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

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Abstract
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 π-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 α-fetoprotein, hepatocyte growth factor, transforming growth factor alpha (TGF-α) and especially TGF-β1 and c-myc. Immunostaining with LC(1–30) antibody demonstrated a progressive increase in expression of mature TGF-β1 protein by hepatocytes over the 5 week feeding period. The overexpression of TGF-β1 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.