Different Toxicity Mechanisms for Citrinin and Ochratoxin A Revealed by Transcriptomic Analysis in Yeast.
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.
Department of Biotechnology, Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia, Ingeniero Fausto Elio s/n, 46022 Valencia, Spain. mevaped@etsia.upv.es.
Elena
E
Vanacloig-Pedros
Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia IBV-CSIC, Jaime Roig 11, 46010 Valencia, Spain. mproft@ibv.csic.es.
Markus
M
Proft
Department of Biotechnology, Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia, Ingeniero Fausto Elio s/n, 46022 Valencia, Spain. apascual@ibmcp.upv.es.
Amparo
A
Pascual-Ahuir
D002953:Citrinin / Q000633:toxicity*; D020869:Gene Expression Profiling; D009793:Ochratoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000099156:Superoxide Dismutase 2
D002953:Citrinin; D009793:Ochratoxins; D010088:Oxidoreductases; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C025589:ochratoxin A; C432953:GRE2 protein, S cerevisiae
Citrinin; Ochratoxin A; Saccharomyces cerevisiae; Transcriptome; dose response; mycotoxins; oxidative stress
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