GSE129622
4-Methylimidazole (4-MEI) exposure in liver and lung of B6C3F1 mice exposed to four concentrations for 2, 5 and 28 days
4-Methylimidazole (4-MEI) increased incidence of lung tumors in 2-year studies in both female and male mice. We evaluated changes in gene expression in B6C3F1 mice exposed to 4-MeI for 2, 5 or 28 days using RNA-seq methods and evaluated possible molecular initiating events (MIEs) and modes-of-action (MoAs) for 4-MeI in both a target tissue for tumors (lungs) and a non-target tissue (liver). Although the magnitude of changes in differential expression was small for any one gene, there were relatively large numbers of differentially expressed genes (DEGs) at 2-days in both tissues followed by a decreasing number of DEGs at the two longer exposures. Pathway enrichment of DEGs was determined either by using specific selection criteria based on absolute value of fold-change expression (|FC|) and a false discovery rate (FDR) or with IDEA (Information Dependent Enrichment Analysis). IDEA ranks all genes in order of fold induction, both for upregulated and downregulated genes, and iteratively calculates enrichment for gene lists of different sizes. Enrichment determines whether the DEGs fall into specific biological pathways as defined by standard gene/protein ontologies, e.g. Reactome or MetaCore (GeneGO). While there were significant differences in gene expression in lungs for male and female at 2-days. There also several consistent changes for the sexes, including coordinated regulation of circadian clock genes at 2-days, downregulation of mitochondrial functions at later times, and various effects on G-protein coupled receptor (GPCR) signaling pathways. In liver, in both genders, there was upregulation of mitotic pathways at early times and downregulation of various metabolic pathways and CYPs at later times. Based on (1) structural similarities with histamine, (2) short-term CNS and testicular toxicity, (3) changes in arachidonic metabolism pathways, (4) rapid accommodation to tissue response over several days and (5) alterations in GPCR pathways, we hypothesize that the MIE for 4-MeI likely involves changes in histaminergic GPCR function. Some suggestions are provided for specific short-term studies to follow up on this hypothesis. Overall design: Time and dose response in liver and lung of both male and female mice. Exposures at 2 days were by gavage, while those at 5 and 28 days used 4-MEI in feed.