Chemical metabolism and toxicity to early life stages of fish

鱼类早期生命阶段的化学代谢和毒性

• 批准号: 184288-2007
• 负责人: Hodson, Peter
• 金额: $ 2.99万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2007
• 资助国家: 加拿大
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=363365
• 关键词: Chemical; metabolism; toxicity; early; life

My objective is to understand how the metabolism of PAH, a large family of Polycyclic Aromatic Hydrocarbons, affects their toxicity to fish embryos and larvae.  PAH are found in  crude oil, creosote, and contaminated sediments of rivers and harbours.  They are taken up by fish, which respond by producing cytochrome-P450 (CYP1A) enzymes.  These enzymes add oxygen to PAH as the first step in their excretion.  However, oxygenation may create metabolites that are more harmful than the parent compound; i.e., faster excretion carries a risk of greater toxicity.  While there are too many PAH to test, research on examples in different structural classes will create an understanding of which are toxic, why, and how.  This knowledge will help to predict the hazards of untested PAH.  It will also provide data and tools for assessing the ecological risks of oil spills in Canada's rapidly expanding petroleum economy.Currently, there are four mechanisms proposed for PAH toxicity, and each may be appropriate for a different class of PAH.  I propose research on the mechanisms of toxicity of alkyl-substituted PAH (PAH with one or more carbon side chains).  While little studied, they comprise more than 90% of total PAH in crude oil, and contributed to the fisheries impacts of the Exxon Valdez oil spill. We were the first to show that alkyl phenanthrenes caused circulatory collapse and death to embryos and larvae of fish. Toxicity may begin with oxidative stress, when CYP1A enzymes add oxygen to alkyl side chains, and oxyradicals and reactive metabolites are released as by-products.  We will examine this hypothesis in detail, and test other families of alkyl PAH to classify them according to their direct or indirect interactions with target tissues.  Each year, this research will train five graduate and two undergraduate students in techniques of toxicology, chemistry, physiology, and pharmacology.

我的目标是了解多环芳烃这一大家族的代谢如何影响其对鱼类胚胎和幼虫的毒性。  PAH 存在于原油、杂酚油以及河流和港口受污染的沉积物中。  它们被鱼类吸收，并通过产生细胞色素 P450 (CYP1A) 酶来做出反应。  这些酶向多环芳烃添加氧气，作为其排泄的第一步。  然而，氧化可能会产生比母体化合物更有害的代谢物；也就是说，更快的排泄会带来更大的毒性风险。  虽然有太多的多环芳烃需要测试，但对不同结构类别的例子进行研究将有助于了解哪些是有毒的、为什么有毒以及如何有毒。  这些知识将有助于预测未经测试的多环芳烃的危害。  它还将为评估加拿大快速扩张的石油经济中石油泄漏的生态风险提供数据和工具。目前，针对多环芳烃毒性提出了四种机制，每种机制可能适用于不同类别的多环芳烃。  我建议研究烷基取代的PAH（具有一个或多个碳侧链的PAH）的毒性机制。  虽然研究很少，但它们占原油中 PAH 总量的 90% 以上，并造成了埃克森·瓦尔迪兹漏油事件对渔业的影响。我们是第一个证明烷基菲会导致鱼类胚胎和幼虫循环衰竭和死亡的人。毒性可能始于氧化应激，此时 CYP1A 酶向烷基侧链添加氧，氧自由基和反应性代谢物作为副产物释放。  我们将详细检验这一假设，并测试其他烷基多环芳烃家族，根据它们与目标组织的直接或间接相互作用对它们进行分类。  每年，该研究将培训五名研究生和两名本科生毒理学、化学、生理学和药理学技术。