Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: Induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate

Abstract

Cadmium is a known human carcinogen based on findings of lung cancer in exposed populations. A more controversial target site for Cadmium is the human prostate gland, for which some studies indicate a link between cadmium exposure and cancer. Our work in various strains of Wistar rats has shown that cadmium can induce tumors in the ventral lobe of the prostate. The relevance of this type of lesion to human prostate cancer has been questioned because the ventral lobe of the rat prostate, unlike the dorsolateral lobe, has no embryological homolog in the human gland. In this study we investigated the chronic toxic and carcinogenic effects of cadmium in the Noble (NBL/Cr) rat, with particular attention to lesions of the prostate. Cadmium chloride (CdCl2) was given as a single sc injection (0, 1, 2, 4, 8, 16, or 32 μmol/kg) to groups (initially n = 30) of 10-week-old rats. Rats were observed for up to 72 weeks following exposure. In rats that were injected with the lower doses of cadmium (≤4 μmol/kg), a clear dose-related increase in proliferative lesions of the dorsolateral prostate occurred (0 μmol/kg = 36% incidence, μmol/kg = 62%, 2 μmol/kg = 65%; 4 μmol/kg = 79%; trend p < 0.003). Lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells, without stromal invasion. At higher doses (≥8 μmol/kg) the proliferative-lesion response in the dorsolateral prostate gradually declined to near control levels (8 μmol/kg = 63%; 16 μmol/kg = 60%; 32 μmol/kg = 52%). The loss of prostatic response at the higher doses of cadmium was probably due to loss of testicular function secondary to cadmium treatment. This was reflected in a very high incidence (>90%) of lesions, indicative of testicular hypofunction, including tubular degeneration, mineralization, and interstitial (Leydig) cell tumors, at doses in excess of 16 μmol/kg. Malignant injection-site sarcomas occurred at the two highest doses of cadmium, while pituitary adenomas were elevated by cadmium exposure at the highest dose. These results show that cadmium induces proliferative lesions in the dorsolateral prostate of the Noble rat, a model having a presumed relevance to human prostate cancers.