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 ␣-smooth muscle actin (␣SMA); (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 redstained liver sections, was similar in both groups. In liver homogenates COL-I, COL-III, TIMP-1 and TGF-␤1 mRNA levels and ␣SMA 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.

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In Sirius red-stained sections of the patient's overgrown gingivae, interstitial collagen content was 29% higher than controls. Her gingival fibroblasts had higher collagen type I, MMP-1 and LH2b gene expression and unmodified interstitial collagen, type I protein levels in the supernatants. These findings would seem to suggest that in this case collagen accumulation in the gingival connective tissue was not associated with increased synthesis and decreased degradation.