Endocrine disruptors effect on inflammatory heart disease

内分泌干​​扰物对炎症性心脏病的影响

• 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
• 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

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）：本项目的长期目标是确定内分泌干扰物（ED）（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iCVD，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位死亡原因。包括心肌炎、扩张型心肌病和动脉粥样硬化在内的自身炎症性心血管疾病主要发生在男性身上，他们患扩张型心肌病和心力衰竭的风险增加。研究人员先前已经发表，睾酮通过增加肥大细胞和激活炎性小体（即TLR 4，caspase-1和白细胞介素（IL）-1）来驱动心肌炎，导致心脏重塑，纤维化和发展为DCM。相反，雌激素（E2）通过提高抗炎免疫应答（包括IL-4/Th 2和调节性T细胞（Treg））来减轻雌性小鼠的心肌炎。临床和实验研究表明，E2，通过雌激素受体（ER），介导的心脏保护对iCVD的女性，而ER信号具有相反的效果。由于心肌炎和扩张型心肌病受到性激素的强烈影响，子宫内或成年后暴露于艾德可能会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，在饮用水中给予成年雌性小鼠25 g/L BPA的高人类相关暴露显著增加了心肌炎，并将雌性小鼠转化为雄性样炎症特征。在该剂量的BPA下，心肌炎期间心脏中的ER显著降低（使用全心脏的qRT-PCR），而ER与对照组相比显著增加，表明BPA对心脏中ER信号传导的失调。基于这些发现和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，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（F1）成年疾病的影响，研究BPA对心肌炎和DCM的作用机制。如果BPA激活肥大细胞增加iCVD，这项研究将对疾病发病机制的理解产生巨大影响。