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，对自身/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），在最近的《柳叶刀》报告中被列为全球第32大死因。自身炎症性心血管疾病包括心肌炎、DCM和动脉粥样硬化主要发生在男性中，他们发生DCM和HF的风险增加。研究人员先前发表的研究表明，睾酮通过增加肥大细胞和激活炎性体（即TLR4、caspase-1和白细胞介素(IL)-1）来驱动心肌炎，导致心脏重塑、纤维化和进展为DCM。相反，雌激素（E2）通过提高抗炎免疫反应（包括IL-4/Th2和调节性T细胞（Treg））来减少雌性小鼠的心肌炎。临床和实验研究表明，E2通过雌激素受体（ER）介导女性对icvd的心脏保护，而ER信号则具有相反的作用。由于心肌炎和DCM受性激素的强烈影响，子宫内或成人暴露于ED可能影响成人自身免疫性CVD。据我们所知，还没有人研究过ed对心肌炎或DCM的潜在影响。在这里提出的初步研究中，研究人员发现，成年雌性小鼠在饮用水中暴露于25 g/L的高剂量BPA，会显著增加心肌炎，并将雌性小鼠转化为雄性小鼠。在该剂量的BPA下，心肌炎期间心脏ER显著降低（使用全心脏qRT-PCR），而与对照组相比，ER显著增加，表明BPA失调心脏ER信号。基于这些发现和关于内质网心脏保护作用的文献，研究人员假设BPA通过内质网作用于肥大细胞而增加雌性小鼠的心肌炎。研究人员将研究BPA对心肌炎和DCM的影响机制，在第1阶段确定成年暴露于BPA是否通过内质网（或其他内质网）增加成年雄性和雌性小鼠的心肌炎，在第2阶段研究产前暴露于BPA对雄性和雌性后代成年疾病的影响（F1）。如果BPA是激活肥大细胞增加iCVD，这项研究将对疾病发病机制的认识产生重大影响。

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.