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 carci nogenicity study of nitrofurazone (NF) in mice can be also produced in a sh ort-term model using transgenic (Tg) mice carrying the human c-Ha-rns gene (rasH2 mice), the following 3 experiments were performed. In experiment 1, both rasH2 mice and their wild CB6F(1) littermates carrying no c-Ha-ms gene (non-Tg mice) that were fed a diet containing 500 to 1,000 ppm NF for 7 we eks demonstrated ovarian atrophy characterized by decreased labeling indice s (LIs) for proliferating cell nuclear antigen (PCNA) in granulosa cells. I n experiment 2, increased numbers of atretic follicles and decreased PCNA L Is 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 m ice given diet containing 1,000 ppm NF for ii days. These results indicate that long-term NF treatment induces ovarian tumors in mice, possibly by con tinuous stimulation with gonadotropins such as LH via a negative-feedback p henomenon secondary to ovarian atrophy (as the tumor-induction mechanism), although we could not completely rule out a genotoxic mechanism.