Could epigenetic changes in parents predispose children to allergies? Recent studies suggest it’s possible. Suggest not prove. Best studied example is for increased risk of asthma in children and grandchildren of smokers, especially mothers and grandmothers who smoked when pregnant. While smoking is a different trigger from childhood allergies, the common thread is whether or not such different triggers induce epigenetic changes that are stably transmitted to the germ cells/gametes (egg and sperm). Chicken-and-egg question w.r.t. epigenetic changes associated with allergies: Do such changes drive the pathology or are they responses to it? This is as yet unresolved.
In this answer, let’s briefly examine
- What are epigenetic changes and how they differ from genetic changes.
- Data that suggest heritable epigenetic changes could predispose to allergies.
- What’s the connection between heritable epigenetic changes and allergies?
- How heritable epigenetic changes influence children’s chances of allergies.
What are epigenetic changes and how they differ from genetic changes
- Epigenetic means not in the classical Mendelian definition of DNA sequence changes but rather reversible but stable, heritable alterations in their genetic architecture (1), in this case during the period parents had allergies.
- The most relevant epigenetic changes
- Include DNA methylation, hydroxyl methylation, chromatin remodeling, expression of non-coding RNAs.
- In DNA methylation, methyl (CH3) groups bind to cytosine residues adjacent to guanine residues (called CpG sites). This results in 5-methylcytosine and leads to gene silencing.
- While many CpG sites in the genome are already methylated, there are CpG islands, i.e., clusters of CpG-rich sites, in many gene promoters, and in locus control and initial exon regions.
- Triggers that drive epigenetic changes relevant to allergies include nutrition, smoking, stress or more accurately distress. As Marshall defines, ‘Stress is a term often used to connote an adverse situation. Yet our use of the term stress derives from an engineering term that is used to reflect the impact of a situation (often called a stressor) on host homeostasis. It is best thought of as a psychophysiological process that is a product of both the appraisal of a given situation (either acutely or chronically over time) and the ability to cope with that situation. If the situation threatens harm, loss, or danger and/or the host-coping ability is deemed inadequate, the stress is termed distress. Most common uses of the term stress actually mean distress‘ (2).
- The most relevant inheritable epigenetic changes are those in germ cells/gametes, i.e., sperms and eggs.
Data that suggest heritable epigenetic changes could predispose to allergies
- Many epidemiological studies (3, 4, 5, 6, 7) show that mothers who smoked when pregnant had children predisposed to low birth weight, sudden unexplained death in infancy, asthma, low lung function and increased respiratory symptoms in infancy.
- Caveat of these studies is that children born to mothers who smoke are exposed to smoke after birth as well. Separating effects of prenatal and postnatal smoking exposure is impossible.
- Mothers’ second-hand smoke exposure also increased children’s asthma risk in at least one study (8).
- Rat asthma models suggest epigenetic changes can be transmitted not only to children but also to grandchildren (9).
- Grandchildren of grandmothers who smoked when pregnant had increased risk of asthma even when the mother herself didn’t smoke when pregnant (10).
- Prospective study of 100000 women and their children.
- Questionnaires included information on grandmothers’ smoking habits.
- In effect, mothers’ attributes stood as proxies for grandmothers.
- Recall bias is a weakness of study.
- Effect of grandmother smoking when pregnant was as strong as mother alone smoking when pregnant.
What’s the connection between heritable epigenetic changes and allergies?
- Tobacco smoking is associated with changes in DNA methylation at several sites across the genome (11).
- DNA derived from cord blood of infants whose mothers smoked when pregnant also showed differential methylation of similar CpG sites (12).
- In one study, the ALOX12 (arachidonate 12-lipoxygenase) gene was hypomethylated in children with persistent early childhood wheezing (13). Hypomethylation means relatively unfettered gene expression, in this case of the ALOX12 gene.
- Hypomethylation was present in DNA collected at birth and at 4 years of age.
- Hypomethylation correlated with maternal exposure to a persistent organic pollutant, dichlorodiphenyldichloroethylene (DDE), a metabolite of the pesticide DDT.
- Maternal exposure was assessed by measuring pollutant levels in serum in early pregnancy.
- ALOX12 encodes the 12-LOX enzyme involved in arachidonic acid metabolism. It leads to inflammatory molecules that may be involved in chronic airway inflammation and remodeling seen in asthma.
How heritable epigenetic changes influence children’s chances of allergies
In order for parental epigenetic changes to be heritable, they
- Should be in germ cells.
- Should escape the inevitable germ cell reprogramming during development (14, 15; see figure below from 15).
- This reprogramming removes epigenetic signatures acquired during life.
- Occurs in both germline (egg and sperm) and zygote.
- Thus, chances of epigenetic inheritance are quite low except in ‘imprinted loci resistant to postzygotic reprogramming‘ (16).
- miRNAs or microRNAs are noncoding RNAs that fold back on themselves forming hair-pin structures (17).
- Binding to protein-coding mRNAs (messenger RNAs), they regulate post-transcriptional gene expression, mainly through repression.
- Human sperm contain >100 miRNAs (18).
- miRNAs have been shown to be a vehicle for heritable epigenetic changes.
Comparison of smokers versus non-smokers
- In one study, 28 known human miRNAs were significantly differentially expressed between sperm of smokers and non-smokers (19).
- 10 of these 28 MiRNAs are known to be involved in pathways essential for healthy sperm and normal embryo development.
- In addition these altered miRNAs target as many as 25 other epigenetic pathways such as a variety of DNA and histone modification pathways.
- This suggests a potential mechanism by which miRNA expression altered by environmental exposure in one generation could be agents of phenotypic change in future generations.
- Deans, Carrie, and Keith A. Maggert. “What Do You Mean,“Epigenetic”?.” Genetics 199.4 (2015): 887-896.
- Marshall, Gailen D. “Neuroendocrine mechanisms of immune dysregulation: applications to allergy and asthma.” Annals of Allergy, Asthma & Immunology 93.2 (2004): S11-S17.
- Stick, Stephen M., et al. “Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants.” The Lancet 348.9034 (1996): 1060-1064.
- Dezateux, C., et al. “Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma.” American journal of respiratory and critical care medicine 159.2 (1999): 403-410.
- Neuman, Åsa, et al. “Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts.” American journal of respiratory and critical care medicine 186.10 (2012): 1037-1043.
- Hollams, Elysia M., et al. “Persistent effects of maternal smoking during pregnancy on lung function and asthma in adolescents.” American journal of respiratory and critical care medicine 189.4 (2014): 401-407.
- Werhmeister, F. C., et al. “Intrauterine exposure to smoking and wheezing in adolescence: the 1993 Pelotas Birth Cohort.” Journal of developmental origins of health and disease 6.03 (2015): 217-224.
- Simons, Elinor, et al. “Maternal second-hand smoke exposure in pregnancy is associated with childhood asthma development.” The Journal of Allergy and Clinical Immunology: In Practice 2.2 (2014): 201-207.
- Rehan, Virender K., et al. “Perinatal nicotine-induced transgenerational asthma.” American Journal of Physiology-Lung Cellular and Molecular Physiology 305.7 (2013): L501-L507.
- Magnus, Maria C., et al. “Grandmother’s smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study.” Thorax 70.3 (2015): 237-243.
- Breitling, Lutz P., et al. “Tobacco-smoking-related differential DNA methylation: 27K discovery and replication.” The American Journal of Human Genetics 88.4 (2011): 450-457.
- Joubert, Bonnie R. “450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking During Pregnancy (vol 120, pg 1425, 2012).” ENVIRONMENTAL HEALTH PERSPECTIVES 120.12 (2012): A455-A455.
- Morales, Eva, et al. “DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.” American journal of respiratory and critical care medicine 185.9 (2012): 937-943.
- Heard, Edith, and Robert A. Martienssen. “Transgenerational epigenetic inheritance: myths and mechanisms.” Cell 157.1 (2014): 95-109.
- Sharma, Abhay. “Transgenerational epigenetic inheritance requires a much deeper analysis.” Trends in molecular medicine 21.5 (2015): 269-270.
- Henderson, A. John. “The sins of the mothers: does grandmaternal smoking influence the risk of asthma in children?.” Thorax 70.3 (2015): 207-208.
- Maccani, Matthew Alan, and Valerie S. Knopik. “Cigarette smoke exposure-associated alterations to non-coding RNA.” Frontiers in genetics 3 (2012): 53.
- Krauss-Etschmann, Susanne, et al. “Clinical Epigenetics.” (2015).
- Marczylo, Emma L., et al. “Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern?.” Epigenetics 7.5 (2012): 432-439.