Assessment of Cardiac End Points in the CLARITY-BPA Study

CLARITY-BPA 研究中心脏终点的评估

• 批准号: 8571046
• 负责人: SCOTT M BELCHER
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-19 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571046
• 关键词: Address; Adult; American; Apical; Arrhythmia; Award; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Chemicals; Chronic; Collaborations; Conflict (Psychology); Data; Data Analyses; Decision Making; Development; Diet; Disease; Dose; Endocrine; Endocrine Disruptors; Ensure; Environment; Epidemiologic Studies; Epidemiology; Estrogen Receptor beta; Estrogens; Exposure to; Female; Fibrosis; Food Packaging; Frequencies; Funding; Goals; Grant; Guidelines; Health; Heart; Heart Diseases; Histopathology; Human; Hypertrophy; Knowledge; Laboratories; Link; Metabolic Diseases; Mission; Modeling; Mus; Muscle Cells; National Health and Nutrition Examination Survey; National Institute of Environmental Health Sciences; National Toxicology Program; Oral; Pathology; Population; Process; Production; Public Health; Public Policy; Publishing; Rattus; Regulation; Research; Research Design; Risk; Risk Assessment; Rodent Model; Sampling; Signal Transduction; Structure; Thick; Tissues; Toxic effect; United States National Institutes of Health; Urine; Work; base; bisphenol A; burden of illness; consumer product; disability; early life exposure; exposed human population; good laboratory practice; human population study; improved; in vivo; insight; male; pollutant; public health relevance; research study; sex

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an endocrine disruptor and high volume production chemical used extensively in a wide- variety of consumer products and food packaging. Monomeric BPA is a pervasive pollutant to which there is wide-spread human exposure. Numerous studies have demonstrated that BPA may have effects on health and disease. However, there remain numerous data gaps and conflicting results that have fueled controversy and concern about the toxic threat of BPA. Our recently published studies and preliminary data presented in this application, establish that environmentally relevant concentrations of BPA are directly harmful to cardiac function in both mice and rats. There are currently no data available directly assessing impacts on cardiac specific endpoints from large GLP compliant studies of BPA toxicity. As a result, there is a pressing need to consider cardiac specific endpoints for establishing the health risks of BPA exposure. In 2010, a consortium-based collaboration between the NIEHS/National Toxicology Program (NTP) and the FDA was established the "Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY- BPA) to perform a comprehensive GLP-compliant 2 year chronic exposure study of the toxicity of BPA augmented by inclusion of hypothesis driven and disease-specific apical endpoints not typically assessed in standard toxicological assessment. Currently, the CLARITY-BPA study design lacks endpoints specifically related to cardiovascular effects resulting from BPA exposure. This is a major and critical data gap. If awarded, the proposed studies will eliminate the critical absence of cardiac specific endpoints from this comprehensive GLP-compliant assessment of BPA toxicity. In so doing, the results from the proposed analysis will: 1) fill a critical data gap that would otherwise remain unaddressed; and 2) contribute critical information that would otherwise not be available for the risk assessment and regulatory process. The Specific AIM of the studies proposed in this application is to add cardiac specific end points assessing the impact of BPA on cardiac histopathology to the comprehensive GLP-compliant 2-year CLARITY-BPA chronic exposure study investigating the toxicity of BPA. That Specific Aim will be addressed by ensuring proper isolation and utilization of cardiac tissue from the GLP compliant CLARITY-BPA 2-year chronic study of oral BPA toxicity for histological and cellular morphometric approaches and to assess hypertrophy, remodeling and fibrosis of hearts from each study group. From hearts of each sex, LV wall thickness; myocyte size and volume, and degree of fibrosis will be assessed and compared to controls. The addition of cardiac specific endpoints to the on-going GLP-compliant 2-year CLARITY-BPA toxicity study will add critical information that would otherwise not be available for the risk assessment and regulatory process. Including analysis of the proposed cardiac endpoints in the CLARITY-BPA study will afford a more informed regulatory decision-making process that will result in improved global human health.

描述（由申请人提供）：双酚A（BPA）是一种内分泌干扰物和大量生产化学品，广泛用于各种消费品和食品包装。单体BPA是一种普遍存在的污染物，人类广泛接触。许多研究表明，BPA可能对健康和疾病有影响。然而，仍然存在许多数据空白和相互矛盾的结果，引发了对BPA毒性威胁的争议和担忧。我们最近发表的研究和本申请中提供的初步数据表明，环境相关浓度的BPA对小鼠和大鼠的心脏功能都有直接危害。目前没有数据直接评估BPA毒性的大型GLP合规性研究对心脏特异性终点的影响。因此，迫切需要考虑心脏特异性终点，以确定BPA暴露的健康风险。2010年，NIEHS/国家毒理学计划（NTP）和FDA之间建立了一个基于联盟的合作，即“BPA毒性学术和监管见解联盟”（Consortium Linking Academic and Regulatory Insights on BPA Toxicity，简称BPA），以进行一项全面的符合GLP的BPA毒性2年长期暴露研究，该研究通过纳入标准毒理学评估中通常未评估的假设驱动和疾病特异性顶端终点来增强。目前，BPA暴露风险研究设计缺乏与BPA暴露导致的心血管效应相关的终点。这是一个重大和关键的数据缺口。如果获得批准，拟议的研究将消除这一全面的符合GLP的BPA毒性评估中缺乏心脏特异性终点的关键。这样做，拟议分析的结果将：1）填补否则将无法解决的关键数据缺口; 2）提供否则将无法用于风险评估和监管过程的关键信息。本申请中提出的研究的具体目的是将评估BPA对心脏组织病理学影响的心脏特异性终点添加到研究BPA毒性的全面GLP合规性2年连续性-BPA慢性暴露研究中。将通过确保适当分离和利用GLP合规性BPA口服BPA毒性2年长期研究中的心脏组织进行组织学和细胞形态学方法，并评估每个研究组的心脏肥大、重塑和纤维化，来解决该特定目标。将评估每种性别心脏的LV壁厚度、肌细胞大小和体积以及纤维化程度，并与对照组进行比较。在正在进行的GLP合规性2年连续性-BPA毒性研究中增加心脏特异性终点将增加风险评估和监管过程中不可用的关键信息。将拟定的心脏终点分析纳入到EQUITY-BPA研究中，将提供更知情的监管决策过程，从而改善全球人类健康。