The effects of continuous testosterone exposure on spontaneous and cadmium-induced tumors in the male Fischer (F344/NCr) rat: loss of testicular response.

In the rodent testes, cadmium induces severe necrosis followed by chronic degeneration. Cadmium is also an effective testicular tumorigen, and a single dose produces a high incidence of Leydig cell tumors. The mechanism of tumor formation is unknown, but pituitary feedback, i.e., increased luteinizing hormone (LH) production due to low circulating androgen, has been implicated in causation of proliferative lesions within degenerate, hypofunctioning testes. Thus, the effects of androgen replacement on the testicular toxicity of cadmium in Fischer (F344/NCr) rats was studied. Groups (n = 50) of 10-week-old rats either received testosterone implants that approximate normal circulating levels in castrated rats or were left untreated. After 2 weeks of stabilization, rats were given either 20 micromol CdCl2/kg, s.c., weekly for the next 5 weeks (total dose 100 micromol/kg) or saline for a total of four treatment groups (control, testosterone alone, testosterone + cadmium, or cadmium alone). Portions of each group were killed either 10 weeks after initiation of cadmium exposure (n = 10), for assessment of endocrine function, or over the next 2 years (n = 40), for assessment of testicular neoplastic lesions. At 10 weeks, cadmium reduced circulating testosterone in nonimplanted rats by nearly 80% and induced a marked weight loss of the testes (>70%) and sex accessory glands (reflected in a 50% reduction in prostate mass). Testosterone implantation restored circulating testosterone levels in cadmium-treated rats and prevented Cd-induced weight loss of the sex accessory glands but not of the testes. Over 2 years, cadmium alone induced a >84% incidence of Leydig cell neoplasia and a >97% incidence of chronic degeneration, both significant increases over control rates (60 and 0%, respectively). Testosterone implantation abolished both cadmium-induced and spontaneously occurring Leydig cell tumors but had no effect on cadmium-induced chronic testicular degeneration. Thus cadmium-induced hypofunction of the testes, and subsequent loss of circulating testosterone, appears to be a critical aspect in cadmium induction of tumors in the rat testes.