The mechanism of retene toxicity in the early life stages of fish
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Alkylphenanthrenes such as retene (7-isopropyl-1-methylphenanthrene) are aquatic contaminants commonly found in anthropogenically-, industrially-, and petroleum-contaminated environments, and have been implicated in crude oil toxicity. In the early life stages (ELS) of fish, exposures to alkylphenanthrenes produce signs of toxicity typical of those observed in exposures to halogenated aromatic hydrocarbons, particularly to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD, the most toxic congener, serves as the basis of the current mechanism-based risk assessment model. The model assumes that congeners that produce TCDD-like toxicity share a common mode of action and act additively. The mechanism of TCDD-like toxicity is assumed to be mediated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor involved in the xenobiotic response (e.g., induction of cytochrome P450 1A enzymes; CYP1A) and in normal development. CYP1A enzymes are not involved in the mechanism of TCDD toxicity. Alkylphenanthrenes toxic to the ELS of fish are AhR ligands, but in contrast to TCDD, are readily metabolized by CYP1A enzymes. The byproducts of CYP1A metabolism have been implicated in retene toxicity. However, the target tissue of retene and the direct roles of AhR and CYP1A in retene toxicity are unknown, but are expected to be similar to those of TCDD. The results presented in this thesis suggest that in the ELS of fish: (1) the primary target of retene is the cardiovascular system (Chapters 2 & 5); (2) retene toxicity is stage-specific (Chapter 2); (3) the mechanism of retene toxicity is mediated by AhR2, and is independent of CYP1A enzymes (Chapter 5); (4) multiple CYP1A-independent toxicities can result from exposures to different mixtures of CYP1A inducing (retene) and CYP1A inhibiting (alpha-naphthoflavone or 2-aminoanthracene) PAHs (Chapters 3 & 4); and (5) multiple concentration-dependent mechanisms of toxicity (i.e., synergism and response addition) can occur in co-exposures of a CYP1A inducer (retene) with a range of CYP1A inhibitor (alpha-naphthoflavone) concentrations (Chapter 3). Thus, retene toxicity is mechanistically similar to that of TCDD toxicity, suggesting alkylphenanthrenes can be included in the current risk assessment model. However, the observed variable mixture toxicities and species differences in retene toxicity raise questions about the effectiveness of this model.