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.
The proposed research is relevant to public health because it will elucidate how chronic and early life exposure to the prevalent environmental endocrine disruptive chemical BPA results in long-term consequences on heart health. This work will contribute new data regarding the potential health impacts of BPA on heart health and the mechanisms by which this compound induces cardiac disease. The results of this research are expected to ultimately improve heart health by yielding knowledge to inform regulators and develop public policy. As a result, the proposed research is relevant to the mission of NIH and NIEHS because it will yield fundamental knowledge of how the environment influences the development and progression of human cardiovascular disease, and will result in an improvement of global human health and reduce the burdens of illness and disability.
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