The effects of deoxynivalenol on gene expression in the murine thymus

• Published in: Toxicology and applied pharmacology 2011-02, Vol.250 (3), p.299-311
• Main Authors: van Kol, Sandra W.M., Hendriksen, Peter J.M., van Loveren, Henk, Peijnenburg, Ad
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ABUNDANCE; ALKALINE EARTH METALS; ANIMAL CELLS; ANIMALS; Biological and medical sciences; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY; BODY FLUIDS; CALCIUM; CELL CONSTITUENTS; Cell Proliferation - drug effects; CONNECTIVE TISSUE CELLS; CYTOPLASM; Deoxynivalenol; Dose-Response Relationship, Drug; ELEMENTS; Fusarium; GENE AMPLIFICATION; Gene Expression Regulation - drug effects; GENES; Genome; human cell-cycle; HUMAN POPULATIONS; immune-response; in-vivo; LEUKOCYTES; LYMPHATIC SYSTEM; Lymphocyte activation; LYMPHOCYTES; Male; MAMMALS; MATERIALS; mechanisms; Medical sciences; METALS; MICE; Mice, Inbred C57BL; MITOCHONDRIA; mouse; Mycotoxins - administration & dosage; Mycotoxins - toxicity; negative selection; NFATC Transcription Factors - metabolism; oral-exposure; ORGANS; Plant poisons toxicology; POLYMERASE CHAIN REACTION; POPULATIONS; PRECURSOR; Protein Array Analysis; Protein Transport; RODENTS; SOMATIC CELLS; SYNTHESIS; t-cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; THYMOCYTES; THYMUS; Thymus Gland - drug effects; Thymus Gland - immunology; Thymus Gland - pathology; tissue distribution; Toxicology; Transcriptomics; trichothecene vomitoxin deoxynivalenol; Trichothecenes - administration & dosage; Trichothecenes - toxicity; VERTEBRATES
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2010.11.001

Deoxynivalenol (DON) is a mycotoxin produced by several Fusarium species and is often detected in grains. Because of its high abundance, there has been a large interest in the effects of DON in animals and humans. DON is known to be immunosuppressive at high concentrations and immunostimulatory at low concentrations. The present study aimed to acquire insight into the modes of action of DON. For this, C57Bl6 mice were orally exposed to 5, 10, or 25mg/kg bw DON for 3, 6, or 24h and thymuses were subjected to genome-wide expression microarray analysis. Gene set enrichment analysis (GSEA) demonstrated that DON downregulated genes involved in proliferation, mitochondria, protein synthesis, and ribosomal proteins. Furthermore, GSEA showed a selective downregulation of genes highly expressed at the early precursor thymocytes stage. This indicates that early precursor thymocytes, particularly at the double-positive CD4+CD8+ stage, are more vulnerable to DON than very early or late precursor thymocytes. There was a large overlap of genes upregulated by DON with genes previously reported to be either upregulated during T cell activation or upregulated during negative selection of thymocytes that recognize “self-antigens”. This indicates that DON induces cellular events that also occur after activation of the T cell receptor, for example, release of calcium from the endoplasmatic reticulum. This T cell activation in the thymus then evokes negative selection and depletion of thymocytes, which provides a plausible explanation for the high sensitivity of the thymus for DON exposure. The expression patterns of four genes indicative for some of the processes that were affected after DON treatment were confirmed using real-time PCR. Immunocytological experiments with primary mouse thymocytes demonstrated the translocation of NFAT from the cytoplasm into the nucleus upon exposure top DON, thus providing further evidence for the involvement of T cell activation.