Early cytotoxic effects of ochratoxin A in rat liver 2006

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Early cytotoxic effects of ochratoxin A in rat liver: A morphological,

biochemical and molecular study

tta Gagliano_a_

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Annoni_e_

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Bertelli_a_

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f3edecd#aff3) and Magda Gioia_a_

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aDepartment of Human Morphology-LITA Segrate, Via Fratelli Cervi 93, 20090

Segrate, Milan, Italy

bDepartment of Biology, University of Milan, Milan, Italy

cDepartment of Neuroscience (Pharmacology Section) and Internal Medicine,

University of Pisa, Italy

dLaboratories of Quantitative Medicine, Istituto Clinico Humanitas IRCCS,

Rozzano, Milan, Italy

eDepartment of Clinical Medicine, Prevention and Medical Biotechnology and

S. Gerardo Hospital, University of Milano-Bicocca, Milan, Italy

fDepartment of Pathology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan,

Italy

Received 9 May 2006; revised 1 June 2006; accepted 6 June 2006. Available

online 10 June 2006.

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 á-smooth muscle actin (áSMA);

(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-â1 mRNA levels and áSMA 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.

Keywords: Ochratoxin A; Collagen turnover; Oxidative stress; Cadherins;

Connexins; HSP70