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BPA对生殖、神经和免疫系统有有害影响， 系统.虽然较高的尿液BPA浓度与人类心血管疾病有关， BPA在环境相关浓度下对心脏的影响尚不清楚。 拟议研究的具体目的是阐明BPA对体内性别特异性的影响。 心脏生理学，以了解潜在的模式和作用机制，并最终 通过了解暴露于BPA的病理作用的影响来改善心脏健康， 典型的环境内分泌干扰物 拟议研究的中心假设是，在发育过程中，BPA会对心脏产生负面影响。 可能在以后的生活中表现出来。我们假设BPA暴露的有害影响将 影响Ca 2+处理，发育暴露可能会改变正常的性别特异性行为， 雌激素在心脏中，并通过增加心律失常，改变血流动力学 心脏的功能，并增加心脏功能障碍，以响应生理条件的压力 (e.g.儿茶酚胺和压力超负荷诱导的肥大/心力衰竭）。 作为其主要终点，拟议的研究重点是了解BPA的心脏特异性作用。 然而，这项建议的交叉性要大得多，而且不限于一个单一的机关或系统。 终点。沿着心脏特异性终点，我们将描述一些生理和 生殖终点“经典”用于评估雌激素EDC活性。这将使直接 在“雌激素敏感”C57 BL/6 J菌株中获得的结果与在“雌激素敏感”C57 BL/6 J菌株中进行的研究的比较 “不敏感”CD 1（Swiss）小鼠。将收集所有动物的详细生理表型数据 在研究结束时，将对采集的所有器官的组织进行完整尸检， 收集并制备用于组织学研究的配对样品， 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 和必要的知识基础，以标准化未来的研究，员工C57 BL/6 J来源的遗传 小鼠模型，并允许使用敲除系统研究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.