A mechanistic study of ovarian carcinogenesis induced by nitrofurazone using rasH2 mice

In order to clarify whether the ovarian tumors induced in a long-term carcinogenicity study of nitrofurazone (NF) in mice can be also produced in a short-term model using transgenic (Tg) mice carrying the human c-Ha-ras gene (rasH2 mice), the following 3 experiments were performed. In experiment 1, both rasH2 mice and their wild CB6F1 littermates carrying no c-Ha-ras gene (non-Tg mice) that were fed a diet containing 500 to 1,000 ppm NF for 7 weeks demonstrated ovarian atrophy characterized by decreased labeling indices (LIs) for proliferating cell nuclear antigen (PCNA) in granulosa cells. In experiment 2, increased numbers of atretic follicles and decreased PCNA LIs in granulosa cells were recognized in rasH2 mice given diets containing 250 or 500 ppm NF for 26 weeks, but no tumor induction was grossly observed. In experiment 3, similar ovarian atrophy was observed in association with increased serum luteinizing hormone (LH) levels in both rasH2 and non-Tg mice given diet containing 1,000 ppm NF for 11 days. These results indicate that long-term NF treatment induces ovarian tumors in mice, possibly by continuous stimulation with gonadotropins such as LH via a negative-feedback phenomenon secondary to ovarian atrophy (as the tumor-induction mechanism), although we could not completely rule out a genotoxic mechanism.