Trichothecene mycotoxin-induced ribotoxic stress activates histone gene transcription

Abstract Mycotoxins are secondary fungal metabolites which have toxic effects on other organisms. The trichothecenes mycotoxins deoxynivalenol (DON) and T2/HT2 are secreted by Fusarium species and are found across the globe. They are under surveillance in many jurisdictions. The main toxic effect of DON and T2/HT2 is the inhibition of protein translation by toxin binding to the peptidyl transfer centre of the large ribosomal subunit. We have characterised the effects of DON and HT2 (at IC75) on the transcriptome of the lung fibroblast cell line V79 over a time course of 15, 30, 60, 90, 120, 180 min and 24 h. The data demonstrate that the gene expression changes found at 24 h post exposure are different to those found at earlier time points. The immediate, albeit transient, effect of DON and HT2 exposure is the activation of the p38–Fos/Jun MAP kinase stress signalling pathway. This rapid response also entails a substantial activation of histone genes; a response typically associated with cell cycle entry. The activation of the p38–Fos/Jun stress pathway peaks at 90 min post exposure in response to DON and at 120 min post exposure for HT2. Gene expression changes triggered by DON exposure during the first 60 min significantly overlap with those elicited by other chemicals. In contrast, longer term exposure to DON elicits transcriptome responses which are specific to treatment with inhibitors of translation.