Project 3: Systems Approach to Define Toxicity of Complex PAH Mixtures (Tanguay,

项目摘要(见说明)：多环芳烃(PAHs)经常出现在超级基金的地点，是广泛存在的环境污染物，已被证明可以通过胎盘。因此，发育过程中暴露于多环芳烃有可能造成不利的健康后果。这一假设得到了最近的流行病学数据的支持，这些数据表明，生命早期接触多环芳烃与出生缺陷的增加以及重大神经行为缺陷和心脏病的增加有很强的相关性。人类对超级基金多环芳烃的暴露是复杂的；暴露总是以复杂的混合物而不是单个母体多环芳烃的形式发生。单个母体多环芳烃产生不利发育结果的效力尚未明确，更重要的是，混合物中多环芳烃的相加、拮抗或协同作用尚不清楚。一个额外的不确定性是，多环芳烃是环境转化的，这些转化的多环芳烃的毒性在很大程度上还没有得到研究。风险评估人员迫切需要相关的体内数据来开发预测毒性的综合模型。一个直接的目标是确定构成危险的与环境相关的混合物，并确定驱动有毒终点的基因反应。该项目将在斑马鱼中使用系统方法来开始定义多环芳烃毒性的机制。我们的基本假设是，暴露在含有多环芳烃的复杂混合物中，通过芳烃受体(AHR)依赖和AHR非依赖的机制产生毒性，这取决于混合物的结构和组成。我们将在三个具体目标上验证这一假说：1)确定胚胎暴露于单个环境相关多环芳烃、复杂混合物和环境转化多环芳烃的表型影响，并确定AHR在反应中的作用；2)继续使用下一代测序来确定多环芳烃暴露于单个环境相关多环芳烃、复杂混合物和环境转化多环芳烃的早期发育生物标志物；3)确定这些胚胎暴露对成人心血管和中枢神经系统的长期影响。

PROJECT SUMMARY (See instructions): Polycyclic aromatic hydrocarbons (PAHs), are routinely found at Superfund sites, are widespread environmental contaminants and have been shown to cross the placenta. Consequently, developmental exposure to PAHs has the potential to cause adverse health outcomes. This supposition is supported by recent epidemiological data indicating strong associations between early life stage PAH exposures and the increased occurrence of birth defects and increases in significant neurobehavioral deficits and heart disease. Human exposure to Superfund PAHs is complex; exposures always occur as complex mixtures rather than as individual parent PAHs. The potency for individual parent PAHs to produce adverse developmental outcomes is not well-defined, and more importantly the additive, antagonistic or synergistic effects of PAHs in mixtures is unknown. An added level of uncertainty is that PAHs are environmentally transformed, and the toxicity of these transformed PAHs is largely unstudied. Risk assessors are desperately in need of relevant in vivo data to develop comprehensive models for predictive toxicity. An immediate goal is to identify the environmentally relevant mixtures that pose hazard, and to identify the gene responses that drive the toxic endpoints. This project will use systems approaches in zebrafish to begin to define the mechanism of PAH toxicity. Our underlying hypothesis is that exposure to complex mixtures containing PAHs produce toxicity by aryl hydrocarbon receptor (AHR)-dependent and AHR-independent mechanisms, dependent on the structure and composition of the mixtures. We will test this hypothesis in three Specific Aims: 1) Determine the phenotypic impact of embryonic exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs and define the role of AHRs in the response; 2) To continue to use next generation sequencing to identify the early developmental biomarkers of PAH exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs; 3) To define the long lasting impacts of these embryonic exposure on the adult cardiovascular and central nervous systems.