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Carcinogenesis, Vol. 20, No. 5, 817-824, May 1999
© 1999 Oxford University Press

Histopathology and gene expression changes in rat liver during feeding of fumonisin B1, a carcinogenic mycotoxin produced by Fusarium moniliforme

Eric R. Lemmer1,5, Pauline de la Motte Hall2,3, Nobuhiko Omori5, Masako Omori5, Enid G. Shephard1,6, Wentzel C.A. Gelderblom4, J. Peter Cruse2, Rochelle A. Barnard2, Walter F.O. Marasas4, Ralph E. Kirsch1 and Snorri S. Thorgeirsson5

1 MRC/UCT Liver Research Centre and
2 Departments of Anatomical Pathology, University of Cape Town, Observatory, Cape 7925, South Africa,
3 Flinders University of South Australia, Bedford Park 5042, South Australia,
4 MRC Programme on Mycotoxins and Experimental Carcinogenesis, Tygerberg 7505, South Africa and
5 Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA

Fumonisin B1 (FB1) is a carcinogenic mycotoxin produced by the fungus Fusarium moniliforme in corn. Feeding of FB1 to rats causes acute liver injury, chronic liver injury progressing to cirrhosis, and sometimes terminates in hepatocellular carcinoma or cholangiocarcinoma. This study describes the histolopathology and changes in gene expression in the rat liver during short-term feeding of FB1. Male Fischer rats were fed either FB1 250 mg/kg or control diet, and were killed weekly for 5 weeks. FB1 caused a predominantly zone 3 `toxic' liver injury, with hepatocyte death due to necrosis and apoptosis. Hepatocyte injury and death were mirrored by hepatic stellate cell proliferation and marked fibrosis, with progressive disturbance of architecture and formation of regenerative nodules. Despite ongoing hepatocyte mitotic activity, oval cell proliferation was noted from week 2, glutathione S-transferase {pi}-positive hepatic foci and nodules developed and, at later time points, oval cells were noted inside some of the `atypical' nodules. Northern blot (mRNA) analysis of liver specimens from weeks 3 to 5 showed a progressive increase in gene expression for {alpha}-fetoprotein, hepatocyte growth factor, transforming growth factor alpha (TGF-{alpha}) and especially TGF-ß1 and c-myc. Immunostaining with LC(1–30) antibody demonstrated a progressive increase in expression of mature TGF-ß1 protein by hepatocytes over the 5 week feeding period. The overexpression of TGF-ß1 may be causally related to the prominent apoptosis and fibrosis seen with FB1-induced liver injury. Increased expression of c-myc may be involved in the cancer promoting effects of FB1.

Abbreviations: AAF, acetylaminofluorene; AFP, {alpha}-fetoprotein; AIN, American Institute of Nutrition; FB1, fumonisin B1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GST{pi}, {pi} class glutathione S-transferase; H & E, haematoxylin and eosin; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; PH, partial hepatectomy; TGF-{alpha}/ß, transforming growth factor alpha/beta.

6 To whom correspondence should be addressed Email: enid{at}liver.uct.ac.za


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