Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53

Chemicals, toxicants, and environmental stressors mediate their biologic effect through specific modes of action (MOAs). These encompass key molecular events that lead to changes in the expression of genes within regulatory pathways. Elucidating shared biologic processes and overlapping gene networks will help to better understand the toxicologic effects on biological systems. In this study we used a weighted network analysis of gene expression data from the livers of male Sprague-Dawley rats exposed to chemicals that elicit their effects through receptor-mediated MOAs (aryl hydrocarbon receptor, orphan nuclear hormone receptor, or peroxisome proliferator-activated receptor-α) or non-receptor-mediated MOAs (cytotoxicity or DNA damage). Four gene networks were highly preserved and statistically significant in each of the two MOA classes. Three of the four networks contain genes that enrich for immunity and defense. However, many canonical pathways related to an immune response were activated from exposure to the non-receptor-mediated MOA chemicals and deactivated from exposure to the receptor-mediated MOA chemicals. The top gene network contains a module with 33 genes including tumor suppressor TP53 as the central hub which was slightly up-regulated in gene expression compared to control. Although, there is crosstalk between the two MOA classes of chemicals at the TP53 gene network, more than half of the genes are dysregulated in opposite directions. For example, Thromboxane A Synthase 1 (Tbxas1), a cytochrome P450 protein coding gene regulated by Tp53, is down-regulated by exposure to the receptor-mediated chemicals but up-regulated by the non-receptor-mediated chemicals. The regulation of gene expression by the chemicals within MOA classes was consistent despite varying alanine transaminase and aspartate aminotransferase liver enzyme measurements. These results suggest that overlap in toxicologic pathways by chemicals with different MOAs provides common mechanisms for discordant regulation of gene expression within molecular networks.