Sex hormone-dependent renal cell carcinogenesis induced by ferric nitrilotriacetate in Wistar rats

Ferric nitrilotriacetate (Fe-NTA), an iron chelate, induces necrosis of renal proximal convoluted tubules as a consequence of lipid peroxidation, and a high incidence of renal cell carcinoma (RCC) is also observed in rats and mice. The incidence of RCC and the extent of lipid peroxidation are greater in males than females. In the present study, the effects of castration or ovariectomy, and sex hormone treatment on Fe-NTA-induced renal carcinogenesis in rats were examined. Male and female Wistar rats were each divided into 5 groups. In group 1, rats were sham-operated and treated intraperitoneally (i.p.) with nitrilotriacetate (NTA). In group 2, sham-operated rats were treated with Fe-NTA (5-10 mg iron/kg/day, i.p.). Castrated or ovariectomized rats treated with Fe-NTA served as group 3. Group 4 or 5 was treated in the same way as group 3, but in addition received either testosterone (group 4) or estradiol (group 5). NTA, Fe-NTA or sex hormone treatments were initiated 4 weeks after the operation. NTA or Fe-NTA treatments were conducted for 12 weeks, and sex hormones were administered for 10 months. After 10 months of treatment, all rats were autopsied and both kidneys were examined histopathologically. In NTA-treated groups, there was no pathological change in the kidneys. In Fe-NTA-treated groups (groups 2-5), testosterone treatment or ovariectomy increased the incidence of RCC, and estradiol treatment or castration decreased the incidence of RCC (male: sham operation, castration and testosterone treatment > castration > castration and estradiol treatment, female: ovariectomy and testosterone treatment > ovariectomy > sham operation, ovariectomy and estradiol treatment). These results indicate that sex differences observed in the incidence of RCC induced by Fe-NTA are dependent upon sex hormones.