BPA Alters Estrogen Receptor Expression in the Heart After Viral Infection Activating Cardiac Mast Cells and T Cells Leading to Perimyocarditis and Fibrosis.

Katelyn Ann Bruno,Allison Ray Stafford,Frank Anthony Molina,George Maxwell Cooper,Delisa Fairweather,Alex Lingyun Yang,John Michael Sousou,Ashley Jennie Scott,Alexandria Christine Coronado,Henry David Greyner,Anna Alisa Mease,Anneliese Ruth Hill,Damian Nicolas Di Florio,J Augusto Frisancho,Merci Shekinah Greenaway,Adriana Bucek,Jessica Elizabeth Mathews,Andrea Carolina Morales-Lara

doi:10.3389/fendo.2019.00598

Katelyn Ann Bruno, Allison Ray Stafford + Show 16 more

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https://doi.org/10.3389/fendo.2019.00598

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Abstract

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 2 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 (25 μg/L) in drinking water, with an estimated exposure of 5 μg BPA/kg BW, significantly increased myocarditis and pericarditis compared to control water without altering viral genome levels in the heart. BPA exposure activated ERα and ERβ in the spleen 24 h after infection and phosphorylated ERα and ERβ during myocarditis, but decreased ERα and increased ERβ mRNA in the heart as measured by qRT-PCR. Exposure to BPA significantly increased CD4+ T cells, IFNγ, IL-17A, TLR4, caspase-1, and IL-1β 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.

Highlights

Myocarditis is an inflammatory heart disease that can lead to dilated cardiomyopathy (DCM) and heart failure and is most often caused by viral infections such as coxsackievirus B3 (CVB3) [1,2,3]
bisphenol A (BPA) Exposure in Drinking Water Increases Viral Myocarditis in Female BALB/c Mice Housed in Plastic Cages To assess the effect of BPA exposure on CVB3-induced myocarditis, female adult BALB/c mice housed in traditional plastic cages were fed varying doses of BPA in drinking water ad libitum for 2 weeks prior to ip infection with CVB3 and heart tissues on day 0 until harvest at day 10 pi during myocarditis
In order to determine whether BPA that may have leached from the plastic cages and plastic water bottles used in our experiments affected myocarditis, in separate experiments we compared glass cages and water bottles to plastic cages and water bottles

Summary

Introduction

Myocarditis is an inflammatory heart disease that can lead to dilated cardiomyopathy (DCM) and heart failure and is most often caused by viral infections such as coxsackievirus B3 (CVB3) [1,2,3]. ERα has been found to protect against CVB3 myocarditis by increasing disease in ERα knockout mice while infected male mice treated with the ERα agonist propylpyrazoletriol were protected [10, 11]. ERβ has been found to increase collagen synthesis from cardiac fibroblasts in male and female mice, while ERα decreases collagen synthesis [13,14,15]. In CVB3 myocarditis, ERβ signaling was found to promote myocarditis in male or female mice treated with the ERβ agonist diarylpropionitrile [10, 11]. Little is known about the effect of estrogen-related receptor (ERR)γ signaling on/in immune cells or on cardiac physiology or disease [16]. Since CVB3 myocarditis is influenced by sex hormones and ERs, endocrine disruptors could play a role in the development and severity of disease

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