Toxicogenomic effects of marine brevetoxins in liver and brain of mouse.

Although the polyether brevetoxins (PbTx's) produced by Karenia brevis (the organism responsible for blooms of the Florida red tide) are known to exert their acute toxic effects through ion-channel mediated pathways in neural tissue, prior studies have also demonstrated that at least one form of the toxin (PbTx-6) is bound avidly by the aryl hydrocarbon receptor (AhR). Since AhR binding of a prototypical ligand such as dioxin is the first step in a cascade pathway producing major changes in gene expression, we reasoned that PbTx-6 might produce similar genomic-wide changes in expression. Mice were injected i.p. with sub-lethal doses of PbTx's (either 1.5 or 3 mg/g body weight of PbTx-6; or 0.15 mg/g body weight of PbTx-2, a toxin not avidly bound by the AhR), and liver and brain tissues were sampled at 8, 24 and 72 h and RNA was isolated. Changes in gene-specific RNA levels were assessed using commercially available mouse cDNA arrays (Incyte) containing >9600 array elements, including many elements from AhR-mediated genes. Histopathology of the two organs was also assessed. We observed minor histopathological effects and a total of only 29 significant (>2.0-fold) changes in gene expression, most of which occurred in the liver, and most of which could be attributable to an 'acute phase' inflammatory response. These results argue against the hypothesis that PbTx-6 acts via a classic AhR-mediated mechanism to evoke gene expression changes. However, given the avidity with which PbTx-6 binds to the AhR, these findings have important implications for how PbTx's may act in concert with other toxicants that are sensed by the AhR.