Expression and regulation of metallothionein mRNA levels in the prostates of Noble rats: Lack of expression in the ventral prostate and regulation by sex hormones in the dorsolateral prostate

Abstract

The rat prostate is composed of two anatomically well-defined regions designated as the ventral prostate (VP) and the dorsolateral prostate (DLP). VP and DLP are known to exhibit marked cytological, biochemical, and functional differences including differential susceptibilities to carcinogens. While the VP is uniquely susceptible to cadmium carcinogenicity [1,2], the DLP is sensitive to sex hormone-induced cancer [3,4]. The role played by the heavy metal binding protein, metallothionein (MT), in the prostate is largely unknown. It is still controversial as to whether MT is expressed in the rat gland. The aim of the present study is to examine the expression pattern of MT mRNA in the rat gland and its probable regulation by heavy metal ions and sex hormones, in order to gain insight into the biological function of MT in the prostate. Northern hybridization and reverse transcriptase-polymerase chain reaction analyses revealed constitutive expression of MT mRNA in the DLP and a lack of expression of the transcript in the VP. In situ hybridization localized the transcript to the epithelium of the DLP, with the lateral prostate epithelium exhibiting the highest level of expression. Administration of cadmium and zinc failed to induce MT transcription in the VP, nor were these treatments effective in elevating levels of MT mRNA in the DLP. A 60% reduction in MT message levels was observed in the DLP following orchiectomy. MT transcript levels in the DLPs of castrates were restored by readministration of androgen to the animals. Long-term treatments (16 weeks) of rats with estradiol-17 beta (E2) or testosterone (T) plus E2 induced a 2.8-fold and a 5-fold increase in MT message content in the DLP, respectively. In sum, MT mRNA was shown to be absent in the VP and was not inducible by heavy metal ions or hormones in this prostatic lobe. These findings substantiate the belief that MT plays a role in heavy metal detoxification and deficiency in its expression may contribute to the unique susceptibility of the VP to cadmium carcinogenicity. By contrast, constitutive expression of MT was demonstrated in the DLP, which was shown to be regulated by androgen and not by exogenously administered heavy metal ions. These results suggest a participatory role of MT in the normal functioning of the DLP. The fact that high levels of MT mRNA were induced in the DLP following long-term estrogenic or conjoint androgenic-estrogenic action alludes to the possibility that MT may serve as an intracellular antioxidant in DLP cells.