Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

Journal Article · Tue Jul 15 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.02.018· OSTI ID:21140894

Arbillaga, Leire; Vettorazzi, Ariane; Gil, Ana G ^[1]; Delft, Joost van ^[2]; Garcia-Jalon, Jose Antonio ^[3]

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1. Department of Nutrition and Food Sciences, Physiology and Toxicology, Faculty of Pharmacy, University of Navarra, C/ Irunlarrea 1, 31008 Pamplona (Spain)
2. Department of Health Risk Analysis and Toxicology, Faculty of Health Sciences, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht (Netherlands)
3. Department of Animal Pathology, Faculty of Veterinary, University of Zaragoza, C/ Miguel Server 177, 50013 Zaragoza (Spain)

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 {mu}g/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.

• OSTI ID: 21140894
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 230; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL PATHWAYS
CALCIUM
CARCINOGENS
DNA DAMAGES
GENES
HOMEOSTASIS
IN VITRO
IN VIVO
KIDNEYS
LIVER
METABOLISM
MICROTUBULES
NECROSIS
OXIDATION
RATS
TIME DEPENDENCE
TOXICITY