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Folic acid supplementation in the juvenile-pubertal period in rats leads to persistent tissue-specific changes in the expresison and methylation of the tumour suppressor gene BRCA1

Published online by Cambridge University Press:  14 October 2011

L. J. Rhodes ,
A. A. Jackson ,
M. A. Hanson ,
G. C. Burdge  and
K. A. Lillycrop
L. J. Rhodes
Affiliation:
Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
A. A. Jackson
Affiliation:
Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
M. A. Hanson
Affiliation:
Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
G. C. Burdge
Affiliation:
Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
K. A. Lillycrop
Affiliation:
Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
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Abstract

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Proceedings of the Nutrition Society , Volume 70 , Issue OCE4: Summer Meeting, 4–6 July 2011, 70th Anniversary: From plough through practice to policy , 2011 , E201
Copyright
Copyright © The Authors 2011

Micronutrient intake has been shown to influence cancer risk at least in part by modifying the epigenome(Reference Jang, Mason and Choi1). However, the effects of folic acid intake during critical phases of development on future cancer risk are not known. We investigated whether variations in folic acid intake in the juvenile-pubertal (JP) period in rats induced lasting changes in the expression of the tumour supressor gene BRCA1, which plays a key role in maintaining genome integrity(Reference Gudmundsdottir and Ashworth2).

The study was carried out in accordance with the Home Office Animals (Scientific Procedures) Act (1986). Female Wistar rats were fed a modified AIN93M semi-purified diet containing either 1 mg/kg feed folic acid (folate adequate (AF)) or 5 mg/kg feed folic acid (folic acid supplemented, FS) for 28 d from PN28 to PN56. After this period all rats were given AIN93M supplemented with 1mg/kg folic acid. Tissues were collected on PN84. mRNA expression measured by real time RT PCR(Reference Lillycrop, Phillips and Jackson3) and BRCA1 promoter methylation was measured by sodium bisulphite pyrosequencing(Reference Lillycrop, Phillips and Torrens4).

JP folic acid supplementation induced tissue specific changes in BRCA1 mRNA expression that persisted beyond the period of supplementation. BRCA1 mRNA expression was significantly increased in adipose tissue, but decreased in muscle. Altered BRCA1 expression was accompanied by tissue-specific changes in the methylation of specific CpGs in its promoter. In adipose tissue, folic acid supplementation increased the methylation of CpGs −15, +14, +33 and +47, while in muscle there was an increase in methylation at CpG+33.

mRNA and methylation levels were compared by Student's unpaired t-test. n 8 per treatment. CpG locations (bp) are relative to the transcription start site.

These data show that FA supplementation induced tissue-specific changes in the expression and methylation of BRCA1 which persist beyond the period of feeding the modified diet. This suggests that altered epigenetic regulation of BRCA1 is one possible mechanism by which folic supplementation, at least during the JP period, may modify cancer risk. Differences in the effect of folic acid between tissues may have implications for understanding variations in the effectiveness of folic acid supplementation in cancer prevention between disease types and clinical trials(5).

References

1.Jang, H, Mason, JB & Choi, SW (2005) J Nutr 135, 2967S–2971S.Google Scholar
2.Gudmundsdottir, K & Ashworth, A (2006) Oncogene 25, 5864–5874.Google Scholar
3.Lillycrop, KA, Phillips, ES, Jackson, AA et al. (2005) J Nutr 135, 1382–1386.CrossRefGoogle Scholar
4.Lillycrop, KA, Phillips, ES, Torrens, C et al. (2008) Br J Nutr 100, 278–282.Google Scholar
5.World Cancer Research Fund/American Institute for Cancer Research (2007) Food, nutrition, physical activity and the prevention of cancer: A global perspective. Washington DC: AICR;Google Scholar