Effect of maternal and postweaning folic acid supplementation on mammary tumor r

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Cancer Res. 2011 Feb 1;71(3):988-97. Epub 2010 Dec 6.

Effect of maternal and postweaning folic acid supplementation on mammary tumor

risk in the offspring.

Ly A, Lee H, Chen J, Sie KK, Renlund R, Medline A, Sohn KJ, Croxford R,

LU, Kim YI.

Department of Nutritional Sciences, University of Toronto, Ontario, Canada.

Abstract

Intrauterine and early life exposure to folic acid has significantly increased

in North America owing to folic acid fortification, widespread supplemental use,

and periconceptional supplementation. We investigated the effects of maternal

and postweaning folic acid supplementation on mammary tumor risk in the

offspring. Female rats were placed on a control or folic acid-supplemented diet

prior to mating and during pregnancy and lactation. At weaning, female pups from

each maternal diet group were randomized to the control or supplemented diet and

mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At

necropsy, mammary tumor parameters, genomic DNA methylation, and DNA

methyltransferase activity were determined in the offspring. Both maternal and

postweaning folic acid supplementation significantly increased the risk of

mammary adenocarcinomas in the offspring (OR = 2.1, 95% CI 1.2-3.8, P = 0.008

and OR = 1.9, 95% CI 1.1-3.3, P = 0.03, respectively). Maternal folic acid

supplementation also significantly accelerated the rate of mammary

adenocarcinoma appearance (P = 0.002) and increased the multiplicity of mammary

adenocarcinomas (P = 0.008) in the offspring. Maternal, but not postweaning,

folic acid supplementation significantly reduced global DNA methylation (P =

0.03), whereas postweaning, but not maternal, folic acid supplementation

significantly decreased DNA methyltransferase activity (P = 0.05) in

nonneoplastic mammary glands of the offspring. Our findings suggest that a high

intrauterine and postweaning dietary exposure to folic acid may increase the

risk of mammary tumors in the offspring. Further, they suggest that this

tumor-promoting effect may be mediated in part by altered DNA methylation and

DNMT activity.