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

描述（由申请人提供）：尽管越来越多的人认识到BPA对生殖系统、神经系统和免疫系统有有害影响。虽然较高的尿液BPA浓度与人类心血管疾病有关，但环境相关浓度的BPA对心脏的影响尚不清楚。本研究的目的是阐明BPA对心脏生理的体内性别特异性影响，了解其潜在的作用模式和机制，并最终通过了解暴露于BPA作为典型环境EDCs的病理作用的影响来改善心脏健康。提出的研究的中心假设是，在发育过程中，BPA会对心脏功能产生负面影响，并可能在以后的生活中表现出来。因此，我们假设BPA暴露的有害影响将影响Ca++处理，并且发育暴露可能改变心脏中雌激素的正常性别特异性行为，并通过增加心律失常，改变血液动力学功能和增加对应激生理条件（例如儿茶酚胺和压力过载诱导的肥壮/心力衰竭）的心功能障碍对心脏健康产生负面影响。作为其主要终点，拟议的研究将侧重于了解BPA对心脏的特异性作用。然而，这一建议更具横切性，并不局限于单个器官或基于系统的端点。除了心脏特定终点外，一些“经典”用于评估雌激素EDC活性的生理和生殖终点也将被表征。这将允许直接比较“雌激素敏感”C57BL/6J菌株与“不敏感”CD1（瑞士）小鼠的研究结果。将收集所有动物的详细生理表型数据，在研究结束时，将对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，并保存成对样本以备将来的分子、表观遗传学和“组学”分析。通过这些研究，我们将建立一个明确的框架和知识库，以规范未来的C57BL/6J遗传小鼠模型的研究，并允许使用基因敲除和转基因模型对BPA的作用机制进行系统的研究。

DESCRIPTION (provided by applicant): 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 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. It is therefore hypothesized that the harmful effects of BPA exposure will impact Ca++ 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 function, 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 will 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, a number of physiological and reproductive endpoints "classically" used to assess estrogenic EDC activity will be characterized. 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 a defining framework and knowledge base necessary to standardize future studies that employee C57BL/6J derived genetic mouse models will be created, and allow systematic investigation of the mechanisms of action of BPA using knockout and transgenic models. PUBLIC HEALTH RELEVANCE: Endocrine disrupting chemicals acting on the estrogen system: estrogenic endocrine-disrupting chemicals (EDCs) are a structurally diverse group of compounds that mimic or antagonize the effects of endogenous estrogens. Bisphenol A (BPA) is an EDC used extensively in the production of consumer products such as polycarbonate plastics, food cans and plastic packaging, dental sealants and water pipes. Analysis of BPA in urine samples showed that BPA is present essentially all of the US population at levels demonstrated to harm negative effects on the reproductive function and have harmful impacts on cancer. Despite increasing recognition that BPA has harmful effects on the reproductive, nervous and immune systems, the effect(s) of BPA at environmentally relevant concentrations on the heart is unknown. Higher urine BPA concentrations are associated with cardiovascular disease in humans. In contrast to the perception that "female hormones" protect women from CV disease, disease of the cardiovascular system is the leading cause of mortality for women in the US. Since 1984, more women than men have died of CV disease every year in the US; fifty-three percent of total CV disease deaths occur in women. Women, especially prior to menopause, have lower rates of coronary heart disease and myocardial infarction (MI). However, women have a much worse prognosis following MI. The overall post-MI mortality rate is higher for women. For peri-menopausal women (<55 years) the post-MI mortality rate is more than double that of same aged men. A significant contributing factor to the worse prognosis following MI for women is arrhythmia. Women have more ventricular fibrillation-complications following MI, and a much higher arrhythmic death rate than men during the first 6 months post-MI Women also have unique sensitivities to arrhythmias. For example, women are at increased risk of arrhythmia during pregnancy coincident with increasing levels of estrogens. To address the role of estrogens in conferring unique benefits or risks associated with CV disease of women, it is critical to understand the differences between the male and female CV system and how endogenous "female hormones" influence cardiac function. Understanding the unique protective or harmful actions of endogenous and environmental estrogens will result in new strategies to decrease the incidence of CV disease and increase survival of both men and women with CV disease. The proposed studies the proposed studies focus on understanding the cardiac-specific actions of BPA and are of very broad and extremely high impact. In fact, the results of these studies could impact understanding related to cardiovascular health of nearly 100% of the US population.