Endocrine disruptors effect on inflammatory heart disease

描述(由申请人提供)：该项目的长期目标是确定内分泌干扰物(EDs)，从双酚A(BPA)开始，对自体/炎症性心血管疾病(ICVD)的影响。心肌炎是一种自身免疫性心血管疾病，可导致扩张型心肌病(DCM)和心力衰竭(HF)，并在最近的《柳叶刀》报告中被列为全球第32位死亡原因。包括心肌炎、扩张性心肌病和动脉粥样硬化在内的自体炎症性心血管疾病主要发生在男性，他们发展为扩张性心肌病和心力衰竭的风险增加。研究人员此前发表的研究报告称，睾酮通过增加肥大细胞和激活炎症小体(即TLR4、caspase-1和IL-1)，导致心脏重构、纤维化和进展为DCM，从而推动心肌炎。相反，雌激素(E2)通过提高包括IL-4/Th2和调节性T细胞(Treg)在内的抗炎免疫反应来减少雌性小鼠的心肌炎。临床和实验研究表明，雌二醇通过雌激素受体(ER)介导对女性心血管疾病的心脏保护作用，而ER信号则具有相反的作用。由于心肌炎和扩张型心肌炎受性激素的强烈影响，宫内或成年后的ED暴露会影响成人自身免疫性心血管疾病。据我们所知，还没有人研究内源性药物对心肌炎或扩张型心肌炎的潜在影响。在这里介绍的初步研究中，研究人员发现，成年雌性小鼠在饮用水中摄入与人类高度相关的25g/L双酚A，显著增加了心肌炎，并将雌性小鼠转化为类似雄性的炎症状态。在心肌炎期间(使用全心脏的qRT-PCR)，该剂量的BPA显著降低了心脏的ER，而与对照组相比ER显著增加，表明BPA对心脏中的ER信号的调节是紊乱的。基于这些发现和有关ER的心脏保护作用的文献，研究人员假设BPA通过肥大细胞上的ER增加雌性小鼠的心肌炎。研究人员将通过在目标1中确定成年暴露于BPA是否通过ER(或其他ER)增加成年雄性和雌性小鼠的心肌炎来研究BPA对心肌炎和DCM的影响的机制，以及在目标2中通过检查产前暴露于BPA对雄性和雌性后代成年疾病的影响(F1)来研究BPA对心肌炎和DCM的影响。如果BPA激活肥大细胞增加ICVD，这项研究将对了解疾病的发病机制产生重大影响。

DESCRIPTION (provided by applicant): 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.