ABSTRACT
Cardiometabolic health is complex and characterized by an ensemble of correlated and/or co-occurring conditions including obesity, dyslipidemia, hypertension, and diabetes mellitus. It is affected by social, lifestyle, and environmental factors, which in-turn exhibit complex correlation patterns. To account for the complexity of (i) exposure profiles and (ii) health outcomes, we propose to use a multitrait Bayesian variable selection approach and identify a sparse set of exposures jointly explanatory of the complex cardiometabolic health status. Using data from a subset (N = 941 participants) of the nutrition, environment, and cardiovascular health (NESCAV) study, we evaluated the link between measurements of the cumulative exposure to (N = 33) pollutants derived from hair and cardiometabolic health as proxied by up to nine measured traits. Our multitrait analysis showed increased statistical power, compared to single-trait analyses, to detect subtle contributions of exposures to a set of clinical phenotypes, while providing parsimonious results with improved interpretability. We identified six exposures that were jointly explanatory of cardiometabolic health as modeled by six complementary traits, of which, we identified strong associations between hexachlorobenzene and trifluralin exposure and adverse cardiometabolic health, including traits of obesity, dyslipidemia, and hypertension. This supports the use of this type of approach for the joint modeling, in an exposome context, of correlated exposures in relation to complex and multifaceted outcomes.
Subject(s)
Dyslipidemias , Exposome , Hypertension , Humans , Bayes Theorem , Obesity/epidemiology , Hair , Environmental ExposureABSTRACT
This randomized crossover study investigated the metabolic and mRNA alterations associated with exposure to high and low traffic-related air pollution (TRAP) in 50 participants who were either healthy or were diagnosed with chronic pulmonary obstructive disease (COPD) or ischemic heart disease (IHD). For the first time, this study combined transcriptomics and serum metabolomics measured in the same participants over multiple time points (2 h before, and 2 and 24 h after exposure) and over two contrasted exposure regimes to identify potential multiomic modifications linked to TRAP exposure. With a multivariate normal model, we identified 78 metabolic features and 53 mRNA features associated with at least one TRAP exposure. Nitrogen dioxide (NO2) emerged as the dominant pollutant, with 67 unique associated metabolomic features. Pathway analysis and annotation of metabolic features consistently indicated perturbations in the tryptophan metabolism associated with NO2 exposure, particularly in the gut-microbiome-associated indole pathway. Conditional multiomics networks revealed complex and intricate mechanisms associated with TRAP exposure, with some effects persisting 24 h after exposure. Our findings indicate that exposure to TRAP can alter important physiological mechanisms even after a short-term exposure of a 2 h walk. We describe for the first time a potential link between NO2 exposure and perturbation of the microbiome-related pathways.
Subject(s)
Air Pollutants , Air Pollution , Gastrointestinal Microbiome , Humans , Male , London , Female , Middle Aged , Cross-Over Studies , Traffic-Related Pollution , Nitrogen DioxideABSTRACT
Bladder cancer, a common neoplasm, is primarily caused by tobacco smoking. Epigenetic alterations including DNA methylation have the potential to be used as prospective markers of increased risk, particularly in at-risk populations such as smokers. We aimed to investigate the potential of smoking-related white blood cell (WBC) methylation markers to contribute to an increase in bladder cancer risk prediction over classical questionnaire-based smoking metrics (i.e., duration, intensity, packyears) in a nested case-control study within the prospective prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial and the alpha-tocopherol, beta-carotene cancer (ATBC) Prevention Study (789 cases; 849 controls). We identified 200 differentially methylated sites associated with smoking status and 28 significantly associated (after correction for multiple testing) with bladder cancer risk among 2670 previously reported smoking-related cytosine-phosphate-guanines sites (CpGs). Similar patterns were observed across cohorts. Receiver operating characteristic (ROC) analyses indicated that cg05575921 (AHHR), the strongest smoking-related association we identified for bladder cancer risk, alone yielded similar predictive performance (AUC: 0.60) than classical smoking metrics (AUC: 0.59-0.62). Best prediction was achieved by including the first principal component (PC1) from the 200 smoking-related CpGs alongside smoking metrics (AUC: 0.63-0.65). Further, PC1 remained significantly associated with elevated bladder cancer risk after adjusting for smoking metrics. These findings suggest DNA methylation profiles reflect aspects of tobacco smoke exposure in addition to those captured by smoking duration, intensity and packyears, and/or individual susceptibility relevant to bladder cancer etiology, warranting further investigation.
Subject(s)
DNA Methylation , Smoking , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/etiology , Male , Prospective Studies , Female , Case-Control Studies , Middle Aged , Smoking/adverse effects , Aged , Leukocytes/metabolism , Risk Factors , Biomarkers, Tumor/geneticsABSTRACT
We investigated the metabolomic profile associated with exposure to trihalomethanes (THMs) and nitrate in drinking water and with colorectal cancer risk in 296 cases and 295 controls from the Multi Case-Control Spain project. Untargeted metabolomic analysis was conducted in blood samples using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. A variety of univariate and multivariate association analyses were conducted after data quality control, normalization, and imputation. Linear regression and partial least-squares analyses were conducted for chloroform, brominated THMs, total THMs, and nitrate among controls and for case-control status, together with a N-integration model discriminating colorectal cancer cases from controls through interrogation of correlations between the exposure variables and the metabolomic features. Results revealed a total of 568 metabolomic features associated with at least one water contaminant or colorectal cancer. Annotated metabolites and pathway analysis suggest a number of pathways as potentially involved in the link between exposure to these water contaminants and colorectal cancer, including nicotinamide, cytochrome P-450, and tyrosine metabolism. These findings provide insights into the underlying biological mechanisms and potential biomarkers associated with water contaminant exposure and colorectal cancer risk. Further research in this area is needed to better understand the causal relationship and the public health implications.
Subject(s)
Colorectal Neoplasms , Drinking Water , Water Pollutants, Chemical , Humans , Drinking Water/analysis , Drinking Water/chemistry , Trihalomethanes/analysis , Nitrates/analysis , Spain/epidemiology , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/epidemiology , Water Pollutants, Chemical/analysisABSTRACT
Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.
Subject(s)
Lung Neoplasms , Smoking , Carcinogenesis , CpG Islands/genetics , DNA Methylation , Epigenesis, Genetic , Humans , Lung , Lung Neoplasms/genetics , Smoking/adverse effectsABSTRACT
Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10-3 ) and of cysteinyl-glycine (p = 7.89 × 10-3 ). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.
Subject(s)
Acetylcysteine/metabolism , Carcinogenesis/genetics , DNA Adducts/blood , Lung Neoplasms/epidemiology , Smoking/adverse effects , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Case-Control Studies , CpG Islands/genetics , DNA Adducts/genetics , DNA Adducts/metabolism , DNA Methylation , Epigenomics/methods , Female , Follow-Up Studies , Humans , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Oxidation-Reduction , Prospective Studies , Risk Assessment/methods , Smoking/blood , Smoking/geneticsABSTRACT
Oxidative stress generates reactive species that modify proteins, deplete antioxidant defenses, and contribute to chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD). To determine whether protein modifications differ between COPD or IHD patients and healthy subjects, we performed untargeted analysis of adducts at the Cys34 locus of human serum albumin (HSA). Biospecimens were obtained from nonsmoking participants from London, U.K., including healthy subjects (n = 20) and patients with COPD (n = 20) or IHD (n = 10). Serum samples were digested with trypsin and analyzed by liquid chromatography-high resolution mass spectrometry. Effects of air pollution on adduct levels were also investigated based on estimated residential exposures to PM2.5, O3 and NO2. For the 39 adducts with sufficient data, levels were essentially identical in blood samples collected from the same subjects on two consecutive days, consistent with the 28 day residence time of HSA. Multivariate linear regression revealed 21 significant associations, mainly with the underlying diseases but also with air-pollution exposures (p-value < 0.05). Interestingly, most of the associations indicated that adduct levels decreased with the presence of disease or increased pollutant concentrations. Negative associations of COPD and IHD with the Cys34 disulfide of glutathione and two Cys34 sulfoxidations, were consistent with previous results from smoking and nonsmoking volunteers and nonsmoking women exposed to indoor combustion of coal and wood.
Subject(s)
Air Pollutants , Air Pollution , Heart Diseases , Lung Diseases , Chronic Disease , Coal , Female , Humans , London , Tandem Mass SpectrometryABSTRACT
Although historic perfluorinated compounds are currently under scrutiny and growing regulatory control in the world, little is known about human exposure to other polyfluorinated compounds presently in use. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphate esters (PAPs) are known to degrade to terminal perfluorinated acids and toxic reactive intermediates through metabolic pathways. Therefore, it is important to characterize their human exposure by the identification of unique biomarkers. With the use of liquid chromatography-mass spectrometry-time-of-flight analysis (LC-MS-TOF), we developed a workflow for the identification of metabolites for the 8:2 FTOH and 8:2 diPAP. Analysis of serum and urine of dosed rats indicated the 8:2 FTOH-sulfate and the 8:2 diPAP as potential biomarkers. These compounds, as well as 25 other fluorinated compounds and metabolites, were analyzed in human serum and urine samples from the general population (n = 100) and office workers (n = 30). The 8:2 FTOH-sulfate was measured for the first time in human samples in 5 to 10% of the serum samples, ranging from 50 to 80 pg/mL. The 8:2 diPAP was measured in 58% of the samples, ranging from 100 to 800 pg/mL. This study indicates the FTOH-sulfate conjugate as a biomarker of exposure to FTOHs and PAPs in humans.
Subject(s)
Alcohols , Biomarkers , Hydrocarbons, Fluorinated/toxicity , Organophosphates/toxicity , Acids , Animals , Chromatography, Liquid , Fluorocarbons , Humans , Mass Spectrometry , RatsABSTRACT
Recent scientific scrutiny and concerns over exposure, toxicity, and risk have led to international regulatory efforts resulting in the reduction or elimination of certain perfluorinated compounds from various products and waste streams. Some manufacturers have started producing shorter chain per- and polyfluorinated compounds to try to reduce the potential for bioaccumulation in humans and wildlife. Some of these new compounds contain central ether oxygens or other minor modifications of traditional perfluorinated structures. At present, there has been very limited information published on these "replacement chemistries" in the peer-reviewed literature. In this study we used a time-of-flight mass spectrometry detector (LC-ESI-TOFMS) to identify fluorinated compounds in natural waters collected from locations with historical perfluorinated compound contamination. Our workflow for discovery of chemicals included sequential sampling of surface water for identification of potential sources, nontargeted TOFMS analysis, molecular feature extraction (MFE) of samples, and evaluation of features unique to the sample with source inputs. Specifically, compounds were tentatively identified by (1) accurate mass determination of parent and/or related adducts and fragments from in-source collision-induced dissociation (CID), (2) in-depth evaluation of in-source adducts formed during analysis, and (3) confirmation with authentic standards when available. We observed groups of compounds in homologous series that differed by multiples of CF2 (m/z 49.9968) or CF2O (m/z 65.9917). Compounds in each series were chromatographically separated and had comparable fragments and adducts produced during analysis. We detected 12 novel perfluoroalkyl ether carboxylic and sulfonic acids in surface water in North Carolina, USA using this approach. A key piece of evidence was the discovery of accurate mass in-source n-mer formation (H(+) and Na(+)) differing by m/z 21.9819, corresponding to the mass difference between the protonated and sodiated dimers.
Subject(s)
Carboxylic Acids/analysis , Fluorocarbons/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Water Pollutants, Chemical/analysis , Carboxylic Acids/chemistry , Chemical Fractionation , Ethers/analysis , Ethers/chemistry , Fluorocarbons/chemistry , Humans , North Carolina , Sulfonic Acids/analysis , Sulfonic Acids/chemistry , Water/analysis , Water Pollutants, Chemical/chemistryABSTRACT
Many environmental endocrine disrupting compounds act as ligands for nuclear receptors. The human pregnane X receptor (hPXR), for instance, is activated by a variety of environmental ligands such as steroids, pharmaceutical drugs, pesticides, alkylphenols, polychlorinated biphenyls and polybromo diethylethers. Some of us have previously reported the occurrence of hPXR ligands in environmental samples but failed to identify them. The aim of this study was to test whether a PXR-affinity column, in which recombinant hPXR was immobilized on solid support, could help the purification of these chemicals. Using PXR ligands of different affinity (10 nM < EC50 < 10 µM), we demonstrated that the PXR-affinity preferentially column captured ligands with medium to high affinities (EC50 < 1 µM). Furthermore, by using the PXR-affinity column to analyze an environmental sample containing ERα, AhR, AR, and PXR activities, we show that (i) half of the PXR activity of the sample was due to compounds with medium to high affinity for PXR and (ii) PXR shared ligands with ERα, AR, and AhR. These findings demonstrate that the newly developed PXR-affinity column coupled to reporter cell lines represents a valuable tool for the characterization of the nature of PXR active compounds and should therefore guide and facilitate their further analysis.
Subject(s)
Receptors, Steroid/metabolism , Water Pollutants, Chemical/toxicity , Cell Line , Cell Line, Tumor , Estrogen Receptor alpha/metabolism , Geologic Sediments , Humans , Ligands , Pregnane X Receptor , Receptors, Androgen/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Recombinant Proteins/metabolismABSTRACT
This study investigated the influence of beverage packaging materials on the presence of endocrine disrupting chemicals (EDCs) in plastic, glass, carton, aluminium, and tin canned non-alcoholic beverages. Results showed that 63 EDCs including perfluoroalkyl and polyfluoroalkyl substances (PFAS), bisphenols, parabens, benzophenone-type UV-filters, biocides, nitrophenols, and alkylphenols, were detected in 144/162 screened products. Detected ∑63EDC concentrations ranged from 1.3 to 19,600 ng/L. EDC concentrations were higher in beverages packaged in metal cans while lower or no levels were detected in glass, plastic, and carton packaged drinks. Bisphenol levels were higher on average in canned beverages compared to glass (p < 0.01) and plastic products (p < 0.05) produced by the same brand and manufacturer. Two structural isomers of bisphenol A (BPA) were identified in 19 beverages, constituting the first detection in foodstuffs. The calculated daily intake of detected EDCs showed that exposure to BPA from per capita beverage consumption of 364 mL/day are up to 2000-fold higher than the newly revised safety guideline for BPA recommended by the EFSA (European Food Safety Authority). Overall, these findings suggest that BPA exposure poses a potential health hazard for individuals who regularly consume non-alcoholic beverages packaged in aluminium or tin cans, particularly young children.
Subject(s)
Endocrine Disruptors , Child , Humans , Child, Preschool , Aluminum , Tin , Beverages/analysis , Risk Assessment , Benzhydryl Compounds/analysisABSTRACT
INTRODUCTION: In this paper, an analytical pipeline designed for untargeted lipidomic profiling in human plasma is proposed. The analytical pipeline was developed for case-control studies nested in prospective cohorts. METHODS: The procedure consisted of isopropanol protein precipitation followed by reverse phase liquid chromatography coupled to high resolution mass spectrometry and software-assisted data processing. The compounds are putatively annotated by matching experimental mass spectrometry data with spectral library data using LipidSearch software. The lipid profile of a pool of plasma samples from 10 healthy volunteers was detected in both positive and negative polarity modes. The impact of the chosen polarity on the number and quality of the lipid identification has been evaluated. RESULTS: More than 1000 lipids from 12 different classes were detected, 1150 in positive mode and 273 in negative mode. Nearly half of them were unambiguously identified by the software in positive mode, and about one-third in negative mode. The method repeatability was assessed on the plasma pool samples by means of variance components analysis. The intra- and inter-assay precision was measured for 10 lipids chosen among the most abundant found within the different lipid classes. The intra-assay coefficients of variation ranged from 2.56% to 4.56% while intra- and inter-day coefficients of variance never exceeded the 15% benchmark adopted. The lipidomic profiles of the 10 healthy volunteers were also investigated. DISCUSSION: This method detects a wide range of lipids and reports their degree of identification. It is particularly fit and well-designed for large case-control epidemiologic studies.
Subject(s)
Lipidomics , Lipids , Humans , Prospective Studies , Lipids/analysis , Lipids/chemistry , Mass Spectrometry/methods , Chromatography, Liquid , SoftwareABSTRACT
The nuclear receptor retinoid X receptor-alpha (RXR-alpha)-peroxisome proliferator-activated receptor-gamma (PPAR-gamma) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-alpha and PPAR-gamma ligands, the mechanism by which these compounds bind to and activate the RXR-alpha-PPAR-gamma heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR-PPAR-alpha, -gamma, -delta heterodimers, primarily through its interaction with RXR. In addition, the 1.9 A resolution structure of the RXR-alpha ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-alpha ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways.
Subject(s)
Endocrine Disruptors/pharmacology , Peroxisome Proliferator-Activated Receptors/metabolism , Protein Multimerization/drug effects , Retinoid X Receptors/metabolism , Trialkyltin Compounds/pharmacology , Cell Line , Chromatography, Liquid , Crystallography, X-Ray , Endocrine Disruptors/chemistry , Fluorescence Polarization , Humans , Mass Spectrometry , Models, Biological , Molecular Structure , Peroxisome Proliferator-Activated Receptors/chemistry , Protein Structure, Secondary , Retinoid X Receptors/chemistry , Trialkyltin Compounds/chemistryABSTRACT
An industrial warehouse illegally storing a large quantity of unknown chemical and industrial waste ignited in an urban area in Melbourne, Australia. The multiday fire required firefighters to use large amounts of fluorine-free foam that carried contaminated firewater runoff into an adjacent freshwater creek. In this study, the occurrence and fate of 42 per- and polyfluoroalkyl substances (PFASs) was determined from triplicate surface water samples (n = 45) from five locations (upstream, point-source, downstream; 8 km) over three sampling campaigns from 2018 to 2020. Out of the 42 target PFASs, perfluorocarboxylates (PFCAs: C4-C14), perfluoroalkane sulfonates (PFSAs: C4-C10), and perfluoroalkyl acid precursors (e.g. 6:2 fluorotelomer sulfonate (6:2 FTSA)) were ubiquitously detected in surface waters (concentration ranges: <0.7-3000 ng/L). A significant difference in ΣPFAS concentration was observed at the point-source (mean 5500 ng/L; 95% CI: 4800, 6300) relative to upstream sites (mean 100 ng/L; 95% CI: 90, 110; p ≤ 0.001). The point-source ΣPFAS concentration decreased from 5500 ± 1200 ng/L to 960 ± 42 ng/L (-83%) after two months and to 430 ± 15 ng/L (-98%) two years later. 6:2 FTSA and perfluorooctanesulfonate (PFOS) dominated in surface water, representing on average 31% and 20% of the ΣPFAS, respectively. Emerging PFASs including a cyclic perfluoroalkanesulfonate (PFECHS) and a C4 perfluoroalkane sulfonamide (FBSA) were repeatedly present in surface water (concentration ranges <0.3-77 ng/L). According to the updated Australian PFAS guidelines for ecological conservation, the water samples collected at the time of monitoring may have posed a short-term risk to aquatic organisms in regard to PFOS levels. These results illustrate that acute high dose exposure to PFASs can result from industrial fires at sites storing or stockpiling PFAS-based waste products. Continued monitoring will be crucial to evaluate potential long-term risk to wildlife in the region.
Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Water Pollutants, Chemical , Alkanesulfonic Acids/analysis , Australia , Environmental Monitoring , Fluorocarbons/analysis , Fresh Water , Water Pollutants, Chemical/analysisABSTRACT
To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.
Subject(s)
Ceramides/metabolism , Lysosomes/enzymology , Prostatic Neoplasms/enzymology , Ubiquitins/metabolism , Acid Ceramidase/genetics , Acid Ceramidase/metabolism , Cell Line, Tumor , Cell Proliferation , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Kinetics , Lysosomes/genetics , Male , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Phosphorylation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Proteolysis , Sequestosome-1 Protein/genetics , Sequestosome-1 Protein/metabolism , Signal Transduction , Ubiquitination , Ubiquitins/geneticsABSTRACT
Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/ß-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms.See related commentary by Itzstein et al., p. 3441.
Subject(s)
Adenocarcinoma of Lung/pathology , Antigens, Neoplasm/blood , Biomarkers, Tumor/blood , Cell Adhesion Molecules/blood , Lung Neoplasms/pathology , Adenocarcinoma of Lung/blood , Case-Control Studies , Follow-Up Studies , Humans , Lung Neoplasms/blood , Prognosis , Prospective StudiesABSTRACT
Endocrin-disrupting compounds (EDCs) are frequently found in wastewater treatment plants (WWTPs). So far, research has been mainly focused on the detection of estrogenic compounds and very little work has been carried out on other receptors activators. In this study, we used reporter cell lines, which allow detecting the activity of estrogen (ERalpha), androgen (AR), pregnane X (PXR), glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR), and aryl hydrocarbon (AhR) receptors, to characterise the endocrine-disrupting profile of the aqueous, suspended particulate matter, and sludge fractions from three Tunisian WWTPs. The aqueous fraction exhibited estrogenic and androgenic activities. Suspended particulate matter and sludge extracts showed estrogenic, aryl hydrocarbon and pregnane X receptor activities. No GR, MR, or PR (ant) agonistic activity was detected in the samples, suggesting that environmental compounds present in sewage might have a limited spectrum of activity. By performing competition experiments with recombinant ERalpha, we demonstrated that the estrogenic activity detected in the aqueous fraction was due to EDCs with a strong affinity for ERalpha. Conversely, in the sludge fraction, it was linked to the presence of EDCs with weak affinity. Moreover, by using different incubation times, we determined that the EDCs present in suspended particulate matter and sludge, which can activate AhR, are metabolically labile compounds. Finally, we showed in this study that environmental compounds are mainly ER, AR, PXR, and AhR activators. Concerning AR and PXR ligands, we do not to know the nature of the molecules. Concerning ER and AhR compounds, competition experiments with recombinant receptor and analysis at different times of exposure of the AhR activation gave some indications of the compound's nature that need to be confirmed by chemical analysis.
Subject(s)
Endocrine Disruptors/toxicity , Environmental Monitoring , Sewage/chemistry , Waste Disposal, Fluid , Water Pollutants, Chemical/toxicity , Androgens/analysis , Androgens/toxicity , Endocrine Disruptors/analysis , Estrogens/analysis , Estrogens/toxicity , Glucocorticoids/analysis , Mineralocorticoids/analysis , Pregnane X Receptor , Progesterone/analysis , Receptors, Aryl Hydrocarbon/analysis , Receptors, Steroid/analysis , Tunisia , Water Pollutants, Chemical/analysisABSTRACT
The exposome concept refers to the totality of exposures from a variety of external and internal sources including chemical agents, biological agents, or radiation, from conception onward, over a complete lifetime. It encompasses also "psychosocial components" including the impact of social relations and socio-economic position on health. In this review we provide examples of recent contributions from exposome research, where we believe their application will be of the greatest value for moving forward. So far, environmental epidemiology has mainly focused on hard outcomes, such as mortality, disease exacerbation and hospitalizations. However, there are many subtle outcomes that can be related to environmental exposures, and investigations can be facilitated by an improved understanding of internal biomarkers of exposure and response, through the application of omic technologies. Second, though we have a wealth of studies on environmental pollutants, the assessment of causality is often difficult because of confounding, reverse causation and other uncertainties. Biomarkers and omic technologies may allow better causal attribution, for example using instrumental variables in triangulation, as we discuss here. Even more complex is the understanding of how social relationships (in particular socio-economic differences) influence health and imprint on the fundamental biology of the individual. The identification of molecular changes that are intermediate between social determinants and disease status is a way to fill the gap. Another field in which biomarkers and omics are relevant is the study of mixtures. Epidemiology often deals with complex mixtures (e.g. ambient air pollution, food, smoking) without fully disentangling the compositional complexity of the mixture, or with rudimentary approaches to reflect the overall effect of multiple exposures or components. From the point of view of disease mechanisms, most models hypothesize that several stages need to be transitioned through health to the induction of disease, but very little is known about the characteristics and temporal sequence of such stages. Exposome models reinforce the idea of a biography-to-biology transition, in that everyone's disease is the product of the individual history of exposures, superimposed on their underlying genetic susceptibilities. Finally, exposome research is facilitated by technological developments that complement traditional epidemiological study designs. We describe in depth one such new tools, adductomics. In general, the development of high-resolution and high-throughput technologies interrogating multiple -omics (such as epigenomics, transcriptomics, proteomics, adductomics and metabolomics) yields an unprecedented perspective into the impact of the environment in its widest sense on disease. The world of the exposome is rapidly evolving, though a huge gap still needs to be filled between the original expectations and the concrete achievements. Perhaps the most urgent need is for the establishment of a new generation of cohort studies with appropriately specified biosample collection, improved questionnaire data (including social variables), and the deployment of novel technologies that allow better characterization of individual environmental exposures, ranging from personal monitoring to satellite based observations.
Subject(s)
Environmental Pollutants , Exposome , Causality , Environmental Exposure/analysis , Environmental Health , Environmental Pollutants/toxicity , HumansABSTRACT
Exposure to air pollution can have both short-term and long-term effects on health. However, the relationships between specific pollutants and their effects can be obscured by characteristics of both the pollution and the exposed population. One way of elucidating the relationships is to link exposures and internal changes at the level of the individual. To this end, we combined personal exposure monitoring (59 individuals, Oxford Street II crossover study) with mass-spectrometry-based analyses of putative serum albumin adducts (fixed-step selected reaction monitoring). We attempted to infer adducts' identities using data from another, higher-resolution mass spectrometry method, and were able to detect a semi-synthetic standard with both methods. A generalised least squares regression method was used to test for associations between amounts of adducts and pollution measures (ambient concentrations of nitrogen dioxide and particulate matter), and between amounts of adducts and short-term health outcomes (measures of lung health and arterial stiffness). Amounts of some putative adducts (e.g., one with a positive mass shift of â¼143â¯Da) were associated with exposure to pollution (11 associations), and amounts of other adducts were associated with health outcomes (eight associations). Adducts did not appear to provide a link between exposures and short-term health outcomes.
Subject(s)
Air Pollutants/analysis , Air Pollution/analysis , Environmental Exposure/adverse effects , Environmental Monitoring/methods , Serum Albumin/chemistry , Cross-Over Studies , Female , Humans , Male , Nitrogen Dioxide/analysis , Particulate Matter/analysis , Regression AnalysisABSTRACT
Chronic inflammation is an established risk factor for colorectal cancer. To study reactive products of gut inflammation and redox signaling on colorectal cancer development, we used untargeted adductomics to detect adduct features in prediagnostic serum from the EPIC Italy cohort. We focused on modifications to Cys34 in human serum albumin, which is responsible for scavenging small reactive electrophiles that might initiate cancers. Employing a combination of statistical methods, we selected seven Cys34 adducts associated with colorectal cancer, as well as body mass index (BMI; a well-known risk factor). Five adducts were more abundant in colorectal cancer cases than controls and clustered with each other, suggesting a common pathway. Because two of these adducts were Cys34 modifications by methanethiol, a microbial-human cometabolite, and crotonaldehyde, a product of lipid peroxidation, these findings further implicate infiltration of gut microbes into the intestinal mucosa and the corresponding inflammatory response as causes of colorectal cancer. The other two associated adducts were Cys34 disulfides of homocysteine that were less abundant in colorectal cancer cases than controls and may implicate homocysteine metabolism as another causal pathway. The selected adducts and BMI ranked higher as potentially causal factors than variables previously associated with colorectal cancer (smoking, alcohol consumption, physical activity, and total meat consumption). Regressions of case-control differences in adduct levels on days to diagnosis showed no statistical evidence that disease progression, rather than causal factors at recruitment, contributed to the observed differences. These findings support the hypothesis that infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer. SIGNIFICANCE: Infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer.