DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women

Paula Dominguez-Salas, Sophie E Moore, Darren Cole, Kerry-Ann da Costa, Sharon E Cox, Roger A Dyer, Anthony J C Fulford, Sheila M Innis, Robert A Waterland, Steven H Zeisel, Andrew M Prentice, Branwen J Hennig, Paula Dominguez-Salas, Sophie E Moore, Darren Cole, Kerry-Ann da Costa, Sharon E Cox, Roger A Dyer, Anthony J C Fulford, Sheila M Innis, Robert A Waterland, Steven H Zeisel, Andrew M Prentice, Branwen J Hennig

Abstract

Background: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season.

Objective: The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers.

Design: In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly.

Results: Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season.

Conclusions: Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641.

Figures

FIGURE 1.
FIGURE 1.
One-carbon metabolism. Adapted from reference . BHMT, betaine-homocysteine methyltransferase; B2, riboflavin; B6, vitamin B-6; B12, vitamin B-12; CBS, cystathionine-β-synthase; CHDH, choline dehydrogenase; CTGL, cystathionine-γ-lyase; DMG, dimethylglycine; DNMT, DNA methyltransferases; GNMT, glycine-N-methyltransferase; MAT, methionine adenosyltrasferase; MTHFR, methylenetetrahydrofolate reductase; MS, methionine synthase; SAH, S-adenosylhomocysteine; SAHH, S-adenosylhomocysteine hydrolase; SAM, S-adenosylmethionine. Methyl groups released from conversion of SAM to SAH are also used for other methylation reactions (eg, proteins).
FIGURE 2.
FIGURE 2.
Seasonal trends in energy and macronutrient intakes and weight. A: n dietary intake measurements were made in an average of 29 women × 12 mo × 2 d. 95% CIs are shown with bars, at 2-mo intervals (different by substance to avoid excessive overlap and help visual clarity). Generalized least-squares regression with one pair of Fourier terms was used (P < 0.05 for fat, protein, and carbohydrate only). B: n = 517 subjects × (1–12 mo) = 2747 measure points. Thick line: arithmetic mean. Thin lines: 95% upper and lower CIs. Generalized least-squares regression with 4 pairs of Fourier terms was used.
FIGURE 3.
FIGURE 3.
Reliability and stability of dietary intakes and blood biomarker concentrations for substances under study. Black lines: solid (A and C, folate; B and D, methionine), dot (A and C, riboflavin; D, SAM), dash (A and C, vitamin B-12; D, SAH), dash-dot-dot (C, active vitamin B-12; D, SAM/SAH). Gray lines: solid (A and C, choline; D, homocysteine), dot (A and C, betaine; B and C, vitamin B-6), dash (C, DMG; D, cysteine). Autocorrelation (internal correlation) of each variable measurement with measurements for the same woman 1 to 5 months apart (lag: 1–5), adjusted by seasonality. Dietary intake measurements were made in an average of 29 women × 12 mo × 2 d. Number of biomarker measurements = 316 (293 for riboflavin). DMG, dimethylglycine; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.
FIGURE 4.
FIGURE 4.
Seasonal trends of methyl donors and cofactors as per dietary intake and blood biomarker concentrations expressed as a percentage of the geometric mean of all measurements (between July 2009 and June 2010). Black lines: solid (A and E, folate; C and G, methionine), dot (A and E, riboflavin; G, SAM), dash (A and E, vitamin B-12; G, SAH), dash-dot-dot (E, active vitamin B-12; G, SAM/SAH). Gray lines: solid (B and F, choline; H, homocysteine), dot (B and F, betaine; D and H, vitamin B-6), dash (F, DMG; H, cysteine), dash-dot-dot (F, DMG/betaine). Dietary intake measurements were made in an average of 29 women × 12 mo × 2 d. Number of biomarker measurements = 316 (293 for riboflavin). Bars indicate 95% CIs at 2-mo intervals (different by substance to avoid excessive overlap and for visual clarity). Generalized least-squares regression with 2 pairs of Fourier terms was used, except for choline dietary intake and plasma vitamin B-12—each of which required 4 pairs of terms. Riboflavin status is shown as the inverse of EGRAC assay results. DMG, dimethylglycine; EGRAC, erythrocyte glutathione reductase activation coefficient; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.
FIGURE 5.
FIGURE 5.
Seasonal trends of folate, B2, and DMG blood concentrations, expressed as a percentage of the geometric mean of all measurements (between July 2009 and June 2010). Interdependence of folate-dependent and betaine-dependent pathways. Number of biomarker measurements = 316 (293 for riboflavin). Bars indicate 95% CIs at 2-mo intervals (different by substance to avoid excessive overlap and for visual clarity). Generalized least-squares regression with 2 pairs of Fourier terms was used. Riboflavin status is shown as the inverse of EGRAC assay results. B2, riboflavin; DMG, dimethylglicine; EGRAC, erythrocyte glutathione reductase activation coefficient.

References

    1. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235–9
    1. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 2009;10:295–304
    1. Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007;27:363–88
    1. Dominguez-Salas P, Cox SE, Prentice AM, Hennig BJ, Moore SE. Maternal nutritional status, C(1) metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 2012;71:154–65
    1. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr 2006;136(suppl):1636S–40S
    1. Kalhan SC, Marczewski SE. Methionine, homocysteine, one carbon metabolism and fetal growth. Rev Endocr Metab Disord 2012;13:109–19
    1. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23:5293–300
    1. Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007;104:19351–6
    1. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008;105:17046–9
    1. Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constancia M, et al. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J 2012;26:1782–90
    1. Khulan B, Cooper WN, Skinner BM, Bauer J, Owens S, Prentice AM, Belteki G, Constancia M, Dunger D, Affara NA. 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;21:2086–101
    1. Waterland RA, Kellermayer R, Laritsky E, Rayco-Solon P, Harris RA, Travisano M, Zhang W, Torskaya MS, Zhang J, Shen L, et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet 2010;6:e1001252.
    1. Prentice A, Laskey MA, Shaw J, Hudson GJ, Day KC, Jarjou LM, Dibba B, Paul AA. The calcium and phosphorus intakes of rural Gambian women during pregnancy and lactation. Br J Nutr 1993;69:885–96
    1. McCrae JE, Paul AA. 2nd ed. Cambridge, United Kingdom: Centre MRC Dunn Nutrition, 1996.
    1. Koc H, Mar MH, Ranasinghe A, Swenberg JA, Zeisel SH. Quantitation of choline and its metabolites in tissues and foods by liquid chromatography/electrospray ionization-isotope dilution mass spectrometry. Anal Chem 2002;74:4734–40
    1. Innis SM, Davidson AG, Melynk S, James SJ. Choline-related supplements improve abnormal plasma methionine-homocysteine metabolites and glutathione status in children with cystic fibrosis. Am J Clin Nutr 2007;85:702–8
    1. Innis SM, Hasman D. Evidence of choline depletion and reduced betaine and dimethylglycine with increased homocysteine in plasma of children with cystic fibrosis. J Nutr 2006;136:2226–31
    1. Midttun O, Hustad S, Solheim E, Schneede J, Ueland PM. Multianalyte quantification of vitamin B6 and B2 species in the nanomolar range in human plasma by liquid chromatography-tandem mass spectrometry. Clin Chem 2005;51:1206–16
    1. Vuilleumier JP, Keller HE, Keck E. Clinical chemical methods for the routine assessment of the vitamin status in human populations. Part III: The apoenzyme stimulation tests for vitamin B1, B2 and B6 adapted to the Cobas-Bio analyzer. Int J Vitam Nutr Res 1990;60(2):126–35.
    1. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr 2002;132(suppl):2361S–6S
    1. Caudill MA, Wang JC, Melnyk S, Pogribny IP, Jernigan S, Collins MD, Santos-Guzman J, Swendseid ME, Cogger EA, James SJ. Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice. J Nutr 2001;131:2811–8
    1. Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 2000;275:29318–23
    1. Fulford AJ, Rayco-Solon P, Prentice AM. Statistical modelling of the seasonality of preterm delivery and intrauterine growth restriction in rural Gambia. Paediatr Perinat Epidemiol 2006;20:251–9
    1. Gibson R. Principles of Nutritional Assessment, 2nd ed. New York: Oxford University Press, Inc., 2005
    1. WHO/FAO Vitamin and mineral requirements in human nutrition. 2nd ed. Rome, Italy: WHO/FAO, 2004
    1. Institute of Medicine, National Academy of Sciences. Dietary reference intakes for folate, thiamine, riboflavin, niacin, vitamin B12, panthothenic acid, biotine, and choline. Washington, DC: IOM, 1998.
    1. Dhonukshe-Rutten RA, de Vries JH, de Bree A, van der Put N, van Staveren WA, de Groot LC. Dietary intake and status of folate and vitamin B12 and their association with homocysteine and cardiovascular disease in European populations. Eur J Clin Nutr 2009;63:18–30
    1. Hill MH, Bradley A, Mushtaq S, Williams EA, Powers HJ. Effects of methodological variation on assessment of riboflavin status using the erythrocyte glutathione reductase activation coefficient assay. Br J Nutr 2009;102:273–8
    1. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr 2011;94:666S–72S
    1. Loikas S, Lopponen M, Suominen P, Moller J, Irjala K, Isoaho R, Kivela SL, Koskinen P, Pelliniemi TT. RIA for serum holo-transcobalamin: method evaluation in the clinical laboratory and reference interval. Clin Chem 2003;49:455–62
    1. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3–32
    1. Prentice AM, Whitehead RG, Roberts SB, Paul AA. Long-term energy balance in child-bearing Gambian women. Am J Clin Nutr 1981;34:2790–9
    1. Roberts SB, Paul AA, Cole TJ, Whitehead RG. Seasonal changes in activity, birth weight and lactational performance in rural Gambian women. Trans R Soc Trop Med Hyg 1982;76:668–78
    1. Stead LM, Brosnan JT, Brosnan ME, Vance DE, Jacobs RL. Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 2006;83:5–10
    1. Mudd SH, Poole JR. Labile methyl balances for normal humans on various dietary regimens. Metabolism 1975;24:721–35
    1. Bates CJ, Prentice AM, Paul AA. Seasonal variations in vitamins A, C, riboflavin and folate intakes and status of pregnant and lactating women in a rural Gambian community: some possible implications. Eur J Clin Nutr 1994;48:660–8
    1. Jacob RA, Jenden DJ, Allman-Farinelli MA, Swendseid ME. Folate nutriture alters choline status of women and men fed low choline diets. J Nutr 1999;129:712–7
    1. Moat SJ, Ashfield-Watt PA, Powers HJ, Newcombe RG, McDowell IF. Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin Chem 2003;49:295–302
    1. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 2002;132(suppl):2333S–5S
    1. Fischer LM, da Costa KA, Kwock L, Galanko J, Zeisel SH. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr 2010;92:1113–9
    1. Hudson GJ. Food intake in a west African village. Estimation of food intake from a shared bowl. Br J Nutr 1995;73:551–69
    1. Block G, Hartman AM. Issues in reproducibility and validity of dietary studies. Am J Clin Nutr 1989;50(Suppl):1133–8, discussion 231–5

Source: PubMed

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