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4-Methylimidazole (4-MEI) exposure in liver and lung of B6C3F1 mice exposed to four concentrations for 2, 5 and 28 days

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE129622 | GEO | 2020/04/30

REPOSITORIES: GEO

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Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes

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4-Methylimidazole (4-MEI) exposure in liver and lung of B6C3F1 mice exposed to four concentrations for 2, 5 and 28 days

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