Environmental Estrogen Effects on the Development of Allergic Asthma

The prevalence of asthma, particularly among children in industrialized countries, has been increasing rapidly over the last 2-3 decades. Asthma is now the most common chronic disease of childhood. Our findings were the first to show experimentally that an environmental estrogen (EE), bisphenol A (BPA) can promote the development of an asthma-like disease, and to identify potential cellular and molecular mechanisms for this effect. This effect of BPA required prenatal exposure. The potential importance of our findings in mice for human asthma is supported by two recent birth cohort studies and an analysis of national survey data, each indicating an association between pre- or postnatal exposure to BPA and the prevalence of wheezing in children. These findings emphasize the need to identify mechanisms by which exposure to environmentally relevant doses of BPA promotes the development of asthma.

Preliminary mechanistic studies on mouse spleen cells suggest that perinatal exposure to BPA exposure followed by allergic sensitization, results in hypomethylation of a key CpG motif in the promoter region of the IFNγ gene and enhances mRNA and protein expression in both CD4+T and CD8+T lymphocytes. We also found that the effect of BPA exposure on asthma persisted through at least three maternal generations, suggesting that these epigenetic alterations of immune development are heritable. Initial relevance studies indicated that exogenous IFNγ stimulates human cord (neonatal) blood basophils to increase their expression of major histocompatibility complex (MHC) class II and inducible costimulatory-ligand (ICOS-L), crucial for effective antigen-presenting activity, which promotes the development of T helper (Th) type 2. In Dr. Midoro-Horiuti’s current project, observations on the epigenetic effects of BPA will be corroborated and extended to the whole DNA methylomes of several immune cell types, providing a road map of BPA’s effects on asthma-related pathways. 

Central hypothesis for this project is that fetal exposure to BPA induces epigenetic modulation of the developing immune systems, which promotes the development of childhood asthma and can persists into adulthood and be passed to future generations. Based on the recent findings, this group will focus on the effects of a single EE, BPA on the DNA methylome of three populations of mouse splenocytes. Bioinformatic analyses will predict patterns of gene expression in CD4+T, CD8+T and antigen presenting cell (APC)s and define pathways and interactions that could promote the development of childhood asthma.

Researchers

  • Terumi Midoro-Horiuti, MD, PhD
  • Cheryl H. Watson, PhD, Co-Investigator, Adjunct Professor of UTMB Department of Biochemistry and Molecular Biology
  • Bhupendra Kaphalia, PhD, Co-Investigator, Professor, UTMB Department of Pathology
  • Kangling Zhang, PhD, Co-Investigator, Department of Pharmacology & Toxicology, Sealy Center for Molecular Medicine
  • Shuk-Mei Ho, PhD, University of Cincinnati, Department of Environmental Health

Funding

  • MIDORO-HORIUTI, TERUMI  (PI), 04/09/15-03/31/18, Epigenomic Effects of Perinatal Exposure to Environmental Estrogens Promote the Development of Allergic Asthma, R21 ES025406
  • MIDORO-HORIUTI, TERUMI  (PI), 09/01/14-08/31/16, Environmental Estrogens Induce Signals in Immune cells that Promote the Development of Asthma, American Lung Association/AAAAI Foundation, AI-310304
  • MIDORO-HORIUTI, TERUMI  (PI), 12/01/07-11/30/10, Perinatal exposure to environmental estrogens and asthma pathogenesis, R21 ES016428

Relevant Publications

  1. Bonds RS, Midoro-Horiuti T. Estrogen effects on asthma and other allergic diseases. Current Opinion in Allergy and Clinical Immunology 2013 Feb;13(1):92-9. PMCID:3537328
  2. Midoro-Horiuti T, Tiwari R, Watson CS, Goldblum RM. Maternal exposure to bisphenol A enhances susceptibility to experimental allergic asthma in their pups. Env Health Perspectives 2010 Feb 1;118(2):273-7. PMCID:2831929
  3. Midoro-Horiuti T., Choudhury BK, Vinas R, Watson TJ, Goldblum RM. Environmental Estrogens Alter Signaling in Immune Cells that Promotes the Development of Childhood Asthma. Journal of Allergy and Clinical Immunology 135. 2015.
  4. Nakajima Y, Goldblum RM, Midoro-Horiuti T. Fetal exposure to bisphenol A as a risk factor for the development of childhood asthma: an animal model study. Environ.Health 2012;11(8):1-7. PMCID:3306825
  5. Narita S, Goldblum RM, Watson CS, Brooks EG, Estes DM, Curran EM, Midoro-Horiuti T. Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators. Env Health Perspectives 2007 Jan 1;115(1):48-52 PMCID: PMC1797832
  6. Watson CS, Jeng YJ, Bulayeva NN, Finnerty CC, Koong LY, Zivadinovic D, Alyea RA, Midoro-Horiuti T, Goldblum RM, Anastasio NC, et al. Multi-well Plate Immunoassays for Measuring Signaling Protein Activations/Deactivations and Membrane vs. Intracellular Receptor Levels. Methods Mol.Biol. 2014;1204:123-33
  7. Zaitsu M, Yamasaki F, Ishii E, Midoro-Horiuti T, Goldblum RM, Hamasaki Y. Interleukin-18 primes human basophilic KU812 cells for higher leukotriene synthesis. Prostaglandins Leukot.Essent.Fatty Acids 2006 Jan;74(1):61-6
  8. Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM, Midoro-Horiuti T. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol.Immunol 2007 Mar;44(8):1987-95 PMCID: PMC2603032