| 1. |
- Ronkainen, Justiina, et al.
(författare)
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LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases
- 2022
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Ingår i: Environmental Epidemiology. - 2474-7882. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our "modern" postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.
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| 2. |
- Bodén, Stina, et al.
(författare)
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Dietary patterns, untargeted metabolite profiles and their association with colorectal cancer risk
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322 .- 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Nordin, Elise, 1985, et al.
(författare)
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IBS randomized study : FODMAPs alter bile acids, phenolic- and tryptophan metabolites, while gluten modifies lipids
- 2023
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 325:3, s. R248-R259
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Tidskriftsartikel (refereegranskat)abstract
- 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. NEW & NOTEWORTHY In irritable bowel syndrome (IBS), fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) affected microbial-derived metabolites relating to positive health outcomes such as reduced risk of colon cancer, inflammation, and type 2 diabetes, as shown in previous studies. The minor IBS symptom induction by FODMAP intake must be weighed against the positive health aspects of FODMAP consumption. Gluten affected lipids weakly with no association to IBS severity.
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| 4. |
- Ribbenstedt, Anton, 1986-, et al.
(författare)
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In Vivo Bioconcentration of 10 Anionic Surfactants in Rainbow Trout Explained by In Vitro Data on Partitioning and S9 Clearance
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:10, s. 6305-6314
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Tidskriftsartikel (refereegranskat)abstract
- Bioconcentration factors (BCFs) in rainbow trout were measured for 10 anionic surfactants with a range of alkyl chain lengths and different polar head groups. The BCFs ranged from 0.04 L kg–1 ww (for C10SO3) to 1370 L kg–1 ww (C16SO3). There was a strong correlation between the log BCF and log membrane lipid–water distribution ratio (DMLW, r2 = 0.96), and biotransformation was identified as the dominant elimination mechanism. The strong positive influence of DMLW on BCF was attributed to two phenomena: (i) increased partitioning from water into the epithelial membrane of the gill, leading to more rapid diffusion across this barrier and more rapid uptake, and (ii) increased sequestration of the surfactant body burden into membranes and other body tissues, resulting in lower freely dissolved concentrations available for biotransformation. Estimated whole-body in vivo biotransformation rate constants kB-BCF are within a factor three of rate constants estimated from S9 in vitro assays for six of the eight test chemicals for which kB-BCF could be determined. A model-based assessment indicated that the hepatic clearance rate of freely dissolved chemicals was similar for the studied surfactants. The dataset will be useful for evaluation of in silico and in vitro methods to assess bioaccumulation.
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| 5. |
- Ribbenstedt, Anton, 1986-, et al.
(författare)
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Rapid in-plate screening of biotransformation products in single zebrafish embryos
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A procedure was developed for rapid screening of xenobiotic biotransformationproducts (bioTPs) in single zebrafish (ZF; Danio rerio) embryos. Exposure was carried out from 0-120 hours post fertilization (hpf) to 6 different concentrations of the model compound propranolol (PPL). Following in-plate extraction and non-target instrumental analysis by high resolution mass spectrometry, suspected bioTPs were identified using custom data filtration scripts and matching to in silico structural predictions. A total of eight PPL bioTPs were identified (two at a level 1 confidence and six at a level 2-3 confidence). These findings supplement previously generated toxicometabolomic models derived from the same dataset, and were obtained without conducting additional exposure experiments. In addition to facilitating assessments of inter-individual variability in bioTP production in ZF embryos, we demonstrate that bioTPs can be elucidated using extremely small quantities of biomass. To the best of our knowledge, this is the first time bioTP elucidation has been carried out in single ZFembryos.
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| 6. |
- Ribbenstedt, Anton, 1986, et al.
(författare)
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Rapid in-plate screening of biotransformation products in single zebrafish embryos
- 2021
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Ingår i: RSC Advances. - 2046-2069. ; 11:45, s. 27812-27819
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Tidskriftsartikel (refereegranskat)abstract
- A procedure was developed for rapid screening of xenobiotic biotransformation products (bioTPs) in single zebrafish (ZF; Danio rerio) embryos. Exposure was carried out from 0–120 hours post fertilization (hpf) to 6 different concentrations of the model compound propranolol (PPL). Following in-plate extraction and non-target instrumental analysis by high resolution mass spectrometry, suspected bioTPs were identified using custom data filtration scripts and matching to in silico structural predictions. A total of eight PPL bioTPs were identified (five at a level 1 confidence and one at a level 2–3 confidence). These findings supplement previously generated toxicometabolomic models derived from the same dataset, and were obtained without conducting additional exposure experiments. In addition to facilitating assessments of inter-individual variability in bioTP production in ZF embryos, we demonstrate that bioTPs can be elucidated using extremely small quantities of biomass (i.e. ∼200 μg). To the best of our knowledge, this is the first time bioTP elucidation has been carried out in single ZF embryos.
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| 7. |
- Ribbenstedt, Anton, 1986-, et al.
(författare)
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Toxicometabolomics and biotransformation in single zebrafish embryos exposed to carbamazepine
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We report here on the high throughput determination of biotransformation products(bioTPs) and toxicometabolomics in single zebrafish (ZF) embryos exposed to carbamazepine(CBZ). Exposures were carried out in 96-well plates with six CBZ concentrations ranging from 0.5 μg/L to 50 mg/L (n=12 embryos/dose). In the 50 mg/L dose group 33% of the embryos developed edema during the exposure (120hpf) while hatching was significantly delayed in three of the lower dose groups (0.46, 3.85 and the 445 μg/L) compared to the control at 48 hpf. Toxicometabolomic analysis together with random forest modelling revealed a total of 80 significantly affected metabolites (22 identified via targeted lipidomics and 58 via non-target analysis). The wide range of doses tested enabled observation of both monotonic and nonmonotonic dose-responses which fit the known mode of action of CBZ. A novel pathway was also proposed based on changes in PE-Cer (d16:2/24:1; CL 2-3) which could be the result of CBZ induced apoptosis via induction of the enzyme SAMD8. In addition, 2 CBZ bioTPs were identified without additional exposure experiments. Overall this work showcases the potential of toxicometabolomics and bioTP determination in single ZF embryos for improved and comprehensive chemical hazard assessment.
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| 8. |
- Ribbenstedt, Anton, 1986-, et al.
(författare)
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Toxicometabolomics and Biotransformation Product Elucidation in Single Zebrafish Embryos Exposed to Carbamazepine from Environmentally-Relevant to Morphologically Altering Doses
- 2022
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 35:3, s. 431-439
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Tidskriftsartikel (refereegranskat)abstract
- Toxicometabolomics and biotransformation product (bioTP) elucidation were carried out in single zebrafish (ZF) embryos exposed to carbamazepine (CBZ). Exposures were conducted in 96-well plates containing six CBZ concentrations ranging from 0.5 μg/L to 50 mg/L (n = 12 embryos per dose). In the 50 mg/L dose group, 33% of embryos developed edema during the exposure (120 hpf), while hatching was significantly delayed in three of the lower-dose groups (0.46, 3.85, and 445 μg/L) compared to the control at 48 hpf. Toxicometabolomic analysis together with random forest modeling revealed a total of 80 significantly affected metabolites (22 identified via targeted lipidomics and 58 via nontarget analysis). The wide range of doses enabled the observation of both monotonic and nonmonotonic dose responses in the metabolome, which ultimately produced a unique and comprehensive biochemical picture that aligns with existing knowledge on the mode of action of CBZ. The combination of high dose exposures and apical endpoint assessment in single embryos also enabled hypothesis generation regarding the target organ for the morphologically altering insult. In addition, two CBZ bioTPs were identified without additional exposure experiments. Overall, this work showcases the potential of toxicometabolomics and bioTP determination in single ZF embryos for rapid and comprehensive chemical hazard assessment.
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| 9. |
- Ribbenstedt, Anton, 1986-
(författare)
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Toxicometabolomics and biotransformation product screening in single zebrafish embryos
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the last decade environmental agencies worldwide have escalated their work to phase out animal testing for the purposes of chemical regulation. Meanwhile the number of commercially available chemicals and the requirements for hazard assessments have both increased, creating a large need for substitution of traditional in vivo assays with in vitro tests. One example of this is the replacement of the OECD acute toxicity test of adult fish (test guideline [TG] 203) with zebrafish embryos (TG 236). With new insights into the toxicological properties of chemicals, the demand on these replacement tests is also changing character with a shifted focus towards mechanistic understanding of toxicity. The omics sciences encompass a group of analytical methods which have proven to be very powerful for unveiling of mechanistic information of biochemical processes. Metabolomics is one of the younger members of this family and entails the large-scale analysis of endogenous metabolites and their perturbation in living organisms. The overall objective of this thesis was to develop modifications to the TG236 OECD assay to obtain omic data suitable for use in chemical hazard assessment. To achieve this goal, we started by developing a targeted and non-targeted metabolomics workflow and evaluated the performance of the two types of analysis (Paper I). We also evaluated the efficiency of three signal drift correction approaches, which is an important step in data quality improvement for non-targeted analysis, and reported previously unlisted biochemicals present in NIST reference material. In Paper II we applied the workflow in Paper I to a newly developed, in-plate extraction method for single zebrafish embryos which were exposed to the pharmaceutical and environmental pollutant propranolol. Data processing workflows were developed to overcome challenges arising from the occurrence of the exposure compound and its biotransformation products (or in-source fragments of these) in the final multivariate statistical models, obscuring their outputs and prediction capabilities. Once developed, the workflow allowed us to detect several probable modes-of-action of propranolol in zebrafish, and link them to apical endpoints in the embryos, which were then confirmed through thorough literature searches. The final output from the models was ultimately used to determine a benchmarking dose based on metabolomics endpoints for the first time. In Paper III, the data processing workflow from Paper II was modified to capture propranolol biotransformation products. A total of 7 structures were identified, of which 4 were confirmed with authentic standards, all from the datasets generated in Paper II. In Paper IV we combined the workflows from Papers I, II and III and applied them to the pharmaceutical carbamazepine, which occurs at high concentrations in wastewater treatment plant effluents. Through this approach we determined several modes-of-action for carbamazepine in zebrafish embryos and measured biotransformation products in both embryos and exposure water. Overall, this thesis demonstrated the possibilities of high-throughput chemical mode-of-action determination in single zebrafish embryos using targeted and non-targeted liquid chromatography mass spectrometry, data filtering scripts and multivariate statistics while simultaneously screening for biotransformation products.
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| 10. |
- Schillemans, Tessa, et al.
(författare)
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Omics signatures linking persistent organic pollutants to cardiovascular disease in the Swedish mammography cohort
- 2024
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 58:2, s. 1036-1047
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular disease (CVD) development may be linked to persistent organic pollutants (POPs), including organochlorine compounds (OCs) and perfluoroalkyl and polyfluoroalkyl substances (PFAS). To explore underlying mechanisms, we investigated metabolites, proteins, and genes linking POPs with CVD risk. We used data from a nested case-control study on myocardial infarction (MI) and stroke from the Swedish Mammography Cohort - Clinical (n = 657 subjects). OCs, PFAS, and multiomics (9511 liquid chromatography-mass spectrometry (LC-MS) metabolite features; 248 proteins; 8110 gene variants) were measured in baseline plasma. POP-related omics features were selected using random forest followed by Spearman correlation adjusted for confounders. From these, CVD-related omics features were selected using conditional logistic regression. Finally, 29 (for OCs) and 12 (for PFAS) unique features associated with POPs and CVD. One omics subpattern, driven by lipids and inflammatory proteins, associated with MI (OR = 2.03; 95% CI = 1.47; 2.79), OCs, age, and BMI, and correlated negatively with PFAS. Another subpattern, driven by carnitines, associated with stroke (OR = 1.55; 95% CI = 1.16; 2.09), OCs, and age, but not with PFAS. This may imply that OCs and PFAS associate with different omics patterns with opposite effects on CVD risk, but more research is needed to disentangle potential modifications by other factors.
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