Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration.
Ochratoxin A (OTA), a naturally occurring mycotoxin, is nephrotoxic in all animal species tested and is considered a potent renal carcinogen, particularly in male rats. Its mechanism of toxicity is still unknown, although oxidative stress appears to be a plausible mechanism. Therefore, the objective of this study was to identify the biological pathways that are modulated in vivo by OTA in male F344 rats in order to gain further insight into its mechanism of renal toxicity. Rats were gavaged daily with OTA (500 microg/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. As was expected, a time-dependent increase of OTA concentrations was found in plasma, kidney and liver, with the concentrations found in both tissues being quite similar. However, histopathological examinations only revealed changes in kidney; signs of nephrotoxicity involving single cell necrosis and karyomegalic nuclei were observed in the treated rats. The number of differentially expressed genes in kidney was much higher than in liver (541 versus 11 at both time points). Several similarities were observed with other in vivo gene expression data. However, great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin) - a gene implicated in calcium homeostasis - was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity.
Arbillaga
Leire
L
Department of Nutrition and Food Sciences, Physiology and Toxicology, Faculty of Pharmacy, University of Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain.
Vettorazzi
Ariane
A
Gil
Ana G
AG
van Delft
Joost Hm
JH
García-Jalón
José Antonio
JA
López de Cerain
Adela
A
D000284:Administration, Oral; D000818:Animals; D017302:Annexins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009336:Necrosis; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017302:Annexins; D009793:Ochratoxins; D012333:RNA, Messenger; C025589:ochratoxin A; D002118:Calcium