Early cytotoxic effects of ochratoxin A in rat liver: A morphological, biochemical and molecular study

• Published in: Toxicology (Amsterdam) Vol. 225; no. 2; pp. 214 - 224
• Main Authors: Gagliano, Nicoletta, Donne, Isabella Dalle, Torri, Carlo, Migliori, Massimiliano, Grizzi, Fabio, Milzani, Aldo, Filippi, Cristina, Annoni, Giorgio, Colombo, Piergiuseppe, Costa, Francesco, Ceva-Grimaldi, Giorgia, Bertelli, Alberto A.E., Giovannini, Luca, Gioia, Magda
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 15.08.2006; Amsterdam Elsevier Science
• Subjects: Animals; Biological and medical sciences; Cadherins; Cadherins - genetics; Cadherins - metabolism; Carcinogens - toxicity; Collagen - genetics; Collagen - metabolism; Collagen turnover; Connexins; Connexins - genetics; Connexins - metabolism; Gene Expression - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; HSP70; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Male; Medical sciences; Mycotoxins - toxicity; Ochratoxin A; Ochratoxins - toxicity; Organ Size - drug effects; Oxidative stress; Oxidative Stress - drug effects; Plant poisons toxicology; Protein Carbonylation - drug effects; Rats; Rats, Wistar; RNA, Messenger - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Toxicology; Oxidative stress; Cadherins; Connexins; HSP70; Ochratoxin A; Collagen turnover; Ochratoxin; Rat; Liver; Mycotoxin; Cytotoxicity; Biochemistry; Connexin; Heat shock protein; Turnover; Heat shock protein 70; Digestive system; Glycoprotein; Rodentia; Cadherin; Toxin; Vertebrata; Mammalia; Animal; Collagen; Early
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2006.06.004

We characterized the overall early effect of chronic ochratoxin A (OTA) treatment on rat liver, analyzing different aspects related to: (i) fibrosis, by measuring collagen content and turnover, and α-smooth muscle actin (αSMA); (ii) oxidative stress and stress response, by analyzing protein carbonylation, superoxide dismutase (SOD) and heat shock protein (HSP70) gene expression; (iii) the possible tumor promoter effect, evaluating cadherin and connexin (CX) mRNA levels. Light microscopy analysis showed no histological differences in OTA-treated and control (CT) rats. Collagen content, determined by computer analysis of Sirius red-stained liver sections, was similar in both groups. In liver homogenates COL-I, COL-III, TIMP-1 and TGF-β1 mRNA levels and αSMA were unaffected by OTA. Matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 protein levels were also similar in the two groups. Protein carbonylation, a marker of severe oxidative stress, was not evident in the homogenates of OTA-treated livers; superoxide dismutase (SOD) mRNA tended to be lower and HSP70 was strongly down-regulated. OTA reduced E-cadherin and DSC-2 transcription, and down-regulated liver CX26, CX32 and CX43. In conclusion, these in vivo results show that OTA-induced liver injury involves a reduction in the ability to counterbalance oxidative stress, maybe leading to altered gap junction intercellular communication and loss of cell adhesion and polarity. This suggests that mild oxidative damage might be a key factor, in combination with other cytotoxic effects, in triggering the promotion of liver tumors after exposure to OTA.