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

描述(申请人提供)：尽管人们越来越认识到双酚A对生殖、神经和免疫系统有有害影响。虽然较高的尿双酚A浓度与人类心血管疾病有关，但环境相关浓度的双酚A对心脏的影响(S)尚不清楚。本研究的目的是阐明BPA对心脏生理的性别特异性影响，了解其潜在的作用模式和机制，并通过了解BPA作为一种典型的环境内皮细胞暴露的病理行为的影响，最终改善心脏健康。拟议研究的中心假设是，在发育过程中，双酚A对心脏功能有负面影响，这可能会在以后的生活中表现出来。因此，假设BPA暴露的有害影响将影响Ca++的处理，发育暴露可能改变心脏中雌激素的正常性别特异性作用，并通过增加心律失常、改变血流动力学功能和增加心脏功能来应对应激的生理条件(如儿茶酚胺和压力超负荷导致的肥大/心力衰竭)而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基于系统的终点。除了心脏特定的终点外，还将描述一些用于评估雌激素样EDC活性的生理和生殖终点。这将使在“雌激素敏感”的C57BL/6J品系中获得的结果与在“不敏感”的CD1(瑞士)小鼠中进行的研究进行直接比较。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的配对样本，用于未来的分子、表观遗传学和“组学”分析。作为拟议研究的结果，将创建员工C57BL/6J衍生的遗传小鼠模型，并允许使用基因敲除和转基因模型系统地研究BPA的作用机制，这是标准化未来研究所必需的定义框架和知识库。 公共卫生相关性：作用于雌激素系统的内分泌干扰物：雌激素内分泌干扰物(EDCs)是一组结构多样的化合物，模仿或拮抗内源性雌激素的影响。双酚A(BPA)是一种广泛用于聚碳酸酯塑料、食品罐头和塑料包装、牙科密封剂和水管等消费品生产的EDC。对尿样中双酚A的分析表明，双酚A基本上存在于所有美国人口中，其水平被证明对生殖功能有害，并对癌症有有害影响。尽管人们越来越认识到双酚A对生殖、神经和免疫系统有有害影响，但环境相关浓度的双酚A对心脏的影响(S)尚不清楚。在人类中，尿中BPA浓度较高与心血管疾病有关。与“女性荷尔蒙”保护女性免受心血管疾病的观念相反，心血管系统疾病是美国女性死亡的主要原因。自1984年以来，美国每年死于心血管疾病的女性多于男性；心血管疾病死亡总数的53%发生在女性身上。女性，尤其是在绝经前，冠心病和心肌梗死(MI)的发生率较低。然而，女性在心肌梗塞后的预后要差得多。女性心肌梗死后的总体死亡率更高。围绝经期妇女(55岁)的心肌梗死后死亡率是同龄男性的两倍多。女性心肌梗死后预后较差的一个重要因素是心律失常。女性有更多的心肌梗塞后的室颤并发症，并且在心肌梗塞后的前6个月中，女性的心律失常死亡率比男性高得多。例如，随着雌激素水平的增加，女性在怀孕期间发生心律失常的风险增加。要解决雌激素在赋予女性心血管疾病相关独特益处或风险方面的作用，关键是要了解男性和女性心血管系统的差异，以及内源性“女性荷尔蒙”如何影响心脏功能。了解内源性和环境雌激素的独特保护或有害作用将导致新的战略，以减少心血管疾病的发生率，并提高心血管疾病的男性和女性的存活率。建议的研究建议的研究侧重于了解双酚A的心脏特异性作用，具有非常广泛和极高的影响。事实上，这些研究的结果可能会影响到近100%的美国人对心血管健康的理解。

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.