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

项目概述（见说明）：多环芳烃（PAHs）是一种广泛存在的环境污染物，已被证明可以穿过胎盘。因此，发育过程中接触多环芳烃有可能造成不良的健康后果。最近的流行病学数据支持了这一假设，表明生命早期多环芳烃暴露与出生缺陷发生率增加、显著神经行为缺陷和心脏病发生率增加之间存在强烈关联。人类暴露于超级基金多环芳烃是复杂的；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。单个亲本多环芳烃产生不良发育结果的效力尚不明确，更重要的是多环芳烃在混合物中的加性、拮抗或协同作用尚不清楚。另一个不确定因素是，多环芳烃是在环境中转化的，而这些转化的多环芳烃的毒性在很大程度上尚未得到研究。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造成危害的环境相关混合物，并确定驱动毒性终点的基因反应。该项目将在斑马鱼中使用系统方法开始确定多环芳烃毒性的机制。我们的基本假设是，暴露于含有多环芳烃的复杂混合物中，根据混合物的结构和组成，通过芳烃受体（AHR）依赖和AHR不依赖的机制产生毒性。我们将通过三个具体目标来验证这一假设：1)确定胚胎暴露于单个环境相关的多环芳烃、复杂混合物和环境转化的多环芳烃的表型影响，并确定ahr在反应中的作用；2)继续利用下一代测序技术鉴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.