Feb21.PAT530 Presentation

8/2/2019 Feb21.PAT530 Presentation

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Maternal B vitamin supplementation from

preconception through weaning suppresses intestinaltumorigenesis in Apc1638N mouse offspring

Eric D Ciappio, Zhenhua Liu, Ryan S Brooks, Joel B Mason,Roderick T Bronson,JimmyW Crott

1Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging atTufts University, Boston, Massachusetts, USA 2Rodent Histopathology Core, Harvard Medical School,

Boston, Massachusetts, USA 2011


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Paradoxical tumour-promoting effect of folate

Maternal diet and environmental exposure arebecoming increasingly recognized as importantdeterminants of the risk for chronic disease inoffspring.

Maternal folate supplementation appears to be protectiveagainst several paediatric cancers.

Background Epidemiological data and controlled animal

studies support a protective role for dietaryfolate and related B vitamins against colorectalcancer.


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Protective role for high maternal folateintake 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)


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.

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

2002 by American Society for Nutrition

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


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Study objective

whether a mothers folate intake might impact on her offsprings risk ofcolorectal carcinogenesis?


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Apc1638N mouse model

The Apc1638N mouse model was utilised, with a targetedmodification of exon 15 of one allele of the Apc geneMice heterozygous for this particular mutationspontaneously develop between one and five small bowel

adenomas or carcinomas.


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Study Design

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

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


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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


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




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



Methylation and Expression


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Methylation and Expression


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



40-fold up regulation

of Wnt pathway


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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)

C l i


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Mechanistically, genomic DNA hypomethylation may causechromosomal instability and loss, both recognized risk factorsfor cancer.

Results from this paper suggest that maternal deficiencymay initiate a specific metabolic programme, which, overtime, results in genomic hypomethylation that might

subsequently promote tumorigenesis.

A de-repression of the Wnt pathway characterisedby the hypermethylation and suppressionof Sfrp1 and accumulation of b-catenin was

observed with declining maternal B vitaminintake

loss of Sfrp1 function An early event in humancolorectal tumorigenesis

Conclusion


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Maternal supplementation with vitamins B2, B6, B12 andfolate markedly suppresses intestinal tumorigenesis in mouse

offspring

Exceedingly mild maternal B vitamin inadequacy increasesthe likelihood of tumours in offspring acquiring an invasivephenotype.

Baesd on this finding: Mothers who initiate B vitaminsupplementation before conception may also be protectingtheir offspring against CRC in adulthood.

Feb21.PAT530 Presentation

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