Effects of ?-tocopherol and ?-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study.
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ABSTRACT:
SUBMITTER: Lai GY
PROVIDER: S-EPMC4264440 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
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Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study.
Lai G Y GY Weinstein S J SJ Taylor P R PR McGlynn K A KA Virtamo J J Gail M H MH Albanes D D Freedman N D ND
British journal of cancer 20141014 12
<h4>Background</h4>Recent data suggest the possible benefits of α-tocopherol and β-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited.<h4>Methods</h4>We evaluated the efficacy of supplemental 50 mg day(-1) α-tocopherol and 20 mg day(-1) β-carotene on incident liver cancer and CLD mortality in a randomised trial of 29,105 Finnish male smokers, who received supplementation for 5-8 years and were followed for 16 additional years for ou ...[more]
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Project description:BackgroundMicronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, β-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers.MethodsBaseline and 3-year follow-up serum were available from 29,046 and 22,805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models.ResultsHigher β-carotene and retinol levels were associated with less liver cancer (β-carotene: 0.35, 0.22-0.55, P-trend <0.0001; retinol: 0.58, 0.39-0.85, P-trend=0.0009) and CLD mortality (β-carotene: 0.47, 0.30-0.75, P-trend=0.001; retinol: 0.55, 0.38-0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40-0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64-1.74, P-trend=0.77). Participants with higher levels of β-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels.ConclusionsOur findings suggest that higher concentrations of β-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases.
| S-EPMC4260018 | biostudies-literature
Project description:In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50-69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α-tocopherol and β-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96-1.11) among β-carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89-1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing ∼8 years postintervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88-1.14) in normal-weight men, 0.87 (95% CI, 0.77-0.98) in overweight men, and 1.25 (95% CI, 1.01-1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98-1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99-1.05) for β-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70-0.99), whereas β-carotene increased it (RR, 1.20; 95% CI, 1.01-1.42). In conclusion, supplementation with α-tocopherol and β-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.
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Project description:The role of retinol in the prevention of multifactorial chronic diseases remains uncertain, and there is sparse evidence regarding biological actions and pathways implicated in its effects on various outcomes. The aim is to investigate whether serum retinol in an un-supplemented state is associated with low molecular weight circulating metabolites. We performed a metabolomic analysis of 1,282 male smoker participants based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We examined the association between 947 metabolites measured by ultra-high performance LC-MS/GC-MS and retinol concentration (from HPLC) using linear regression that estimated the difference in metabolite concentrations per unit difference in retinol concentration as standardized ?-coefficients and standard errors (SE). We identified 63 metabolites associated with serum retinol below the Bonferroni-corrected P-value (p?<?5.3?×?10-5). The strongest signals were for N-acetyltryptophan (??=?0.27; SE?=?0.032; p?=?9.8?×?10-17), myo-inositol (??=?0.23; SE?=?0.032; p?=?9.8?×?10-13), and 1-palmitoylglycerophosphoethanolamine (??=?0.22; SE?=?0.032; p?=?3.2?×?10-12). Several chemical class pathways were strongly associated with retinol, including amino acids (p?=?1.6?×?10-10), lipids (p?=?3.3?×?10-7), and cofactor/vitamin metabolites (3.3?×?10-7). The strongest sub-pathway association was for inositol metabolism (p?=?2.0?×?10-14). Serum retinol concentration is associated with circulating metabolites in various metabolic pathways, particularly lipids, amino acids, and cofactors/vitamins. These interrelationships may have relevance to the biological actions of retinol, including its role in carcinogenesis.
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Project description:BackgroundVitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification.MethodsBaseline serum 25-hydroxy-vitamin D [25(OH)D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH)D levels.ResultsA majority of the metabolites associated with 25(OH)D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) [beta-estimate 0.38 per 1 standard deviation (SD) increment], stearoyl-arachidonoyl-glycerophosphoethanolamine (GPPE) (-0.38 per SD) and two essential fatty acids: eicosapentaenoate (EPA; 0.17 per SD) and docosahexaenoate (DHA; 0.13 per SD). Each of these lipid metabolites was associated with 25(OH)D at the principal components corrected P-value of 3.09?×?10-4 CONCLUSIONS: The large number of metabolites, particularly lipid compounds, found to be associated with serum 25(OH)D provide new biological clues relevant to the role of vitamin D status and human health outcomes. The present findings should be re-examined in other metabolomics studies of diverse populations.
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Project description:BackgroundTwo chemoprevention trials found that supplementation with β-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood.ObjectiveThe objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive β-carotene supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.DesignThe ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) α-tocopherol, 2) β-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (β-carotene or no β-carotene) was estimated by linear regression.ResultsWe measured 489 metabolites, and 17 changed significantly (P < 0.05) in response to β-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a marker of glycemic control (β = -0.379, P = 0.0071).ConclusionsMale smokers supplemented with β-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with β-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992.
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Project description:Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high-performance liquid chromatography/mass spectrometry-gas chromatography/mass spectrometry. We used Cox regression to estimate mortality hazard ratios for a 1-standard-deviation difference in metabolite signals. The strongest associations with overall mortality were N-acetylvaline (hazard ratio (HR) = 1.28; P < 4.1 × 10-5, below Bonferroni statistical threshold) and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23 ≤ HR ≤ 1.32; 5 × 10-5 ≤ P ≤ 1 × 10-4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3β,17β-diol disulfate were statistically significantly associated with CVD mortality (1.49 ≤ HR ≤ 1.62, P < 4.1 × 10-5). No metabolite was associated with cancer mortality, at a false discovery rate of <0.1. Individuals with a 1-standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test set (HR = 1.4, P = 0.05; HR = 1.8, P = 0.003, respectively). The several serum metabolites and their composite risk score independently associated with all-cause and CVD mortality may provide potential leads regarding the molecular basis of mortality.
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Project description:Background: Although circulating 25-hydroxyvitamin D [25(OH)D] concentrations were linked to liver cancer and chronic liver disease (CLD) in laboratory studies, few epidemiologic studies have addressed the associations.Methods: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we measured 25(OH)D in baseline serum of 202 incident liver cancer cases and 225 CLD deaths that occurred during nearly 25 years of follow-up, and 427 controls. ORs and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. We examined predetermined clinically defined cut-points, and season-specific and season-standardized quartiles.Results: Low serum 25(OH)D concentrations were associated with higher risk of liver cancer (<25 nmol/L vs. ?50 nmol/L: 1.98; 95% CI, 1.22-3.20; Ptrend across categories = 0.003) and CLD mortality (1.93; 95% CI, 1.23-3.03; Ptrend = 0.006) in models adjusted for age and date of blood draw. After additional adjustment for body mass index, diabetes, smoking, and other potential confounders, the association remained statistically significant for liver cancer (1.91; 95% CI, 1.16-3.15; Ptrend = 0.008), but was somewhat attenuated for CLD mortality (1.67; 95% CI, 1.02-2.75; Ptrend = 0.05). Associations were similar for analyses using season-specific and season-standardized quartiles, and after excluding participants with diabetes, or hepatitis B or C.Conclusions: Our results suggest a possible preventive role for vitamin D against liver cancer and CLD, although the importance of the liver for vitamin D metabolism and the lack of information about underlying liver disease makes reverse causality a concern.Impact: Future studies are needed to evaluate associations of vitamin D with liver cancer and liver disease in other populations, particularly those with a different constellation of risk factors. Cancer Epidemiol Biomarkers Prev; 27(9); 1075-82. ©2018 AACR.
| S-EPMC6148352 | biostudies-literature
Project description:BACKGROUND:Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). METHODS:We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis. RESULTS:Serum iron metrics were not associated with GCC, except for a potential "n"-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a "u"-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations. CONCLUSIONS:We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency. IMPACT:Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted.
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Project description:A study of herd-level risk factors for calf mortality in large Swedish dairy herds showed low serum concentrations of α-tocopherol and β-carotene in 1-7 day old calves to be more common in high mortality herds. Therefore, we aimed to investigate if calf mortality risk at herd level is associated with concentrations of α-tocopherol and/or β-carotene at individual level in feed, colostrum, cow and calf serum, while controlling for herd level covariates. Inclusion criteria were affiliation to the Swedish official milk recording scheme, herd size of ≥ 120 milking cows/year, calf mortality risk (day 1-90) of at least 6% (high mortality; HM) or less than 1% (low mortality; LM) and located within one of two regions in southern Sweden. This cross-sectional study was performed in 2010 in 19 (nHM = 9; nLM = 10) dairy herds. Questionnaires were used to collect information about feed and routines for colostrum feeding. Feed (n = 57), colostrum (n = 162), cow serum (n = 189) and calf serum samples (n = 187) were collected and analysed for α-tocopherol and β-carotene. Other analyses e.g. total serum protein, fat content, and total solids in colostrum were also performed. Linear regression models with vitamin concentrations in feed, colostrum, cow and calf serum as outcome were performed.Calves in HM herds had lower concentrations of α-tocopherol in serum than calves in LM herds, but the effect depended on total protein status in serum of the calf (P = 0.036). Calves from herds that fed transition milk for 3 days or more had higher α-tocopherol concentrations in serum than calves from herds feeding transition milk up to 2 days (P = 0.013). Fat percentage in colostrum was positively associated with α-tocopherol (P < 0.001) and β-carotene concentrations in colostrum (P < 0.001). A diet containing ≥ 20% (in kg dry matter) maize silage of the total ration was negatively associated with β-carotene concentration in cow serum (P = 0.001).High calf mortality risks were associated with lower concentrations of α-tocopherol in calf serum for calves with failure of passive transfer. Feeding transition milk longer was associated with higher concentrations of α-tocopherol in calf serum. In HM herds, evaluation of the calves' α-tocopherol status is recommended.
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Project description:The effectiveness of rabbit-sperm cryopreservation is still below average compared to other domestic species. After the sperm cryopreservation process, post-thawing parameters like motility and membrane integrity are significantly compromised. The use of new extender constituents is an approach that can be used to improve the effectiveness of cryopreservation. Accordingly, we used honey (1.25, 2.5, 5, and 10%), coenzyme Q10 (100 and 200 μM), and β-carotene/α-tocopherol (500 μM/620 μM and 250 μM/310 μM) as candidate components for rabbit-sperm extenders during cryopreservation. Ejaculates from commercial adult rabbit bucks (n = 5) were cryopreserved using conventional freezing. Several post-thawing sperm parameters were assessed, including total motility, membrane integrity, viability, nuclear membrane integrity, acrosome reaction, and mitochondrial membrane potential and activation. Additionally, we performed hormonal analyses of the seminal plasma. Moreover, we analyzed the post-thawing levels of a molecular marker of sperm quality, proAKAP4, which was used in rabbits for the first time. Our findings showed that the 2.5% honey supplementation increased the post-thawing sperm motility (13.75 ± 3.75%) compared to the greater concentrations employed. However, the post-thawing motility was negatively affected by the coenzyme Q10 (0%, in both groups) but was not affected by the β-carotene/α-tocopherol supplementation (22 ± 18.15%, and 11.67 ± 10.17%). In conclusion, the cryopreservation protocols of this study did not help to maintain the sperm parameters after thawing. Further studies are required to identify novel protocols to mitigate the damage caused to rabbit sperm during cryopreservation.
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