Genes & Nutrition

, Volume 6, Issue 2, pp 189–196

Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring

  • Jill A. McKay
  • Kevin J. Waltham
  • Elizabeth A. Williams
  • John C. Mathers
Research Paper

Abstract

The developmental origins of adult health and disease (DOHaD) hypothesis that argues for a causal relationship between under-nutrition during early life and increased risk for a range of diseases in adulthood is gaining epidemiological support. One potential mechanism mediating these effects is the modulation of epigenetic markings, specifically DNA methylation. Since folate is an important methyl donor, alterations in supply of this micronutrient may influence the availability of methyl groups for DNA methylation. We hypothesised that low folate supply in utero and post-weaning would alter the DNA methylation profile of offspring. In two separate 2 × 2 factorial designed experiments, female C57Bl6/J mice were fed low- or control/high-folate diets during mating, and through pregnancy and lactation. Offspring were weaned on to either low- or control/high-folate diets, resulting in 4 treatment groups/experiment. Genomic DNA methylation was measured in the small intestine (SI) of 100-day-old offspring. In both experiments, SI genomic DNA from offspring of low-folate-fed dams was significantly hypomethylated compared with the corresponding control/high folate group (P = 0.009/P = 0.006, respectively). Post-weaning folate supply did not affect SI genomic DNA methylation significantly. These observations demonstrate that early life folate depletion affects epigenetic markings, that this effect is not modulated by post-weaning folate supply and that altered epigenetic marks persist into adulthood.

Keywords

Folate DNA methylation Pregnancy Development Mouse 

References

  1. 1.
    Balaghi M, Wagner C (1993) DNA methylation in folate deficiency: use of cpg methylase. Biochem Biophys Res Commun 193(3):1184–1190PubMedCrossRefGoogle Scholar
  2. 2.
    Barker DJ (2004) The developmental origins of well-being. Philos Trans R Soc Lond B Biol Sci 359(1449):1359–1366PubMedCrossRefGoogle Scholar
  3. 3.
    Basten GP, Hill MH, Duthie SJ, Powers HJ (2004) Effect of folic acid supplementation on the folate status of buccal mucosa and lymphocytes. Cancer Epidemiol Biomarkers Prev 13(7):1244–1249PubMedGoogle Scholar
  4. 4.
    Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE (2004) Developmental plasticity and human health. Nature 430(6998):419–421PubMedCrossRefGoogle Scholar
  5. 5.
    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21PubMedCrossRefGoogle Scholar
  6. 6.
    Calvanese V, Lara E, Kahn A, Fraga MF (2009) The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8(4):268–276PubMedCrossRefGoogle Scholar
  7. 7.
    Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfan E (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14(4):551–557PubMedCrossRefGoogle Scholar
  8. 8.
    Cooney CA, Dave AA, Wolff GL (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132(8 Suppl):2393S–2400SPubMedGoogle Scholar
  9. 9.
    Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL (2006) Maternal genistein alters coat color and protects avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114(4):567–572PubMedCrossRefGoogle Scholar
  10. 10.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767PubMedCrossRefGoogle Scholar
  11. 11.
    Ferguson LR, Karunasinghe N, Philpott M (2004) Epigenetic events and protection from colon cancer in New Zealand. Environ Mol Mutagen 44(1):36–43PubMedCrossRefGoogle Scholar
  12. 12.
    Frey L, Hauser WA (2003) Epidemiology of neural tube defects. Epilepsia 44(Suppl 3):4–13PubMedCrossRefGoogle Scholar
  13. 13.
    Hughes LA, van den Brandt PA, de Bruine AP, Wouters KA, Hulsmans S, Spiertz A, Goldbohm RA, de Goeij AF, Herman JG, Weijenberg MP, van Engeland M (2009) Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms. PLoS One 4(11):e7951PubMedCrossRefGoogle Scholar
  14. 14.
    Johnson KJ, Springer NM, Bielinsky AK, Largaespada DA, Ross JA (2009) Developmental origins of cancer. Cancer Res 69(16):6375–6377PubMedCrossRefGoogle Scholar
  15. 15.
    Kim JM, Hong K, Lee JH, Lee S, Chang N (2009) Effect of folate deficiency on placental DNA methylation in hyperhomocysteinemic rats. J Nutr Biochem 20(3):172–176PubMedCrossRefGoogle Scholar
  16. 16.
    Kim MS, Lee J, Sidransky D (2010) DNA methylation markers in colorectal cancer. Cancer Metastasis Rev 29 (1):181–206Google Scholar
  17. 17.
    Kotsopoulos J, Sohn KJ, Kim YI (2008) Postweaning dietary folate deficiency provided through childhood to puberty permanently increases genomic DNA methylation in adult rat liver. J Nutr 138(4):703–709PubMedGoogle Scholar
  18. 18.
    Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K (2006) Red blood cell folate concentrations increase more after supplementation with [6 s]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 84(1):156–161PubMedGoogle Scholar
  19. 19.
    Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135(6):1382–1386PubMedGoogle Scholar
  20. 20.
    Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa JP (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20(3):332–340PubMedCrossRefGoogle Scholar
  21. 21.
    McKay JA, Williams EA, Mathers JC (2008) Gender-specific modulation of tumorigenesis by folic acid supply in the apc mouse during early neonatal life. Br J Nutr 99(3):550–558PubMedCrossRefGoogle Scholar
  22. 22.
    Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247(4940):322–324PubMedCrossRefGoogle Scholar
  23. 23.
    Ozanne SE, Constancia M (2007) Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab 3(7):539–546PubMedCrossRefGoogle Scholar
  24. 24.
    Pogribny I, Yi P, James SJ (1999) A sensitive new method for rapid detection of abnormal methylation patterns in global DNA and within cpg islands. Biochem Biophys Res Commun 262(3):624–628PubMedCrossRefGoogle Scholar
  25. 25.
    Pogribny IP, Karpf AR, James SR, Melnyk S, Han T, Tryndyak VP (2008) Epigenetic alterations in the brains of fisher 344 rats induced by long-term administration of folate/methyl-deficient diet. Brain Res 1237:25–34PubMedCrossRefGoogle Scholar
  26. 26.
    Pogribny IP, Ross SA, Wise C, Pogribna M, Jones EA, Tryndyak VP, James SJ, Dragan YP, Poirier LA (2006) Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency. Mutat Res 593(1–2):80–87PubMedGoogle Scholar
  27. 27.
    Reeves PG, Nielsen FH, Fahey GC Jr (1993) Ain-93 purified diets for laboratory rodents: final report of the American institute of nutrition ad hoc writing committee on the reformulation of the ain-76a rodent diet. J Nutr 123(11):1939–1951PubMedGoogle Scholar
  28. 28.
    Sakanashi TM, Rogers JM, Fu SS, Connelly LE, Keen CL (1996) Influence of maternal folate status on the developmental toxicity of methanol in the cd-1 mouse. Teratology 54(4):198–206PubMedCrossRefGoogle Scholar
  29. 29.
    Scholl TO, Johnson WG (2000) Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 71(5 Suppl):1295S–1303SPubMedGoogle Scholar
  30. 30.
    Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE (2007) DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional b vitamin and methionine status. Proc Natl Acad Sci USA 104(49):19351–19356PubMedCrossRefGoogle Scholar
  31. 31.
    Slattery ML, Wolff RK, Curtin K, Fitzpatrick F, Herrick J, Potter JD, Caan BJ, Samowitz WS (2009) Colon tumor mutations and epigenetic changes associated with genetic polymorphism: Insight into disease pathways. Mutat Res 660(1–2):12–21PubMedGoogle Scholar
  32. 32.
    Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA, Slagboom PE, Heijmans BT (2009) Periconceptional maternal folic acid use of 400 μg per day is related to increased methylation of the igf2 gene in the very young child. PLoS One 4(11):e7845PubMedCrossRefGoogle Scholar
  33. 33.
    Trentin GA, Moody J, Heddle JA (1998) Effect of maternal folate levels on somatic mutation frequency in the developing colon. Mutat Res 405(1):81–87PubMedGoogle Scholar
  34. 34.
    Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23(15):5293–5300PubMedCrossRefGoogle Scholar
  35. 35.
    Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in avy/a mice. Faseb J 12(11):949–957PubMedGoogle Scholar
  36. 36.
    Xiao S, Hansen DK, Horsley ET, Tang YS, Khan RA, Stabler SP, Jayaram HN, Antony AC (2005) Maternal folate deficiency results in selective upregulation of folate receptors and heterogeneous nuclear ribonucleoprotein-e1 associated with multiple subtle aberrations in fetal tissues. Birth Defects Res Clin Mol Teratol 73(1):6–28CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jill A. McKay
    • 1
  • Kevin J. Waltham
    • 1
  • Elizabeth A. Williams
    • 2
  • John C. Mathers
    • 1
  1. 1.Human Nutrition Research Centre, Institute for Ageing and HealthNewcastle UniversityNewcastleUK
  2. 2.Human Nutrition Unit, Department of OncologyUniversity of SheffieldSheffieldUK

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