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.

Developmental Programming and Transgenerational Transmission of Obesity

“…Embryo transfer experiments have revealed that methionine synthase reductase deficiency (necessary for the utilisation of methyl groups from the folate cycle) in mice leads to two distinct, separable phenotypes: adverse effects on their wild-type daughters' uterine environment, leading to growth defects in wild-type grandprogeny, and the appearance of congenital malformations independent of maternal environment that persist for five generations, likely through transgenerational epigenetic inheritance [49]. The data on maternal folate status are less clear, with some evidence that maternal folate supplementation can lead to insulin resistance and transgenerational transmission of respiratory disorders in offspring [50,51]. …”

Strategies to Prevent or Reduce Allergic Disease

“…Many of these factors have been shown to modify early immune function even in pregnancy, including maternal microbial exposure [20,21], diet [22] and pollutants such as cigarette smoke [23]. Moreover, there is now evidence that these can modify early immune gene expression through potentially heritable epigenetic changes [18,20,24,25,26,27]. Therefore, these have been logical targets for disease prevention strategies.…”

“…Other immunomodulatory approaches focus on factors which may be causally implicated in the considerable changes in lifestyle, notably factors with both epidemiological associations with allergic disease and evidence of plausible immune mechanisms, including microbial exposure, environmental pollutants and complex dietary changes. Of considerable interest are emerging epigenetic paradigms which provide new perspectives on how these environmental factors may be producing heritable change in gene expression to increase the risk of allergic disease [20,25,33,34,35,36]. …”

“…Notably, a dietary change is one of the leading environmental mechanisms implicated in the ‘epigenetic modifications’ that may underpin the rise in many modern diseases, including allergic diseases [52,53]. Animal models demonstrate that maternal diet can have epigenetic effects on immune function which predispose to an allergic phenotype [25]. This highlights that pregnancy provides an important window of opportunity for disease prevention, and that diet may be a useful noninvasive strategy.…”

“…Interest in many of these factors has been fuelled by evidence from animal or in vitro models demonstrating immune effects which either promote an allergic phenotype (i.e. folate [25]) or protect (i.e. vitamin D [67] and antioxidants [76]) against allergy.…”