Chemical metabolism and toxicity to early life stages of fish

我的目标是了解多环芳烃（PAH）的代谢如何影响它们对鱼类胚胎和幼虫的毒性。多环芳烃存在于原油、杂酚油以及河流和港口的污染沉积物中。它们被鱼类吸收，并产生细胞色素p450 （CYP1A）酶。这些酶将氧气添加到多环芳烃中，作为其排泄的第一步。然而，氧化可能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，但对不同结构类中的示例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检测的多环芳烃的危害。它还将为评估加拿大迅速发展的石油经济中石油泄漏的生态风险提供数据和工具。目前，有四种多环芳烃毒性机制被提出，每种机制可能适用于不同类型的多环芳烃。我建议对烷基取代的多环芳烃（具有一个或多个碳侧链的多环芳烃）的毒性机制进行研究。虽然研究很少，但它们占原油中多环芳烃总量的90%以上，并导致埃克森瓦尔迪兹号石油泄漏对渔业的影响。我们是第一个证明烷基菲会导致鱼类胚胎和幼虫的循环衰竭和死亡的人。毒性可能始于氧化应激，当CYP1A酶向烷基侧链添加氧时，氧化自由基和反应性代谢物作为副产物被释放。我们将详细研究这一假设，并测试烷基多环芳烃的其他家族，根据它们与靶组织的直接或间接相互作用对它们进行分类。本研究每年将培养毒理学、化学、生理学和药理学技术方面的5名研究生和2名本科生。

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.