Bisphenol A (BPA) and Bisphenol S (BPS) increase Coxsackievirus B3 myocarditis in female and male BALB/c mice by activating mast cells, increasing immune cell infiltrate and activating the inflammasome

Abstract

Abstract Myocarditis is an inflammatory heart disease that is the leading cause of heart failure in young adults. Sex hormones play a vital role in development of myocarditis with testosterone driving disease in males. Whereas, estrogen, via Estrogen Receptor α (ERα) mediates cardioprotection in females. Since myocarditis is influenced by sex hormones, it is highly probable that endocrine disruptors (EDs); which interfere with natural hormones, will play a part in the progression of the disease. The human population is exposed to Bisphenol A (BPA), a known ED that binds the ER, from plastics, such as water bottles and plastic food containers. BPA could increase myocarditis through deleterious actions of the ERβ rather than beneficial effects via ERα. To our knowledge no one has examined the role of EDs like BPA on myocarditis. We found that clinically relevant doses (25 μg/L and 250 μg/L) of BPA increased acute myocarditis compared to control water in females. In females we found BPA significantly decreased ERα, while ERβ was significantly increased. We found that mast cells (cKit) are largely responsible for the increase in inflammation along with CD4 Thelper cells, IL-1β, IFN-γ, TLR4, Caspase-1, Mmp9, and ST2. In male mice, we found that at the high dose of BPA increased myocarditis and increased all immune cell markers and the inflammasome. We also investigated the compound Bisphenol S (BPS) which has replaced BPA in a number of products and found that BPS also increases myocarditis. Interestingly this effect was only seen in Balb/c mice and not BL/6 suggesting that race could be a factor in evaluating ED role in disease. We have found that ED exposure is having a significant effect on myocarditis and could potentially influence a number of human diseases.