Skip to main content

Maternal diet as a modifier of offspring epigenetics

  • K. A. Lillycrop (a1) and G. C. Burdge (a2)

There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Maternal diet as a modifier of offspring epigenetics
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Maternal diet as a modifier of offspring epigenetics
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Maternal diet as a modifier of offspring epigenetics
      Available formats
Corresponding author
*Address for correspondence: Dr K. A. Lillycrop, Institute of Developmental Sciences Building (MP887), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. (Email
Hide All
1. Hossain, P, Kawar, B, El Nahas, M. Obesity and diabetes in the developing world – a growing challenge. N Engl J Med. 2007; 356, 213215.
2. Ramachandran, A, Snehalatha, C. Rising burden of obesity in Asia. J Obes. 2010; 2010, vol. 2010, Article ID 868573, 8 pages, 2010. doi:10.1155/2010/868573.
3. Manolio, TA, Collins, FS, Cox, NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009; 461, 747753.
4. Godfrey, KM, Barker, DJ. Fetal programming and adult health. Public Health Nutr. 2001; 4, 611624.
5. Curhan, GC, Willett, WC, Rimm, EB, et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation. 1996; 94, 32463250.
6. McCance, DR, Pettitt, DJ, Hanson, RL, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994; 308, 942945.
7. Hanson, MA, Gluckman, PD. Developmental origins of health and disease: new insights. Basic Clin Pharmacol Toxicol. 2008; 102, 9093.
8. Roseboom, T, de, RS, Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006; 82, 485491.
9. Bertram, CE, Hanson, MA. Animal models and programming of the metabolic syndrome. Br Med Bull. 2001; 60, 103121.
10. Samuelsson, AM, Matthews, PA, Argenton, M, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension. 2008; 51, 383392.
11. Burns, SP, Desai, M, Cohen, RD, et al. Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest. 1997; 100, 17681774.
12. Torrens, C, Poston, L, Hanson, MA. Transmission of raised blood pressure and endothelial dysfunction to the F2 generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1 generation. Br J Nutr. 2008; 100, 760766.
13. Calder, PC, Yaqoob, P. The level of protein and type of fat in the diet of pregnant rats both affect lymphocyte function in the offspring. Nutr Res. 2000; 20, 9951005.
14. Langley, SC, Seakins, M, Grimble, RF, Jackson, AA. The acute phase response of adult rats is altered by in utero exposure to maternal low protein diets. J Nutr. 1994; 124, 15881596.
15. Bellinger, L, Lilley, C, Langley-Evans, SC. Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr. 2004; 92, 513520.
16. Bellinger, L, Sculley, DV, Langley-Evans, SC. Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats. Int J Obes. 2006; 30, 729738.
17. Bertram, CE, Hanson, MA. Prenatal programming of postnatal endocrine responses by glucocorticoids. Reproduction. 2002; 124, 459467.
18. Ozanne, SE, Hales, CN. Lifespan: catch-up growth and obesity in male mice. Nature. 2004; 427, 411412.
19. Zambrano, E, Bautista, CJ, Deas, M, et al. A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol. 2006; 571(Pt 1), 221230.
20. Carone, BR, Fauquier, L, Habib, N, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010; 143, 10841096.
21. Ng, SF, Lin, RC, Laybutt, DR, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010; 467, 963966.
22. Waddington, CH. Canalization of development and the inheritance of aquired characters. Nature. 1942; 150, 563565.
23. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16, 621.
24. Ramsahoye, BH, Biniszkiewicz, D, Lyko, F, et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A. 2000; 97, 52375242.
25. Fuks, F, Hurd, PJ, Wolf, D, et al. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem. 2003; 278, 40354040.
26. Santos, F, Hendrich, B, Reik, W, Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol. 2002; 241, 172182.
27. Okano, M, Bell, DW, Haber, DA, Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99, 247257.
28. Bacolla, A, Pradhan, S, Roberts, RJ, Wells, RD. Recombinant human DNA (cytosine-5) methyltransferase. II. Steady-state kinetics reveal allosteric activation by methylated dna. J Biol Chem. 1999; 274, 3301133019.
29. Ooi, SK, Bestor, TH. The colorful history of active DNA demethylation. Cell. 2008; 133, 11451148.
30. Reik, W, Santos, F, Mitsuya, K, Morgan, H, Dean, W. Epigenetic asymmetry in the mammalian zygote and early embryo: relationship to lineage commitment? Philos Trans R Soc Lond B Biol Sci. 2003; 358, 14031409.
31. Miller, CA, Sweatt, JD. Covalent modification of DNA regulates memory formation. Neuron. 2007; 53, 857869.
32. Kersh, EN, Fitzpatrick, DR, Murali-Krishna, K, et al. Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells. J Immunol. 2006; 176, 40834093.
33. Tahiliani, M, Koh, KP, Shen, Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324, 930935.
34. Ito, S, D'Alessio, AC, Taranova, OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010; 466, 11291133.
35. Bhattacharya, SK, Ramchandani, S, Cervoni, N, Szyf, M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature. 1999; 397, 579583.
36. Zhu, B, Zheng, Y, Angliker, H, et al. 5-methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Res. 2000; 28, 41574165.
37. Barreto, G, Schafer, A, Marhold, J, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007; 445, 671675.
38. Jost, JP. Nuclear extracts of chicken embryos promote an active demethylation of dna by excision repair of 5-methyldeoxycytidine. Proc Natl Acad Sci U S A. 1993; 90, 46844688.
39. Turner, BM. Histone acetylation and an epigenetic code. Bioessays. 2000; 22, 836845.
40. Strahl, BD, Ohba, R, Cook, RG, Allis, CD. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in tetrahymena. Proc Natl Acad Sci U S A. 1999; 96, 1496714972.
41. Nakayama, J, Rice, JC, Strahl, BD, Allis, CD, Grewal, SI. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001; 292, 110113.
42. Fuks, F, Hurd, PJ, Deplus, R, Kouzarides, T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003; 31, 23052312.
43. Fuks, F, Burgers, WA, Brehm, A, Hughes-Davies, L, Kouzarides, T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000; 24, 8891.
44. Rountree, MR, Bachman, KE, Baylin, SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000; 25, 269277.
45. Vire, E, Brenner, C, Deplus, R, et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006; 439, 871874.
46. Djebali, S, Davis, CA, Merkel, A, et al. Landscape of transcription in human cells. Nature. 2012; 489, 101108.
47. Bartel, DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136, 215233.
48. Tan, Y, Zhang, B, Wu, T, et al. Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. BMC Mol Biol. 2009; 10, 12.
49. Mercer, TR, Dinger, ME, Mattick, JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009; 10, 155159.
50. Drinkwater, RD, Blake, TJ, Morley, AA, Turner, DR. Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat Res. 1989; 219, 2937.
51. Feil, R, Fraga, MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2011; 13, 97109.
52. Maleszka, R. Epigenetic integration of environmental and genomic signals in honey?bees. Epigenetics. 2008; 3, 188192.
53. Kucharski, R, Maleszka, J, Foret, S, Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science. 2008; 319, 18271830.
54. Waterland, RA, Jirtle, RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003; 23, 52935300.
55. Lillycrop, KA, Phillips, ES, Jackson, AA, Hanson, MA, Burdge, GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005; 135, 13821386.
56. Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA, et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr. 2007; 97, 10641073.
57. Burdge, GC, Phillips, ES, Dunn, RL, Jackson, AA, Lillycrop, KA. Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator-activated receptors in the liver and adipose tissue of the offspring. Nutr Res. 2004; 24, 639646.
58. Gluckman, PD, Lillycrop, KA, Vickers, MH, et al. Metabolic plasticity during mammalian development is directionally dependent on early nutritional?status. Proc Natl Acad Sci U S A. 2007; 104, 1279612800.
59. Gluckman, PD, Hanson, MA, Spencer, HG. Predictive adaptive responses and human evolution. Trends Ecol Evol. 2005; 20, 527533.
60. Vucetic, Z, Kimmel, J, Totoki, K, Hollenbeck, E, Reyes, TM. Maternal high-fat diet?alters methylation and gene expression of dopamine and opioid-related?genes. Endocrinology. 2010; 151, 47564764.
61. Li, CC, Young, PE, Maloney, CA, et?al. Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic?mice. Epigenetics. 2013; 8, 602611.
62. Sandovici, I, Smith, NH, Nitert, MD, et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic?islets. Proc Natl Acad Sci USA. 2011; 108, 54495454.
63. Tosh, DN, Fu, Q, Callaway, CW, et al. Epigenetics of programmed obesity: alteration in IUGR rat hepatic IGF1 mRNA expression and histone structure in rapid vs. delayed postnatal catch-up?growth. Am J Physiol Gastrointest Liver Physiol. 2010; 299, G1023G1029.
64. Lie, S, Morrison, JL, Williams-Wyss, O, et al. Periconceptional undernutrition programs changes in insulin-signaling molecules and microRNAs in skeletal muscle in singleton and twin fetal?sheep. Biol Reprod. 2014; 306, E1013E1024.
65. Lie, S, Morrison, JL, Williams-Wyss, O, et al. Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal?sheep. Am J Physiol Endocrinol Metab. 2014; 306, E1013E1024.
66. Plagemann, A, Harder, T, Brunn, M, et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol. 2009; 587(Pt 20), 49634976.
67. Burdge, GC, Lillycrop, KA, Phillips, ES, et al. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr. 2009; 139, 10541060.
68. Ly, A, Lee, H, Chen, J, et al. Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res. 2011; 71, 988997.
69. Waterland, RA, Lin, JR, Smith, CA, Jirtle, RL. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2)?locus. Hum Mol Genet. 2006; 15, 705716.
70. Christman, JK, Sheikhnejad, G, Dizik, M, Abileah, S, Wainfan, E. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis. 1993; 14, 551557.
71. Hoile, SP, Irvine, NA, Kelsall, CJ, et al. Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring?liver. J Nutr Biochem. 2013; 24, 12131220.
72. Heijmans, BT, Tobi, EW, Stein, AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in?humans. Proc Natl Acad Sci U S A. 2008; 105, 1704617049.
73. Tobi, EW, Lumey, LH, Talens, RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009; 18, 40464053.
74. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D, et al. Periconceptional maternal folic acid use of 400 microg per?day is related to increased methylation of the IGF2 gene in the very young?child. PLoS One. 2009; 4, e7845.
75. Khulan, B, Cooper, WN, Skinner, BM, et al. Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the?Gambia. Hum Mol Genet. 2012; 21, 20862101.
76. Dominguez-Salas, P, Moore, SE, Baker, MS, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014; 5, 37463753.
77. Jacobsen, SC, Brons, C, Bork-Jensen, J, et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young?men. Diabetologia. 2012; 55, 33413349.
78. Teh, AL, Pan, H, Chen, L, et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 2014; 24, 10641074.
79. Murphy, SK, Huang, Z, Hoyo, C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS One. 2012; 7, e40924.
80. Waterland, RA, Kellermayer, R, Laritsky, E, et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 2010; 6, e1001252.
81. Talens, RP, Boomsma, DI, Tobi, EW, et al. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J. 2010; 24, 31353144.
82. Byun, HM, Siegmund, KD, Pan, F, et al. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum Mol Genet. 2009; 18, 48084817.
83. Godfrey, KM, Sheppard, A, Gluckman, PD, et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes. 2011; 60, 15281534.
84. Barres, R, Yan, J, Egan, B, et al. Acute exercise remodels promoter methylation in human skeletal?muscle. Cell Metab. 2012; 15, 405411.
85. Tarantini, L, Bonzini, M, Apostoli, P, et al. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect. 2009; 117, 217222.
86. Wong, CC, Caspi, A, Williams, B, et al. A longitudinal study of epigenetic variation in?twins. Epigenetics. 2010; 5, 516526.
87. Clarke-Harris, R, Wilkin, TJ, Hosking, J, et al. Peroxisomal proliferator activated receptor-gamma-co-activator-1 alpha promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird?50). Diabetes. 2014; 63, 25282537.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 43
Total number of PDF views: 299 *
Loading metrics...

Abstract views

Total abstract views: 737 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 19th March 2018. This data will be updated every 24 hours.