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Prenatal maternal diet affects asthma risk in offspring
Rachel L. Miller
Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Address correspondence to: Rachel. L. Miller, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, PH8E, 630 W. 168th Street, New York, New York 10032, USA. Phone: (212) 305-7759; Fax: (212) 305-2277; E-mail: rlm14@columbia.edu.
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Published September 18, 2008 - More info
J Clin Invest. 2008;118(10):3265–3268. https://doi.org/10.1172/JCI37171.
© 2008 The American Society for Clinical Investigation
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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
More and more, it seems that our traditional view of asthma as a complex disease that is mediated by a genetic predisposition and childhood or later environmental exposures needs updating. At this point, a mounting body of literature has established that prenatal exposures can influence the risk for developing asthma (1). This link has been most firmly documented in epidemiological studies of prenatal exposure to cigarette smoke and subsequent wheeze. For example, in a large prospective Danish cohort study of over 11,000 children, maternal smoking at the 36th week of gestation was associated with transient wheezing in children before age 3 years (2). In a Stockholm cohort of over 4,000 newborns, maternal smoking during but not following pregnancy was associated with an increased risk of recurrent wheezing in offspring up to age two years (3). In mouse models, exposure during pregnancy to an air pollutant aerosol (residual oil fly ash) led to a greater susceptibility to an asthma-like phenotype in the offspring mice (4).
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So how does this happen? Epigenetic regulation
Current hypotheses tend to consider either immune-mediated or epigenetic-mediated mechanisms. It now appears evident that antigen-specific B cell and T cell immune responses can develop following antigen exposures during pregnancy, as our group has demonstrated following prenatal vaccination against influenza antigens (11). Prenatal environmental exposures may be able to alter the intrauterine cytokine milieu (12). However, proof that prenatal dietary exposure delays or prevents early sensitization to food antigens and hence risk for clinical atopy has so far been more elusive (13). Lately, epigenetic-mediated mechanisms that entail heritable changes in gene expression that occur in the absence of alterations in DNA sequences have been proposed (14). These changes usually involve either DNA methylation (covalent addition of a methyl group to cytosines in CpG dinucleotides) or chromatin packaging of DNA via posttranslational modifications of histones (Figure 1).
Figure 1Prenatal maternal diet affects asthma risk in offspring. Prenatal maternal environmental exposure to diets high in folate, vitamin B12, choline, and methionine, which provide methyl donors, as well as to cigarette smoking may be associated with the covalent addition of a methyl group to cytosines in CpG dinucleotides and other epigenetic changes. These changes in turn may repress gene transcription and induce asthma phenotypes (i.e., airway allergic inflammation) in the offspring. As reported by Hollingsworth and colleagues in their study in mice in this issue of the JCI (25), prenatal methyl-rich diets may promote DNA methylation and reduce transcription of genes associated with the downregulation of allergic immune responses in the airway, such as runt-related transcription factor 3 (Runx3).
In their seminal studies, Cooney and colleagues and Waterland and Jirtle demonstrated that methyl supplementation of the maternal diet during pregnancy with folic acid, vitamin B12, and other agents increased DNA methylation of the long terminal repeat controlling the expression of the agouti gene and thereby influenced the methylation-dependent phenotype (coat color distribution) in mouse offspring (15, 16). Maternal stress and impaired nurturing in addition to environmental exposures to xenobiotic chemicals, endocrine disrupters, and low-dose radiation all have been associated with epigenetic gene regulation without changing the DNA sequence (reviewed in refs. 17, 18).
Epigenetic regulation also may be inherited across multiple generations, implying that not only prenatal maternal but also grandmaternal exposures may influence subsequent gene expression in the children. Examples of multigenerational effects on phenotype have been demonstrated in studies on the kinked tail (AxinFu) and agouti-viable yellow (Avy) allele, associations between endocrine disrupters and male infertility, and hormone-dependent cancer risk (18). While clearly multigenerational effects of prenatal environmental exposures are difficult to demonstrate in human epidemiological studies, one study is quite suggestive. In a provocative nested case control study by the Children’s Health Study of children diagnosed with asthma by age 5 years versus control subjects, grandmaternal smoking during pregnancy was associated with a greater risk for developing asthma in grandchildren. Borderline statistical significance was achieved when the effect was studied independently of maternal smoking (19).
In the asthma literature, articles supporting epigenetic mechanisms are just beginning to be published. These include mouse studies demonstrating that inhaled diesel exposure and intranasal Aspergillus fumigatus allergen induced hypermethylation at multiple sites of the IFN-γ promoter and hypomethylation at the CpG-408 site of the IL-4 promoter. Altered methylation of both gene promoters was correlated significantly with changes in IgE levels (20). In other recent work, cell-specific DNA methylation at the A disintegrin and metalloprotease 33 (ADAM33) gene promoter, an area whose expression has been implicated in severe asthma, has been reported. In this study, promoter methylation levels differed considerably between epithelial cells and fibroblasts, and this in turn differentially regulated ADAM33 gene expression (21). In another study, bronchial biopsies obtained from untreated asthmatics possessed greater levels of histone acetyltransferase and lower levels of histone deacetylase (HDAC) enzymatic activity. Levels reversed following treatment with inhaled steroids (22). Because, in general, acetylation of histones is associated with gene induction and deacetylation is associated with gene silencing (23), the study suggests that one antiinflammatory mode of action in the pharmacological treatment of asthma may be epigenetic. Finally, trichostatin A–induced inhibition of endogenous HDAC upregulated Th2 cytokine (IL-13, IL-5) and GATA3–mediated CD45RO+ T cell recall responses (24), suggesting that Th polarization can be directly epigenetically regulated.
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