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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00598

BPA alters estrogen receptor expression in the heart after viral infection activating cardiac mast cells and T cells leading to perimyocarditis and fibrosis

 Katelyn A. Bruno1, 2, 3, 4, Jessica E. Mathews1,  Alex L. Yang1, 4, J. A. Frisancho4,  Ashley J. Scott4,  Henry D. Greyer4,  Frank D. Greyer4,  Merci S. Greenaway4, George M. Cooper4, Adriana Bucek4,  Andrea C. Morales-Lara1,  Anneliese R. Hill1, Anna A. Mease1,  Damian N. Di Florio1, 2, John M. Sousou1, Alexandria C. Coronado1, Allison R. Stafford1 and  DeLisa Fairweather1, 2, 3, 4*
  • 1Division of Cardiovascular Diseases Research, Mayo Clinic, United States
  • 2Center for Clinical and Translational Science (CCaTS), Mayo Clinic, United States
  • 3Department of Immunology, Mayo Clinic, United States
  • 4Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins, United States

Myocarditis is an inflammatory heart disease that leads to dilated cardiomyopathy (DCM) and heart failure. Sex hormones play an important role in the development of myocarditis with testosterone driving disease in males and estrogen being cardioprotective in females. The human population is widely exposed to the endocrine disruptor bisphenol A (BPA) from plastics such as water bottles, plastic food containers, copy paper and receipts. Several clinical and numerous animal studies have found an association between elevated BPA levels and cardiovascular disease. A recent report found elevated levels of BPA in the serum of patients with DCM compared to healthy controls. In this study we examined whether exposure to BPA for two weeks prior to viral infection and leading up to myocarditis at day 10 altered inflammation in female BALB/c mice housed in standard plastic cages/water bottles with soy-free food and bedding. We found that a human relevant dose of BPA (25µg/L) in drinking water, with an estimated exposure of 5µg BPA/kg BW, significantly increased myocarditis and pericarditis compared to control water without altering viral genome levels in the heart. BPA exposure activated ERa and ERb in the spleen 24 hours after infection and phosphorylated ERa and ERb during myocarditis, but decreased ERa and increased ERb mRNA in the heart as measured by qRT-PCR. Exposure to BPA significantly increased CD4+ T cells, IFNg, IL-17A, TLR4, caspase-1, and IL-1b in the heart. BPA exposure also increased cardiac fibrosis compared to controls. Mast cells, which are associated with cardiac remodeling, were found to increase in number and degranulation, particularly along the pericardium. Interestingly, plastic caging/water bottle exposure alone led to increased mast cell numbers, pericardial degranulation and fibrosis in female BALB/c mice compared to animals housed in glass cages/water bottles with soy-free food and bedding. These data suggest that BPA exposure may increase the risk of developing myocarditis after a viral infection in women.

Keywords: Myocarditis, Endocrine disruptor, bisphenol A, estrogen receptor, Mast Cells

Received: 30 Mar 2019; Accepted: 14 Aug 2019.

Copyright: © 2019 Bruno, Mathews, Yang, Frisancho, Scott, Greyer, Greyer, Greenaway, Cooper, Bucek, Morales-Lara, Hill, Mease, Di Florio, Sousou, Coronado, Stafford and Fairweather. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. DeLisa Fairweather, Division of Cardiovascular Diseases Research, Mayo Clinic, Rochester, United States,