Maternal B vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc1638N mouse offspring

Abstract

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.

Folate and DNA Methylation

“…In contrast, maternal FA supplementation at the same level and duration significantly increased colorectal genomic methylation by 3%, and reduced the odds of developing colorectal tumors in the offspring (143). Similarly, in the Apc 1638N spontaneous mouse model of CRC, the offspring of B-vitamin (including FA) supplemented mothers displayed a mild degree of genomic hypomethylation in the small intestine mucosa and decreased tumor occurrence (24). This suggests that the effect of maternal FA supplementation on cancer risk in the offspring may be organ specific, and the outcome may be mediated by changes in global DNA methylation.…”

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

“…Thus, formation of phosphatidy-linositol is required for phosphorylation of Lrp6, which then stimulates Wnt/β-catenin signaling [Tanneberger et al, 2011]. In the gut, Wnt signaling is also stimulated under conditions of a low folate diet, causing a higher incidence of APC-dependent tumors [Ciappio et al, 2011]. Folate and Vitamin B supplementation to pregnant dams lowered tumor incidence in the offspring.…”

One-Carbon Metabolism Nutrients and Epigenetics: A Mechanistic Link Between Aberrant One-Carbon Metabolism and Cancer Risk?

“…Evidence for the potential cancer modulating effects of maternal environment in the offspring is largely demonstrated in animal studies, since cancer is an age-related disease and requires a lengthy follow-up period for diagnosis. Two animal studies have demonstrated the protective effects of maternal folic acid supplementation alone or in combination with vitamins B 2 , B 6 , and B 12 (Ciappio et al 2011a ) on colorectal and small intestinal tumorigenesis, respectively, in the offspring. In contrast, another animal study demonstrated that a maternal diet defi cient in folic acid had a protective effect on small intestinal cancer in the offspring , whereas another study found no effect of maternal folate depletion on small intestinal tumorigenesis (McKay et al 2011c ).…”