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Understanding Root Causes of Asthma Perinatal Environmental Exposures and Epigenetic Regulation Rachel L

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Understanding Root Causes of Asthma Perinatal Environmental Exposures and Epigenetic Regulation Rachel L THOMAS A. NEFF LECTURE Understanding Root Causes of Asthma Perinatal Environmental Exposures and Epigenetic Regulation Rachel L. Miller1,2 and Jennifer Lawrence1 1Division of Pulmonary, Allergy and Critical Care of Medicine, Department of Medicine, and 2Division of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York ORCID ID: 0000-0002-4214-3347 (R.L.M.). Abstract explain the immunopathology underlying asthma. Third, we outline specific evidence that environmental exposures induce A common explanation for the origins and rising prevalence of epigenetic regulation, both from animal models and robust asthma is that they involve complex interactions between hereditary human epidemiological research. Finally, we review some predispositions and environmental exposures that are incompletely emerging topics, including the importance of coexposures, understood. Yet, emerging evidence substantiates the paradigm that population divergence, and how epigenetic regulation may environmental exposures prenatally and during very early childhood change over time. Despite all the inherent complexity, great induce epigenetic alterations that affect the expression of asthma progress has been made toward understanding what we still consider genes and, thereby, asthma itself. Here, we review much of the key reversible asthma risk factors. These, in time, may impact patient evidence supporting this paradigm. First, we describe evidence that care. the prenatal and early postnatal periods are key time windows of susceptibility to environmental exposures that may trigger asthma. Keywords: asthma mechanisms; environmental epigenetic Second, we explain how environmental epigenetic regulation may regulation; perinatal environmental exposures (Received in original form June 30, 2017; accepted in final form August 30, 2017) Supported by National Institutes of Health grants 4R01ES13163 (R.L.M.) and 1R01HL118612A1 (R.L.M.). Author Contributions: R.L.M. and J.L. co-authored the manuscript. Correspondence and requests for reprints should be addressed to Rachel L. Miller, M.D., Division of Pulmonary, Allergy, Critical Care Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, PH8E-101, 630 West 168th Street, New York, NY 10032. E-mail: [email protected]. Ann Am Thorac Soc Vol 15, Supplement 2, pp S103–S108, Apr 2018 Copyright © 2018 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201706-514MG Internet address: www.atsjournals.org The prevalence of current asthma environmental exposures increase the asthma appears evident, as recently continues to rise in the United States. susceptibility for later asthma. Although demonstrated by Barr and colleagues (7). Recently, the U.S. Centers for Disease thoroughly reviewed in past publications They found that the estimated prevalence Control and Prevention reported that 7.8% (3, 4), notable findings document that of self-reported asthma among Hispanics of the population is diagnosed with current prenatal exposure to stress (5) and air was higher when the age of immigration asthma (8.4% of children and 7.6% of pollution (6) are prime examples of to the four U.S. cities under investigation adults) (1). Of great concern are the exposures that heighten the subsequent risk (New York, NY; Chicago, IL; Miami, FL; disparities associated with asthma rates, for asthma development. For the latter, and San Diego, CA) was within the first hospitalization, and death by race and sex, greater exposure to fine particulate matter few years of life. This study, therefore, with Puerto Ricans (13.7%), African less than 2.5 mm in aerodynamic diameter, implicates the urban physical environment Americans (10.3%), and females (9.1%) specifically during 16–25 weeks gestation, experienced at a young age, more so than having higher prevalence of current and in interaction with male sex, was during an older age or during adulthood, as asthma (2). Both the prenatal and early associated with early childhood asthma impacting prevalence rates. postnatal periods have been identified development (6). Shortly after birth, Epigenetic regulation after environmental as key time windows, when specific another time period of susceptibility to exposures prenatally and during very Miller and Lawrence: Perinatal Environmental Exposures and Epigenetics S103 THOMAS A. NEFF LECTURE 1 early childhood may underlie much patterns of DNA methylation and hypermethylated CD4 T-cell genes, of these observations. Methylation, transcription in dendritic cells. Most of including fatty acid desaturase 1, fanconi post-translational modifications of the genes with differential methylation in anemia complementation group A, histones via acetylation, phosphorylation, offspring mice also showed transcriptional and zinc finger protein 1. Specifically ubiquitination, and the expression of changes after the first encounter with highlighted was the GATA binding protein inhibitory microRNAs are all regulatory the allergen, the majority of the genes 3–regulating zinc finger protein 1 gene, mechanisms that alter gene expression identified as involved in asthma or the decreased expression and increased without changing the coding sequence, allergic inflammation (14). Another group enhancer methylation of which was and appear to be affected by external studied the effect of prenatal exposure observed in the prenatally phthalate- environmental exposures, as reviewed to the gram-negative, farm-derived exposed children of the LINA cohort. elsewhere (8). For example, during DNA isolate, Acinetobacter lwoffii F78, to Robust human studies also suggest methylation, the covalent addition of a model the mechanisms of asthma that environmental exposures induce methyl group to the 59 position of the and allergy prevention and immune epigenetic outcomes relevant to asthma. cytosine pyrimidine ring, often at CpG modulation among children raised on These include ex vivo studies, such as one sites, may affect the metabolism of farms (15). The effect of this exposure on that isolated airway epithelial cells from environmental compounds, degree histone 4 acetylation (associated with adults with asthma versus those without of proinflammatory response, efficacy of transcriptionally active chromatin) and its asthma and cultured them in the presence pharmacological treatment, or the risk mitigation of T-helper cytokine activity of IL-13 as a cellular model of the 1 of disease development. Exposures to in CD4 T-cells, after ovalbumin proallergic external environment. After allergens, air pollution, and various dietary sensitization of offspring, was assessed. discovering an IL-13 epigenetic signature components have been observed to induce Ovalbumin sensitization and challenge of in culture, validation experiments were gene-specific epigenetic alterations that the offspring of prenatally sham-exposed performed on the airway epithelial cells affect the transcription of asthma-related mothers demonstrated lower levels of isolated from subjects with and without genes and subsequent phenotypic histone 4 acetylation at the counter- asthma. Epigenetic findings clustered expression of asthma or its biomarkers (9). regulatory interferon-g promoter when into one distinct module that correlated One demonstration of this phenomenon is compared with levels measured among with asthma severity and lung function, that the presence of maternal asthma is sham-exposed offspring. This effect was and another distinct module that a greater risk factor for offspring asthma associated with altered interferon-g correlated with eosinophilia, suggesting than paternal asthma, implicating the expression, and reversed among environmental epigenetic regulation of importance of the intrauterine environment ovalbumin-sensitized and -challenged distinct asthma endotypes (18). Also (10). In addition, uncontrolled maternal offspring of mothers exposed to A. supportive of the importance of the asthma has been observed recently to lwoffii F78. Prenatal A. lwoffii also childhood environment was recent work increase the risk of childhood early-onset reduced histone 4 acetylation levels in from a study of monozygotic twins, a persistent or transient asthma (11). Also sensitized/challenged A. lwoffii–exposed cohort that allows natural controls for the in recent related work, maternal asthma offspring at the proallergic IL-4 (but not genetic background and, presumably, the was associated with neonatal methylation IL-5 or conserved noncoding sequence 1) intrauterine, and to some extent, early of a gene called mothers against promoter. Notably, prenatal A. lwoffii did postnatal environment. Murphy and decapentaplegic homolog 3, which was not induce any changes in the CpG colleagues (19) examined numerous previously linked to asthma in genome- methylation at these sites (16). The authors differences in genome-wide DNA wide association studies (12), corroborating interpreted these results to indicate that methylation patterns by the presence the epigenetic paradigm. A. lwoffii modulated the allergic immune or absence of childhood asthma at age Experimental models in mice have response through the transcriptional 10 years, when the external environments provided direct evidence of prenatal control of histone 4 acetylation. Jahreis and have started to diverge. The data also environmental epigenetic regulation. In colleagues (17) observed, in the LINA suggested that some of these differences one study, our group examined CpG (Lifestyle
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