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Alterations in MAPK Signaling in Alveolar Bronchiolar Carcinomas From B6C3F1/N Mice Exposed to Antimony Trioxide by Inhalation for 2 Years

ABSTRACT: To identify transcripts differentially expressed between control samples and spontaneous tumors, or control samples and antimony treated lung tumors, we collected RNA from male and female B6C3F1 mice from a 2-year inhalation NTP bioassay exposed to 0 to 30 mg/m3 antimony trioxide. These samples were interrogated with the Affymetrix Mouse Genome 430 2.0 GeneChip Array. A total of 9941 gene transcripts were differentially expressed between control samples and spontaneous tumors, and 12441 gene transcripts were differentially expressed between control samples and treated antimony tumors (false discovery rate (FDR) < 0.05).

ORGANISM(S): Mus musculus

PROVIDER: GSE152629 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Purpose: In this study, we have used a translatomic approach by coupling polysome profiling and deep RNA-sequencing to estimate changes in the translatome of antimony-resistant Leishmania parasites Methods: Leishmania tropica promastigotes were stepwise selected for resistance to trivalent antimony. Two different strains were studied, the L. tropica SbIII-sensitive or wildtype strain (WT) and the derived highly resistant strain (HR). After polysome profiling four types of samples were evaluated by deep RNAseq: total mRNA used as input, monosomes (MS), light polysomes (LP), and heavy polysomes (HP). The DESeq2 algorithm was used for differential expression analysis to identify translational changes at the basal level (HR Vs. WT), translational changes to combat the drug (HR+SbIII Vs. HR), and to compare translatomic Vs. transcriptomic changes (HP Vs. Total input) [see overall design section below]. Results: Differential translational analysis (cutoff of fold change ≥ 1.5 and p-value corrected by Benjamini-Hochberg FDR ≤ 0.05) showed that transcripts composition per polysome fraction was different in the resistant strain. It included several upregulated (Up) and downregulated (Down) transcripts. At the basal level, 2431 different transcripts were differentially translated: monosome (Down: 4, Up: 0), light polysomes (Down: 906, Up: 951), and heavy polysomes (Down: 1096, Up: 1064). Under the antimony challenge, 189 different transcripts were differentially translated: monosome (Down: 0, Up: 2), light polysomes (Down: 9, Up: 57), and heavy polysomes (Down: 30, Up: 134). Overall, most of the changes were identified in polysome fraction when compared with monosomes or total transcriptome. Conclusions: Our study shows evidence that translational control has a main role in coordinating the resistance to antimony in Leishmania parasites. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania parasites.

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Alterations in MAPK Signaling in Alveolar Bronchiolar Carcinomas From B6C3F1/N Mice Exposed to Antimony Trioxide by Inhalation for 2 Years

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