Developmental Effects of Superfund Hydrocarbon Mixtures

该项目之前的工作表明，VA一个多环芳烃占主导地位的超级基金附近的河口沉积物提取物对鳉鱼胚胎具有高度致畸性，其中观察到的心血管缺陷最明显。多环芳烃模型研究表明，多环芳烃型AHR激动剂和CYP1A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设了多环芳烃毒性的加性模型。缺氧是影响河口发育的重要变量，也是构成河口自然应激源的重要因素。因此，本项目的总体目标是阐明多环芳烃混合物和眼底缺氧对发育的相互作用及其机制。具体目标是：1。利用影像学、生化和分子手段表征Superfund位点多环芳烃混合物对眼底发育的影响。2. 阐明典型CYP1A诱导剂（AHR激动剂）和抑制剂在发育中的相互作用和潜在机制。3. 探讨模型多环芳烃与缺氧对眼底发育的交互作用及其机制。确定选定的多环芳烃混合物对中心使用的其他模型的发育的影响。开发碳氢化合物混合物对脊椎动物发育影响的实用生物标志物。本研究将整合三个互补实验

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.