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In utero supplementation with methyl donors enhances allergic airway disease in mice
John W. Hollingsworth, … , David M. Brass, David A. Schwartz
John W. Hollingsworth, … , David M. Brass, David A. Schwartz
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3462-3469. https://doi.org/10.1172/JCI34378.
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In utero supplementation with methyl donors enhances allergic airway disease in mice

Abstract

Asthma is a complex heritable disease that is increasing in prevalence and severity, particularly in developed countries such as the United States, where 11% of the population is affected. The contribution of environmental and genetic factors to this growing epidemic is currently not well understood. We developed the hypothesis, based on previous literature, that changes in DNA methylation resulting in aberrant gene transcription may enhance the risk of developing allergic airway disease. Our findings indicate that in mice, a maternal diet supplemented with methyl donors enhanced the severity of allergic airway disease that was inherited transgenerationally. Using a genomic approach, we discovered 82 gene-associated loci that were differentially methylated after in utero supplementation with a methyl-rich diet. These methylation changes were associated with decreased transcriptional activity and increased disease severity. Runt-related transcription factor 3 (Runx3), a gene known to negatively regulate allergic airway disease, was found to be excessively methylated, and Runx3 mRNA and protein levels were suppressed in progeny exposed in utero to a high-methylation diet. Moreover, treatment with a demethylating agent increased Runx3 gene transcription, further supporting our claim that a methyl-rich diet can affect methylation status and consequent transcriptional regulation. Our findings indicate that dietary factors can modify the heritable risk of allergic airway disease through epigenetic mechanisms during a vulnerable period of fetal development in mice.

Authors

John W. Hollingsworth, Shuichiro Maruoka, Kathy Boon, Stavros Garantziotis, Zhuowei Li, John Tomfohr, Nathaniel Bailey, Erin N. Potts, Gregory Whitehead, David M. Brass, David A. Schwartz

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Equivocal evidence for a methyl donor-induced effect on epigenetically mediated changes in allergic airway disease risk

Submitter: Caroline Relton | c.l.relton@ncl.ac.uk

Authors: Lucilla Poston

Newcastle University

Published October 29, 2008

The role of epigenetic mechanisms in common complex disease is receiving increasing attention and it is unsurprising that the recent findings of Hollingsworth et al. (1) who reported a link between in utero supplementation with methyl donors and increased severity of allergic airway disease, received such prominence (JCI Oct 2008).

The study clearly indicates that nutritional intervention alters the epigenome and suggests that epigenetic mechanisms may well be important in the pathogenesis of asthma however, we contend that the association between the methyl content of the diet and allergic airway disease proposed by the authors cannot be inferred due to flaws in the reported study design. A major oversight is the lack of recognition that several of the components of the experimental diet (information provided only in the supplemental data) might influence DNA methylation status or relevant phenotypic characteristics of the offspring.

The authors describe how methyl-supplemented diets were based on AIN-93G, supplemented with folic acid, vitamin B12, choline, L-methionine, zinc and betaine. We note that there was a large difference in the genistein concentration of the diets (300mg/kg v 0mg/kg) between the high methyl donor diet and the low methyl donor diet. Genistein has well documented effects on DNA methylation (administered at 250mg/kg), particularly during critical periods during embryonic development (2, 3) and environmental endocrine disruptors including phytoestrogens are widely implicated in programming of altered offspring body composition (4). No data is provided on the offspring fat mass which in turn could influence airways smooth muscle reactivity. The fat composition of the two diets was also different which may profoundly influence offspring phenotype (5, 6). Furthermore, these interventions are compared to a standard NIH-31 chow diet.

Claims are also not supported by epidemiological evidence which shows no association between folate metabolism and childhood asthma risk (7).

We consider that the conclusions pertaining to the increased prevalence of asthma in humans relating to increased perinatal folic acid supplementation are unwarranted by the data presented.

Dr Caroline Relton Lecturer, Genetic Epidemiology Institute of Human Genetics Newcastle University

Prof Lucilla Poston Head of Division of Reproduction and Endocrinology Director Maternal and Fetal Research Unit King’s College London

References

  1. Hollingsworth, J.W. et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J. Clin. Invest. 118:3462-3469 (2008)
  2. Dolinoy, D.C. et al. Maternal genistein alters coat colour and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect. 114:567-572 (2006)
  3. Dolinoy, D.C. et al. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl. Acad. Sci. U.S.A. 104:13056-13061 (2007)
  4. Newbold, R.R. et al. Effects of endocrine disruptors on obesity. Int. J. Androl. 31:201-208 (2008)
  5. Korotkova, M. et al. Gender-related long-term effects in adult rats by perinatal dietary ratio of n-6/n-3 fatty acids. Am. J. Physiol. Integr. Comp. Physiol. 288:R575-579 (2005)
  6. Taylor, P.D. and Poston, L. Developmental programming of obesity in mammals. Exp. Physiol. 92:287-298 (2007)
  7. Granell, R. et al. The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort. Clin. Exp. Allergy 38:320-328 (2008)

    8. Response to Relton and Poston

    Submitter: John W. Hollingsworth | holli017@mc.duke.edu

    Authors: Shuichiro Maruoka, Kathy Boon, David A. Schwartz

    Division of Pulmonary, Allergy, Critical Care Medicine Duke University Medical Center, Durham, NC

    Published October 29, 2008

    Drs. Relton and Poston have raised several interesting points in response to our report published in the Journal (1). The intent of our study was to determine whether epigenetic changes in DNA methylation influenced the development of allergic airway disease in mice. Our findings indicate that dietary modification during gestation with supplemental folate, B12, choline, L-methionine, zinc, and betaine, and genistein resulted in changes in DNA methylation that altered the development of allergic airway disease. We chose this diet because it had been used previously to alter DNA methylation (2, 3).

    Drs. Relton and Poston are absolutely correct in their assertion that “several of the components of the experimental diet might influence DNA methylation status”. While we believe that the methyl donors are most likely to alter DNA methylation during gestation, it is also possible that other components of the diet, including genistein, may affect DNA methylation. However, our conclusions with regard to the effect of dietary modifications on CpG methylation and allergic airways disease remain unaltered. In the discussion of our report, we encourage future work to determine which component of this diet is primarily altering DNA methylation.

    The concern about dietary effects on fat mass on airway smooth muscle is reasonable, given recent evidence suggesting that there is an association between obesity and airways disease (4). However, we did not observe significant differences in total body weight in animals on respective diets studied for airway hyperresponsiveness (high methylation diet - 23.8g +/-1.4 versus low methylation diet - 21.1 +/- 0.3). Therefore, it is unlikely that observed differences in airway hyperresponsiveness could be explained by alterations in fat mass.

    In the report, we were careful not to draw any conclusions about perinatal folic acid supplementation and human asthma risk. In fact, we discouraged any conclusions be drawn about altering recommendations to pregnant mothers because of obvious differences between murine/human biology and the limitations of our study design. Additionally, at the time of our publication, there was no epidemiologic evidence to support the role of folate supplements on the development of allergic airways disease. However, recent epidemiologic evidence has emerged from a birth cohort of Norwegian children, which suggests that perinatal folic acid supplements are associated with an increased risk of wheeze at 18 months of age (5).

    In conclusion, we agree with the commentary by Dr. Rachael Miller (6) that our study needs to be interpreted with caution and validated in human cohort-driven epigenetic research. We provide evidence in a murine model raising a novel hypothesis for the etiology and pathogenesis of allergic asthma. Future well-designed studies in both mice and humans may provide further insight into the importance of epigenetic mechanisms in the development and pathogenesis of asthma.

    John W. Hollingsworth MD Division of Pulmonary, Allergy, Critical Care Medicine Duke University Medical Center, Durham, NC

    Shuichiro Maruoka MD PhD Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences Research Triangle Park, NC

    Kathy Boon PhD Office of Cancer Genomics National Cancer Institute, Bethesda, MD

    David A. Schwartz MD MPH Division of Pulmonary, Allergy, Critical Care Medicine National Jewish Medical Center, Denver, CO

    References

    1. Hollingsworth, J. W., S. Maruoka, K. Boon, S. Garantziotis, Z. Li, J. Tomfohr, N. Bailey, E. N. Potts, G. Whitehead, D. M. Brass, and D. A. Schwartz. 2008. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 118:3462.
    2. Waterland, R. A., and R. L. Jirtle. 2003. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293.
    3. Dolinoy, D. C., J. R. Weidman, R. A. Waterland, and R. L. Jirtle. 2006. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114:567.
    4. Johnston, R. A., M. Zhu, Y. M. Rivera-Sanchez, F. L. Lu, T. A. Theman, L. Flynt, and S. A. Shore. 2007. Allergic airway responses in obese mice. Am J Respir Crit Care Med 176:650.
    5. Haberg, S., S. London, H. Stigum, P. Nafstad, and W. Nystad. 2008. Folic acid supplements in pregnancy and early childhood respiratory health. Archives of Disease in Childhood In Press.
    6. Miller, R. L. 2008. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest 118:3265.

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