Search

We investigated data-driven and hypothesis-driven dietary patterns and their association to plasma metabolite profiles and subsequent colorectal cancer (CRC) risk in 680 CRC cases and individually matched controls. Dietary patterns were identified from combined exploratory/confirmatory factor analysis. We assessed association to LC–MS metabolic profiles by random forest regression and to CRC risk by multivariable conditional logistic regression. Principal component analysis was used on metabolite features selected to reflect dietary exposures. Component scores were associated to CRC risk and dietary exposures using partial Spearman correlation. We identified 12 data-driven dietary patterns, of which a breakfast food pattern showed an inverse association with CRC risk (OR per standard deviation increase 0.89, 95% CI 0.80–1.00, p = 0.04). This pattern was also inversely associated with risk of distal colon cancer (0.75, 0.61–0.96, p = 0.01) and was more pronounced in women (0.69, 0.49–0.96, p = 0.03). Associations between meat, fast-food, fruit soup/rice patterns and CRC risk were modified by tumor location in women. Alcohol as well as fruit and vegetables associated with metabolite profiles (Q2 0.22 and 0.26, respectively). One metabolite reflecting alcohol intake associated with increased CRC risk, whereas three metabolites reflecting fiber, wholegrain, and fruit and vegetables associated with decreased CRC risk. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, but if discovered at an early stage, the survival rate is high. The aim of this study was to identify novel markers predictive of future CRC risk using untargeted metabolomics. Methods: This study included prospectively collected plasma samples from 902 CRC cases and 902 matched cancer-free control participants from the population-based Northern Sweden Health and Disease Study (NSHDS), which were obtained up to 26 years prior to CRC diagnosis. Using reverse-phase liquid chromatography–mass spectrometry (LC–MS), data comprising 5015 metabolic features were obtained. Conditional logistic regression was applied to identify potentially important metabolic features associated with CRC risk. In addition, we investigated if previously reported metabolite biomarkers of CRC risk could be validated in this study population. Results: In the univariable analysis, seven metabolic features were associated with CRC risk (using a false discovery rate cutoff of 0.25). Two of these could be annotated, one as pyroglutamic acid (odds ratio per one standard deviation increase = 0.79, 95% confidence interval, 0.70–0.89) and another as hydroxytigecycline (odds ratio per one standard deviation increase = 0.77, 95% confidence interval, 0.67–0.89). Associations with CRC risk were also found for six previously reported metabolic biomarkers of prevalent and/or incident CRC: sebacic acid (inverse association) and L-tryptophan, 3-hydroxybutyric acid, 9,12,13-TriHOME, valine, and 13-OxoODE (positive associations). Conclusions: These findings suggest that although the circulating metabolome may provide new etiological insights into the underlying causes of CRC development, its potential application for the identification of individuals at higher risk of developing CRC is limited. [ABSTRACT FROM AUTHOR]

Diet is considered a culprit for symptoms in irritable bowel syndrome (IBS), although the mechanistic understanding of underlying causes is lacking. Metabolomics, i.e., the analysis of metabolites in biological samples may offer a diet-responsive fingerprint for IBS. Our aim was to explore alterations in the plasma metabolome after interventions with fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) or gluten versus control in IBS, and to relate such alterations to symptoms. People with IBS (n = 110) were included in a double-blind, randomized, crossover study with 1-wk provocations of FODMAPs, gluten, or placebo. Symptoms were evaluated with the IBS severity scoring system (IBS-SSS). Untargeted metabolomics was performed on plasma samples using LC-qTOF-MS. Discovery of metabolite alterations by treatment was performed using random forest followed by linear mixed modeling. Associations were studied using Spearman correlation. The metabolome was affected by FODMAP [classification rate (CR) 0.88, P < 0.0001], but less by gluten intake CR 0.72, P = 0.01). FODMAP lowered bile acids, whereas phenolic-derived metabolites and 3-indolepropionic acid (IPA) were higher compared with placebo. IPA and some unidentified metabolites correlated weakly to abdominal pain and quality of life. Gluten affected lipid metabolism weakly, but with no interpretable relationship to IBS. FODMAP affected gut microbial-derived metabolites relating to positive health outcomes. IPA and unknown metabolites correlated weakly to IBS severity. Minor symptom worsening by FODMAP intake must be weighed against general positive health aspects of FODMAP. The gluten intervention affected lipid metabolism weakly with no interpretable association to IBS severity. Registration: www.clinicaltrials.gov as NCT03653689. [ABSTRACT FROM AUTHOR]

Adults are mainly exposed to per- and polyfluoroalkyl substances (PFASs) via ingestion of food, inhalation of air and ingestion of dust, whereas for children the exposure to PFASs is largely unknown. This study aimed to reconstruct the serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) in children after infancy up to 10.5 years of age and to test if dietary intake is the major exposure pathway for children to PFOA, PFOS and PFHxS after infancy. For this work, a dataset from a Finnish child cohort study was available, which comprised serum concentrations of the studied perfluoroalkyl acids (PFAAs) and PFAS concentration measurements in dust and air samples from the children's bedrooms. The calculated PFAA intakes were used in a pharmacokinetic model to reconstruct the PFAA serum concentrations from 1 to 10.5 years of age. The calculated PFOA and PFOS intakes were close to current regulatory intake thresholds and diet was the major exposure medium for the 10.5 year-olds. The one-compartment PK model reconstructed median PFOA and PFOS serum concentrations well compared to corresponding measured median serum concentrations, while the modelled PFHxS serum concentrations showed a constant underestimation. The results imply that children's exposure to PFOA and PFOS after breastfeeding and with increasing age resembles the exposure of adults. Further, the children in the Finnish cohort experienced a rather constant exposure to PFOA and PFOS between 1 and 10.5 years of age. The PFHxS exposure sources and respective pharmacokinetic parameter estimations need further investigation. [ABSTRACT FROM AUTHOR]

The antidepressant amitriptyline is a widely used selective serotonin reuptake inhibitor that is found in the aquatic environment. The present study investigates alterations in the brain and the liver metabolome of gilt‐head bream (Sparus aurata) after exposure at an environmentally relevant concentration (0.2 µg/L) of amitriptyline for 7 d. Analysis of variance–simultaneous component analysis is used to identify metabolites that distinguish exposed from control animals. Overall, alterations in lipid metabolism suggest the occurrence of oxidative stress in both the brain and the liver—a common adverse effect of xenobiotics. However, alterations in the amino acid arginine are also observed. These are likely related to the nitric oxide system that is known to be associated with the mechanism of action of antidepressants. In addition, changes in asparagine and methionine levels in the brain and pantothenate, uric acid, and formylisoglutamine/N‐formimino‐L‐glutamate levels in the liver could indicate variation of amino acid metabolism in both tissues; and the perturbation of glutamate in the liver implies that the energy metabolism is also affected. These results reveal that environmentally relevant concentrations of amitriptyline perturb a fraction of the metabolome that is not typically associated with antidepressant exposure in fish. Environ Toxicol Chem 2019;00:1–13. © 2019 SETAC [ABSTRACT FROM AUTHOR]

The potential of a metabolomics method to detect statistically significant perturbations in the metabolome of an organism is enhanced by excellent analytical precision, unequivocal identification, and broad metabolomic coverage. While the former two metrics are usually associated with targeted metabolomics and the latter with non-targeted metabolomics, a systematic comparison of the performance of both approaches has not yet been carried out. The present work reports on the development and performance evaluation of separate targeted and non-targeted metabolomics methods. The targeted approach facilitated determination of 181 metabolites (quantitative analysis of 18 amino acids, 11 biogenic amines, 5 neurotransmitters, 5 nucleobases and semi-quantitative analysis of 50 carnitines, 83 phosphatidylcholines, and 9 sphingomyelins) using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and flow injection-tandem mass spectrometry (FI-MS/MS). Method accuracy and/or precision were assessed using replicate samples of NIST SRM1950 as well as fish liver and brain tissue from Gilthead Bream (Sparus aurata). The non-target approach involved UPLC-high resolution (Orbitrap) mass spectrometry (UPLC-HRMS). Testing of ionization mode and stationary phase revealed that a combination of positive electrospray ionization and HILIC chromatography produced the largest number of chromatographic features during non-target analysis. Furthermore, an evaluation of 4 different sequence drift correction algorithms, and combinations thereof, revealed that batchCorr produced the best precision in almost every test. However, even following correction of non-target data for signal drift, the precision of targeted data was better, confirming our existing assumptions about the strengths of targeted metabolomics. Finally, the accuracy of the online MS2-library mzCloud was evaluated using reference standards for 38 different metabolites. This is among the few studies that have systematically evaluated the performance of targeted and non-targeted metabolomics and provides new insight into the advantages and disadvantages of each approach. [ABSTRACT FROM AUTHOR]

Ecotoxicity testing is a crucial component of chemical risk assessment. Still, due to methodological difficulties related to controlling exposure concentrations over time, data on long-term effects of organic chemicals at low concentrations are limited. The aim of the present study was, therefore, to test the applicability of passive dosing to maintain stable concentrations of the organochlorine bacteriocide triclosan in the water phase during a 6-wk multigeneration population development test with the harpacticoid copepod Nitocra spinipes. Triclosan was loaded into silicone (1000 mg), which was used as passive dosing phase in the exposure vials. The distribution ratio for triclosan between silicone and water (Dsilicone-water) was 10466 ± 1927. A population development test was conducted at 3 concentration levels of triclosan that were measured to be 3 μg/L to 5 μg/L, 7 μg/L to 11 μg/L and 16 μg/L to 26 μg/L. The results demonstrate that passive dosing is applicable for long-term ecotoxicity testing of organic chemicals, including during significant growth of the test organism population. Shifts in the demographic structure of the population during exposure suggest the most severe effects were exerted on juvenile development. Progressively lower development index values in the populations exposed to increasing triclosan concentrations suggest developmental retardation. The results further stress the need for chronic exposure during ecotoxicity testing in chemical risk assessment because even the most sensitive endpoint was not significant until after 7 d of exposure. Environ Toxicol Chem 2017;36:1254-1260. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Most amphibians breed in water, including the terrestrial species, and may therefore be exposed to water-borne pharmaceuticals during critical phases of the reproductive cycle, i.e. sex differentiation and gamete maturation. The objectives of this paper were to (i) review available literature regarding adverse effects of hormonally active pharmaceuticals on amphibians, with special reference to environmentally relevant exposure levels and (ii) expand the knowledge on toxicity of progestagens in amphibians by determining effects of norethindrone (NET) and progesterone (P) exposure to 0, 1, 10 or 100 ng l-1 (nominal) on oogenesis in the test species Xenopus tropicalis. Very little information was found on toxicity of environmentally relevant concentrations of pharmaceuticals on amphibians. Research has shown that environmental concentrations (1.8 ng l-1) of the pharmaceutical oestrogen ethinylestradiol (EE2) cause developmental reproductive toxicity involving impaired spermatogenesis in frogs. Recently, it was found that the progestagen levonorgestrel (LNG) inhibited oogenesis in frogs by interrupting the formation of vitellogenic oocytes at an environmentally relevant concentration (1.3 ng l-1). Results from the present study revealed that 1 ng NET l-1 and 10 ng P l-1 caused reduced proportions of vitellogenic oocytes and increased proportions of previtellogenic oocytes compared with the controls, thereby indicating inhibited vitellogenesis. Hence, the available literature shows that the oestrogen EE2 and the progestagens LNG, NET and P impair reproductive functions in amphibians at environmentally relevant exposure concentrations. The progestagens are of particular concern given their prevalence, the range of compounds and that several of them (LNG, NET and P) share the same target (oogenesis) at environmental exposure concentrations, indicating a risk for adverse effects on fertility in exposed wild amphibians. [ABSTRACT FROM AUTHOR]