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

Eric D Ciappio, Zhenhua Liu, Ryan S Brooks, Joel B Mason,Roderick T Bronson,Jimmy W Crott
1Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA 2Rodent Histopathology Core, Harvard Medical School, Boston, Massachusetts, USA 2011

Background

Epidemiological data and controlled animal studies support a protective role for dietary folate and related B vitamins against colorectal cancer. Paradoxical tumour-promoting effect of folate

Maternal diet and environmental exposure are becoming increasingly recognized as important determinants of the risk for chronic disease in offspring.
Maternal folate supplementation appears to be protective against several paediatric cancers.

Protective role for high maternal folate intake against certain paediatric cancers in offspring
Retinoblastoma (French AE et al.,2003) Non-Hodgkins lymphoma (Schuz J et al.,2007) Acute lymphoblastic leukaemia (Thompson JR et al.,2001) Childhood brain tumours (GohYI et al.,2007)

The varying coat patterns reflect the degree of agouti gene expression from the Avy allele in the hair .follicle melanocytes

Cooney C A et al. J. Nutr. 2002;132:2393S-2400S

2002 by American Society for Nutrition

Study objective whether a mothers folate intake might impact on her offsprings risk of colorectal carcinogenesis?

Apc1638N mouse model The Apc1638N mouse model was utilised, with a targeted modification of exon 15 of one allele of the Apc gene Mice heterozygous for this particular mutation spontaneously develop between one and five small bowel adenomas or carcinomas.

Study Design

Ciappio E D et al. Gut 2011;60:1695-1702

Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Methods:

Vitamin analyses: Folate, B12, B6, B2 Nucleic acid analyses: Genomic DNA methylation Apoptosis and Proliferation: Caspase 3 activity, Ki-67 positive cells in the crypt

Periconceptional maternal B vitamin supplementation suppresses tumour occurrence, while depletion promotes tumour invasiveness in the small intestine of Apc1638N offspring.

Ciappio E D et al. Gut 2011;60:1695-1702

Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Effect of maternal B vitamin intake on the expression of select genes in the small intestine of weanling wild-type and adult Apc1638N offspring.

Ciappio E D et al. Gut 2011;60:1695-1702

Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Methylation and Expression

Effect of maternal B vitamin intake on the abundance of total -catenin protein in the small intestine mucosa of offspring.

Ciappio E D et al. Gut 2011;60:1695-1702

40-fold up regulation of Wnt pathway

Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Maternal B vitamin deficiency elevates apoptosis in the small intestine of offspring.

Caspase-3 activity as a prognostic factor in colorectal carcinoma (Jonges LE et al.,2001)

Ciappio E D et al. Gut 2011;60:1695-1702

Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Conclusion

Mechanistically, genomic DNA hypomethylation may cause chromosomal instability and loss, both recognized risk factors for cancer. Results from this paper suggest that maternal deficiency may initiate a specific metabolic programme, which, over time, results in genomic hypomethylation that might subsequently promote tumorigenesis. A de-repression of the Wnt pathway characterised by the hypermethylation and suppression of Sfrp1 and accumulation of b-catenin was observed with declining maternal B vitamin intake

loss of Sfrp1 function colorectal tumorigenesis

An early event in human

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 tumours in offspring acquiring an invasive phenotype. Baesd on this finding: Mothers who initiate B vitamin supplementation before conception may also be protecting their offspring against CRC in adulthood.