R.T. 2011. Maternal B-vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc+/1638N mouse offspring. Gut. 60(12):1695-1702. Interpretive Summary: Epidemiological data and controlled animal studies support a protective role for dietary folate and related B vitamins against colorectal cancer. Maternal diet and environmental exposure are becoming increasingly recognized as important determinants of the risk for chronic disease in offspring. In addition to its established role in preventing birth defects, maternal folate supplementation appears to be protective against several pediatric cancers. We now show that maternal supplementation with vitamins B2, B6, B12 and folate markedly suppresses intestinal tumorigenesis in mouse offspring. Exceedingly mild maternal B vitamin inadequacy increases the likelihood of tumors in offspring invading surrounding tissue. These findings might impact clinical practice in the foreseeable future. Mild deficiencies of vitamins B2, B6 and B12 persist in 10-50% of the population of industrialized nations such as the US and UK. In addition, although maternal folic acid supplementation is widespread, it frequently is not initiated until after conception. These data indicate that maternal B vitamin supplementation may not only protect offspring against birth defects but also against colorectal cancer in adulthood.
Technical Abstract: Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however the outcome appears to be dependent on timing. We sought to determine the effect of altering folate (and related B vitamin) availability during in utero development and the suckling period on intestinal tumorigenesis. Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B2, B6, B12 and folate for 4 wk 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. At 8 months of age tumor incidence was markedly lower amongst offspring of supplemented mothers (21%) compared to those of replete (59%) and deficient (55%) mothers (P=0.03). Furthermore, tumors in pups born to deficient dams were most likely to be invasive (P=0.03). Expression of Apc, Sfrp1, Wif1 and Wnt5a - all of which are negative regulatory elements of the Wnt signaling 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. b-catenin protein was elevated in offspring of deficient dams. 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 Apc+/1638N offspring.