Chemical metabolism and toxicity to early life stages of fish

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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.