Toenail mercury levels positively correlate with obesity and abdominal obesity among Korean adults.

BACKGROUND: Although previous studies have shown that short-term exposure to mercury is associated with obesity, it should be noted that mercury is not easily released and that it constantly accumulates in the body. However, few studies have explored the association between chronic mercury exposure and obesity. This study aimed to examine the association between chronic mercury exposure and obesity in Korean adults. METHODS: The study used baseline data from the Trace Element Study of Korean Adults in Yeungnam area. A total of 495 participants aged 40-69 years who provided the required information (demographic, diet, lifestyle, toenail mercury levels, and health examination results) were included. Toenail mercury levels were measured using neutron-activation analysis. Body mass index and waist circumference were obtained from medical examination. Multivariable-adjusted logistic regression and restricted cubic spline regression were used in the analysis. RESULTS: In the fully adjusted logistic regression models, participants with the highest toenail mercury levels had a higher prevalence of obesity (odds ratio [OR]: 3.26, 95 % confidence interval [CI]: 1.79-5.93) and abdominal obesity (OR: 2.30, 95 % CI: 1.15-4.59). In the cubic spline regression model, linear relationships were confirmed between increased toenail mercury levels and higher prevalence of obesity and abdominal obesity (all p > 0.05 for nonlinearity). CONCLUSIONS: In summary, chronic mercury exposure was associated with higher prevalence of obesity and abdominal obesity in Korean adults. Therefore, the development of public health interventions against environmental exposure of foods is required to manage and prevent obesity.

A Prospective Study of Toenail Trace Element Levels and Risk of Skin Cancer.

BACKGROUND: Few epidemiologic studies have investigated trace element exposure and skin cancer risk. METHODS: Toenail levels of mercury, selenium, chromium, iron, and zinc were measured from 6,708 women in the Nurses' Health Study (1984-2012) and 3,730 men in the Health Professionals Follow-up Study (1986-2012) with data from prior nested case-control studies. Participants were free of skin cancer at toenail collection and followed for incident basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of skin cancer associated with the elements in each study. We calculated pooled multivariable HRs using a fixed-effects model. During 26 to 28 years of follow-up, 2,433 BCC, 334 SCC, and 130 melanoma cases were documented. RESULTS: Higher toenail mercury levels were associated with risk of BCC [pooled HR for top vs. bottom quintiles = 1.34 (95% CI, 1.18-1.52), P trend < 0.0001]. Similar direct associations were found with risks of SCC [pooled HR for top vs. bottom quartiles = 1.41 (95% CI, 1.03-1.94), P trend = 0.04] and melanoma [pooled HR for top vs. bottom quartiles = 1.88 (95% CI, 1.12-3.16), P trend = 0.02]. Chromium was positively associated with BCC in women only. No associations were found between other metals and skin cancer risk. CONCLUSIONS: Our prospective data found that increased toenail mercury concentrations were associated with increased skin cancer risk. IMPACT: If our novel findings are confirmed, mercury may play a role in skin carcinogenesis.

Exposure to Trace Elements and Risk of Skin Cancer: A Systematic Review of Epidemiologic Studies.

Exposure to environmental trace elements has been studied in relation to many cancers. However, an association between exposure to trace elements and skin cancer remains less understood. Therefore, we conducted a systematic review of published epidemiologic literature examining the association between exposure to trace elements, and risk of melanoma and keratinocyte carcinoma in humans. We identified epidemiologic studies investigating exposure to arsenic, cadmium, chromium, copper, iron, selenium, and zinc and risk of skin cancer in humans. Among the minerals, arsenic, selenium, and zinc had more than five studies available. Exposure to arsenic was associated with increased risk of keratinocyte carcinoma, while too few studies existed on melanoma to draw conclusions. Exposure to selenium was associated with possible increased risk of keratinocyte carcinoma. Studies of zinc and skin cancer were case-control in design and were found to have inconsistent associations. The data on the association between cadmium, chromium, copper, and iron and risk of skin cancer remain too sparse to draw any conclusions. In summary, epidemiologic studies on exposure to trace elements and cutaneous malignancies are limited. Studies with larger sample sizes and prospective designs are warranted to improve our knowledge of trace elements and skin cancer.

Toenail Chromium Concentration and Metabolic Syndrome among Korean Adults.

Although in vivo and in vitro studies have shown that chromium has protective effects against metabolic diseases, few studies have examined this association in humans. The present study examined chronic chromium (Cr) exposure among Koreans based on the measurement of toenail Cr concentrations, and analyzed the associations between toenail Cr concentrations and metabolic syndrome (MetS) and its components. We conducted a cross-sectional analysis using baseline data from the prospective cohort study in the Yeungnam area of South Korea that included 232 men and 268 women. Toenail Cr concentration was quantified by neutron activation analysis, and metabolic biomarker levels were obtained through medical examinations. The odd ratios (OR) of prevalent MetS and its components in correlation with Cr concentrations were calculated using multivariable logistic regression. After multiple confounding variables were adjusted for, participants with higher concentrations of Cr had a prevalence rate of MetS similar to those with lower concentrations (OR, 1.84; 95% confidence interval, 0.65-5.23). Our results do not support an association between long-term exposure to Cr and a lower prevalence of MetS in Koreans, whose Cr concentrations are relatively low compared to those of populations in Europe and the United States.

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.

Diet and toenail arsenic concentrations in a New Hampshire population with arsenic-containing water.

BACKGROUND: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest. METHODS: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) (n = 852). As part of the analysis, we assessed whether associations between log-transformed toenail arsenic and each diet item differed between subjects with household drinking water arsenic concentrations <1 µg/L versus ≥1 µg/L. RESULTS: As expected, toenail arsenic concentrations increased with household water arsenic concentrations. Among the foods known to be high in arsenic, no clear relationship between toenail arsenic and rice consumption was detected, but there was a positive association with consumption of dark meat fish, a category that includes tuna steaks, mackerel, salmon, sardines, bluefish, and swordfish. Positive associations between toenail arsenic and consumption of white wine, beer, and Brussels sprouts were also observed; these and most other associations were not modified by exposure via water. However, consumption of two foods cooked in water, beans/lentils and cooked oatmeal, was more strongly related to toenail arsenic among those with arsenic-containing drinking water (≥1 µg/L). CONCLUSIONS: This study suggests that diet can be an important contributor to total arsenic exposure in U.S. populations regardless of arsenic concentrations in drinking water. Thus, dietary exposure to arsenic in the US warrants consideration as a potential health risk.

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.

Serum zinc and prostate cancer risk in a nested case-control study: The multiethnic cohort.

BACKGROUND: Experimental studies have provided evidence that zinc has a protective effect against development and progression of prostate cancer. However, epidemiological studies have reported inconsistent findings. We evaluated the association between prediagnostic serum zinc and prostate cancer risk in a cohort of multiethnic population. METHODS: This case-control study is nested within the Multiethnic Cohort of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in Hawaii and California. The analysis included 392 prostate cancer cases and 783 controls matched on age, race/ethnicity, date/time of blood draw and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean serum zinc concentrations did not significantly differ between cases (94.9 µg/dl) and controls (93.9 µg/dl). No association was found between serum zinc levels and prostate cancer either overall or by tumor stage/grade. In ethnic-specific analyses, positive associations were found in Japanese Americans (OR for the highest vs. the lowest tertile = 2.59, 95% CI: 1.09-6.17) and Latinos (OR = 2.74, 95% CI: 1.05-7.10), whereas no association was observed in African Americans and whites. CONCLUSIONS: We found no evidence to support an inverse relationship between serum zinc and prostate cancer risk, and, to the contrary, found a suggestion in the ethnic-specific results of a possible increase in risk; however, blood concentrations of zinc may not adequately reflect the levels in prostate tissue. Further study with a larger sample size, and if possible, with assessment of zinc tissue levels, is warranted to confirm these findings.

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.

Mercury exposure and risk of hypertension in US men and women in 2 prospective cohorts.

Cross-sectional studies and animal experiments suggest that methylmercury exposure could increase the risk of hypertension. This relationship has not been evaluated in large prospective studies. Using data from previous nested case-control studies in 2 separate prospective cohorts, we measured toenail mercury, a valid biomarker of long-term methylmercury exposure, among 6045 US men and women free of hypertension at baseline. Geometric mean toenail mercury concentrations were 0.08 µg/g in the lowest quintile and 0.74 µg/g in the highest quintile, the latter corresponding with exposures ≈2.0-fold higher than the US Environmental Protection Agency reference dose. Participants were followed prospectively (mean±SD follow-up, 14.9±7.9 years) for a new self-report of physician-diagnosed hypertension (3540 cases), shown to be >95% sensitive and specific for diagnosing hypertension in these cohorts as compared with review of medical charts and direct blood pressure measurement, respectively. After adjustment for demographic, clinical, and lifestyle risk factors, the hazard ratio (95% CI) for incident hypertension in the highest versus lowest quintile of mercury exposure was 0.96 (0.84-1.09) in women, 0.82 (0.62-1.08) in men, and 0.94 (0.84-1.06) in both cohorts combined. Findings were similar when more extreme categories of mercury were compared (across deciles, with geometric mean levels in highest decile ≈2.9-fold higher than the reference dose) and in analyses stratified by fish or omega-3 consumption, selenium levels, body mass index, and age. These findings from 2 separate large prospective cohort studies do not support any clinically apparent adverse effects of methylmercury exposure on the risk of hypertension in men or women, including at levels ≤2.5-fold higher than the reference dose.

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.

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer.

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.

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.