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(497) The toxicological significance of CYP1A induction in salmonids.
Billiard, Sonya*,1, Hodson, Peter1, Kiparissis, Yiannis1, Hawkins, Stephanie1, 1 Queen's University, Kinsgton, ON, Canada
ABSTRACT- Fish, especially at early life stages, are among the most sensitive vertebrates to PHH toxicity, making them an excellent model to assess the risk of PHH to aquatic species and their hazards to human health. PHH toxicity is thought to be AHR-dependent in all vertebrates. The rank order potency of PHH for binding to the AHR and inducing CYP1A predicts their rank order toxicity. CYP1A induction has been used as a model system to illustrate altered gene expression following PHH and PAH exposure. For PHH, induction is also an excellent correlate of dioxin-like toxicity in early life stages of fish. Alternatively, the role of the AHR in mediating PAH toxicity (excluding carcinogenesis) is not clear. We have shown that non-chlorinated PAH can mimic embryotoxic effects of dioxin and that, like PHH, their rank order for binding to teleost AHR agrees with their rank order for inducing CYP1A. However, toxicity of PAH to the embryolarval stages of fish does not vary with their affinity for teleost AHR or their potency for inducing CYP1A enzymes. These data suggest that while induction is a consistent and reliable index of PAH exposure, it does not predict PAH toxicity. This appears to be especially true for the USEPA's 16 priority PAH, all of which are unsubstituted. However, further investigation indicates that PAH toxicity may be associated with CYP function and is not simply an early biochemical response to PAH exposure. There are two lines of evidence to support this. First, alkyl-substituted PAH homologs may represent a sub-class of PAH that are toxic because of selective hydroxylation on the alkyl side chain. Recent structure-activity relationships for embryotoxicity support this hypothesis. Dioxin-like toxicity of substituted phenanthrenes varies with both the size and location of the alkyl side chain(s) and their rank order toxicity agrees with their rank order potency for inducing CYP1A. Second, we have shown that CYP1A activity can modulate the toxicity of PAH to developmental stages of salmonids.
Key words: PHH, PAH, CYP1A, dioxin-like toxicity
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