Dataset Information

RNA-sequencing (transcriptomic) data collected in liver and lung of male and female B6C3F1 mice exposed to various dose levels of 4-methylimidazole for 2, 5, or 28 days.

ABSTRACT: The National Toxicology Program (NTP) reported that chronic exposure to varying dietary concentrations of 4-methylimidazole (4-MeI) increased lung tumors in female and male mice [1]. In this study, mice (male and female B6C3F1 mice) were either administered 4-MeI by oral gavage (0, 50, 100, 200, or 300 mg/kg/day) for 2 days or exposed for 5 and 28 days to 4-MeI in the diet (0, 150, 300, 1250, or 2500 ppm) and whole transcriptome (RNA-Sequencing) data from 4-MeI-exposed B6C3F1 mice to determine whether changes occurred in the target (lung) and nontarget (liver) tissues. This analysis was conducted to provide information with which to evaluate biological processes affected by exposure to 4-MeI, with a focus on identifying key events that could be used to propose a plausible mode of action (MoA) for mouse lung tumors [2].

SUBMITTER: Black MB

PROVIDER: S-EPMC8502903 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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RNA-sequencing (transcriptomic) data collected in liver and lung of male and female B6C3F1 mice exposed to various dose levels of 4-methylimidazole for 2, 5, or 28 days.

Black Michael B MB Andersen Melvin E ME Pendse Salil N SN Borghoff Susan J SJ Streicker Michael M McMullen Patrick D PD

Data in brief 20210923

The National Toxicology Program (NTP) reported that chronic exposure to varying dietary concentrations of 4-methylimidazole (4-MeI) increased lung tumors in female and male mice [1]. In this study, mice (male and female B6C3F1 mice) were either administered 4-MeI by oral gavage (0, 50, 100, 200, or 300 mg/kg/day) for 2 days or exposed for 5 and 28 days to 4-MeI in the diet (0, 150, 300, 1250, or 2500 ppm) and whole transcriptome (RNA-Sequencing) data from 4-MeI-exposed B6C3F1 mice to determine w ...[more]

PMID: 34660856

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Project description: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.

Project description:Our recent study revealed that continuous prenatal low-dose-rate irradiation did not induce cellular changes in the dentate gyrus of the hippocampus in male B6C3F1 mice exposed to gamma rays during prenatal development. However, changes in body weight, body mass index (BMI), locomotor ability, and mRNA and miRNA expressions in the hippocampus and blood were observed. To investigate potential sex differences in the effects of prenatal gamma irradiation, we conducted a parallel study on female B6C3F1 mice. The results showed significant reductions in the weight of the lungs and left kidney in prenatally irradiated female offspring, accompanied by significantly increased fat deposits in the mesentery, retroperitoneal, and left perigonadal areas. Despite these systemic changes, no cellular alterations were observed in the subgranular zone (immature neurons) or the hilus of the dentate gyrus (mature neurons and glial cells, including astrocytes, microglia, and oligodendrocyte progenitor cells). However, significant increases in hippocampal mRNA expression were detected for genes such as H2bc24, Fos, Cd74, Tent5a, Traip, and Sap25. Conversely, downregulation of mRNAs Inpp5j and Gdf3 was observed in whole blood. A Venn diagram highlighted the differential expression of two mRNAs, Ttn and Slc43a3, between the hippocampus and whole blood. Comparisons between prenatally irradiated male and female B6C3F1 mice revealed sex-specific differences. In whole blood, 4 mRNAs (Scd1, Cd59b, Vmn1r58, and Gm42427) and 1 miRNA (mmu-miR-8112) exhibited differential expression. In the hippocampus, 12 mRNAs and 2 novel miRNAs were differentially expressed between the sexes. qRT-PCR analysis validated the upregulation of H2bc24, Fos, Cd74, and Tent5a in the female hippocampus. These gene expression changes may be associated with the increased fat deposition observed following chronic low-dose-rate gamma irradiation exposure. This study underscores the importance of investigating sex-specific biological responses to prenatal gamma irradiation and highlights potential molecular pathways linked to observed physiological changes.

Dataset Information

RNA-sequencing (transcriptomic) data collected in liver and lung of male and female B6C3F1 mice exposed to various dose levels of 4-methylimidazole for 2, 5, or 28 days.

Publications

RNA-sequencing (transcriptomic) data collected in liver and lung of male and female B6C3F1 mice exposed to various dose levels of 4-methylimidazole for 2, 5, or 28 days.

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