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From the Townsend Letter
May 2014

Environmental Medicine Update
The Role of Epigenetics in the Development of Allergies
by Marianne Marchese, ND
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As allergy season is about to swing into full gear, some are starting to ask if allergies are heritable. Allergic diseases have increased dramatically over the past 25 years reaching epidemic proportions. But when does a person develop allergies? Is it in the womb or later in life? New research on the role of epigenetics is helping to answer this question. Epigenetics is the study of changes in certain characteristics that can be passed from one generation to the next without changing the DNA code itself. It has become apparent that changes in gene function, aside from those related to DNA mutations, are factors in numerous health conditions, including allergies.1 Epigenetics explains why individuals with the same or similar DNA may have different health issues. Environmental factors are known to create epigenetic changes. These changes are also called epigenetic modifications. Low-dose chemical exposures affect genes that code for inflammation, asthma, obesity, cognitive development, hormone receptors, and allergies, among others. Prenatal and early childhood exposures increase the risk of allergies through epigenetics.2

Most health conditions and disease involve changes in gene function. These changes might be caused by mechanisms other than changes in the deoxyribonucleic acid (DNA) sequence. The genome is programmed by the epigenome, which is composed of chromatin and a covalent modification of DNA by methylation. Epigenetics refers to the study of heritable changes in gene expression, caused by environmental modifications in a chromosome. Various chemicals in the environment are responsible for such changes. Epigenetic mechanisms mediate the effects of environmental exposures early in life, as well as lifelong environmental exposures and the development of disease later in life. The epigenetic program is encoded by DNA methylation, histone modifications, and noncoding RNAs. The epigenetic code provides flexibility of gene expression in response to environmental changes, allowing for adaptations across generations.2 Epigenetic modifications may be inherited across multiple generations. Prenatal, parental, or grandparental exposures affect gene expression in offspring without altering DNA sequences.3 These changes can be passed from generation to generation.
Changes in DNA methylation have been linked to seasonal allergies. Epigenetic regulation plays a key role in T-helper cell differentiation. Changes in DNA methylation patterns are observed at several key loci during this differentiation. Upregulation of IL4, IL5, and IL13 gene expression in Th2 cells is accompanied by a loss of DNA methylation and gain of permissive histone marks.4 Allergies involve an inappropriate Th2 response to an allergen such as pollen, grass, or trees. Several known allergy, atopic, and asthma genes have been found to be susceptible to epigenetic regulation, including genes important to interferon (IFN)-g, IL4, IL13, and IL17.9

The Allergy Link
In 2011, North and Ellis published a review of current literature on epigenetics and allergies. After reviewing both animal and human studies, they found evidence which indicates that transient environmental factors may have permanent effects on gene regulation and expression which potentially leads to the development of allergic disease.5 Short-term exposure to environmental chemicals can have permanent effects on gene regulation and expression through epigenetic mechanisms. Histone modifications have been associated bronchial hyperresponsiveness and spasm in allergies and asthma. Animal studies have shown that a maternal diet rich in methyl donors can enhance susceptibility to allergic inflammation in the offspring, mediated through increased DNA methylation.5 Animal studies have also implicated epigenetically modified dendritic cells in the transmission of allergic risk from mothers to offspring.5 Prenatal exposures are a link to the development of allergies through epigenetic changes.
Recent research has linked air pollution and environmental tobacco smoke to seasonal allergies via epigenetic changes. Short-term exposure to particulate matter 10 (PM10) is associated with decreased methylation of the inducible nitric oxide synthase gene.6 Nitric oxide plays a significant role in the regulation of the Th1/Th2 balance and contributes to the development of allergic diseases. Another study showed that exposure of adults to diesel and PM 2.5 over seven days was associated with DNA demethylation.7 Again, these modifications can trigger allergies.
Medications can also trigger epigenetic modifications leading to allergic disease. Procainamide and hydralazine are two drugs that induce immune changes and autoimmune conditions through this mechanism. By affecting gene transcription, epigenetic changes can lead to changes in activation of promoter genes, ultimately affecting important signaling pathways such as NF-kB and apoptosis.8 Procainamide is a cardiac drug known to induce autoimmunity, and hydralazine is used to treat hypertension.
Other environmental factors strengthen the link between epigenetic changes and allergies, especially when exposure occurs prenatally. Allergies and asthma are more likely to develop in children if the mother has allergies or asthma than if the father does.9 This suggests the possibility of intrauterine programming. Prenatal smoking is linked to allergies, asthma, and atopic disease in offspring.10 This raises the question, if allergies can be triggered prenatally or in utero, can they be reversed? Is it possible to utilize the information on epigenetic changes and allergies to reprogram the genome, offering a method of treatment or early intervention?

Reprogramming or Worsening?
Is there any evidence to support treatment or interventions other than avoiding the environmental triggers known to induce epigenetic changes? Based on previous published research finding that changes in DNA methylation resulting in aberrant gene transcription may enhance the risk of developing allergic airway disease, Hollinsworth and colleagues set out to see what happens with prenatal methyl donor supplementation. In mice, supplementation of the maternal diet with methyl donors was associated with greater airway allergic inflammation and IgE production in offspring and passed through generations. The mechanism was through epigenetic modifications regulating the differentiation of T lymphocytes.11 However, diets rich in methyl donors did not significantly affect the airway disease phenotype of mice when exposed during either lactation or adulthood. There appears to be a period of vulnerability that is limited to in utero.11 This study suggests that suppression of regulatory genes might contribute to enhanced allergic disease observed in animals exposed to dietary methyl donors.11 Too much supplementation with methyl donors during pregnancy may have unexpected consequences, such as the development of allergic diseases. These consequences can affect generations of offspring. This animal study needs to be confirmed and duplicated in humans.
Other studies support that epigenetic changes are reversible. Nutrients can reverse or change epigenetic phenomena such as DNA methylation and histone modifications. They may do so either by directly inhibiting enzymes that catalyze DNA methylation or histone modifications, or by altering the availability of substrates necessary for those enzymatic reactions.12 Folate, vitamin B12, methionine, choline, and betaine can affect DNA methylation and histone methylation through altering 1-carbon metabolism. Biotin, niacin, and pantothenic acid also play important roles in histone modifications.12 Nutritional epigenetics may be a way to prevent the developmental of diseases; however, it is very hard to delineate the precise effect of nutrients on each epigenetic modulation. Unintended side effects can occur.
Researchers are investigating many drugs that function through epigenetic mechanisms as a way to reverse modifications linked to disease. Azacitidine has been approved for use in the US to treat myelodysplastic syndrome, a blood disease that can progress to leukemia. The drug turns on genes that had been shut off by methylation.13 Only 15% of those who take it receive benefit, and there are serious side effects of nausea, vomiting, anemia, and fever. It is difficult to predict which epigenetic modifications can be reversed with drugs, since they can turn on hundreds of genes while also turning off hundreds of others.

Epigenetics is the inheritance of changes occurring in gene expression that does not depend on changes to the DNA sequence. Most epigenetic changes occur as a result of DNA methylation or by modification of chromatin or histone proteins. Micro-RNAs have been discovered recently that may also effect changes in gene expression by their ability to act as inhibitors of transcription. Epigenetics could provide an explanation for well documented gene–environment interactions and the development of allergies. Epigenetic mechanisms are dynamic and potentially reversible with therapeutic intervention. Although the possibility of developing a treatment or discovering preventative measures of these diseases is being explored, current knowledge in nutritional epigenetics is limited. Further studies are needed to better understand the use of nutrients, bioactive food components, or drugs for maintaining our health and preventing diseases through modifiable epigenetic mechanisms. More research need to be done on the possible interventions related to epigenetic changes in the development of allergies.

Dr. Marchese is the author of 8 Weeks to Women's Wellness. She maintains private practice in Phoenix, Arizona, and teaches gynecology at Southwest College of Naturopathic Medicine. She was named in Phoenix magazine's Top Doctor Issue as one of the top naturopathic physicians in Phoenix. Dr. Marchese is vice president of the Council on Naturopathic Medical Education and was recently appointed by Arizona Governor Jan Brewer to the State of Arizona Naturopathic Physicians Medical Board.

Marianne Marchese, ND

1.   Weinhold B. A steep learning curve: decoding epigenetic influence on behavior and mental health. Environ Health Perspect.2012;120(10):A397–A401. Accessed online Jan 26, 2014. Available at
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3.   Kuriakose JS, Miller RL. Environmental epigenetics and allergic diseases: recent advances. Clin Exp Allergy. 2010;40(11):1602–1610.
4.   Nestor, C, Barrenäs, F, Wang, H. DNA methylation changes separate allergic patients from healthy controls and may reflect altered CD4 T-cell population structure. PLoS Genetics. 2014;10(1):1–9.
5.   North ML, Ellis AK. The role of epigenetics in the developmental origins of allergic disease. Ann Allergy Asthma Immunol. 2011;106(5):355–336.
6.   Tarantini L et al. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect. 2009;117:217–222.
7.   Baccarelli A et al. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med. 2009;179:572–578.
8.   Richardson B. Primer: epigenetics of autoimmunity. Nat Clin Pract Rheumatol. 2007 Sep;3(9):521–527.
9.   Lim RH, Kobzik L, Dahl M. Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis. PLoS One. 2010;5(4):e10134.
10. Alati R et al. In utero and postnatal maternal smoking and asthma in adolescence. Epidemiology. 2006;17(2):138–144.
11. Hollingsworth JW et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;118(10):3462–3469.
12. Choi SW, Frisco S. Epigenetics: a new bridge between nutrition and health. Adv Nutr. 2010;1:8–16.
13. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114(3):A160–A167.

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