Defining the Impact of Dietary Bisphenol A on Heart Health in the C57BL/6 Mouse

摘要 尽管越来越多的人认识到双酚A对生殖、神经和免疫系统有有害影响 系统。虽然尿液中BPA浓度较高与人类的心血管疾病有关， 环境相关浓度的双酚A对心脏的影响(S)尚不清楚。 拟议研究的具体目的是阐明双酚A在体内对性别的特定影响。 心脏生理学，以了解潜在的作用模式和机制，并最终 通过了解接触双酚A的病理行为的影响来改善心脏健康 典型的环境EDC。 拟议研究的中心假设是在发育过程中，双酚A对心脏有负面影响 可能在以后的生活中表现出来的功能。我们假设接触双酚A的有害影响 影响钙离子的处理，以及发育过程中暴露可能改变正常的性别特异性行为 心脏中的雌激素，通过增加心律失常，改变血流动力学，对心脏健康产生负面影响 心脏功能，以及因应激生理条件而增加的心功能不全 (例如，儿茶酚胺和压力超负荷导致的肥大/心力衰竭)。 作为其主要终点，拟议的研究侧重于了解BPA的心脏特异性作用。 然而，该提案的交叉性要大得多，并不局限于单一机构或以系统为基础 终结点。随着心脏特定的终点，我们将表征一些生理和 生殖终点“经典”用于评估雌激素样的EDC活性。这将允许直接 对“雌激素敏感”的C57BL/6J株的研究结果与在 “不敏感”CD1(瑞士)小鼠。将收集所有动物的详细生理表型数据 在研究结束时，将用采集的所有器官的组织进行完整的尸检， 收集并准备用于组织学研究的成对样本，为未来的分子保存， 表观遗传学和“组学”分析。作为拟议研究的结果，我们将创建一个定义框架 以及标准化员工C57BL/6J派生基因的未来研究所需的知识库 小鼠模型，并利用基因敲除技术系统研究BPA的作用机制 和转基因模型。

Abstract Despite increasing recognition that BPA has harmful effects on the reproductive, nervous and immune systems. While higher urine BPA concentrations are associated with cardiovascular disease in humans, the effect(s) of BPA at environmentally relevant concentrations on the heart is unknown. The Specific Aim of the proposed studies is to elucidate the in vivo sex-specific impacts that BPA has on cardiac physiology, to understand the underlying modes and mechanisms of action, and ultimately improve heart health through understanding the impact of pathological actions of exposure to BPA as a protypical environmental EDCs. The central hypothesis of the proposed studies is during development BPA negatively impacts cardiac function which may manifest later in life. We hypothesis that the harmful effects of BPA exposure will impact Ca2+ handling, and that developmental exposures may alter the normal sex-specific actions of estrogen in the heart, and negatively impact heart health by increasing arrhythmias, altering hemodynamic functions of the heart, and increasing cardiac dysfunction in response to physiologic conditions of stress (e.g. catecholamine and pressure overload induced hypertrophy/heart failure). As its primary endpoints, the proposed studies focus on understanding the cardiac-specific actions of BPA. However, the proposal is far more crosscutting, and not limited to a single organ or system-based endpoint. Along with the cardiac specific end-points, we will characterize a number of physiological and reproductive endpoints "classically" used to assess estrogenic EDC activity. This will allow direct comparison of results obtained in the "estrogen-sensitive" C57BL/6J strain with studies performed in the "insensitive" CD1 (Swiss) mouse. Detailed physiological phenotype data will be collected for all animals and at termination of the study complete necropsy will be performed with tissues from all organs harvested, collected and prepared for histological studies with paired samples preserved for future molecular, epigenetic, and "omics" analysis. As a result of the proposed studies we will create a defining framework and knowledge base necessary to standardize future studies that employee C57BL/6J derived genetic mouse models, and allow systematic investigation of the mechanisms of action of BPA using knockout and transgenic models.