Several mechanisms of Cd induced
Several mechanisms of Cd-induced carcinogenicity have been reported and are comprehensively summarized by Hartwig . As early as 1980, basic science studies supported a role for endocrine disruption of AR by Cd. Donovan et al. , using extracts of mouse prostate cytosol, showed Cd to be the most effective divalent metal ion to inhibit dihydrotestosterone binding to the AR. Ye et al.  and Martin et al.  have both shown that Cd increases AR activity in LNCaP cells, and the latter also reported lower AR protein expression with increasing content of Cd (10−10–10−6 M). Originally derived from a lymph node of a European American prostate cancer patient, the LNCaP cell line is known to contain a functional mutation in the hormone-binding domain of AR at amino Benzoquinonium dibromide receptor 877. The mutation alters steroid specificity and antiandrogen sensitivity . Therefore, Martin et al.  also transfected wild-type AR into Cos-1 cells and showed that Cd affects the normal receptor as well. Using Wistar rats given Cd via drinking water, Lacorte et al.  showed increased AR protein expression and proliferation, as measured by Ki-67, in both the ventral and dorsal lobes of the prostate in treatment versus control rats. As mentioned previously, Wilson et al.  used cytosol AR from Dunning rats to show that Cd and other divalent metal ions alter the molecular size of the receptor and may, therefore, play a role in altering the state of transformation of the receptor. These studies all support Cd as an endocrine disruptor of AR. However, these cell culture studies are often criticized for using higher, non-physiological concentrations of Cd than what would be reasonably expected in humans. There may be other and less direct pathways through which Cd may influence the AR, as well.
Epidemiological prostate cancer studies to date are equivocal in terms of translating experimental observations of Cd as an endocrine disruptor of the AR. Human studies have used proxy measures of prostate Cd content, such as blood, urine and seminal fluid Cd concentrations, and have used PSA as a measure for AR activity. In a National Health and Nutrition Examination Survey analysis of 422 men over 40 years of age, van Wijngaarden et al.  found no overall association between urinary Cd and PSA concentration in blood samples but noted a potential protective interaction between Cd and Zn with regard to PSA concentrations (P = 0.09). Among husbands/male partners (>18 years of age) of pregnant women living in Poland, Ukraine, and Greenland, Andreucci et al.  reported a significant inverse trend (log(β) = −0.121, P = 0.01) between blood Cd and seminal fluid PSA only in Greenlandic men. The concentration of Zn in semen significantly modified the association between Cd and PSA levels (overall P value for interaction = 0.01, Greenland p-value for interaction P = 0.04); associations were slightly stronger in men with semen Zn concentrations below the median values. In addition, Andreucci et al.  noted an inverse association between Cd and PSA concentrations in men with AR CAG repeat length of 24 (37% of subjects, log(β) = −0.23, P = 0.0009). The association was not significant for other AR CAG strata. In our study, we observed a non-significant inverse relationship between Cd and AR for European American cases, but a positive association for African-American cases. We were able to account for tumor tissue Zn content as well as dietary Zn or Se intake. Our limited sample size did not allow us to examine the influence of AR CAG repeat length. However, our observed difference by race suggests AR CAG should be considered further as a potential modifier of Cd and AR associations, as African American men on average carry shorter CAG repeat length than European American men [, , ].
Strengths and weaknesses This study revealed a correlation between tumor tissue Cd-content and AR protein expression in prostate tissues of African American men which was not found in European American men. This work, however has a number of limitations. We measured metals in just a small number of formalin-fixed, paraffin-embedded tissues. Moreover, the process of embedding tissue has been shown to reduce metal content . As this is a substudy of an earlier large research study focused in part on occupational metal exposures (1999–2004), the tissues were stored for nearly 10 years before tissue metal analysis began. However, all of our prostatectomy specimens were originally processed and archived in the same room and manner in a single pathology facility at Henry Ford Health System, which would reduce the chance of variations in metals loss across subjects. Accounting for tissue Zn or Pb -content, dietary Zn or Se, or median household income did not modify our results. However, we are unable to account for all of these factors simultaneously due to our small sample size. Also tissue Se-content was not assessed and dietary nutrient intake was only assessed after diagnosis of prostate cancer and in most cases after prostatectomy. Patients may have changed their dietary habits after diagnosis, making it difficult to accurately assess Zn and Se intake at the time of prostatectomy. An additional concern that we were unable to address is the difference in use of menthol versus non-menthol cigarettes that has been observed between African Americans and European Americans , although our sample included only three current smokers, one African American and two European Americans. Menthol in general has been shown to decrease prostate cell proliferation  although it may increase Cd content associated with smoking . We did not have comprehensive exposure information for potentially important windows of susceptibility (e.g. in-utero, neo-natal, adolescent and pubertal exposure). Finally, due to our sample size, we were also unable to account for genetic factors that may explain our observed difference by race.