Developmental Effects of Superfund Hydrocarbon Mixtures

该项目以前的工作表明，在退伍军人事务部以多环芳烃为主导的超级基金站点附近的河口，沉积物的提取物对千里鱼胚胎具有高度的致畸作用，其中最显著的影响是心血管缺陷。用模型多环芳烃进行的研究表明，多环芳烃类AHR激动剂和细胞色素P1a抑制剂之间存在显著的协同作用。然而，目前的多环芳烃风险评估方法假定多环芳烃的毒性是一个相加模型。低氧是影响发育的一个重要变量，也是河口的一个自然应激源。因此，这个项目的首要目标是阐明多环芳烃混合物和低氧对发育的交互影响以及这种影响下的机制。具体目的是：1.用成像、生化和分子工具表征超级基金站点多环芳烃混合物对Fundulus发育的影响。2.阐明具有代表性的细胞色素P1a激动剂(AHR激动剂)和抑制剂在发育过程中的相互作用及其机制。3.阐明模型多环芳烃与低氧对底核发育的交互作用及其机制。4.确定选定的多环芳烃混合物对中心采用的其他模型的发展的影响。5.开发实用的碳氢化合物混合物对脊椎动物发育影响的生物标志物。这项研究将整合三个免费的实验 方法：(1)成像和病理学，(2)基因表达分析，特别是通过微阵列，以及(3)生化分析，特别是芳烃受体途径、低氧诱导因子途径和氧化应激介导的反应。该项目将阐明一类化学品(PAHs)的毒性相互作用，这些化学品(PAHs)在环境中稳步增加，总是发生在混合物中，目前的评估可能低估了其发展影响的风险。该项目的模式Fundulus具有很大的生态学相关性，是沿海生态系统的优秀哨兵物种，并为与人类健康有关的发展研究提供了有用的模式。

Previous work in this project demonstrated that extracts of sediments from an estuary adjacent to a PAH-dominated Superfund site in VA are highly teratogenic to embryos of the killifish, Fundulus heteroclitus, with cardiovascular defects the most pronounced effect observed. Studies with model PAHs demonstrated marked synergistic interactions between PAH-type AHR agonists and CYP1A inhibitors. Current risk assessment approaches for PAHs, however, assume an additive model of toxicity for PAHs. Hypoxia is an important variable affecting development as well as comprising a natural stressor in estuaries. Thus, the overarching goal of this project is to elucidate interactive effects on development and mechanisms underling such effects by PAH mixtures and hypoxia in Fundulus. The Specific Aims are: 1. To characterize the effects of a Superfund site PAH mixture on development in Fundulus with imaging, biochemical and molecular tools. 2. To elucidate interactive effects and underlying mechanisms of representative CYP1A inducers (AHR agonists) and inhibitors on development. 3. To elucidate interactive effects and underlying mechanisms of model PAHs and hypoxia on development in Fundulus. 4. To determine effects of selected PAH mixtures on development in other models employed in the Center. 5. To develop practical biomarkers for developmental effects of hydrocarbon mixtures in vertebrates. This study will integrate three complimentary experimental methodologies: (1) imaging and pathology, (2) analysis of gene expression, particularly by microarray, and (3) biochemical analyses, particularly of responses mediated by the aryl hydrocarbon receptor pathway, the hypoxia inducible factor pathway, and oxidative stress. This project will elucidate toxic interactions of a class of chemicals (PAHs) that is exhibiting steady increase in the environment, invariably occurs in mixtures, and for which current assessments may underestimate risks for developmental effects. The model for this project, Fundulus, has great ecological relevance, is an excellent sentinel species for coastal ecosystems, and provides a useful model for developmental studies relevant to human health.