Potential of deoxynivalenol to induce transcription factors in human hepatoma cells.
To assess the hepatotoxicity of deoxynivalenol (DON), human hepatoma cells (Hep-G2) were used as an in vitro model. After exposing Hep-G2 cells to low (1 mciroM) and high dose (10 mciroM), gene expression profiles were analysed by microarray. More than 5% of genes were up-regulated, most of them being involved in transcriptional regulation. By real-time RT-PCR, elevated expression of transcription factors, commonly induced by activation of MAPK-pathway, was demonstrated for Hep-G2 cells on mRNA and protein level. Further studies, involving U937 human monocytes, showed that effects of DON treatment on mRNA and protein level were concentration-dependent and cell-specific. An inverse relation was noticed for the level of DON induced expression of transcription factors (JUN, FOS, EGR1 and ATF3) and the susceptibility of the cell lines towards the mycotoxin. This is the first report giving evidence that on a molecular level the mild hepatotoxic effects of DON are probably caused by the induction of transcription factors which are known to be associated with injury-induced liver regeneration processes. With ATF3, a novel downstream target gene was identified in DON-related cell signalling suggesting a potential linkage between molecular action and biological effects like reduction of glycogen storage in liver tissue.
Central Institute of the Bundeswehr Medical Service, Department of Food Chemistry and Environmental Chemistry, Garching-Hochbrück, Germany. c.nielsen@mh.vetmed.uni-muenchen.de
Carina
C
Nielsen
Harald
H
Lippke
Andrea
A
Didier
Richard
R
Dietrich
Erwin
E
Märtlbauer
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009183:Mycotoxins / Q000633:toxicity*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014255:Trichothecenes / Q000633:toxicity*
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D009183:Mycotoxins; D014157:Transcription Factors; D014255:Trichothecenes; D048049:Extracellular Signal-Regulated MAP Kinases; C007262:deoxynivalenol