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

Abstract

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.

Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes

“…Nevertheless, this mycotoxin has been shown to affect other target organs as well. It is hepatotoxic in rats and induces hepatocellular carcinomas in mice (NTP 2005;Gagliano et al 2006). Although the liver is not the main target organ for OTA, hepatocytes are exposed to OTA since it has to pass the liver after intestinal absorption.…”

“…Furthermore, this mycotoxin is hepatotoxic in rats, probably as a consequence of oxidative stress (Gagliano et al 2006), and OTA induces the formation of hepatocellular tumors in mice (NTP 2005). In 1997, the International Agency for Research on Cancer (IARC) classified OTA as a class 2B carcinogen ("Ochratoxin A is possibly carcinogenic to humans"; IARC 1997).…”

Prevalence of Ochratoxigenic Fungi and Ochratoxin A Residues in Animal Feeds and Modulation of Their Toxic Effects by Glutathione

“…OTA acts as a carcinogen in the liver by epigenetic mechanisms, which modifying the hepatocyte gap junction apparatus and influencing the expression of specific markers such as alpha-fetoprotein (AFP) (Gagliano et al, 2006).…”

ikinci

“…Hydroxy radical can cause oxidative stress and GSH is regarded as an early biological marker of oxidative stress [35] . The MDA production induces alteration of membrane fluidity and increase of membrane fragility [36][37][38] . Early research has shown that LPS could result in oxidative damage, in which the GSH levels and the CAT activity decreased while the MDA levels increased in mice after LPS injection [14] .…”