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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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Research Article

In utero supplementation with methyl donors enhances allergic airway disease in mice

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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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Figure 1

Gestational exposure to dietary methyl donors regulates severity of allergic asthma.

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Gestational exposure to dietary methyl donors regulates severity of alle...
Adult C57BL/6J progeny exposed to HMD in utero demonstrate enhanced allergic inflammation when compared with those exposed to LMD. C57BL/6J breeding pairs were fed HMD, RD (NIH-31), or LMD beginning 2 weeks prior to mating and during pregnancy. Experimental diets were continued until the time of weaning, when F1 progeny were placed on RD (NIH-31). At 6 to 10 weeks of age, F1 mice were immunized and subjected to an OVA challenge. In utero exposure to HMD was associated with enhanced (A) airway responsiveness to methacholine (n = 5–6; *P < 0.05) (HMD, squares; LMD, diamonds), (B) concentration of lung lavage eosinophils (n = 31–63; HMD, white bars; LMD, black bars), (C) percentage of lung lavage eosinophils (n = 31–63), (D) IL-13 levels in whole-lung lavage fluid (n = 15–26), (E) total serum IgE (n = 15–26; *P < 0.05, HMD versus LMD), (F) OVA-specific IgE (n = 15–26; †P = 0.05, HMD versus LMD), and (G) OVA-specific IgG1 (n = 15–26; *P < 0.05, HMD versus LMD). Avg, average.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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