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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 Article has an altmetric score of 15

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 4

Diet modifies production of cytokines and chemokines in splenocytes.

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Diet modifies production of cytokines and chemokines in splenocytes.
Spl...
Spleens from mice gestated on either HMD or LMD were harvested following immunization and challenge with OVA. To determine functional consequences of perinatal diet, splenocytes were minced, passed through a 50-μm cell strainer, and isolated by density gradient centrifugation with Histopaque 1083 as described in Methods. (A) CD4+/CD8+ ratios in the spleen were determined by flow cytometry (n = 5; *P < 0.05, HMD versus LMD). To determine the functional implications of respective diets on splenocytes, 1 × 106 cells were exposed to saline or 4 μg OVA in vitro for 72 hours. Supernatants were collected and evaluated for cytokines/chemokines by Bio-Plex profiling. (B) Splenocytes derived from animals exposed to HMD demonstrate enhanced production of KC, CCL4, and CCL5 (†P < 0.01, HMD versus LMD). (C) Next, we harvested splenocytes from mice with gestational exposure to HMD or LMD without immunization and challenge with OVA and isolated CD4+ lymphocytes by negative selection. These cells were challenged with antibodies to CD3+CD28+ (1 μg/ml each) for 48 hours. CD4+ cells from HMD mice demonstrate enhanced levels of IL-4 and no difference in IFN-γ.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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