Toenail selenium levels and prevalence of dyslipidaemia among Korean adults.

Multiple studies have elucidated the antioxidant properties of Se, which are now well known among the nutrition and biomedical science communities. Recently, considerable interest has been focused on the possible association between Se exposure and risk of metabolic disease, such as lipid dysregulation; however, there is limited epidemiological data on this topic. The present study aimed to investigate associations between toenail Se levels and dyslipidaemia or individual lipid levels, and to examine the effect of dietary supplement use on these associations. We analysed baseline data from a cohort in the Yeungnam area, including 232 men and 269 women. Information on demographic, dietary and lifestyle characteristics was obtained through a self-reported questionnaire. Se levels in toenail specimens were measured using neutron activation analysis. Fasting blood lipid levels were measured during medical examinations. After adjusting for multiple confounding variables, we observed no association between toenail Se levels and dyslipidaemia or individual lipid profiles. However, the association was modified by dietary supplement use. Among the supplement users, higher toenail Se levels were associated with a higher prevalence of lipid dysregulation, whereas non-users exhibited a lower prevalence of lipid dysregulation. Associations between toenail Se levels, lipid levels and dyslipidaemia may be influenced by taking dietary supplements. Future large-scale, prospective cohort studies should be conducted to further evaluate the association between Se levels in the body and metabolic health effects in light of increasing rates of dietary supplement use.

Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk.

BACKGROUND: The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer (PCa) risk but a 17% increased risk from vitamin E supplementation. This case-cohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status. METHODS: There were 1739 total and 489 high-grade (Gleason 7-10) PCa cases and 3117 men in the randomly selected cohort. Proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effects of supplementation within quintiles of baseline toenail selenium. Cox proportional hazards models were used to estimate hazard ratios, and all statistical tests are two-sided. RESULTS: Toenail selenium, in the absence of supplementation, was not associated with PCa risk. Selenium supplementation (combined selenium only and selenium + vitamin E arms) had no effect among men with low selenium status (<60th percentile of toenail selenium) but increased the risk of high-grade PCa among men with higher selenium status by 91% (P = .007). Vitamin E supplementation (alone) had no effect among men with high selenium status (≥40th percentile of toenail selenium) but increased the risks of total, low-grade, and high-grade PCa among men with lower selenium status (63%, P = .02; 46%, P = .09; 111%, P = .008, respectively). CONCLUSIONS: Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status. Vitamin E increased the risk of PCa among men with low selenium status. Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes.

Methylmercury exposure and incident diabetes in U.S. men and women in two prospective cohorts.

OBJECTIVE: Emerging in vitro and animal evidence suggests that methylmercury could increase type 2 diabetes, but little evidence exists in humans. We aimed to prospectively determine associations of mercury exposure, as assessed by biomarker measurement, with incident diabetes. RESEARCH DESIGN AND METHODS: We used neutron activation analysis to measure toenail mercury, an objective biomarker of methylmercury exposure, in 9,267 adults free of diabetes at baseline in two separate U.S. prospective cohorts. Incident diabetes was identified from biennial questionnaires and confirmed by validated supplementary questionnaire using symptoms, diagnostic tests, and medical therapy. Associations of mercury exposure with incident diabetes were assessed using Cox proportional hazards. RESULTS: During mean ± SD follow-up of 19.7 ± 7.0 years, 1,010 new cases of diabetes were diagnosed. The 95th percentile of toenail mercury was 1.32 µg/g in men and 0.76 µg/g in women, corresponding to exposures ∼3.5-fold and 2-fold higher than the U.S. Environmental Protection Agency reference dose. In multivariable analyses, toenail mercury concentrations were not associated with higher incidence of diabetes in women, men, or both cohorts combined. Comparing the highest to lowest quintile of exposure, the hazard ratio (95% CI) for incident diabetes was 0.86 (0.66-1.11) in women, 0.69 (0.42-1.15) in men, and 0.77 (0.61-0.98) in the combined cohorts. Findings were similar when more extreme categories (deciles) of mercury were compared, and in analyses stratified by fish or omega-3 consumption, BMI, and age. CONCLUSIONS: These findings from two separate large prospective cohorts do not support adverse effects of methylmercury on development of diabetes in men or women at usual levels of exposure seen in these populations.

Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis.

Prostate cancer is the product of dysregulated homeostasis within the aging prostate. Supplementation with selenium in the form of selenized yeast (Se-yeast) significantly reduced prostate cancer incidence in the Nutritional Prevention of Cancer Trial. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no such cancer-protective advantage using selenomethionine (SeMet). The possibility that SeMet and Se-yeast are not equipotent in promoting homeostasis and cancer risk reduction in the aging prostate has not been adequately investigated; no direct comparison has ever been reported in man or animals. Here, we analyzed data on prostatic responses to SeMet or Se-yeast from a controlled feeding trial of 49 elderly beagle dogs-the only non-human species to frequently develop prostate cancer during aging-randomized to one of five groups: control; low-dose SeMet, low-dose Se-yeast (3 µg/kg); high-dose SeMet, high-dose Se-yeast (6 µg/kg). After seven months of supplementation, we found no significant selenium form-dependent differences in toenail or intraprostatic selenium concentration. Next, we determined whether SeMet or Se-yeast acts with different potency on six markers of prostatic homeostasis that likely contribute to prostate cancer risk reduction-intraprostatic dihydrotestosterone (DHT), testosterone (T), DHT:T, and epithelial cell DNA damage, proliferation, and apoptosis. By analyzing dogs supplemented with SeMet or Se-yeast that achieved equivalent intraprostatic selenium concentration after supplementation, we showed no significant differences in potency of either selenium form on any of the six parameters over three different ranges of target tissue selenium concentration. Our findings, which represent the first direct comparison of SeMet and Se-yeast on a suite of readouts in the aging prostate that reflect flux through multiple gene networks, do not further support the notion that the null results of SELECT are attributable to differences in prostatic consequences achievable through daily supplementation with SeMet, rather than Se-yeast.

Associations between toenail arsenic concentration and dietary factors in a New Hampshire population.

BACKGROUND: Dietary factors such as folate, vitamin B12, protein, and methionine are important for the excretion of arsenic via one-carbon metabolism in undernourished populations exposed to high levels of arsenic via drinking water. However, the effects of dietary factors on toenail arsenic concentrations in well-nourished populations exposed to relatively low levels of water arsenic are unknown. METHODS: As part of a population-based case-control study of skin and bladder cancer from the USA, we evaluated relationships between consumption of dietary factors and arsenic concentrations in toenail clippings. Consumption of each dietary factor was determined from a validated food frequency questionnaire. We used general linear models to examine the associations between toenail arsenic and each dietary factor, taking into account potentially confounding effects. RESULTS: As expected, we found an inverse association between ln-transformed toenail arsenic and consumption of vitamin B12 (excluding supplements) and animal protein. Unexpectedly, there were also inverse associations with numerous dietary lipids (e.g., total fat, total animal fat, total vegetable fat, total monounsaturated fat, total polyunsaturated fat, and total saturated fat). Finally, increased toenail arsenic concentrations were associated with increased consumption of long chain n-3 fatty acids. CONCLUSION: In a relatively well-nourished population exposed to relatively low levels of arsenic via water, consumption of certain dietary lipids may decrease toenail arsenic concentration, while long chain n-3 fatty acids may increase toenail arsenic concentration, possibly due to their association with arsenolipids in fish tissue.

Toenail selenium and incidence of type 2 diabetes in U.S. men and women.

OBJECTIVE: Compelling biological pathways suggest that selenium (Se) may lower onset of type 2 diabetes mellitus (T2DM), but very few studies have evaluated this relationship, with mixed results. We examined the association between toenail Se and incidence of T2DM. RESEARCH DESIGN AND METHODS: We performed prospective analyses in two separate U.S. cohorts, including 3,630 women and 3,535 men, who were free of prevalent T2DM and heart disease at baseline in 1982-1983 and 1986-1987, respectively. Toenail Se concentration was quantified using neutron activation analysis, and diabetes cases were identified by biennial questionnaires and confirmed by a detailed supplementary questionnaire. Hazard ratios of incident T2DM according to Se levels were calculated using Cox proportional hazards. RESULTS: During 142,550 person-years of follow-up through 2008, 780 cases of incident T2DM occurred. After multivariable adjustment, the risk of T2DM was lower across increasing quintiles of Se, with pooled relative risks across the two cohorts of 1.0 (reference), 0.91 (95% CI 0.73-1.14), 0.78 (0.62-0.99), 0.72 (0.57-0.91), and 0.76 (0.60-0.97), respectively (P for trend = 0.01). Results were similar excluding the few individuals (4%) who used Se supplements. In semiparametric analyses, the inverse relationship between Se levels and T2DM risk appeared to be linear. CONCLUSIONS: At dietary levels of intake, individuals with higher toenail Se levels are at lower risk for T2DM. Further research is required to determine whether varying results in this study versus prior trials relate to differences in dose, source, statistical power, residual confounding factors, or underlying population risk.

Demographic and lifestyle factors and selenium levels in men and women in the U.S.

Selenium is an antioxidant trace element linked to cardiovascular disease and cancer. Although diet is a major source, relatively little else is known about independent determinants of selenium levels in free-living humans. In this study, we aimed to investigate the independent demographic, lifestyle, and dietary determinants of selenium levels in 1,997 men and 1,905 women in two large prospective U.S. cohorts. Toenail selenium levels were quantified using neutron activation analysis. Diet, geographic residence, demographic, and environmental factors were assessed by validated self-administered questionnaires. Multivariate generalized linear models were conducted to assess the independent relations of these factors with toenail selenium levels, correcting for measurement error in the diet. In multivariable-adjusted analyses, independent predictors of higher selenium were male gender (6.3% higher levels); living in West and Northern-Midwest U.S. regions (8.9% and 7.4% higher than Southern-Midwest regions, respectively); consumption of beef and bread products (between 0.7 - 2.5% higher per daily serving); and selenium supplement use (6.9% higher than non-users); whereas cigarette smoking (5-10% lower than never smokers) , older age (0.6% lower per 5 years), and consumption of eggs, white rice, dairy products, coffee, and alcohol (between 0.1 to 2.0% lower per daily serving) were associated with lower selenium. Multiple dietary and non-dietary factors independently predicted selenium levels, suggesting that both consumption and non-dietary processes (e.g., related to oxidant status) may affect levels. Significant geographic variation in selenium levels exists in the US.

Mercury exposure and risk of cardiovascular disease in two U.S. cohorts.

BACKGROUND: Exposure to methylmercury from fish consumption has been linked to a potentially increased risk of cardiovascular disease, but evidence from prior studies is equivocal. Beneficial effects of the ingestion of fish and selenium may also modify such effects. METHODS: Among subjects from two U.S. cohorts (a total of 51,529 men and 121,700 women) whose toenail clippings had been stored, we prospectively identified incident cases of cardiovascular disease (coronary heart disease and stroke) in 3427 participants and matched them to risk-set-sampled controls according to age, sex, race, and smoking status. Toenail mercury and selenium concentrations were assessed with the use of neutron-activation analysis. Other demographic characteristics, cardiovascular risk factors, fish consumption, and lifestyle habits were assessed by means of validated questionnaires. Associations between mercury exposure and incident cardiovascular disease were evaluated with the use of conditional logistic regression. RESULTS: Median toenail mercury concentrations were 0.23 µg per gram (interdecile range, 0.06 to 0.94) in the case participants and 0.25 µg per gram (interdecile range, 0.07 to 0.97) in the controls. In multivariate analyses, participants with higher mercury exposures did not have a higher risk of cardiovascular disease. For comparisons of the fifth quintile of mercury exposure with the first quintile, the relative risks were as follows: coronary heart disease, 0.85 (95% confidence interval [CI], 0.69 to 1.04; P=0.10 for trend); stroke, 0.84 (95% CI, 0.62 to 1.14; P=0.27 for trend); and total cardiovascular disease, 0.85 (95% CI, 0.72 to 1.01; P=0.06 for trend). Findings were similar in analyses of participants with low selenium concentrations or low overall fish consumption and in several additional sensitivity analyses. CONCLUSIONS: We found no evidence of any clinically relevant adverse effects of mercury exposure on coronary heart disease, stroke, or total cardiovascular disease in U.S. adults at the exposure levels seen in this study. (Funded by the National Institutes of Health.).

A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.

The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (P(interaction) = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype.

Associations of toenail selenium levels with inflammatory biomarkers of fibrinogen, high-sensitivity c-reactive protein, and interleukin-6: The CARDIA Trace Element Study.

The authors examined the associations of toenail selenium levels with blood concentrations of fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) in an 18-year follow-up study comprising 4,032 Americans aged 20-32 years at baseline (1987) from the Coronary Artery Risk Development in Young Adults (CARDIA) Trace Element Study. Toenail samples were collected in 1987, and selenium concentrations were measured by means of instrumental neutron-activation analysis. Fibrinogen level was analyzed in 1990, 1992, and 2005; hs-CRP was assessed in 1992, 2000, and 2005; and IL-6 was measured in 2005. After adjustment for potential confounders, no statistically significant associations between toenail selenium levels and any of the 3 inflammatory biomarkers were documented. Comparing the highest quintile of toenail selenium level with the lowest, odds ratios for elevated levels of fibrinogen (>460 mg/mL), hs-CRP (>3 microg/mL), and IL-6 (>3.395 pg/mL, 80th percentile) were 1.03 (95% confidence interval (CI): 0.77, 1.38; P for trend = 0.76), 1.02 (95% CI: 0.83, 1.27; P for trend = 0.92), and 0.98 (95% CI: 0.71, 1.36; P for trend = 0.82), respectively. Gender, race/ethnicity, smoking status, and selenium supplementation did not appreciably modify these results. This study found no associations between toenail selenium and inflammation as measured by fibrinogen, hs-CRP, and IL-6.

Longitudinal association between toenail selenium levels and measures of subclinical atherosclerosis: the CARDIA trace element study.

OBJECTIVES: To examine the longitudinal association between toenail selenium levels and subclinical atherosclerosis over an 18-year period. METHODS: Toenail selenium concentrations were examined among 3112 Americans age 20-32 years in 1987 and measured by instrumental neutron-activation analysis. Subclinical atherosclerosis, including common, bulb and internal carotid intima-media thickness (CIMT), was measured in 2005 and coronary artery calcium (CAC) score in 2000 and 2005. General linear regression was developed examining the relation between toenail selenium levels and CIMTs, and logistic regression for repeated outcomes was employed estimating the risk of having CAC>0. RESULTS: After adjustment for potential confounders, no associations were observed between toenail selenium levels and CIMTs as well as CAC score. Comparing participants in the highest with the lowest quintile of selenium, the CIMT was 0.005 mm (SE=0.008 mm, Ptrend=0.39), 0.018 mm (SE=0.019 mm, Ptrend=0.49), and 0.017 mm (SE=0.014 mm, Ptrend=0.21) thicker measured in common, bulb and internal carotid, respectively. The adjusted odds ratio of having CAC>0 was 0.95 (95% CI: 0.67-1.35; Ptrend=0.999). CONCLUSIONS: No associations were observed between toenail selenium and measures of subclinical atherosclerosis among American young adults. This study does not support an atherosclerotic mechanism of selenium for risk reduction of cardiovascular disease.

Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue.

BACKGROUND: Low serum selenium concentration has been associated with increased risk of prostate cancer. A possible mechanism is through the antioxidant activity of selenoenzymes. However, the effect of selenium intake on selenoenzymes at target tissues is not well established. Hence, we investigated the correlation between serum and prostate tissue selenium concentrations and prostate tissue activity of glutathione peroxidase (GPX), a major selenoenzyme with antioxidant properties. METHODS: In an ongoing study investigating gene expression in prostate tissue, we measured serum selenium concentration in 98 men using atomic absorption spectrometry. Of these men, we selected 12 men with the highest and 12 men with the lowest serum selenium concentrations and measured selenium concentration and GPX activity in fresh frozen prostate tissue using the cyclic neutron activation analysis and a direct spectrophotometric procedure, respectively. RESULTS: The mean serum selenium concentrations among low and high selenium groups were 123.7 +/- 5.9 and 196.7 +/- 16.6 microg/L (P < 0.0001), respectively. The corresponding mean prostate tissue selenium concentrations were 1.39 +/- 0.28 and 1.65 +/- 0.42 microg/g (P = 0.08), resulting in a positive correlation between serum and prostate tissue selenium concentrations (r = 0.56, P = 0.02). The mean prostate tissue GPX activity was non-significantly greater in the low serum selenium group (32.2 +/- 8.4 U/g protein) than in the high serum selenium group (29.6 +/- 5.9 U/g protein) (P = 0.39) and it was not correlated with serum or prostate tissue selenium concentrations (r = -0.22, P = -0.37 for serum and r = -0.33, P = 0.18 for prostate tissue). CONCLUSION: Serum and prostate tissue selenium concentrations were moderately correlated. In this population with relatively high selenium concentration, neither prostate tissue nor serum selenium concentrations were associated with prostate tissue GPX activity.

How might selenium moderate the toxic effects of mercury in stream fish of the western U.S.?

The ability of selenium (Se) to moderate mercury (Hg) toxicity is well established in the literature. Mercury exposures that might otherwise produce toxic effects are counteracted by Se, particularly when Se:Hg molar ratios approach or exceed 1. We analyzed whole body Se and Hg concentrations in 468 fish representing 40 species from 137 sites across 12 western U.S. states. The fish samples were evaluated relative to a published wildlife protective Hg threshold (0.1 sg Hg x g(-1) wet wt.), the currenttissue based methylmercury (MeHg) water quality criterion (WQC) for the protection of humans (0.3 microg Hg x g(-1) wet wt) and to presumed protections against Hg toxicity when Se:Hg molar ratios are >1. A large proportion (56%) of our total fish sample exceeded the wildlife Hg threshold, whereas a smaller, but significant proportion (12%), exceeded the MeHg WQC. However, 97.5% of the total fish sample contained more Se than Hg (molar ratio >1) leaving only 2.5% with Se: Hg ratios <1. All but one of the fish with Se:Hg <1, were of the genus Ptychochelius (pikeminnow). Scientific literature on Se counteracting Hg toxicity and our finding that 97.5% of the freshwater fish in our survey have sufficient Se to potentially protect them and their consumers against Hg toxicity suggests that Se in fish tissue (Se:Hg molar ratio) must be considered when assessing the potential toxic effects of Hg.

Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: the multiethnic cohort study.

Although smoking is the primary risk factor for lung cancer, there is evidence to suggest that fruit and vegetable intake are important cofactors. The present case-control study, nested within the Multiethnic Cohort Study, examined the associations of biomarkers of fruit and vegetable intake (individual plasma micronutrient levels), serum selenium, and a urinary biomarker for total lipid peroxidation with lung cancer risk. Two hundred seven incident cases were matched to 414 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection, and hours of fasting. We measured prediagnositic circulating levels of individual tocopherols and carotenoids, retinol, and serum selenium, and urinary 15-isoprostane F(2t). Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI). For men, strong reductions in risk were seen with increasing tertiles of each plasma carotenoid, with the ORs for the third tertile, compared with the first tertile, ranging from 0.24 to 0.45 (P(trends), 0.002-0.04). No associations were found among women for carotenoids or among either sex for tocopherols, selenium, and retinol. A doubling in risk was seen for men in the second and third tertiles, compared with the first tertile of urinary 15-isoprostane F(2t) (OR, 2.31; 95% CI, 1.02-5.25; and OR, 2.16; 95% CI, 0.98-4.78). This study supports the previously observed association between circulating carotenoids and lung cancer risk in men, and adds to the limited literature regarding urinary 15-isoprostane F(2t) as a marker of cancer risk. Future research examining the possible relationship between isoprostanes and lung cancer is warranted.

Selenium and risk of bladder cancer: a population-based case-control study.

Emerging evidence indicates a potential role of selenium in the prevention of several types of cancer, including bladder cancer. We investigated the association between toenail selenium concentrations and bladder cancer risk in a population-based case-control study in New Hampshire. We analyzed data from 857 incidence cases diagnosed between July 1, 1994 and June 30, 2001 and 1,191 general population controls. Newly diagnosed cases of bladder cancer were identified from the New Hampshire State Cancer Registry, which operates a rapid reporting system. Controls were selected from population lists (driver's license and Medicare enrollment). We used logistic regression analyses to generate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, and pack-years of smoking and conducted separate analyses according to the intensity of p53 immunohistochemical staining of the tumor. Overall, toenail selenium concentrations were not significantly related to bladder cancer [OR Q4 versus Q1, 0.90 (95% CI, 0.68-1.19); P(trend) = 0.15]. However, within specific subgroups there were inverse associations, i.e., among moderate smokers [OR, 0.61 (95% CI, 0.39-0.96); P(trend) = 0.004], women [OR, 0.66 (95% CI, 0.40-1.10); P(trend) = 0.11], and those with p53-positive cancers [OR Q4 versus Q1, 0.57 (95% CI, 0.34-0.94); P(trend) = 0.01]. Our results indicate that selenium is not inversely related to risk of bladder cancer overall; however, they raise the possibility that selenium may be preventive in certain molecular phenotypes of tumors (e.g., p53 positive) or within certain subsets of a population (e.g., women or moderate smokers).

Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis.

Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or selenium-refractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

Effect of dietary selenium on the promotion of hepatocarcinogenesis by 3,3', 4,4'-tetrachlorobiphenyl and 2,2', 4,4', 5,5'-hexachlorobiphenyl.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that have promoting activity in the liver. PCBs induce oxidative stress, which may influence carcinogenesis. Epidemiological studies strongly suggest an inverse relationship between dietary selenium (Se) and cancer. Despite evidence linking Se deficiency to hepatocellular carcinoma and liver necrosis, the underlying mechanisms for Se cancer protection in the liver remain to be determined. We examined the effect of dietary Se on the tumor promoting activities of two PCBs congeners, 3,3', 4,4'-tetrachlorobiphenyl (PCB-77) and 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB-153) using a 2-stage carcinogenesis model. An AIN-93 torula yeast-based purified diet containing 0.02 (deficient), 0.2 (adequate), or 2.0 mg (supplemental) selenium/kg diet was fed to Sprague-Dawley female rats starting ten days after administering a single dose of diethylnitrosamine (150 mg/kg). After being fed the selenium diets for 3 weeks, rats received four i.p. injections of either PCB-77 or PCB-153 (150 micromol/kg) administered every 14 days. The number of placental glutathione S-transferase (PGST)-positive foci per cm(3) and per liver among the PCB-77-treated rats was increased as the Se dietary level increased. Unlike PCB-77, rats receiving PCB-153 did not show the same Se dose-response effect; nevertheless, Se supplementation did not confer protection against foci development. However, the 2.0 ppm Se diet reduced the mean focal volume, indicating a possible protective effect by inhibiting progression of preneoplastic lesions into larger foci. Cell proliferation was not inhibited by Se in the liver of the PCB-treated groups. Se did not prevent the PCB-77-induced decrease of hepatic Se and associated reduction in glutathione peroxidase (GPx) activity. In contrast, thioredoxin reductase (TrxR) activity was not affected by the PCBs treatment or by Se supplementation. These findings indicate that Se does not inhibit the number of PGST-positive foci induced during promotion by PCBs, but that the size of the lesions may be inhibited. The effects of Se on altered hepatic foci do not correlate with its effects on GPx and TrxR.

Toenail and plasma levels as biomarkers of selenium exposure.

PURPOSE: Both blood and toenail selenium are used to assess selenium exposure in epidemiologic studies. Little is known about the relationship of these biomarkers with each other or about whether there are differences in the relationships of these biomarkers with diet, supplement use, or participant characteristics. METHODS: Data are from 220 participants in a large cohort study of supplement use and cancer risk. Measures of selenium exposure included supplement use (current and 10-year) from a self-administered questionnaire, an inventory of currently used supplements (multivitamins and single supplements), dietary intake from a food frequency questionnaire (FFQ), and selenium concentration in toenails and plasma. RESULTS: Plasma and toenail selenium concentrations were significantly correlated (r=.56 [95% confidence interval: .46, .64]). Supplemental selenium was the strongest predictor of both selenium biomarkers, and these associations were slightly stronger when based on the supplement inventory and 10-year self-reported use compared to current self-reported use. Correlations of current and 10-year questionnaire dose and inventory dose with toenail selenium were .26, .36, and .33; for plasma selenium, these were .27, .36, and .36. Neither dietary selenium nor any participant characteristics, except smoking, was related to either biomarker. Current smokers had lower toenail, but not plasma, selenium levels compared to nonsmokers (.89 versus 1.03 microg/g, p = .03); however, the difference was not significant after control for supplement use (p = .09). CONCLUSIONS: Both toenail and plasma selenium levels similarly reflect selenium intake exposure. There do not appear to be independent associations of toenail or plasma selenium with FFQ-derived selenium intakes, health-related behaviors, or demographic characteristics.

Toenail selenium and cardiovascular disease in men with diabetes.

OBJECTIVE: Selenium as a component of glutathione peroxidase may be beneficial in insulin resistance, hence potentially may modify the risk of diabetes and cardiovascular disease (CVD). The aim of this study is to evaluate the association between toenail selenium and CVD among men with diabetes. METHODS: We performed cross-sectional and nested case-control analyses within the Health Professionals Follow-up Study, a cohort of men aged 40 to 75 years in 1986. The cross-sectional analysis compared healthy controls (n = 361) to men with diabetes only (n = 688), and men with prevalent diabetes and CVD (n = 198). The nested case-control study included 202 diabetic men who developed incident CVD during follow-up and 361 matched controls. RESULTS: After controlling for potential confounders, the odds ratio (OR) for prevalent diabetes was 0.43 (95% CI: 0.28, 0.64; p-trend <0.001) for the highest compared to the lowest quartile of selenium. Comparison between diabetic men with CVD and healthy controls yielded an OR of 0.86 (95% CI: 0.47, 1.56, p-trend = 0.37) between extreme quartiles. In the nested case-control analysis, the OR between extreme quartiles was 0.57 (95% CI: 0.29, 1.03; p-trend = 0.07), comparing diabetic men with incident CVD to healthy controls. CONCLUSIONS: Our results suggest that levels of toenail selenium are lower among diabetic men with or without CVD than among healthy controls. However, this study could not distinguish between the effects of selenium on diabetes and those on CVD. Randomized clinical trials are needed to study potential benefits of selenium supplementation in the prevention and treatment of diabetes and CVD.

Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model.

Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.