Minimal basal activity and lack of metal-induced activation of the metallothionein gene correlates with lobe-specific sensitivity to the carcinogenic effects of cadmium in the rat prostate.

Abstract

Metallothionein (MT), a high-affinity metal-binding protein, is known to detoxicate cadmium and may play an important role in cadmium carcinogenesis. In the rat, the ventral lobe of the prostate is sensitive to cadmium carcinogenesis, while the dorsolateral lobe is refractory. The possibility exists that the basis of this lobe-specific sensitivity may lie in the expression of the MT gene. Thus, the expression of the MT gene in lobes of the rat prostate was studied and, for comparative purposes, the expression of the MT gene in the liver, a tissue with well-defined high activity, was also assessed. MT gene expression was determined using a cDNA probe specific for MT-I, oligonucleotide probes specific for MT-I and MT-II, and an assay for cadmium-binding protein capacity. Basal levels of MT-I mRNA and cadmium-binding protein were much less in the ventral prostate than in the liver or dorsolateral prostate. Cadmium, given at a dose known to induce tumors of the ventral prostate (2.5 mumol/kg, sc), did not result in an increase in MT gene expression in the ventral prostate, as assessed by cadmium-binding protein levels or MT-I mRNA, over 72 hr. Small elevations of cadmium-binding protein capacity were detected at high doses of cadmium (25 and 40 mumol/kg) in the ventral prostate but no corresponding increases in MT mRNA were seen. In sharp contrast, hepatic MT gene expression was highly activated throughout the dosage range. Dose-response analysis 24 hr after cadmium administration (0.25 to 40 mumol/kg, sc) showed that MT-I and MT-II mRNA levels were increased in liver in a dose-dependent manner, while no evidence was found for MT gene activation in ventral prostate. In the dorsolateral prostate the high basal activity of the MT gene was shown, as assessed by MT-I and MT-II mRNA levels, which was not further elevated by cadmium treatments. Cadmium accumulation was much lower in the ventral prostate than in the liver. However, levels of cadmium that were sufficient to activate the hepatic MT gene had, in fact, reached the ventral prostate. Thus, the poor basal expression and lack of activation of the MT gene within the ventral lobe of the rat prostate may be the genetic basis to this tissue's sensitivity to the carcinogenic effects of cadmium.