TCDD-induced hepatic transcriptomic responses in transgenic AHR-variant mice

The aryl hydrocarbon receptor (AHR) mediates most of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, TCDD toxicity phenotypes vary widely between species, strains and even between sexes within a strain. While the exact reasons for this variation remain unclear, it is thought to be related to differences in the structure of the AHR. Previous studies comparing the downstream effects of TCDD exposure between animals with different AHR isoforms have been confounded by the genetic differences between these model systems. To address this issue conclusively, we evaluated three transgenic mouse lines, each of which express a different rat AHR isoform (rWT, DEL, and INS) from two strains of rat with highly divergent TCDD-susceptibilities, within identical genetic backgrounds. Here we profile hepatic transcriptomic responses following exposure to TCDD, and use these to identify transcripts associated with toxicity. We have confirmed that the variation in toxicity is inherent to the AHR isoform. Additionally, we note the enhanced activity of the modified transactivation domain of the DEL isoform, relative to the INS isoform, and provide further evidence that the INS isoform is responsible for the high resistance to TCDD observed in H/W rats. We also uncover several candidate genes that were consistently differentially expressed in TCDD-sensitive mice and rats.

60