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 chro nic degeneration. Cadmium is also an effective testicular tumorigen, a nd 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 wi thin degenerate, hypofunctioning testes. Thus, the effects of androgen replacement on the testicular toxicity of cadmium in Fischer (F344/NC r) rats was studied. Groups (n = 50) of 10-week-old rats either receiv ed testosterone implants that approximate normal circulating levels in castrated rats or were left untreated. After 2 weeks of stabilization , rats were given either 20 mu mol CdCl2/kg, sc, weekly for the next 5 weeks (total dose 100 mu mol/kg) or saline for a total of four treatm ent groups (control, testosterone alone, testosterone + cadmium, or ca dmium 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 testicu lar neoplastic lesions. At 10 weeks, cadmium reduced circulating testo sterone 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 circ ulating testosterone levels in cadmium-treated rats and prevented Cd-i nduced weight loss of the sex accessory glands but not of the testes. Over 2 years, cadmium alone induced a >84% incidence of Leydig cell ne oplasia 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 occurrin g Leydig cell tumors but had no effect on cadmium-induced chronic test icular degeneration. Thus cadmium-induced hypofunction of the testes, and subsequent loss of circulating testesterone, appears to be a criti cal aspect in cadmium induction of tumors in the rat testes. (C) 1997 Academic Press.