Among scientists and the public there is considerable interest in determining whether daily supplementation with the essential trace mineral selenium (Se) can substantively reduce the incidence of human prostate cancer. We have conducted experiments to define the dose of Se that minimizes DNA damage in the aging dog prostate. This work revealed an intriguing U-shaped dose response between toenail Se levels and prostatic DNA damage (alkaline Comet assay) that remarkably parallels the relationship between dietary Se and prostate cancer risk in men, suggesting that more Se is not necessarily better. Herein, we extend this work to test the hypothesis that the Se dose that minimizes prostatic DNA damage upregulates apoptosis in prostatic epithelial cells. In a randomized feeding trial, 62 elderly beagle dogs (equivalent to 65 year-old men) received nutritionally adequate or supranutritional levels of Se for 7 months to mimic the range of dietary Se intake in U.S. men. Apoptosis was measured by TUNEL staining of formalin-fixed prostate tissues collected at necropsy. Se status was determined by neutron activation analysis of toenail specimens. The extent of epithelial cell apoptosis was compared between dogs with low Se status (<.67 ppm in toenails, the level above which selenoenzymes like GPx are maximally expressed), moderate Se status (.67-.92 ppm), and high Se status (>.92 ppm, which exceeds one s.d. above the mean Se level of U.S. men). Dogs with moderate Se status were 84% less likely to have high prostatic DNA damage than dogs in the low Se group (OR, 95% CI = 0.16, 0.04-0.63), whereas the extent of prostatic damage in the low and high Se groups was not significantly different. Apoptosis was higher in dogs with moderate Se status than in dogs with low Se (average of 2.6 versus 1.0 apoptotic cells/200X field, p=.025). Foci of intense apoptosis ("hot spots" with >30 apoptotic cells/200X field) were seen 4.1X (95% CI, 1.1-15.3) more often in the moderate Se group than in the low Se group. Moreover, this significant association between moderate Se status and elevated apoptosis was strengthened (OR=5.3) in multivariate analysis including age, body weight change, serum testosterone, and sensitivity of PBLs to oxidative stress. Consistent with the concept of a U-shaped dose-response between Se intake and apoptosis, there was no significant difference between the frequency of apoptotic hot spots in the high and low Se groups. We conclude the dose range of .67-.92 ppm Se in toenails that minimizes prostatic DNA damage also maximizes prostatic epithelial cell apoptosis. These data support the notion that the triggering of apoptosis in prostatic cells by Se is an important determinant of the U-shaped dose-response between Se and DNA damage, and moves us closer to defining the optimal dose of Se for human prostate cancer prevention.
[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]