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  • 1.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions2016In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 805, p. 38-45Article in journal (Refereed)
    Abstract [en]

    Glycidol (Gly) is an electrophilic low-molecular weight epoxide that is classified by IARC as probably carcinogenic to humans. Humans might be exposed to Gly from food, e.g. refined vegetable oils, where Gly has been found as a food process contaminant. It is therefore important to investigate and quantify the genotoxicity of Gly as a primary step towards cancer risk assessment of the human exposure. Here, quantification of the mutagenic potency expressed per dose (AUC: area under the concentration time curve) of Gly has been performed in Chinese hamster ovary (CHO) cells, using the HPRT assay. The dose of Gly was estimated in the cell exposure medium by trapping Gly with a strong nucleophile, cob(I)alamin, to form stable cobalamin adducts for analysis by LC-MS/MS. Gly was stable in the exposure medium during the time for cell treatment, and thus the dose in vitro is the initial concentration x cell treatment time. Gly induced mutations in the hprt-gene at ante of 0.08 +/- 0:01 mutations/10(5) cells/mMh. Through comparison with the effect of ionizing radiation in the same system a relative mutagenic potency of 9.5 rad-eq./mMh was obtained, which could be used for comparison of genotoxicity of chemicals and between test systems and also in procedures for quantitative cancer risk assessment. Gly was shown to induce strand breaks, that were repaired by base excision repair. Furthermore, Gly-induced lesions, present during replication, were found to delay the replication fork elongation. From experiments with repair deficient cells, homologous recombination repair and the ERCC1-XPF complex were indicated to be recruited to support in the repair of the damage related to the stalled replication elongation. The type of DNA damage responsible for the mutagenic effect of Gly could not be concluded from the present study.

  • 2.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Osterman Golkar, Siv
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Characterization of a Hemoglobin Adduct from Ethyl Vinyl Ketone Detected in Human Blood Samples2015In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 11, p. 2120-2129Article in journal (Refereed)
    Abstract [en]

    Electrophiles have the ability to form adducts to nudeophilic sites in proteins and DNA. Internal exposure to such compounds thus constitutes a risk for toxic effects. Screening of adducts using mass spectrometric methods by adductomic approaches offers possibilities to detect unknown electrophiles present in tissues. Previously, we employed untargeted adductomics to detect 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. This article describes the characterization of one of these adducts, which was identified as the adduct from ethyl vinyl ketone (EVK). The mean adduct level was 40 +/- 12 pmol/g Hb in 12 human blood samples; adduct levels from acrylamide (AA) and methyl vinyl ketone (MVK) were quantified for comparison. Using L-valine p-nitroanilide (Val-pNA), introduced as a model of the N-terminal valine, the rate of formation of the EVK adduct was studied, and the rate constant determined to 200 M(-1)h(-1) at 37 degrees C. In blood, the reaction rate was too fast to be feasibly measured, EVK showing a half-life <1 min. Parallel experiments with AA and MVK showed that the two vinyl ketones react approximately 2 x 10(3) times faster than AA. The EVK-Hb adduct was found to be unstable, with a half-life of 7.6 h. From the mean adduct level measured in human blood, a daily dose (area under the concentration-time-curve, AUC) of 7 nMh EVK was estimated. The AUC of AA from intake via food is about 20 times higher. EVK is naturally present in a wide range of foods and is also used as a food additive. Most probably, naturally formed EVK is a major source to observed adducts. Evaluation of available toxicological data and information on occurrence of EVK indicate that further studies of EVK are motivated. This study illustrates a quantitative strategy in the initial evaluation of the significance of an adduct detected through adduct screening.

  • 3.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Göpfert, Lisa
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Larsen, Kristian
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Reaction kinetic studies for comparison of mutagenic potency between butadiene monoxide and glycidamide2018In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 288, p. 57-64Article in journal (Refereed)
    Abstract [en]

    DNA adducts can be formed from covalent binding of electrophilic reactive compounds to the nucleophilic Nand O-atoms of the biomolecule. The O-sites on DNA, with nucleophilic strength (n) of ca. 2, is recognized as a critical site for mutagenicity. Characterization of the reactivity of electrophilic compounds at the O-sites can be used to predict their mutagenic potency in relative terms. In the present study, reaction kinetic experiments were performed for butadiene monoxide (BM) in accordance with the Swain-Scott relation using model nucleophiles representing N- and O-sites on DNA, and earlier for glycidamide (GA) using a similar approach. The epoxide from the kinetic experiments was trapped by cob(I)alamin, resulting in formation of an alkylcobalamin which was analyzed by liquid chromatography tandem mass spectrometry. The Swain-Scott relationship was used to determine selectivity constant (s) of BM and GA as 0.86 and 1.0, respectively. The rate constant for the reaction at n of 2 was extrapolated to 0.023 and 0.038M(-1) h(-1) for BM and GA, respectively, implying a higher mutagenic potency per dose unit of GA compared to BM. The reaction kinetic parameters associated with mutagenic potency were also estimated by a density functional theory approach, which were in accordance to the experimental determined values. These types of reaction kinetic measures could be useful in development of a chemical reactivity based prediction tool that could aid in reduction of animal experiments in cancer risk assessment procedures for relative mutagenicity.

  • 4.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach2014In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 281, no 3, p. 276-284Article in journal (Refereed)
    Abstract [en]

    1,3-Butadiene (BD) is a rodent and human carcinogen. In the cancer tests, mice have been much more susceptible than rats with regard to BD-induced carcinogenicity. The species-differences are dependent on metabolic formation/disappearance of the genotoxic BD epoxy-metabolites that lead to variations in the respective in vivo doses, i.e. "area under the concentration-time curve" (AUC). Differences in AUC of the most gentoxic BD epoxy-metabolite, diepoxybutane (DEB), are considered important with regard to cancer susceptibility. The present work describes: the application of cob(I)alamin for accurate measurements of in vitro enzyme kinetic parameters associated with BD epoxy-metabolites in human, mouse and rat; the use of published data on hemoglobin (Hb) adduct levels of BD epoxides from BD exposure studies on the three species to calculate the corresponding AUCs in blood; and a parallelogram approach for extrapolation of AUC of DEB based on the in vitro metabolism studies and adduct data from in vivo measurements. The predicted value of AUC of DEB for humans from the parallelogram approach was 0.078 nM . h for 1 ppm . h of BD exposure compared to 0.023 nM . h/ppm . h as calculated from Hb adduct levels observed in occupational exposure. The corresponding values in nM . h/ppm . h were for mice 41 vs. 38 and for rats 126 vs. 137 from the parallelogram approach vs. experimental exposures, respectively, showing a good agreement This quantitative inter-species extrapolation approach will be further explored for the clarification of metabolic rates/pharmacokinetics and the AUC of other genotoxic electrophilic compounds/metabolites, and has a potential to reduce and refine animal experiments.

  • 5.
    Motwani, Hitesh V.
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Frostne, Cecilia
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Parallelogram based approach for in vivo dose estimation of genotoxic metabolites in humans with relevance to reduction of animal experiments2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17560Article in journal (Refereed)
    Abstract [en]

    When employing metabolism studies of genotoxic compounds/metabolites and cancer tests for risk estimation, low exposure doses in humans are roughly extrapolated from high exposure doses in animals. An improvement is to measure the in vivo dose, i.e. area under concentration-time curve (AUC), of the causative genotoxic agent. In the present work, we propose and evaluate a parallelogram based approach for estimation of the AUC of genotoxic metabolites that incorporates in vitro metabolic data and existing knowledge from published in vivo data on hemoglobin (Hb) adduct levels, using glycidamide (GA) as a case study compound that is the genotoxic metabolite of acrylamide (AA). The estimated value of AUC of GA per AUC of AA from the parallelogram approach vs. that from Hb adduct levels measured in vivo were in good agreement; 0.087 vs. 0.23 in human and 1.4 vs. 0.53 in rat, respectively. The described parallelogram approach is simple, and can be useful to provide an approximate estimation of the AUC of metabolites in humans at low exposure levels for which sensitive methods for analyzing the metabolites are not available, as well as aid in reduction of animal experiments for metabolism studies that are to be used for cancer risk assessment.

  • 6.
    Motwani, Hitesh V.
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Kyushu University, Japan.
    Shimakoshi, Hisashi
    Golding, Bernard T.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Hisaeda, Yoshio
    Alkylcobyrinate from sucralose and mechanistic aspects of its Co-C bond cleavage2014In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, no 16, p. 2667-2670Article in journal (Refereed)
    Abstract [en]

    Reaction of heptamethyl cob(I)yrinate with 1',6'-dichloro-1',6'-dideoxy-beta-D-fructofuranosyl-4-chloro-4-deoxy-alpha-D-galactopyranoside (sucralose) gave an alkylcobyrinate, heptamethyl-6'-[alpha-D-galactopyranoside- 1'-chloro-1',6'-dideoxy-beta-D-fructofuranosyl-4-chloro-4-deoxy]cobyrinate perchlorate, [(Suc)Cob(III) 7C(1)ester]ClO4. Cleavage behavior of Co-C bond of the alkylcobyrinate was investigated under various conditions (hv, H+ and reduction) using UV-vis spectroscopy combined with the EPR spin-trapping technique, and by cyclic voltammetry.

  • 7.
    Motwani, Hitesh V.
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Westberg, Emelie
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Interaction of benzo[a] pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36243Article in journal (Refereed)
    Abstract [en]

    Carcinogenicity of benzo[a] pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a] P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti-and syn-BPDE and between (+)- and (-)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a] P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.

  • 8.
    Riboni, Nicolò
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Parma, Italy.
    Quaranta, Alessandro
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Motwani, Hitesh
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Österlund, Nicklas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bianchi, Federica
    Ilag, Leopold
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Solvent-Assisted Paper Spray Ionization (SAPSI) for the Analysis of Biomolecules and BiofluidsManuscript (preprint) (Other academic)
  • 9.
    Riboni, Nicoló
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Parma, Italy.
    Quaranta, Alessandro
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Motwani, Hitesh
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Österlund, Nickles
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bianchi, Federica
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Solvent-Assisted Paper Spray Ionization Mass Spectrometry (SAPSI-MS) for the Analysis of Biomolecules and Biofluids2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10296Article in journal (Refereed)
    Abstract [en]

    Paper Spray Ionization (PSI) is commonly applied for the analysis of small molecules, including drugs, metabolites, and pesticides in biological fluids, due to its high versatility, simplicity, and low costs. In this study, a new setup called Solvent Assisted Paper Spray Ionization (SAPSI), able to increase data acquisition time, signal stability, and repeatability, is proposed to overcome common PSI drawbacks. The setup relies on an integrated solution to provide ionization potential and constant solvent flow to the paper tip. Specifically, the ion source was connected to the instrument fluidics along with the voltage supply systems, ensuring a close control over the ionization conditions. SAPSI was successfully applied for the analysis of different classes of biomolecules: amyloidogenic peptides, proteins, and N-glycans. The prolonged analysis time allowed real-time monitoring of processes taking places on the paper tip, such as amyloid peptides aggregation and disaggregation phenomena. The enhanced signal stability allowed to discriminate protein species characterized by different post translational modifications and adducts with electrophilic compounds, both in aqueous solutions and in biofluids, such as serum and cerebrospinal fluid, without any sample pretreatment. In the next future, application to clinical relevant modifications, could lead to the development of quick and cost-effective diagnostic tools.

  • 10.
    Westberg, Emelie
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Motwani, Hitesh
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Lindh, Christian
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Comparison of specific biomarkers of internal dose and genotoxic effect after exposure to BP with the aim to use in risk assessmentManuscript (preprint) (Other academic)
  • 11.
    Zurita, Javier
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Souliotos, Vassilis L
    Kyrtopoulos, Soterios A
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Detection of benzo[a]pyrene diol epoxide adducts to histidine and lysine in serum albumin in vivo by high-resolution-tandem mass spectrometryManuscript (preprint) (Other academic)
1 - 11 of 11
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