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

确定膳食双酚 A 对 C57BL/6 小鼠心脏健康的影响

• 批准号: 7942899
• 负责人: SCOTT M BELCHER
• 金额: $ 54.98万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942899
• 关键词: Address; Age; Animals; Arrhythmia; Autopsy; Biological; C57BL/6 Mouse; Canned Foods; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cessation of life; Collection; Conceptions; Coronary heart disease; Custom; Data; Death Rate; Development; Diet; Disease; Dose; Employee; Employment; Endocrine Disruptors; Environmental Estrogen; Epigenetic Process; Estradiol; Estrogens; Exposure to; Female; Functional disorder; Future; Genetic; Goals; Health; Heart; Heart failure; Hormones; Housing; Human; Hypertrophy; Immune system; Incidence; Investigation; Knock-out; Life; Malignant Neoplasms; Menopause; Modeling; Molecular; Mouse Strains; Mus; Myocardial Infarction; Occupations; Organ; Organ Harvestings; Perception; Phenotype; Physiological; Physiology; Pit and Fissure Sealants; Plastics; Population; Positioning Attribute; Pregnancy; Preparation; Production; Research; Risk; Rodent; Role; Sampling; Stress; Swiss Mice; System; Testing; Time; Tissue Sample; Tissues; Transgenic Model; Transgenic Organisms; Urine; Ventricular Fibrillation; Woman; aged; base; bisphenol A; consumer product; heart function; hemodynamics; hookah; improved; in vivo; knowledge base; male; men; mortality; mouse model; outcome forecast; polycarbonate plastic; pressure; public health relevance; reproductive; reproductive function; response; sex

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.

描述（由申请人提供）：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。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。拟议研究的目的是阐明BPA对心脏生理学的体内性别特异性影响，了解潜在的作用模式和机制，并最终通过了解暴露于BPA作为典型环境内分泌干扰物的病理作用的影响来改善心脏健康。拟议研究的中心假设是，在发育过程中，BPA会对心脏功能产生负面影响，这可能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++处理，发育暴露可能会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、改变血液动力学功能和增加应激生理条件下的心功能障碍（例如，儿茶酚胺和压力超负荷诱导的肥大/心力衰竭）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，该提案更具跨领域性，而且不限于单一的器官或基于系统的终点。沿着心脏特异性终点，将表征“经典”用于评估雌激素EDC活性的许多生理和生殖终点。这将允许直接比较在“雌激素敏感”C57 BL/6 J品系中获得的结果与在“不敏感”CD 1（Swiss）小鼠中进行的研究。将收集所有动物的详细生理表型数据，并在研究结束时对采集、收集和制备的所有器官组织进行完整尸检，用于组织学研究，并保留配对样本用于未来的分子、表观遗传和“组学”分析。作为拟议研究的结果，将创建员工C57 BL/6 J衍生遗传小鼠模型，并允许使用敲除和转基因模型系统研究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基础。 公共卫生相关性：作用于雌激素系统的内分泌干扰化学品：雌激素性内分泌干扰化学品（EDCs）是一组结构多样的化合物，模拟或拮抗内源性雌激素的作用。双酚A（BPA）是一种EDC，广泛用于生产消费品，如聚碳酸酯塑料，食品罐和塑料包装，牙科密封剂和水管。对尿样中BPA的分析表明，BPA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负面影响，并对癌症有有害影响。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，但BPA在环境相关浓度下对心脏的影响尚不清楚。较高的尿液BPA浓度与人类心血管疾病有关。与“女性激素”保护女性免受心血管疾病的看法相反，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CV疾病的女性多于男性; CV疾病死亡总数的53%发生在女性中。妇女，特别是绝经前的妇女，患冠心病和心肌梗塞的比率较低。然而，女性在MI后的预后更差。女性的总体MI后死亡率较高。对于围绝经期妇女（<55岁），MI后死亡率是同龄男性的两倍多。心律失常是导致女性心肌梗死预后不良的一个重要因素。女性心肌梗死后有更多的室颤并发症，在心肌梗死后的前6个月内，女性的心肌梗死死亡率比男性高得多。女性对心律失常也有独特的敏感性。例如，女性在怀孕期间心律失常的风险增加，与雌激素水平的增加相一致。为了解决雌激素在赋予女性CV疾病相关的独特益处或风险方面的作用，了解男性和女性CV系统之间的差异以及内源性“女性激素”如何影响心脏功能至关重要。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策略，以降低CV疾病的发病率和增加男性和女性CV疾病的生存率。拟议的研究重点是了解BPA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近100%美国人口对心血管健康的理解。