Skip to main content Accessibility help
Hostname: page-component-5cfd469876-phsm7 Total loading time: 0.282 Render date: 2021-06-23T13:02:34.091Z Has data issue: false Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true }

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight

Published online by Cambridge University Press:  06 March 2017

S. Pauwels
Department of Public Health and Primary Care, Environment and Health, KU Leuven- University of Leuven, Leuven, Belgium Unit Environmental Risk and Health, Flemish Institute of Technological Research (VITO), Mol, Belgium
I. Truijen
Department of Public Health and Primary Care, Environment and Health, KU Leuven- University of Leuven, Leuven, Belgium
M. Ghosh
Department of Public Health and Primary Care, Environment and Health, KU Leuven- University of Leuven, Leuven, Belgium
R. C. Duca
Department of Public Health and Primary Care, Environment and Health, KU Leuven- University of Leuven, Leuven, Belgium
S. A. S. Langie
Unit Environmental Risk and Health, Flemish Institute of Technological Research (VITO), Mol, Belgium Faculty of Sciences, Hasselt University, Diepenbeek, Belgium
B. Bekaert
Department of Imaging & Pathology, KU Leuven – University of Leuven, Leuven, Belgium Department of Forensic Medicine, Laboratory of Forensic Genetics and Molecular Archeology, KU Leuven – University of Leuven, University Hospitals Leuven, Leuven, Belgium
K. Freson
Center for Molecular and Vascular Biology, KU Leuven – University of Leuven, Leuven, Belgium
I. Huybrechts
Dietary Exposure Assessment Group, International Agency for Research on Cancer, Lyon, France
G. Koppen
Unit Environmental Risk and Health, Flemish Institute of Technological Research (VITO), Mol, Belgium
R. Devlieger
Department of Development and Regeneration, KU Leuven-University of Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, Belgium
L. Godderis
Department of Public Health and Primary Care, Environment and Health, KU Leuven- University of Leuven, Leuven, Belgium External Service for Prevention and Protection at Work, IDEWE, Heverlee, Belgium


Most nutritional studies on the development of children focus on mother–infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Original Article
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2017 

Access options

Get access to the full version of this content by using one of the access options below.


1. Painter, RC, Roseboom, TJ, Bleker, OP. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol. 2005; 20, 345352.CrossRefGoogle ScholarPubMed
2. Anderson, LM, Riffle, L, Wilson, R, Travlos, GS, Lubomirski, MS, Alvord, WG. Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition. 2006; 22, 327331.CrossRefGoogle Scholar
3. Soubry, A, Hoyo, C, Jirtle, RL, Murphy, SK. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays. 2014; 36, 359371.CrossRefGoogle ScholarPubMed
4. Marques, CJ, João Pinho, M, Carvalho, F, Bièche, I, Barros, A, Sousa, M. DNA methylation imprinting marks and DNA methyltransferase expression in human spermatogenic cell stages. Epigenetics. 2011; 6, 13541361.CrossRefGoogle ScholarPubMed
5. Chen, ZX, Riggs, AD. DNA methylation and demethylation in mammals. J Biol Chem. 2011; 286, 1834718353.CrossRefGoogle ScholarPubMed
6. McKay, JA, Mathers, JC. Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf). 2011; 202, 103118.CrossRefGoogle Scholar
7. Boeke, CE, Baccarelli, A, Kleinman, KP, Burris, HH, Litonjua, AA, Rifas-Shiman, SL, et al. Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population. Epigenetics. 2012; 7, 253260.CrossRefGoogle ScholarPubMed
8. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D, Lindemans, J, Siebel, C, Steegers, EA, 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.CrossRefGoogle Scholar
9. Mejos, KK, Kim, HW, Lim, EM, Chang, N. Effects of parental folate deficiency on the folate content, global DNA methylation, and expressions of FRα, IGF-2 and IGF-1R in the postnatal rat liver. Nutr Res Pract. 2013; 7, 281286.CrossRefGoogle ScholarPubMed
10. Carone, BR, Fauquier, L, Habib, N, Shea, JM, Hart, CE, Li, R, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010; 143, 10841096.CrossRefGoogle ScholarPubMed
11. Dao, T, Cheng, RY, Revelo, MP, Mitzner, W, Tang, W. Hydroxymethylation as a novel environmental biosensor. Curr Environ Health Rep. 2014; 1, 110.CrossRefGoogle ScholarPubMed
12. Langie, SA, Achterfeldt, S, Gorniak, JP, Halley-Hogg, KJ, Oxley, D, van Schooten, FJ, et al. Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring. FASEB J.. 2013; 27, 33233334.CrossRefGoogle ScholarPubMed
13. Bae, S, Ulrich, CM, Bailey, LB, Malysheva, O, Brown, EC, Maneval, DR, et al. Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort. Epigenetics. 2014; 9, 396403.CrossRefGoogle ScholarPubMed
14. Crider, KS, Quinlivan, EP, Berry, RJ, Hao, L, Li, Z, Maneval, D, et al. Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age. PLoS One. 2011; 6, e28144.CrossRefGoogle Scholar
15. Pufulete, M, Al-Ghnaniem, R, Khushal, A, Appleby, P, Harris, N, Gout, S, et al. Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut. 2005; 54, 648653.CrossRefGoogle ScholarPubMed
16. Axume, J, Smith, SS, Pogribny, IP, Moriarty, DJ, Caudill, MA. The MTHFR 677TT genotype and folate intake interact to lower global leukocyte DNA methylation in young Mexican American women. Nutr Res. 2007; 27, 13171365.CrossRefGoogle ScholarPubMed
17. Yin, R, Mao, SQ, Zhao, B, Chong, Z, Yang, Y, Zhao, C, et al. Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc. 2013; 135, 1039610403.CrossRefGoogle ScholarPubMed
18. Soubry, A, Schildkraut, JM, Murtha, A, Wang, F, Huang, Z, Bernal, A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 2013; 11, 29.CrossRefGoogle ScholarPubMed
19. Soubry, A, Murphy, SK, Wang, F, Huang, Z, Vidal, AC, Fuemmeler, BF, et al., Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond); 2013; 39, 650657.Google Scholar
20. Soubry, A, Guo, L, Huang, Z, Hoyo, C, Romanus, S, Price, T, et al. Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenetics. 2016; 8, 51.CrossRefGoogle ScholarPubMed
21. Chao, W, D’Amore, PA. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 2008; 19, 111120.CrossRefGoogle ScholarPubMed
22. World Health Organization. Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy. WHO/NMH/MND/13.2, 2013. WHO: Geneva.Google Scholar
23. Willett, W. Nutritional Epidemiology. 3rd edn, 2012. Oxford University Press: Oxford, 529pp.Google Scholar
24. Nubel Voedingsplanner. v.z.w. NUBEL, Brussels, Belgium, 2010.Google Scholar
25. Hoge Gezondheidsraad. Maten en gewichten. Handleiding voor gestandaardiseerde kwantificering van voedingsmiddelen in België: revisie januari 2005, 2nd edn, 2005. Hoge Gezondheidsraad: Brussels, Belgium.Google Scholar
26. NUBEL. Belgain Food Composition Table, 5th edn, 2010. Ministry of Public Health: Brussels, Belgium.Google Scholar
27. NEVO. Dutch Food Composition Table, 2011. NEVO Foundation, Zeist, the Netherlands.Google Scholar
28. Kristine, YP, Seema, AB, Juhi, RW, et al. USDA Database for the Choline Content of Common Foods, Release 2, 2008. US Department of Agriculture, Agricultural Research Service: Beltsville, Maryland, USA.Google Scholar
29. Dehne, LI, Klemm, C, Henseler, G, Hermann-Kunz, E. The German Food Code and Nutrient Data Base (BLS II.2). Eur J Epidemiol. 1999; 15, 355359.CrossRefGoogle Scholar
30. Pexsters, A, Daemen, A, Bottomley, C, Van Schoubroeck, D, De Catte, L, De Moor, B, et al. New crown-rump length curve based on over 3500 pregnancies. Ultrasound Obstet Gynecol. 2010; 35, 650655.CrossRefGoogle ScholarPubMed
31. Villar, J, Cheikh Ismail, L, Victora, CG, Ohuma, EO, Bertino, E, Altman, DG, et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet. 2014; 384, 857868.CrossRefGoogle ScholarPubMed
32. Sambrook, J, Russell, DW. Molecular Cloning: A Laboratory Manual, 2001. Cold Spring Harbor Laboratory Press: Long Island, New York, USA.Google Scholar
33. Godderis, L, Schouteden, C, Tabish, A, Poels, K, Hoet, P, Baccarelli, AA, et al. Global methylation and hydroxymethylation in DNA from blood and saliva in healthy volunteers. Biomed Res Int. 2015; 2015, 845041.CrossRefGoogle ScholarPubMed
34. Murphy, SK, Huang, Z, Hoyo, C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS One. 2012; 7, e40924.CrossRefGoogle ScholarPubMed
35. Burris, HH, Braun, JM, Byun, HM, Tarantini, L, Mercado, A, Wright, RJ, et al. Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements LINE-1 and Alu. Epigenomics. 2013; 5, 271281.CrossRefGoogle ScholarPubMed
36. Hoyo, C, Fortner, K, Murtha, AP, Schildkraut, JM, Soubry, A, Demark-Wahnefried, W, et al. Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight. Cancer Causes Control. 2012; 23, 635645.CrossRefGoogle Scholar
37. World Health Organization FaAOotUN, United Nations University. Protein and amino acid requirements in human nutrition. Report of a joint FAO/WHO/UNU expert consultation (WHO Technical Report, Series 935), 2007.Google Scholar
38. Janssen, BG, Byun, HM, Gyselaers, W, Lefebvre, W, Baccarelli, AA, Nawrot, TS. Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment: an ENVIRONAGE birth cohort study. Epigenetics. 2015; 10, 536544.CrossRefGoogle ScholarPubMed
39. Li, X, Franke, AA. High-throughput and cost-effective global DNA methylation assay by liquid chromatography-mass spectrometry. Anal Chim Acta. 2011; 703, 5863.CrossRefGoogle ScholarPubMed
40. Dwi Putra, SE, Neuber, C, Reichetzeder, C, Hocher, B, Kleuser, B. Analysis of genomic DNA methylation levels in human placenta using liquid chromatography-electrospray ionization tandem mass spectrometry. Cell Physiol Biochem. 2014; 33, 945952.CrossRefGoogle ScholarPubMed
41. Drummond, EM, Gibney, ER. Epigenetic regulation in obesity. Curr Opin Clin Nutr Metab Care. 2013; 16, 392397.Google ScholarPubMed
42. Dominguez-Salas, P, Moore, SE, Cole, D, da Costa, KA, Cox, SE, Dyer, RA, et al. DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr. 2013; 97, 12171227.CrossRefGoogle ScholarPubMed
43. Iurlaro, M, Ficz, G, Oxley, D, Raiber, E-A, Bachman, M, Booth, MJ, et al. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Genome biology. 2013; 14, 1.CrossRefGoogle ScholarPubMed
44. Spruijt, CG, Gnerlich, F, Smits, AH, Pfaffeneder, T, Jansen, PW, Bauer, C, et al. Dynamic readers for 5-(hydroxy) methylcytosine and its oxidized derivatives. Cell. 2013; 152, 11461159.CrossRefGoogle ScholarPubMed
45. Bachman, M, Uribe-Lewis, S, Yang, X, Williams, M, Murrell, A, Balasubramanian, S. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat Chem. 2014; 6, 10491055.CrossRefGoogle ScholarPubMed
46. Tellez-Plaza, M, Tang, WY, Shang, Y, Umans, JG, Francesconi, KA, Goessler, W, et al. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect. 2014; 122, 946954.Google ScholarPubMed
47. Takumi, S, Okamura, K, Yanagisawa, H, Sano, T, Kobayashi, Y, Nohara, K. The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways. J Appl Toxicol. 2015; 35, 15501556.CrossRefGoogle ScholarPubMed
48. Sanchez-Guerra, M, Zheng, Y, Osorio-Yanez, C, Zhong, J, Chervona, Y, Wang, S, et al. Effects of particulate matter exposure on blood 5-hydroxymethylation: results from the Beijing truck driver air pollution study. Epigenetics. 2015; 10, 633642.CrossRefGoogle ScholarPubMed
49. Pauwels, S, Ghosh, M, Duca, RC, Bekaert, B, Freson, K, Huybrechts, I, et al. Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation. Epigenetics. 2016; 12, 110.CrossRefGoogle ScholarPubMed
50. Hoyo, C, Murtha, AP, Schildkraut, JM, Jirtle, RL, Demark-Wahnefried, W, Forman, MR, et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics. 2011; 6, 928936.CrossRefGoogle ScholarPubMed
51. Ba, Y, Yu, H, Liu, F, Geng, X, Zhu, C, Zhu, Q, et al. Relationship of folate, vitamin B12 and methylation of insulin-like growth factor-II in maternal and cord blood. Eur J Clin Nutr. 2011; 65, 480485.CrossRefGoogle ScholarPubMed
52. Jiang, X, Yan, J, West, AA, Perry, CA, Malysheva, OV, Devapatla, S, et al. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J. 2012; 26, 35633574.CrossRefGoogle ScholarPubMed
53. Waterland, RA. Assessing the effects of high methionine intake on DNA methylation. J Nutr. 2006; 136(6 Suppl.), 1706S1710S.CrossRefGoogle ScholarPubMed
54. Fan, C, Huang, T, Cui, F, Gao, M, Song, L, Wang, S. Paternal factors to the offspring birth weight: the 829 birth cohort study. Int J Clin Exp Med. 2015; 8, 1137011378.Google ScholarPubMed
55. Schagdarsurengin, U, Steger, K. Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health. Nat Rev Urol. 2016; 13, 584595.Google Scholar
56. Lambrot, R, Xu, C, Saint-Phar, S, Chountalos, G, Cohen, T, Paquet, M, et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun. 2013; 4, 2889.CrossRefGoogle ScholarPubMed
57. Wu, BT, Dyer, RA, King, DJ, Richardson, KJ, Innis, SM. Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants. PLoS One. 2012; 7, e43448.CrossRefGoogle ScholarPubMed
58. Zeisel, SH. Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis. Clin Chem Lab Med. 2013; 51, 467475.CrossRefGoogle ScholarPubMed
59. Finer, S, Mathews, C, Lowe, R, Smart, M, Hillman, S, Foo, L, et al. Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring. Hum Mol Genet. 2015; 24, 30213029.CrossRefGoogle ScholarPubMed
60. Hochberg, Z, Feil, R, Constancia, M, Fraga, M, Junien, C, Carel, JC, et al. Child health, developmental plasticity, and epigenetic programming. Endocr Rev. 2011; 32, 159224.CrossRefGoogle ScholarPubMed
61. Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA, Godfrey, KM, Jackson, AA, Burdge, GC. 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.CrossRefGoogle ScholarPubMed
62. Hall, JM, Lingenfelter, P, Adams, SL, Lasser, D, Hansen, JA, Bean, MA. Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization. Blood. 1995; 86, 28292832.Google ScholarPubMed
63. Faulk, C, Dolinoy, DC. Timing is everything: the when and how of environmentally induced changes in the epigenome of animals. Epigenetics. 2011; 6, 791797.CrossRefGoogle ScholarPubMed
64. Kravetz, JD, Federman, DG. Toxoplasmosis in pregnancy. Am J Med. 2005; 118, 212216.CrossRefGoogle ScholarPubMed
65. Pauwels, S, Duca, RC, Devlieger, R, Freson, K, Straetmans, D, Van Herck, E, et al. Maternal methyl-group donor intake and global DNA (hydroxy)methylation before and during pregnancy. Nutrients. 2016; 8, 474.CrossRefGoogle ScholarPubMed
Cited by

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.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight
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.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight
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.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *