Different Toxicity Mechanisms for Citrinin and Ochratoxin A Revealed by Transcriptomic Analysis in Yeast

Abstract

Citrinin (CIT) and ochratoxin A (OTA) are important mycotoxins, which frequently co-contaminate foodstuff. In order to assess the toxicologic threat posed by the two mycotoxins separately or in combination, their biological effects were studied here using genomic transcription profiling and specific live cell gene expression reporters in yeast cells. Both CIT and OTA cause highly transient transcriptional activation of different stress genes, which is greatly enhanced by the disruption of the multidrug exporter Pdr5. Therefore, we performed genome-wide transcription profiling experiments with the pdr5 mutant in response to acute CIT, OTA, or combined CIT/OTA exposure. We found that CIT and OTA activate divergent and largely nonoverlapping gene sets in yeast. CIT mainly caused the rapid induction of antioxidant and drug extrusion-related gene functions, while OTA mainly deregulated developmental genes related with yeast sporulation and sexual reproduction, having only a minor effect on the antioxidant response. The simultaneous exposure to CIT and OTA gave rise to a genomic response, which combined the specific features of the separated mycotoxin treatments. The application of stress-specific mutants and reporter gene fusions further confirmed that both mycotoxins have divergent biological effects in cells. Our results indicate that CIT exposure causes a strong oxidative stress, which triggers a massive transcriptional antioxidant and drug extrusion response, while OTA mainly deregulates developmental genes and only marginally induces the antioxidant defense.

Protein and transcript profiling analysis of the response of Yarrowia lipolytica Y‐2 in the degradation of ochratoxin A

“…Furthermore, the genes of icdA , acoB , sdh1 and sdh3 were all up‐regulated, especially, the relative expression of sdh1 in Y. lipolytica Y‐2 treated with OTA was 14.6 folds higher than the control (Figure h). These results were consistent with the reports that some genes of TCA cycle in S. cerevisiae such as IDP3 (encoding peroxisomal NADP‐dependent IDH), were up‐regulated to provide more energy to defend against OTA stress (Vanacloig‐Pedros et al, ). This implies that energy supply for Y. lipolytica Y‐2 by TCA cycle and respiratory chain was enhanced to defend against the oxidative stress caused by OTA.…”

“…It was reported that some genes associated with antioxidant metabolism of Arabidopsis thaliana leaf were up‐regulated to defend against oxidative stress caused by OTA (Y. Wang et al, ). Also, OTA could induce the expression of some drug transport genes to expel the toxin from Saccharomyces cerevisiae and alleviate its toxicity (Vanacloig‐Pedros, Proft, & Pascual‐Ahuir, ). Furthermore, some genes associated with detoxification of xenobiotics and some pathogenesis‐related genes involved in the resistance of cells were up‐regulated in A. thaliana leaf in response to OTA treatment (Y. Wang et al, ).…”

“…Furthermore, some genes associated with detoxification of xenobiotics and some pathogenesis‐related genes involved in the resistance of cells were up‐regulated in A. thaliana leaf in response to OTA treatment (Y. Wang et al, ). In addition, proteomic analysis results showed that several enzymes involved in glycolytic pathway, Calvin cycle and tricarboxylic acid (TCA) cycle, were up‐regulated to provide more energy for cells under OTA stress (Vanacloig‐Pedros et al, ; Y. Wang et al, ). Besides, the expression of PJ15_1540 (encoding serine‐type d ‐Ala‐ d ‐Ala carboxypeptidase) which hydrolyse the amide bond of OTA was up‐regulated when a Acinetobacter sp.…”

Transcriptome Analysis of Ochratoxin A-Induced Apoptosis in Differentiated Caco-2 Cells

“…In this study, we chose instead to search for related pathways from a holistic perspective because transcriptome data can quickly and economically supply accurate genome information, particularly in identifying the effects of biological pathways and processes [51,52]. Elena et al (2016) used transcriptomic analysis to reveal the different toxicity mechanisms of OTA and citrinin [53]. Hence, we used a transcriptomic study to provide a genome-wide biological view of changes that occurred after treatment of differentiated Caco-2 cells with different concentrations of OTA.…”

MCH4is a multicopy suppressor of glycine toxicity inSaccharomyces cerevisiae

“…Other transcription factors that bind to P MCH4 are Cad1p and Yap1p (stress response), Yap7p (unknown function) and Pho2p (an activator involved in several metabolic pathways). Previous reports indicated that MCH4 is upregulated in response to osmotic and possibly other kinds of stress (Causton et al, 2001;Jelinsky et al, 2000;Epstein et al, 2001;Vanacloig-Pedros et al, 2016).…”