Identifying qualitative differences in PPAR signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods

In this paper, we evaluate the PPAR alpha signaling network in rats, examining transcriptional responses in primary hepatocytes exposed to a PPARa specific ligand, GW7647. These transcriptomic studies were complemented with ChIP-seq studies of PPAR alpha binding and transcription binding motif identification for PPAR alpha responsive genes. We also conducted a limited study of GW7647 dosing the in intact rat to examine differences in transcriptional responses for primary hepatocytes in vitro and in the intact liver. The rat network has a much larger number of down-regulated genes and pathways than we had found in the human and the PPAR alpha binding motifs in rat differed for upregulated and down regulated genes. Based on these results and comparison with our previous work with the human PPAR alpha signaling network, we identified qualitative differences in the transcriptional networks controlled by PPAR alpha activation in the two species that provide an explanation of the interspecies differences in the responses of humans and rodents to GW7647 and likely to other PPAR alpha agonists. These studies also allow some observations on the manner in which in vitro, fit-for-purpose assays in human hepatocytes could form the basis for risk assessment without recourse to in-life studies in rodents or other test species.