Endocrine disruptors effect on inflammatory heart disease

内分泌干扰物对炎症性心脏病的影响

基本信息

批准号：
8765093
负责人：
DeLisa Fairweather
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8765093
关键词：
Accidents Adult Age Anaphylatoxins Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Autoimmune Diseases Autoimmune Process Cardiac Cardiovascular Diseases Caspase-1 Cause of Death Cell Count Clinical Research Complement 1 Inactivators Complement Receptor Development Dilated Cardiomyopathy Disease Disease Progression Dose Endocrine Disruptors Endocrine disruption Environmental Exposure Estrogen Receptors Estrogens Exposure to Female Fibrosis Genes Goals Gonadal Steroid Hormones Heart Heart Diseases Heart Transplantation Heart failure Hormones Human Immune response Immunologic Adjuvants Incidence Inflammation Inflammatory Interleukin-1 Interleukin-4 Knockout Mice Literature Mediating Mus Myocarditis Pathogenesis Publishing Receptor Signaling Regulatory T-Lymphocyte Reporting Research Personnel Risk Role Severities Sudden Death TLR4 gene Testosterone Woman base bisphenol A drinking water endocrine disruptor exposure in utero male mast cell men mouse model offspring prenatal exposure public health relevance receptor reproductive research study sex young adult

项目摘要

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.

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）的影响（EDS），以双酚A（BPA）（BPA），对自动/炎症性心血管疾病（ICVD）的影响。心肌炎是一种自身免疫性ICVD，导致心肌病（DCM）和心力衰竭（HF）的扩张，并在最近的柳叶刀报告中被列为全球第32号死亡原因。包括心肌炎，DCM和动脉粥样硬化在内的自身炎症CVD主要发生在患有DCM和HF的风险增加的男性中。研究人员先前已经发表了睾丸激素通过增加肥大细胞并激活炎性体（即TLR4，caspase-1和白介素（IL）-1）来驱动心肌炎，从而导致心脏重塑，纤维化，纤维化和发展为DCM。相反，雌激素（E2）通过升高包括IL-4/TH2和调节T细胞（TREG）在内的抗炎性免疫反应来降低雌性小鼠的心肌炎。临床和实验研究表明，通过雌激素受体（ER）E2介导对女性ICVD的心脏保护，而ER信号传导具有相反的作用。由于心肌炎和DCM受性激素的强烈影响，因此在子宫内或成年人的ED暴露可能会影响成人自身免疫性CVD。据我们所知，没有人检查ED对心肌炎或DCM的潜在影响。在此处介绍的初步研究中，研究人员发现，在饮用水中向成年雌性小鼠施用的25 g/L的人类相关暴露显着增加了心肌炎，并将雌性转化为雄性样炎症性。在这种BPA剂量下，心肌炎（使用全心脏的QRT-PCR）在心脏中的ER显着降低，而与对照组相比，ER显着增加，表明BPA在心脏中的ER信号传导不调。基于这些发现以及有关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增加了雌性小鼠的心肌炎。研究人员将通过在AIM 1中确定成年人对BPA的暴露是否通过ER（或其他ERS）来研究BPA对心肌炎和DCM的影响，以增加成年男性和雌性小鼠的心肌炎，以及通过检查BPA对BPA对BPA对男性和女性雌性的影响（F1）的作用。如果BPA激活肥大细胞以增加ICVD，则该研究将对对疾病发病机理的理解产生重大影响。