Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel ...method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine.
We compared metabolite profiles of habitual diet measured from serum with those measured from urine.
We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case-control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine.
We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with ≥1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids.
Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies.
During the past several decades, an increasing incidence of thyroid cancer has been reported in many parts of the world. To date, no study has compared the trends in thyroid cancer incidence across ...continents. We examined incidence data from cancer incidence in five continents (CI5) over the 30-year period 1973–2002 from 19 populations in the Americas, Asia, Europe, and Oceania. Thyroid cancer rates have increased from 1973–1977 to 1998–2002 for most of the populations except Sweden, in which the incidence rates decreased about 18% for both males and females. The average increase was 48.0% among males and 66.7% among females. More recently, the age-adjusted international thyroid cancer incidence rates from 1998 to 2002 varied 5-fold for males and nearly 10-fold for females by geographic region. Considerable variation in thyroid cancer incidence was present for every continent but Africa, in which the incidence rates were generally low. Our analysis of published CI5 data suggests that thyroid cancer rates increased between 1973 and 2002 in most populations worldwide, and that the increase does not appear to be restricted to a particular region of the world or by the underlying rates of thyroid cancer.
Previous studies established a causal relationship between occupational benzene exposure and acute myeloid leukemia (AML). However, mixed results have been reported for associations between benzene ...exposure and other myeloid and lymphoid malignancies. Our work examined whether occupational benzene exposure is associated with increased mortality from overall lymphohaematopoietic (LH) cancer and major subtypes.
Mortality records were linked to a Swiss census-based cohort from two national censuses in 1990 and 2000. Cases were defined as having any LH cancers registered in death certificates. We assessed occupational exposure by applying a quantitative benzene job-exposure matrix (BEN-JEM) to census-reported occupations. Exposure was calculated as the products of exposure proportions and levels (P × L). Cox proportional hazards models were used to calculate LH cancer death hazard ratios (HR) and 95% confidence intervals (CI) associated with benzene exposure, continuously and in ordinal categories.
Our study included approximately 2.97 million persons and 13 415 LH cancer cases, including 3055 cases with benzene exposure. We observed increased mortality risks per unit (P × L) increase in continuous benzene exposure for AML (HR 1.03, 95% CI 1.00-1.06) and diffuse large B-cell lymphoma (HR 1.09, 95% CI 1.04-1.14). When exposure was assessed categorically, increasing trends in risks were observed with increasing benzene exposure for AML (P=0.04), diffuse large B-cell lymphoma (P=0.02), and follicular lymphoma (P=0.05).
In a national cohort from Switzerland, we found that occupational exposure to benzene is associated with elevated mortality risks for AML, diffuse large B-cell lymphoma, and possibly follicular lymphoma.
Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease ...aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk.
To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology.
In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.
Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development ...of these diseases in humans is not well understood.
Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers full shift exposure range of 0.4 to 230 parts-per-million of air (ppm
) and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population.
Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10
), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = -1.6, P-value = 0.0043), taurine (β = -2.4, P-value = 0.0011) and chenodeoxycholic acid (β = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations.
High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology.
Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and ...cooking. However, the key components of coal that drive lung cancer risk have not been identified.
We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer.
Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables.
The strongest association with lung cancer was for a cluster of 25 PAHs odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change, within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide (Formula: see text) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter Formula: see text (Formula: see text) were associated with lung cancer in the multipollutant models.
To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913.
Abstract
Background
Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between ...coffee and tea consumption and mortality in Asian populations.
Methods
We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model.
Results
In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% 95% confidence interval (CI) 17%, 29% and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption.
Conclusions
In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.
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Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) ...affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems.
Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers.
Supra-linear exposure response associations were observed between air benzene concentrations (range ∼ 0.1 – 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints.
We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis.
•Occupational exposures were associated with DNA methylation aging biomarkers.•Benzene and trichloroethylene exposures increased epigenetic age acceleration.•Epigenetic aging biomarkers capture ...impacts of environmental chemicals on health.
Epigenetic aging biomarkers are associated with increased morbidity and mortality. We evaluated if occupational exposure to three established chemical carcinogens is associated with acceleration of epigenetic aging. We studied workers in China occupationally exposed to benzene, trichloroethylene (TCE) or formaldehyde by measuring personal air exposures prior to blood collection. Unexposed controls matched by age and sex were selected from nearby factories. We measured leukocyte DNA methylation (DNAm) in peripheral white blood cells using the Infinium HumanMethylation450 BeadChip to calculate five epigenetic aging clocks and DNAmTL, a biomarker associated with leukocyte telomere length and cell replication. We tested associations between exposure intensity and epigenetic age acceleration (EAA), defined as the residuals of regressing the DNAm aging biomarker on chronological age, matching factors and potential confounders. Median differences in EAA between exposure groups were tested using a permutation test with exact p-values. Epigenetic clocks were strongly correlated with age (Spearman r > 0.8) in all three occupational studies. There was a positive exposure-response relationship between benzene and the Skin-Blood Clock EAA biomarker: median EAA was −0.91 years in controls (n = 44), 0.78 years in workers exposed to <10 ppm (n = 41; mean benzene = 1.35 ppm; p = 0.034 vs. controls), and 2.10 years in workers exposed to ≥10 ppm (n = 9; mean benzene = 27.3 ppm; p = 0.019 vs. controls; ptrend = 0.0021). In the TCE study, control workers had a median Skin-Blood Clock EAA of −0.54 years (n = 71) compared to 1.63 years among workers exposed to <10 ppm of TCE (n = 27; mean TCE = 4.22 ppm; p = 0.035). We observed no evidence of EAA associations with formaldehyde exposure (39 controls, 31 exposed). Occupational benzene and TCE exposure were associated with increased epigenetic age acceleration measured by the Skin-Blood Clock. For TCE, there was some evidence of epigenetic age acceleration for lower exposures compared to controls. Our results suggest that some chemical carcinogens may accelerate epigenetic aging.
ObjectivesThe increase in production of multiwalled carbon nanotubes (MWCNTs) has led to growing concerns about health risks. In this study, we assessed the association between occupational exposure ...to MWCNTs and cardiovascular biomarkers.MethodsA cross-sectional study was performed among 22 workers of a company commercially producing MWCNTs (subdivided into lab personnel with low or high exposure and operators), and a gender and age-matched unexposed population (n=42). Exposure to MWCNTs and 12 cardiovascular markers were measured in participants’ blood (phase I). In a subpopulation of 13 exposed workers and six unexposed workers, these measures were repeated after 5 months (phase II). We analysed associations between MWCNT exposure and biomarkers of cardiovascular risk, adjusted for age, body mass index, sex and smoking.ResultsWe observed an upward trend in the concentration of endothelial damage marker intercellular adhesion molecule-1 (ICAM-1), with increasing exposure to MWCNTs in both phases. The operator category showed significantly elevated ICAM-1 geometric mean ratios (GMRs) compared with the controls (phase I: GMR=1.40, P=1.30E-3; phase II: GMR=1.37, P=0.03). The trends were significant both across worker categories (phase I: P=1.50E-3; phase II: P=0.01) and across measured GM MWCNT concentrations (phase I: P=3.00E-3; phase II: P=0.01). No consistent significant associations were found for the other cardiovascular markers.ConclusionThe associations between MWCNT exposure and ICAM-1 indicate endothelial activation and an increased inflammatory state in workers with MWCNT exposure.
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