The long term goal of this project is to determine the effect of endocrine disruptors (EDs), beginning with bisphenol A (BPA), on auto/inflammatory cardiovascular diseases (iCVDs). Myocarditis is an autoimmune iCVD that leads to dilated cardiomyopathy (DCM) and heart failure (HF) and was listed in a recent Lancet report as the 32nd cause of death globally. Autoinflammatory CVDs including myocarditis, DCM, and atherosclerosis occur predominantly in men, who are at an increased risk of developing DCM and HF. The investigators have previously published that testosterone drives myocarditis by increasing mast cells and by activating the inflammasome (i.e. TLR4, caspase-1 and interleukin (IL)-1), resulting in cardiac remodeling, fibrosis and progression to DCM. In contrast, estrogen (E2) decreases myocarditis in female mice by elevating anti- inflammatory immune responses including IL-4/Th2 and regulatory T cells (Treg). Clinical and experimental studies indicate that E2, via the estrogen receptor (ER), mediates cardio-protection against iCVDs in females, while ER signaling has the opposite effect. Since myocarditis and DCM are strongly influenced by sex hormones, ED exposure in utero or as an adult could influence adult autoimmune CVD. To our knowledge no one has examined the potential effect of EDs on myocarditis or DCM. In preliminary studies presented here, the investigators found that a high human relevant exposure of 25 g/L of BPA administered to adult female mice in drinking water significantly increased myocarditis and converted females to a male-like inflammatory profile. ER was significantly decreased in the heart during myocarditis (using qRT-PCR of the whole heart) at this dose of BPA, while ER was significantly increased compared to controls, indicating BPA disregulation of ER signaling in the heart. Based on these findings and the literature on the cardioprotective role of ER, the investigators hypothesize that BPA increases myocarditis in female mice via ER on mast cells. The investigators will investigate the mechanisms of BPA effects on myocarditis and DCM by determining in Aim 1 whether adult exposure to BPA is acting through ER (or other ERs) to increase myocarditis in adult male and female mice, and in Aim 2 by examining the effect of prenatal exposure to BPA on adult disease in male and female offspring (F1). If BPA is activating mast cells to increase iCVD, this study will have a great impact on the understanding of disease pathogenesis.

Public Health Relevance

Men have a higher incidence and severity of cardiovascular diseases including myocarditis, dilated cardiomyopathy and heart failure than women. Although women are usually protected from heart disease, the endocrine disruptor BPA has been found to convert the immune response of women to a cardiodamaging profile. This project will examine the mechanisms involved in endocrine disruption of inflammation by BPA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES024414-01
Application #
8765093
Study Section
Special Emphasis Panel (ZES1-JAB-J (AU))
Program Officer
Humble, Michael C
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$243,000
Indirect Cost
$93,000
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Root-Bernstein, Robert; Fairweather, DeLisa (2015) Unresolved issues in theories of autoimmune disease using myocarditis as a framework. J Theor Biol 375:101-23