Effect of Maternal Dietary B-Vitamin Intake on Offspring DNA Methylation Patterns, Gene Expression, Cytokinetics, and Intestinal Tumorigenesis in the Apc+/1638N Mouse Model.
Ciappio, Eric.
2011
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Abstract:
Epidemiological and laboratory data have repeatedly implicated one-carbon nutrients such
as folate, riboflavin (vitamin B2), vitamin B6, and vitamin B12 as being protective
against various cancers, most notably those of the colorectum. Deficiencies in one or
all of these nutrients have been shown in a variety of experimental settings to lead to
increases in genotoxic events associated ... read morewith cancer such as dysregulation of DNA
methylation as well as altered expression of several genes in the Wnt signaling pathway.
The role of maternal nutriture in determining offspring disease susceptibility is
increasingly recognized. Therefore, we aimed to determine whether a relationship between
maternal dietary B-vitamin intake and intestinal tumorigenesis in offspring was present
in a genetically engineered model of colorectal cancer. It was our central hypothesis
that supplemental levels of one-carbon nutrients in the maternal diet from preconception
through weaning would decrease, while deficient levels would increase, dysregulation in
DNA methylation patterns in Wnt pathway genes in the offspring that preserve apoptotic
function leading to a reduction in tumorigenesis. Three groups of 6-week old female
C57BL/6 mice were fed diets either deficient, replete, or supplemented with folate,
vitamin B2, B6, and B12 for 4 weeks, then mated with male Apc+/1638N mice. Females
remained on their respective diets throughout mating, pregnancy and the suckling period
(11 weeks total). Pups were genotyped at 3 weeks of age, and all wild type pups were
sacrificed. After weaning, all Apc+/1638N pups were fed a replete diet (AIN-93)
regardless of the maternal diet. At 32 weeks of age, 56% and 59% of Apc+/1638N pups born
to deficient and replete mothers, respectively, exhibited tumors in the small intestine
compared to 21% of pups born to supplemented mothers (p=0.031). Furthermore, a
significantly (p=0.026) higher percentage of tumors collected from pups of deficient
mothers (54%) displayed invasive features compared to tumors from pups of replete
mothers (18%). In the small intestine of 3-week old wild type pups as well as 32-week
old Apc+/1638N pups, the expression of several negative regulators of Wnt signaling such
as Apc, Sfrp1, Wif1, and Wnt5a was proportional to the concentration of B-vitamins in
the maternal diet. Furthermore, the expression of Sfrp1 was significantly and inversely
correlated with the degree of methylation within the promoter region of the gene.
Contrary to our expectations, an increase in apoptosis was observed among pups born to
deficient dams in both genotypes. Along with an elevation of beta-catenin in the small
intestine, these data are consistent with the hypothesis that the maternal diet affects
offspring tumorigenesis through a methylation induced de-repression of the Wnt pathway.
The results of the project described herein are among the first observations regarding
maternal B-vitamin intake and offspring colorectal carcinogenesis and provide the most
comprehensive dataset available to date regarding the potential mechanism mediating this
effect.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Joel Mason.
Committee: Jimmy Crott, Larry Feig, and Xiang-Dong Wang.
Keywords: Nutrition, Molecular biology, and Biology.read less - ID:
- c821gw98f
- Component ID:
- tufts:20286
- To Cite:
- TARC Citation Guide EndNote
