Expression of myc, fos, and Ha-ras in the livers of furan-treated F344 rats and B6C3F1 mice.

Abstract

Furan administered by gavage for 2 yr has been reported to induce hepatocellular carcinomas in male and female B6C3F1 mice and in male but not female F344 rats. Chronic exposure studies in our laboratory using bioassay conditions showed extensive hepatocellular toxicity and sustained increases in regenerative cell proliferation after 1, 3, and 6 wk of treatment in male and female rats and male mice. Altered expression of growth-control genes associated with this hyperproliferative state may enhance the susceptibility of these genes to mutation or may provide a selective growth advantage to preneoplastic cells. Quantitative northern blot analysis of mRNA was used to examine the expression of the oncogenes myc, fos, and Ha-ras in the livers of animals treated with furan. In male rats, a single administration of 30 mg/kg furan produced necrosis and a subsequent wave of cell proliferation 48 h after treatment and induced transient peaks in the expression of myc, fos, and Ha-ras 6-24 h after treatment. In male rat liver from our cell proliferation studies, only a slight increase in myc expression was seen at the end of week 1 of treatment. However, beginning at week 3 and increasing at week 6, up to a 15-fold increase over control values was observed in the expression of myc in the treated animals. The only other notable increase in expression observed in any animals from the cell proliferation study was a threefold increase in myc at week 6 in treated female rats. The absence of an increase in Ha-ras expression in the male mouse liver suggests that the unique pattern of Ha-ras mutations previously reported in furan-induced mouse liver tumors is not due to increased mutational susceptibility related to overexpression of this gene. The lack of sustained expression of myc, fos, and Ha-ras in rapidly proliferating liver suggests that continuous expression of these genes is not necessary to maintain increased rates of cell replication. The large increase in myc expression in male but not female rats suggests an adaptive change that may be related to the sex-specific incidence of furan-induced hepatocellular carcinomas in rats.