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  • 1.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Carlsson, Henrik
    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.
    The genotoxic potency of glycidol established from micronucleus frequency and hemoglobin adduct levels in mice2017In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 100, p. 168-174Article in journal (Refereed)
    Abstract [en]

    Glycidol is a genotoxic animal carcinogen that has raised concern due to its presence in food, as glycidyl fatty acid esters. Here we investigated the genotoxicity of glycidol in BalbC mice (0-120 mg/kg) by monitoring the induction of micronuclei in peripheral blood as a marker of chromosomal damage. The scoring of the micronuclei was assessed by flow cytometry. In the treated mice, the internal dose of glycidol, expressed as area under the concentration-time curve, AUC (mol x L-1 x h; Mh), was measured by dihydroxypropyl adducts to hemoglobin (Hb). The study showed that glycidol induced linear dose dependent increases of Hb adducts (20 pmol/g Hb per mg/kg) and of micronuclei frequencies (12 parts per thousand per mMh). Compared to calculations based on administered dose, an improved dose-response relationship was observed when considering internal dose, achieved through the applied combination of sensitive techniques used for the scoring of micronuclei and AUC estimation of glycidol in the same mice. By comparing with earlier studies on micronuclei induction in mice exposed to ionizing radiation we estimated the radiation dose equivalent (rad-eq.) of glycidol to be ca 15 rad-eq./mMh.

  • 2.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetry2019In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 128, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic compounds. According to this model, cancer risk is proportional to the background tumor incidence and to the internal dose of the genotoxic compound. Furthermore, the relative risk coefficient per internal dose is considered to be approximately the same across tumor sites, sex, and species. In the present study, we demonstrate that the relative risk model is valid for cancer risk estimation of glycidol, a common food contaminant. Published tumor data from glycidol carcinogenicity studies in mice and rats were evaluated in combination with internal dose estimates from hemoglobin adduct measurements in blood from mice and rats treated with glycidol in short-term studies. A good agreement between predicted and observed tumor incidence in responding sites was demonstrated in the animals, supporting a relative risk coefficient that is independent of tumor site, sex, and species. There was no significant difference between the risk coefficients for mice (5.1% per mMh) and rats (5.4% per mMh) when considering internal doses of glycidol. Altogether, this mechanism-based risk model gives a reliable risk coefficient, which then was extrapolated to humans considering internal dose, and background cancer incidence.

  • 3.
    Aasa, Jenny
    et al.
    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.
    Abramsson-Zetterberg, Lilianne
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. National Food Agency, Sweden.
    Measurement of micronuclei and internal dose in mice demonstrates that 3-monochloropropane-1,2-diol (3-MCPD) has no genotoxic potency in vivo2017In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 109, p. 414-420Article in journal (Refereed)
    Abstract [en]

    In this study 3-monochloropropane-1,2-diol (3-MCPD), a compound that appears as contaminant in refined cooking oils, has been studied with regard to genotoxicity in vivo (mice) with simultaneous measurement of internal dose using state-of-the-art methodologies. Genotoxicity (chromosomal aberrations) was measured by flow cytometry with dual lasers as the frequency of micronuclei in erythrocytes in peripheral blood from BalbC mice intraperitoneally exposed to 3-MCPD (0, 50, 75, 100, 125 mg/kg). The internal doses of 3-MCPD in the mice were calculated from N-(2,3-dihydroxypropyl)-valine adducts to hemoglobin (Hb), quantified at very low levels by high-resolution mass spectrometry.

    Convincing evidence for absence of genotoxic potency in correlation to measured internal doses in the mice was demonstrated, despite relatively high administered doses of 3-MCPD. The results are discussed in relation to another food contaminant that is formed as ester in parallel to 3-MCPD esters in oil processing, i.e. glycidol, which has been studied previously by us in a similar experimental setup. Glycidol has been shown to be genotoxic, and in addition to have ca. 1000 times higher rate of adduct formation compared to that observed for 3-MCPD. The conclusion is that at simultaneous exposure to 3-MCPD and glycidol the concern about genotoxicity would be glycidol.

  • 4.
    Aasa, Jenny
    et al.
    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.
    Granath, Fredrik
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetryManuscript (preprint) (Other academic)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for more reliable cancer risk estimations of genotoxic compounds. According to this model, cancer risk is proportional to background tumor incidence and to internal dose of the genotoxic compound. A relative risk coefficient is considered to be common across species, sex, and tumor sites. The model has previously been shown to be successfully applied to rodent carcinogenicity data for a few genotoxic compounds. The aim of the present study was to evaluate this risk model for glycidol, a common food contaminant. Tumor data from published glycidol carcinogenicity studies in mice and rats were evaluated with the model, using internal doses estimated from hemoglobin adduct measurements in blood of B6C3F1 mice and Sprague Dawley rats treated with glycidol in short-term exposure studies.

    The evaluation demonstrated that the relative risk model is valid for glycidol. A good agreement between predicted and observed tumor incidence was demonstrated in the animals, supporting a relative risk coefficient that is independent of species, sex, and tumor site. There was no significant difference of the risk coefficients between mice (5.1 % per mMh) and rats (7.1 % per mMh) when the internal doses of glycidol were considered. Altogether, this mechanism-based risk model gives a common and more reliable risk coefficient which could be extrapolated to humans via internal dose measurements, and by considering the background cancer incidence.

  • 5.
    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.

  • 6.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vryonidis, Efstathios
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Internal dose of glycidol in children and estimation of associated cancer riskManuscript (preprint) (Other academic)
    Abstract [en]

    Children are more susceptible to exposures to harmful compounds compared to adults. Monitoring of the actual exposures in vivo is important to enable risk mitigation actions. The general population, including children, is exposed to the carcinogen glycidol through food. A possible exposure source to glycidol is food containing refined cooking oils where it is present as a process-induced contaminant in the form of fatty acid esters.

    In the present study internal (in vivo) doses of the genotoxic and carcinogenic compound glycidol have been determined in a cohort of 50 children and in a reference group of 12 adults (non-smokers and smokers). The lifetime in vivo doses of glycidol have been calculated from the levels of the hemoglobin (Hb) adduct N-(2,3-dihydroxypropyl)-valine in blood samples from the subjects, demonstrating about a 5-fold variation between the children (71–322 µMh). This variation is likely due to different dietary habits and/or different genotypes/phenotypes of the enzymes involved in the detoxification of glycidol. Data from the adults indicate that the non-smoking subjects are exposed to about the same level as the children, whereas the smoking subjects have about double levels, likely due to the presence of glycidol in tobacco smoke. The estimated exposure to glycidol in the children is higher than those estimated by European Food Safety Authority.

    The calculated relative cancer risk increment due to glycidol exposure demonstrated an unacceptable risk for all subjects. The excess lifetime risk based on the estimated lifetime in vivo doses of glycidol exceeded 1/1000, which should be compared to a generally applied acceptable lifetime risk level of 1/100 000. A small contribution to the internal dose of glycidol from other precursors to the measured Hb adduct, and corresponding contribution to estimated risks from intake of glycidol from food cannot though be excluded.

  • 7.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vryonidis, Efstathios
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Internal Doses of Glycidol in Children and Estimation of Associated Cancer Risk2019In: Toxics, ISSN 2305-6304, Vol. 7, no 1, article id 7Article in journal (Refereed)
    Abstract [en]

    The general population is exposed to the genotoxic carcinogen glycidol via food containing refined edible oils where glycidol is present in the form of fatty acid esters. In this study, internal (in vivo) doses of glycidol were determined in a cohort of 50 children and in a reference group of 12 adults (non-smokers and smokers). The lifetime in vivo doses and intakes of glycidol were calculated from the levels of the hemoglobin (Hb) adduct N-(2,3-dihydroxypropyl)valine in blood samples from the subjects, demonstrating a fivefold variation between the children. The estimated mean intake (1.4 mu g/kg/day) was about two times higher, compared to the estimated intake for children by the European Food Safety Authority. The data from adults indicate that the non-smoking and smoking subjects are exposed to about the same or higher levels compared to the children, respectively. The estimated lifetime cancer risk (200/10(5)) was calculated by a multiplicative risk model from the lifetime in vivo doses of glycidol in the children, and exceeds what is considered to be an acceptable cancer risk. The results emphasize the importance to further clarify exposure to glycidol and other possible precursors that could give a contribution to the observed adduct levels.

  • 8. Abramsson-Zetterberg, Lilianne
    et al.
    Vikström, Anna C
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Hellenäs, Karl-Erik
    Differences in the frequency of micronucleated erythrocytes in humans in relation to consumption of fried carbohydrate-rich food.2008In: Mutat Res, ISSN 0027-5107, Vol. 653, no 1-2, p. 50-6Article in journal (Refereed)
  • 9.
    Alsberg, T.
    et al.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Minten, J.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Haglund, J.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, M.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Determination of hydroxyalkyl derivatives of cobalamin (vitamin B12) using reversed phase high performance liquid chromatography with electrospray tandem mass spectrometry and ultraviolet diode array detection2001In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 15, no 24, p. 2438-45Article in journal (Refereed)
    Abstract [en]

    Electrospray ionization tandem mass spectrometry (ESI-MS/MS) and ultraviolet diode array detection (UV-DAD), coupled on-line to reversed phase high performance liquid chromatography (HPLC), was used for the characterization of hydroxyalkyl derivatives of cob(I)alamin. The reduced form of vitamin B12, cob(I)alamin, denoted a supernucleophile due to its high nucleophilic strength, has shown promise as an analytical tool in studies of electrophilically reactive compounds in vitro and in vivo. A method for analysis of DNA-phosphate adducts was developed earlier utilizing the supernucleophilicity of cob(I)alamin to transfer alkyl groups from the phosphotriester configuration in DNA, with the formation of a Co-substituted alkyl-cobalamin (alkyl-Cbl) complex. For the purpose of identification and quantification of alkyl-Cbls at high sensitivity, an MS/MS method has been developed with application to a number of 2-hydroxyalkyl-cobalamins (OHalkyl-Cbls). The precursor oxiranes were reacted with cob(I)alamin, followed by clean-up and mass spectrometric analysis of the resulting OHalkyl-Cbls. It was found that ionization was highly dependent on solvent composition. By using acetonitrile/water/trifluoroacetic acid (TFA) (eluent I), the base peak was the doubly protonated molecule [M + 2H](2+), whereas acetonitrile/water/1-methylpiperidine (eluent II) yielded the singly protonated molecule [M + H](+) as the base peak. Excellent separation was obtained with eluent II, with good separation between stereoisomers, thus enabling the characterization of these by means of UV spectra. Limits of quantitation for 2-hydroxypropyl-cobalamin (OHPr-Cbl) were 0.2 and 2 pg/microL (or 0.1 and 1 fmol/microL) using selected ion recording (SIR) with eluent I and II, respectively. The obtained detection level should be sufficient for analysis of alkyl-Cbls from a wide range of toxicological applications.

  • 10.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kotova, Natalia
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Adductomic Screening of N-terminal Hemoglobin Adducts and Measurement of Micronuclei in Blood Samples from Swedish School ChildrenArticle in journal (Refereed)
  • 11.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kotova, Natalia
    National Food Agency.
    Vare, Daniel
    National Food Agency.
    Sousa, Pedro F. M.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Rydberg, Per
    Department of Oncology-Pathology, Karolinska Institute.
    Abramsson-Zetterberg, Lilianne
    National Food Agency.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Adductomic Screening of Hemoglobin Adducts and Monitoring of Micronuclei in School-Age Children2017In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 30, no 5, p. 1157-1167Article in journal (Refereed)
    Abstract [en]

    Electrophilic compounds/metabolites present in humans, originating from endogenous processes or exogenous exposure, pose a risk to health effects through their reactions with nucleophilic sites in proteins and DNA, forming adducts. Adductomic approaches are developed to screen for adducts to biomacromolecules in vivo by mass spectrometry (MS), with the aim to detect adducts corresponding to unknown exposures from electrophiles. In the present study, adductomic screening was performed using blood samples from healthy children about 12 years old (n = 51). The frequencies of micronuclei (MN) in erythrocytes in peripheral blood were monitored as a measure of genotoxic effect/genotoxic exposure. The applied adductomic approach has been reported earlier by us and is based on analysis of N-terminal valine adducts in hemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). High resolution MS was introduced for refined screening of previously unknown N-terminal Hb adducts. Measured adduct levels were compared with MN frequencies using multivariate data analysis. In the 51 individuals, a total of 24 adducts (whereof 12 were previously identified) were observed and their levels quantified. Relatively large interindividual variations in adduct levels were observed. The data analysis (with partial least-squares regression) showed that as much as 60% of the MN variation could be explained by the adduct levels. This study, for the first time, applies the combination of these sensitive methods to measure the internal dose of potentially genotoxic chemicals and genotoxic effects, respectively. The results indicate that this is a valuable approach for the characterization of exposure to chemical risk factors for the genotoxic effects present in individuals of the general population.

  • 12.
    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.

  • 13.
    Carlsson, Henrik
    et al.
    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.
    Strategy for identifying unknown hemoglobin adducts using adductome LC-MS/MS data: Identification of adducts corresponding to acrylic acid, glyoxal, methylglyoxal, and 1-octen-3-one2016In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 92, p. 94-103Article in journal (Refereed)
    Abstract [en]

    Electrophilic compounds have the ability to form adducts with nucleophilic sites in proteins and DNA in tissues, and thereby constitute risks for toxic effects. Adductomic approaches are developed for systematic screening of adducts to DNA and blood proteins, with the aim to detect unknown internal exposures to electrophiles. In a previous adductomic screening of adducts to N-terminals in hemoglobin, using LC-MS/MS, 19 unknown adducts were detected in addition to seven previously identified adducts. The present paper describes the identification of four of these unknown adducts, as well as the strategy used to identify them. Using LC-MS data from the screening, hypotheses about adduct identities were formulated: probable precursor electrophiles with matching molecular weights were suggested based on the molecular weights of the modifications and the retention times of the analytes, in combination with comparisons of theoretical Log P calculations and databases. Reference adducts were generated by incubation of blood samples with the hypothesized precursor electrophiles. The four identified precursor electrophiles, corresponding to the observed unknown adducts, were glyoxal, methylglyoxal, acrylic acid and 1-octen-3-one. Possible origins/exposure sources and toxicological information concerning the electrophilic precursors are discussed. The identified adducts could be explored as possible biomarkers for exposure.

  • 14.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    LC–MS/MS Screening Strategy for Unknown Adducts to N-Terminal Valine in Hemoglobin Applied to Smokers and Nonsmokers2014In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 27, no 12, p. 2062-2070Article in journal (Refereed)
    Abstract [en]

    Electrophilically reactive compounds have the ability to form adducts with nucleophilic sites in DNA and proteins, constituting a risk for toxic effects. Mass spectrometric detection of adducts to N-terminal valine in hemoglobin (Hb) after detachment by modified Edman degradation procedures is one approach for in vivo monitoring of exposure to electrophilic compounds/metabolites. So far, applications have been limited to one or a few selected reactive species, such as acrylamide and its metabolite glycidamide. This article presents a novel screening strategy for unknown Hb adducts to be used as a basis for an adductomic approach. The method is based on a modified Edman procedure, FIRE, specifically developed for LC-MS/MS analysis of N-terminal valine adducts in Hb detached as fluorescein thiohydantoin (FTH) derivatives. The aim is to detect and identify a priori unknown Hb adducts in human blood samples. Screening of valine adducts was performed by stepwise scanning of precursor ions in small mass increments, monitoring four fragments common for the FTH derivative of valine with different N-substitutions in the multiple-reaction mode, covering a mass range of 135 Da (m/z 503-638). Samples from six smokers and six nonsmokers were analyzed. Control experiments were performed to compare these results with known adducts and to check for artifactual formation of adducts. In all samples of smokers and nonsmokers, seven adducts were identified, of which six have previously been studied. Nineteen unknown adducts were observed, and 14 of those exhibited fragmentation patterns similar to earlier studied FTH derivatives of adducts to valine. Identification of the unknown adducts will be the focus of future work. The presented methodology is a promising screening tool using Hb adducts to indicate exposure to potentially toxic electrophilic compounds and metabolites.

  • 15. Dalmo, Johanna
    et al.
    Westberg, Emelie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Barregård, Lars
    Svedbok, Lisa
    Johansson, Martin
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Forssell-Aronsson, Eva
    Evaluation of retinol binding protein 4 and carbamoylated haemoglobin as potential renal toxicity biomarkers in adult mice treated with Lu-177-octreotate2014In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, no 59Article in journal (Refereed)
    Abstract [en]

    Background: The kidneys are regarded as one of the main dose-limiting organs in the treatment of neuroendocrine tumours with Lu-177-[DOTA(0), Tyr(3)]-octreotate (Lu-177-octreotate), despite the successful use of kidney uptake blocking agents such as lysine and arginine. To avoid renal toxicity but still give each patient as high amount of Lu-177-octreotate as possible, there is a need for methods/biomarkers that indicate renal injury in an early stage of the treatment. The aim of this study was to investigate the potential of using urinary retinol binding protein 4 (RBP4) and carbamoylated haemoglobin (Hb) in blood as biomarkers of nephrotoxic effects on adult mice after Lu-177-octreotate treatment. Methods: Adult BALB/c nude mice were injected with 60 MBq or 120 MBq of Lu-177-octreotate or with saline (control). Urine was collected before injection and concentrations of urinary RBP4 and creatinine were determined 14 to 90 days after injection Blood samples were collected after 90 days, and carbamoylated N-terminal valine in Hb, formed from urea, was measured as valine hydantoin (VH) after detachment from Hb. Results: The RBP4 values increased with administered activity and time. For the 60 and 120 MBq groups, statistically significantly higher RBP4 levels (p <0.05) were found at day 60 and 90 compared to baseline, also at day 30 for 120 MBq group. For VH, the mean values were similar for the 60 MBq and control groups, while a small increase was observed for the 120 MBq group; but there were no statistically significant differences between any of the groups (p >0.05). No morphological changes in the kidney tissue were found. Conclusions: Urinary RBP4 is a promising new biomarker for radiation-induced renal toxicity. For the conditions used in this experiment, carbamoylated Hb (from urea) measured as VH may not be a sufficiently sensitive biomarker to be used for renal toxicity.

  • 16.
    Davies, R.
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Hedebrant, U.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Athanassiadis, I.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Rydberg, P.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, M.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Improved method to measure aldehyde adducts to N-terminal valine in hemoglobin using 5-hydroxymethylfurfural and 2,5-furandialdehyde as model compounds2009In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 47, no 8, p. 1950-1957Article in journal (Refereed)
    Abstract [en]

    Hemoglobin (Hb) adducts are used to measure reactive compounds/metabolites in vivo. Schiff base adducts from aldehydes to N-termini in Hb have been measured by GC-MS/MS after stabilisation through reduction, and detachment by a modified Edman procedure. This paper describes a further development using 5-hydroxymethylfurfural (HMF) and its probable metabolite, 2,5-furandialdehyde (FDA), as model compounds. Reference compounds were synthesized and characterized. The conditions for the reduction of the Schiff bases were optimized using NaBH(3)CN as a mild reducing agent, and steps used in the earlier method could be deleted. The adduct from FDA could not be specifically analysed, as selective reduction of the imine could not be achieved. In a few samples of human blood, background levels of 10-35 pmol/g globin of the HMF adduct were observed. Half-lifes of the reversible Schiff base adduct from HMF were determined to 3.4h at 37 degrees C and 10.9h at 25 degrees C. The developed method showed good sensitivity and reproducibility for the analysis of the Schiff base from HMF, with improvements regarding simplicity of work-up procedures due to mild conditions. The developed method could be explored for application to adducts from other aldehydes bound as Schiff bases to N-termini in Hb.

  • 17.
    Davies, Ronnie
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Hedebrant, Ulla
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Athanassiadis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Improved method for the analysis of reactive aldehydes in human blood2008In: 6:e Svensk-norskt miljökemiskt möte: SNMM 2008 22-24 September, 2008Conference paper (Refereed)
  • 18.
    Davies, Ronnie
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Westberg, Emelie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Johnstone, Erik
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    A New General Pathway for Synthesis of Reference Compounds of N-Terminal Valine-Isocyanate Adducts2010In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 23, no 3, p. 540-546Article in journal (Refereed)
    Abstract [en]

    Adducts to Hb could be used as biomarkers to monitor exposure to isocyanates. Particularly useful is the measurement of carbamoylation of N-terminal valines in Hb, after detachment as hydantoins. The synthesis of references from the reactive isocyanates, especially diisocyanates, has been problematic due to side reactions and polymerization of the isocyanate starting material. A simpler, safer, and more general method for the synthesis of valine adducts of isocyanates has been developed using N-[(4-nitrophenyl)-carbamate]valine methylamide (NPCVMA) as the key precursor to adducts of various mono- and diisocyanates of interest. By reacting NPCVMA with a range of isocyanate-related amines, carbamoylated valines are formed without the use of the reactive isocyanates. The carbamoylated products synthesized here were cyclized with good yields of the formed hydantoins. The carbamoylated derivative from phenyl isocyanate also showed quantitative yield in a test with cyclization tinder the conditions used in blood. This new pathway for the preparation of N-carbamoylated model compounds overcomes the above-mentioned problems in the synthesis and is a general and simplified approach, which could make such reference compounds of adducts to N-terminal valine from isocyanates accessible for biomonitoring purposes. The synthesized hydantoins corresponding to adducts from isocyanic acid, methyl isocyanate, phenyl isocyanate, and 2,6-toluene diisocyanate were characterized by LC-MS analysis. The background level of the hydantoin from isocyanic acid in human blood was analyzed with the LC-MS conditions developed.

  • 19. Degner, Amanda
    et al.
    Carlsson, Henrik
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Karlsson, Isabella
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Eriksson, Johan
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Pujari, Suresh S.
    Tretyakova, Natalia Y.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood2018In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 31, no 12, p. 1305-1314Article in journal (Refereed)
    Abstract [en]

    Humans are exposed to a wide range of electrophilic compounds present in our diet and environment or formed endogenously as part of normal physiological processes. These electrophiles can modify nucleophilic sites of proteins and DNA to form covalent adducts. Recently, powerful untargeted adductomic approaches have been developed for systematic screening of these adducts in human blood. Our earlier untargeted adductomics study detected 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. We now describe a full characterization of one of these adducts, which corresponds to the addition of a 4-hydroxybenzyl (4-OHBn) group to N-terminal valine in Hb to form N(4-hydroxybenzyl)valine (4-OHBn-Val). The adduct structure was determined by comparison of its accurate mass, HPLC retention time, and MS/MS fragmentation to that of authentic standards prepared by chemical synthesis. Average 4-OHBn-Val adduct concentrations in 12 human blood samples were estimated to 380 +/- 160 pmol/g Hb. Two possible routes of 4-OHBnVal adduct formation are proposed using two different precursor electrophiles: 4-quinone methide (4-QM) and 4-hydroxybenzaldehyde (4-OHBA). We found that 4-QM reacts rapidly with valine to form the 4-OHBn-Val adduct; however, the quinone methide is unstable under physiological conditions due to hydrolysis. It was shown that 4-OHBA forms reversible Schiff base adducts with valine, which can be stabilized via reduction in blood generating the 4-OHBn-Val adduct. In addition, trace amounts of isomeric 2-hydroxybenzyl-valine (2-OHBn-Val) adducts were detected in 12 human blood samples (estimated mean adduct level, 5.0 +/- 1.4 pmol/g Hb). Further studies are needed to quantify the contributions from identified possible precursor electrophiles to the observed hydroxybenzyl adducts in humans.

  • 20. Duarte-Salles, Talita
    et al.
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Granum, Berit
    Gutzkow, Kristine B.
    Rydberg, Per
    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.
    Mendez, Michelle A.
    Brunborg, Gunnar
    Brantsaeter, Anne Lise
    Meltzer, Helle Margrete
    Alexander, Jan
    Haugen, Margaretha
    Dietary Acrylamide Intake during Pregnancy and Fetal Growth-Results from the Norwegian Mother and Child Cohort Study (MoBa)2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 3, p. 374-379Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acrylamide has shown developmental and reproductive toxicity in animals, as well as neurotoxic effects in humans with occupational exposures. Because it is widespread in food and can pass through the human placenta, concerns have been raised about potential developmental effects of dietary exposures in humans. OBJECTIVES: We assessed associations of prenatal exposure to dietary acrylamide with small for gestational age (SGA) and birth weight. METHODS: This study included 50,651 women in the Norwegian Mother and Child Cohort Study (MoBa). Acrylamide exposure assessment was based on intake estimates obtained from a food frequency questionnaire (FFQ), which were compared with hemoglobin (Hb) adduct measurements reflecting acrylamide exposure in a subset of samples (n = 79). Data on infant birth weight and gestational age were obtained from the Medical Birth Registry of Norway. Multivariable regression was used to estimate associations between prenatal acrylamide and birth outcomes. RESULTS: Acrylamide intake during pregnancy was negatively associated with fetal growth. When women in the highest quartile of acrylamide intake were compared with women in the lowest quartile, the multivariable-adjusted odds ratio (OR) for SGA was 1.11 (95% CI: 1.02, 1.21) and the coefficient for birth weight was -25.7 g (95% CI: -35.9, -15.4). Results were similar after excluding mothers who smoked during pregnancy. Maternal acrylamide-and glycidamide-Hb adduct levels were correlated with estimated dietary acrylamide intakes (Spearman correlations = 0.24; 95% CI: 0.02, 0.44; and 0.48; 95% CI: 0.29, 0.63, respectively). CONCLUSIONS: Lowering dietary acrylamide intake during pregnancy may improve fetal growth.

  • 21.
    Eriksson, Sune
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Karlsson, Patrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Measurement of evaporated acrylamide during heat treatment of food and other biological materials2007In: LWT – Food Science and Technology, ISSN 0023-6438, Vol. 40, no 7, p. 706-712Article in journal (Refereed)
    Abstract [en]

    It is established that acrylamide could be formed during heating of food products. In the present work we have studied whether the formed acrylamide could evaporate from food at elevated temperatures used in cooking (>160 °C) or used in determination of dry matter in laboratory analysis (ca. 105 °C). It was demonstrated that acrylamide evaporates from food samples during both cooking and temperatures used for drying. Up to ca. 4 μg/m3 could be measured above the fry pan during frying of potato. In parallel we have also studied whether acrylamide could be formed and evaporate during the elevated temperatures of 65–130 °C used for dry matter determinations in other types of samples containing biological material, like agricultural and environmental samples. It was found that acrylamide is formed during conditions for drying of soil, sediment and silage samples, as well as cereals, animal feed, etc. After drying, levels of acrylamide up to about 100 μg/kg were found, e.g. in samples of sediment and sludge. The measurements showed in the food, agricultural and environmental samples tested a minor fraction, roughly estimated to be 0.15–7.2% of the formed acrylamide evaporates at the used elevated temperatures.

  • 22. Eriksson, Sune
    et al.
    Karlsson, Patrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Measurement of evaporated acrylamide during heat treatment of food and other biological materials2007In: LWT - Food Science and Technology, Vol. 40, no 4, p. 706-712Article in journal (Refereed)
    Abstract [sv]

    It is established that acrylamide could be formed during heating of food products. In the present work we have studied whether the formed acrylamide could evaporate from food at elevated temperatures used in cooking (>160 °C) or used in determination of dry matter in laboratory analysis (ca. 105 °C). It was demonstrated that acrylamide evaporates from food samples during both cooking and temperatures used for drying. Up to ca. 4 μg/m3 could be measured above the fry pan during frying of potato. In parallel we have also studied whether acrylamide could be formed and evaporate during the elevated temperatures of 65–130 °C used for dry matter determinations in other types of samples containing biological material, like agricultural and environmental samples. It was found that acrylamide is formed during conditions for drying of soil, sediment and silage samples, as well as cereals, animal feed, etc. After drying, levels of acrylamide up to about 100 μg/kg were found, e.g. in samples of sediment and sludge. The measurements showed in the food, agricultural and environmental samples tested a minor fraction, roughly estimated to be 0.15–7.2% of the formed acrylamide evaporates at the used elevated temperatures.

  • 23.
    Fred, Charlotta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Cantillana, Tatiana
    Henderson, Alistair
    Golding, Bernard T.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Adducts to N-terminal valines in hemoglobin from isoprene di-epoxide, a metabolite of isoprene2004In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 18, p. 2177-2184Article in journal (Refereed)
    Abstract [en]

    Isoprene (2-methylbuta-1,3-diene) is a multi-site carcinogen in rodents. To evaluate the role of the diepoxide metabolite (1,2:3,4-diepoxy-2-methylbutane) in carcinogenesis, measurements of in vivo doses of the diepoxide are needed. The in vivo dose may be inferred from levels of reaction products with hemoglobin (Hb adducts). This report presents in vitro studies of the adduct formation by the diepoxide of isoprene with valinamide and oligopeptides as model compounds of N-terminal valines in hemoglobin (Hb). In the reaction with valinamide it was shown that isoprene diepoxide forms as the main product a ring-closed adduct, which is a pyrrolidine derivative [N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valinamide, MPyr-Val]. The analysis was performed by gas chromatography/mass spectrometry (GC/MS) (EI and PICI) after acetylation. The ring-closed adduct was also identified by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) as the main product in the reaction between isoprene diepoxide and standard hepta- or (2H8)octapeptides, corresponding to the N-terminal peptides of the α-chains in mouse and rat Hb. These peptides, alkylated with isoprene diepoxide, to be used as internal standards and calibration standards for quantification of MPyr-adduct levels in vitro and in vivo, were analyzed with respect to the degree of MPyr-alkylation by two independent methods, amino acid analysis and HPLC-UV; similar results were obtained using these methods. A method for measurement of Hb adducts as modified peptides, used earlier to measure a similar adduct to N-terminal valines in Hb from the diepoxide of 1,3-butadiene, has in the present work been tested for application to isoprene diepoxide. The method is based on tryptic degradation of globin and LC/ESI-MS analysis of N-terminal Pyr-heptapeptides of the Hb α-chain enriched by HPLC. MPyr-adduct levels in isoprene diepoxide alkylated hemolysate from mouse erythrocytes incubated with different concentrations of isoprene diepoxide (2 and 10 mM) for 1 h were quantified. The adduct level was about 50 nmol/g α-chain Hb per mM × h. From the adduct levels the rate constant of isoprene diepoxide for reaction with N-terminal valine was calculated to be about 1.6 times faster than for diepoxybutane

  • 24.
    Fred, Charlotta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Grawé, Jan
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide2005In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 585, no 1-2, p. 21-32Article in journal (Refereed)
    Abstract [en]

    1,3-Butadiene and isoprene (2-methyl-1,3-butadiene) are chemically related substances that are carcinogenic to rodents. The overall aim of this work is to elucidate the role of the genotoxic action of diepoxide metabolites in the carcinogenesis of the dialkenes. In vivo doses of the diepoxide metabolites were measured through reaction products with hemoglobin (Hb adducts) in studies of induced micronuclei (MN) in rodents. In the reaction with N-terminal valine in Hb, diepoxybutane and isoprenediepoxide form ring-closed adducts, pyrrolidines [N,N-(2,3-dihydroxy-1,4-butadiyl)valine and N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valine, respectively]. The method applied for Hb-adduct measurement is based on tryptic degradation of the protein and liquid chromatography electrospray ionisation tandem mass spectrometry (LC–ESI-MS/MS) analysis. Mice were given single i.p. injections of the monoepoxides of butadiene and isoprene, 1,2-epoxy-3-butene or 1,2-epoxy-2-methyl-3-butene, respectively. Rats were treated in the same way with 1,2-epoxy-3-butene. In mice pyrrolidine adduct levels increased with increasing administered doses of the monoepoxides. The in vivo dose of diepoxybutane was on average twice as high (0.29 ± 0.059 mMh) as the in vivo dose of isoprenediepoxide (0.15 ± 0.053 mMh) per administered dose (mmol/kg body weight) of the monoepoxides. In mice the genotoxic effects of the two monoepoxides, measured as the increase in the frequencies of micronuclei (MN), were approximately linearly correlated to the in vivo doses of the diepoxides (except at the highest dose of diepoxybutane). In rats the pyrrolidine-adduct levels from diepoxybutane were below the limit of quantification at all administered doses of 1,2-epoxy-3-butene and no significant increase was observed in the frequency of MN. Measurement of the ring-closed adducts to N-termini in Hb by the applied method permits analysis of in vivo doses of diepoxybutane and isoprenediepoxide, which may be further used for the elucidation of the mechanisms of carcinogenesis of butadiene and isoprene.

  • 25.
    Fred, Charlotta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Haglund, Johanna
    Alsberg, Thomas
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Minten, Johanna
    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.
    Characterization of alkyl-cobalamins formed in trapping of epoxide metabolites of 1,3-butadiene2004In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 27, no 7-8, p. 607-612Article in journal (Refereed)
    Abstract [en]

    Analytical methods facilitating studies of electrophilically reactive and genotoxic compounds in vitro and in vivo are needed. The strong nucleophile, cob(I)alamin, formed by reduction of Vitamin B12 [cob(III)alamin], may be used for trapping and analysis of 1,2-epoxides and other electrophiles. In the present study, cob(I)alamin is evaluated as an analytical tool for 1,2-epoxide metabolites (oxiranes) of 1,3-butadiene. Products of reaction of cob(I)alamin with 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EBdiol) have been analyzed by reversed phase high performance liquid chromatography (HPLC) coupled on-line to electrospray ionization mass spectrometry (ESI-MS) and ultraviolet diode array detection (UV-DAD). It was shown that a specific alkyl-Cbl complex is formed for each metabolite and that it was possible to discriminate between the products by HPLC-UV and by LC-MS. Quantification of DEB with the method by use of another 1,2-epoxide as an internal standard was successfully performed. The possibility of using cob(I)alamin for trapping and analysis of the three oxirane metabolites of 1,3-butadiene will facilitate quantitative comparisons of species in vitro with regard to metabolism of 1,3-butadiene.

  • 26.
    Fred, Charlotta
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Kautiainen, Antti
    Athanassiadis, Ioannis
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hemoglobin adduct levels in rat and mouse treated with 1,2:3,4-diepoxybutane2004In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 17, no 6, p. 785-794Article in journal (Refereed)
    Abstract [en]

    For cancer risk assessment of 1,3-butadiene from rodent cancer test data, the in vivo doses of formed 1,2:3,4-diepoxybutane (DEB) should be known. In vivo doses of DEB were measured through a specific reaction product with hemoglobin (Hb), a ring-closed adduct, N,N-(2,3-dihydroxy-1,4-butadiyl)valine (Pyr-Val), to N-terminal valines. An analytical method based on tryptic digestion of Hb and quantification of Pyr-modified heptapeptides by LC-MS/MS has been further developed and applied in vivo to DEB-treated rats. Furthermore, N-(2,3,4-trihydroxybutyl)valine adducts (THB-Val) to the N-terminal valine in Hb were measured in rats and mice treated with DEB and in a complementary experiment with 1,2-epoxy-3,4-butanediol (EBdiol), using a modified Edman degradation method and GC-MS/MS. In vitro reactions of hemolysate with DEB and EBdiol were used to measure reaction rates for adduct formation needed for calculation of doses and rates elimination in vivo. The results showed that the level of the Pyr-Val adduct per administered dose of DEB was approximately the same in rats as had earlier been observed in mice [Kautiainen et al. (2000) Rapid Commun. Mass Spectrom. 14, 1848−1853]. Levels of the THB-Val adduct after DEB treatment were 3−4 times higher in rat than in mouse, probably reflecting an enhanced hydrolysis of DEB to EBdiol catalyzed by epoxide hydrolase. After EBdiol treatment, the THB-Val adduct levels were about the same in rat and mouse. Calculations from in vitro data show that the Pyr-Val adduct is a relevant monitor for the in vivo dose of DEB and that THB-Val primarily reflects doses to EBdiol. The calculated rates of formation of adducts and rates of elimination agree with expectations. Procedures for quantification of Hb adducts as modified peptides as well as preparation and characterization of peptide standards have been evaluated.

  • 27. Fred, Charlotta
    et al.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Granath, Fredrik
    Evaluation of cancer tests of 1,3-butadiene using internal dose, genotoxic potency, and a multiplicative risk model.2008In: Cancer Res, ISSN 1538-7445, Vol. 68, no 19, p. 8014-21Article in journal (Refereed)
    Abstract [en]

    In cancer tests with 1,3-butadiene (BD), the mouse is much more sensitive than the rat. This is considered to be related to the metabolism of BD to the epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane, and 1,2-epoxy-3,4-butanediol. This study evaluates whether the large difference in outcome in cancer tests with BD could be predicted quantitatively on the basis of the concentration over time in blood (AUC) of the epoxide metabolites, their mutagenic potency, and a multiplicative cancer risk model, which has earlier been used for ionizing radiation. Published data on hemoglobin adduct levels from inhalation experiments with BD were used for the estimation of the AUC of the epoxide metabolites in the cancer tests. The estimated AUC of the epoxides were then weighed together to a total genotoxic dose, by using the relative genotoxic potency of the respective epoxide inferred from in vitro hprt mutation assays using EB as standard. The tumor incidences predicted with the risk model on the basis of the total genotoxic dose correlated well with the earlier observed tumor incidences in the cancer tests. The total genotoxic dose that leads to a doubling of the tumor incidences was estimated to be the same in both species, 9 to 10 mmol/Lxh EB-equivalents. The study validates the applicability of the multiplicative cancer risk model to genotoxic chemicals. Furthermore, according to this evaluation, different epoxide metabolites are predominating cancer-initiating agents in the cancer tests with BD, the diepoxide in the mouse, and the monoepoxides in the rat.

  • 28. Gutzkow, K. B.
    et al.
    Duale, N.
    Danielsen, T.
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Shahzadi, S.
    Instanes, C.
    Olsen, A. -K.
    Steffensen, I. -L.
    Hofer, T.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Brunborg, G.
    Lindeman, B.
    Enhanced susceptibility of obese mice to glycidamide-induced sperm chromatin damage without increased oxidative stress2016In: Andrology, ISSN 2047-2919, E-ISSN 2047-2927, Vol. 4, no 6, p. 1092-1114Article in journal (Refereed)
    Abstract [en]

    Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.

  • 29.
    Hedenbrant, Ulla
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Haglund, Johanna
    Alsberg, Tomas
    Eriksson, Johan
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Development of a method for determination of serum albumin adducts of benzo(a)pyrene by LC/ESI-MS2008Conference paper (Other academic)
  • 30. Hochstenbach, Kevin
    et al.
    van Leeuwen, Danitsja M.
    Gmuender, Hans
    Gottschalk, Ralf W.
    Lovik, Martinus
    Granum, Berit
    Nygaard, Unni
    Namork, Ellen
    Kirsch-Volders, Micheline
    Decordier, Ilse
    Loock, Kim Vande
    Besselink, Harrie
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Kleinjans, Jos C. S.
    van Loveren, Henk
    van Delft, Joost H. M.
    Global gene expression analysis in cord blood reveals gender specific differences in response to carcinogenic exposure in utero2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 10, p. 1756-1767Article in journal (Refereed)
    Abstract [en]

    Background: It has been suggested that fetal carcinogenic exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the fetal transcriptome. Because gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of fetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and nongenotoxic carcinogens show gender-specific mechanisms-of-action relevant for chemical carcinogenesis. Methods: Global gene expression was applied in umbilical cord blood samples, the CALUX-assay was used for measuring dioxin(-like), androgen(-like), and estrogen(-like) internal exposure, and acrylamide-hemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedure (TM). To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated. Results: While exposure levels did not differ between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures linked with cell cycle, the immune system and more general cellular processes such as posttranslation. Moreover, oppositely correlating leukemia/lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure that might be relevant to male-specific predisposition to develop these cancers in childhood. Conclusions/Impact: This study reveals different transcriptomic responses to environmental carcinogens between the sexes. In particular, male-specific TNF-alpha-NF-kB signaling upon dioxin exposure and activation of the Wnt-pathway in boys upon acrylamide exposure might represent possible mechanistic explanations for gender specificity in the incidence of childhood leukemia.

  • 31. Honda, Hiroshi
    et al.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nishiyama, Naohiro
    Kasamatsu, Toshio
    Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose2014In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 275, no 3, p. 213-220Article in journal (Refereed)
    Abstract [en]

    Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75 mg/kg bw, and diHOPrVal levels were measured 24 h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R-2 = 0.943). Blood sampling at different time points (1, 10, 20, or 40 days) from four groups administered glycidol at 12 mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61 days), with the calculated first-order elimination rate constant (k(el)) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (k(val)) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The k(val) was 6.7 (+/-) 1.1 and 5.6 +/- 1.3 (pmol/g globin per mu Mh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from k(val) and diHOPrVal levels were in agreement with the area under the (concentration-time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment.

  • 32.
    Karlsson, Isabella
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Samuelsson, Kristin
    Ponting, David J.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Peptide Reactivity of Isothiocyanates - Implications for Skin Allergy2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21203Article in journal (Refereed)
    Abstract [en]

    Skin allergy is a chronic condition that affects about 20% of the population of the western world. This disease is caused by small reactive compounds, haptens, able to penetrate into the epidermis and modify endogenous proteins, thereby triggering an immunogenic reaction. Phenyl isothiocyanate (PITC) and ethyl isothiocyanate (EITC) have been suggested to be responsible for allergic skin reactions to chloroprene rubber, the main constituent of wetsuits, orthopedic braces, and many types of sports gear. In the present work we have studied the reactivity of the isothiocyanates PITC, EITC, and tetramethylrhodamine-6-isothiocyanate (6-TRITC) toward peptides under aqueous conditions at physiological pH to gain information about the types of immunogenic complexes these compounds may form in the skin. We found that all three compounds reacted quickly with cysteine moieties. For PITC and 6-TRITC the cysteine adducts decomposed over time, while stable adducts with lysine were formed. These experimental findings were verified by DFT calculations. Our results may suggest that the latter are responsible for allergic reactions to isothiocyanates. The initial adduct formation with cysteine residues may still be of great importance as it prevents hydrolysis and facilitates the transport of isothiocyanates into epidermis where they can form stable immunogenic complexes with lysine-containing proteins.

  • 33.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. The Swedish National Food Agency, Sweden.
    Frostne, Cecilia
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Abramsson-Zetterberg, Lilianne
    Tareke, Eden
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bergman, Rolf
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Paulsson, Birgit
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Segerbäck, Dan
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Grawé, Jan
    Differences in micronucleus frequency and acrylamide adduct levels with hemoglobin between vegetarians and non-vegetarians2015In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 54, no 7, p. 1181-1190Article in journal (Refereed)
    Abstract [en]

    Nutrients and food constituents can prevent or contribute to genotoxicity. In this study, the possible influence of a vegetarian/non-vegetarian diet on genotoxic effects was investigated in 58 non-smoking healthy vegetarians (V) and non-vegetarians (NV), age 21-37 years from the Stockholm area in Sweden. Physical activity and dietary habits were similar in both groups, with the exception of the intake of meat and fish. Using flow cytometry, we determined the formation of micronuclei (MN) in transferrin-positive immature peripheral blood reticulocytes (Trf-Ret) (Total: n = 53; V: n = 27; NV: n = 26). Dietary exposure to acrylamide was measured through hemoglobin (Hb) adducts in peripheral erythrocytes (Total: n = 53; V: n = 29; NV: n = 24). Hb adducts of both acrylamide and its genotoxic metabolite glycidamide were monitored as a measure of the corresponding in vivo doses. Our data demonstrated that compared with the non-vegetarians, the vegetarians exhibited lower frequencies of MN (fMN) in the Trf-Ret (p < 0.01, Student's t test). A multivariate analysis demonstrated that there was no association between the fMN and factors such as age, sex, intake of vitamins/minerals, serum folic acid and vitamin B12 levels, physical activity, and body mass index. The mean Hb adduct levels of acrylamide and glycidamide showed no significant differences between vegetarians and non-vegetarians. Furthermore, there were no significant relationships between the adduct levels and fMN in the individuals. The ratio of the Hb adduct levels from glycidamide and acrylamide, however, showed a significant difference (p < 0.04) between the two groups. These data suggest that the vegetarian diet might be beneficial in lowering genomic instability in healthy individuals. The measured Hb adduct levels indicate that the total intake of acrylamide does not differ between the two studied groups and does not contribute to the observed difference in fMN, although an influence of the diet on the metabolic rates of acrylamide was indicated. In addition, the observed significant difference in the background fMN in the two groups demonstrated that the MN analysis method has a sensitivity applicable to the biomonitoring of human lifestyle factors.

  • 34.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Prochaska, Gabriela
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Lundin, Cecilia
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Dreij, Kristian
    Segerbäck, Dan
    Department of Biosciences and Nutrition, Novum, Karolinska Institute.
    Jernström, Bengt
    The Institute for Environmental Medicine (IMM), Karolinska Institute.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Seidel, Albrecht
    Biochemical Institute for Environmental Carcinogens, Lurup .
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo(a)pyrene-diol-epoxide and dibenzo(a,l)-pyrene-diol-epoxide.2008In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, DNA repair, Vol. 7, no 8, p. 1202-1012Article in journal (Refereed)
    Abstract [en]

    Mutations induced by polycyclic aromatic hydrocarbons (PAH) are expected to be produced when error-prone DNA replication occurs across unrepaired DNA lesions formed by reactive PAH metabolites such as diol epoxides. The mutagenicity of the two PAH-diol epoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. We applied the 32P-postlabelling assay to analyze adduct levels and the hprt gene mutation assay for monitoring mutations. It was found that the mutagenicity per target dose was 4 times higher for DBPDE compared to BPDE in NER proficient cells while in NER deficient cells, the mutagenicity per target dose was 1.4 times higher for BPDE. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the hprt gene. The results suggest that NER of BPDE lesions are 5 times more efficient than for DBPDE lesions, in NER proficient cells. However, DBPDE adducts block replication more efficiently and also induce 6 times more recombination events in the hprt gene than adducts of BPDE, suggesting that DBPDE adducts are, to a larger extent, bypassed by homologous recombination. The results obtained here indicate that the mutagenicity of PAH is influenced not only by NER, but also by replication bypass fidelity. This has been postulated earlier based on results using in vitro enzyme assays, but is now also being recognized in terms of forward mutations in intact mammalian cells.

  • 35.
    Lagerqvist, Anne
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lundin, Cecilia
    Prochazka, Gabriela
    Dreij, Kristian
    Segerbäck, Dan
    Jernström, Bengt
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Franke, Heinz
    Seidel, Albrecht
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    DNA repair and replication influence the number of mutations per adduct of polycyclic aromatic hydrocarbons in mammalian cells2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 877-886Article in journal (Refereed)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAH) are an important class of environmental contaminants many of which require metabolic activation to DNA-reactive bay or fjord region diolepoxides (DE) in order to exert their mutagenic and carcinogenic effects. In this study, the mutagenicity of the bay region diolepoxides (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and ()-anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrodibenzo[a,h]anthracene (DBADE) and the fjord region diolepoxides ()-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]-pyrene (DBPDE) and (+/-)-anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene (BPhDE) was compared in nucleotide excision repair (NER) proficient and deficient hamster cell lines. The (32)P-postlabelling assay was applied to analyze DNA adduct levels and the Hprt gene mutation assay for monitoring mutations. Previously, we found that the mutagenicity per adduct was four times higher for DBPDE compared to BPDE in NER proficient cells. In these same cells, the mutagenicity of DBADE and BPhDE adducts was now found to be significantly lower compared to that of BPDE. In NER deficient cells the highest mutagenicity per adduct was found for BPDE and there was a tenfold and fivefold difference when comparing the BPDE data with the DBADE and BPhDE data, respectively. In order to investigate to what extent the mutagenicity of the different adducts in NER proficient cells was influenced by repair or replication bypass, we measured the overall NER incision rate, the rate of adduct removal, the rate of replication bypass and the frequency of induced recombination in the Hprt gene. Since NER turned out to be an important pathway for the yield of mutations, we further analyzed the role of transcription coupled NER versus global genome NER. However, our data demonstrate that neither of these pathways seems to be the sole factor determining the mutation frequency of the four PAH-DE and that the differences in the repair efficiency of these compounds could not be related to the presence of a bay or fjord region in the parent PAH.

  • 36. Merlo, Domenico Franco
    et al.
    Agramunt, Silvia
    Anna, Livia
    Besselink, Harrie
    Botsivali, Maria
    Brady, Nigel J.
    Ceppi, Marcello
    Chatzi, Leda
    Chen, Bowang
    Decordier, Ilse
    Farmer, Peter B.
    Fleming, Sarah
    Fontana, Vincenzo
    Foersti, Asta
    Fthenou, Eleni
    Gallo, Fabio
    Georgiadis, Panagiotis
    Gmuender, Hans
    Godschalk, Roger W.
    Granum, Berit
    Hardie, Laura J.
    Hemminki, Kari
    Hochstenbach, Kevin
    Knudsen, Lisbeth E.
    Kogevinas, Manolis
    Kovacs, Katalin
    Kyrtopoulos, Soterios A.
    Lovik, Martinus
    Nielsen, Jeanette K.
    Nygaard, Unni Cecilie
    Pedersen, Marie
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Schoket, Bernadette
    Segerbäck, Dan
    Singh, Rajinder
    Sunyer, Jordi
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    van Loveren, Henk
    van Schooten, Frederik J.
    vande Loock, Kim
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Wright, John
    Kleinjans, Jos C.
    Kirsch-Volders, Micheline
    van Delft, Joost H. M.
    Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort2014In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    Background: Leukemia incidence has increased in recent decades among European children, -suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M(1)dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M(1)dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX (R) (chemically activated luciferase expression for androgens) (8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX (R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/ 2 and CYP2E1 were associated with MNBN. Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.

  • 37.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Fred, Charlotta
    Haglund, Johanna
    Golding, Bernard
    Törnqvist, Margareta
    Cob(I)alamin as an analytical tool to study 1,3-butadiene metabolism in human, mouse and rat S9 liver fractions2007In: Gordon Research Conference on Vitamin B12 and Corphins, 2007Conference paper (Other (popular science, discussion, etc.))
  • 38.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Shimakoshi, Hisashi
    Department of Chemistry and Biochemistry, Kyushu University.
    Golding, Bernard
    School of Chemistry, Newcastle University.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hisaeda, Yoshio
    Department of Chemistry and Biochemistry, Kyushu University.
    Formation of an alkylcobyrinate from sucralose and mechanistic aspects of its Co-C bond cleavagesIn: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948Article in journal (Other academic)
  • 39.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Shimakoshi, Hisashi
    Hisaeda, Yoshio
    Golding, Bernard
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Reductive dechlorination of sucralose mediated by vitamin B12 derivatives2008Conference paper (Other academic)
  • 40.
    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.
    Cob(I)alamin for measuring interspecies variation in butadiene epoxide metabolism in S9 liver fractions and evaluation of in vivo doses estimated from enzyme kinetics and from hemoglobin adductsIn: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333Article in journal (Other academic)
  • 41.
    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.

  • 42.
    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.
    Quantitative analysis by liquid chromatography-tandem mass spectrometry of glycidamide using cob(I)alamin trapping method: Validation and application to in vitro metabolism of acrylamideIn: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778Article in journal (Other academic)
  • 43.
    Motwani, Hitesh V
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Fred, Charlotta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Haglund, Johanna
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Golding, Bernard T
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Cob(I)alamin for trapping butadiene epoxides in metabolism with rat S9 and for determining associated kinetic parameters2009In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 22, no 9, p. 1509-1516Article in journal (Refereed)
    Abstract [en]

    The reduced state of vitamin B(12), cob(I)alamin, acts as a supernucleophile that reacts ca. 10(5) times faster than standard nucleophiles, for example, thiols. Methods have been developed for trapping electrophilically reactive compounds by exploiting this property of cob(I)alamin. 1,3-Butadiene (BD) has recently been classified as a group 1 human carcinogen by the International Agency for Research on Cancer (IARC). The carcinogenicity of BD is considered to be dependent on the activation or deactivation of the reactive metabolites of BD, that is, the epoxides (oxiranes) 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EBdiol). Cytochrome P450 (P450) isozymes are involved in oxidation of BD to EB and further activation to DEB. EB and DEB are hydrolyzed by epoxide hydrolases (EH) to 3,4-dihydroxy-1-butene (BDdiol) and EBdiol, respectively. EBdiol can also be formed by oxidation of BDdiol. In the present study, cob(I)alamin was used for instant trapping of the BD epoxide metabolites generated in in vitro metabolism to study enzyme kinetics. The substrates EB, DEB, and BDdiol were incubated with rat S9 liver fraction, and apparent K(m) and apparent V(max), were determined. The ratio of conversion of EB to DEB (by P450) to the rate of deactivation of DEB by EH was 1.09. Formation of EBdiol from hydrolysis of DEB was ca. 10 times faster than that from oxidation of BDdiol. It was also found that the oxidation of EB to DEB was much faster than that of BDdiol to EBdiol. The study offers comparative enzyme kinetic data of different BD metabolic steps, which is useful for quantitative interspecies comparison. Furthermore, a new application of cob(I)alamin was demonstrated for the measurement of enzyme kinetics of compounds that form electophilically reactive metabolites.

  • 44.
    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.

  • 45.
    Motwani, Hitesh V.
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Qiu, Shiran
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Golding, Bernard T.
    Kylin, Henrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Cob(I)alamin reacts with sucralose to afford an alkylcobalamin: Relevance to in vivo cobalamin and sucralose interaction2011In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 49, no 4, p. 750-757Article in journal (Refereed)
    Abstract [en]

    Vitamin B(12), viz., cyano- or hydroxo-cobalamin, can be chemically or enzymatically converted into the derivatives methyl- and adenosyl-cobalamin, which are complex organometallic cofactors associated with several cobalamin-dependent enzymes. The reduced form of vitamin B(12), cob(I)alamin {Cbl(I)}, obtained by reduction of hydroxocobalamin (OH-Cbl) with e.g. sodium borohydride, is one of the most powerful nucleophiles known. Cbl(I) was shown to react readily with the synthetic sweetener sucralose (1,6-dichloro-1,6-dideoxy-β-d-fructofuranosyl-4-chloro-4-deoxy-α-d-galactopyranoside) in an aqueous system to form an alkylcobalamin (Suc-Cbl). This occurred by replacement of one of the three chlorine atoms of sucralose with a cobalamin moiety. The efficiency of trapping sucralose in presence of excess Cbl(I) was estimated to be >90%. Furthermore, in an in vitro study using human liver S9 with NADPH regeneration, in presence of OH-Cbl and sucralose, Suc-Cbl was shown to be formed. The Suc-Cbl was characterized primarily by LC-ESI(+)-MS/MS. Given the human consumption of sucralose from food and beverages, such a reaction between the sweetener and reduced vitamin B(12) could occur in vivo.

  • 46.
    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.

  • 47. Motwani, Hitesh V.
    et al.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Quantitative analysis by liquid chromatography-tandem mass spectrometry of glycidamide using the cob(I)alamin trapping method: Validation and application to in vitro metabolism of acrylamide2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 28, p. 4389-4394Article in journal (Refereed)
    Abstract [en]

    Glycidamide (GA) is the epoxy metabolite of acrylamide (AA). A sensitive analytical method for quantitative measurement of GA from in vitro metabolism studies is useful in several contexts, e.g. in studies of enzyme kinetics in different species and factors influencing the metabolism of AA to GA. It is however difficult to analyse compounds like GA, mainly due to their inherent reactivity. In the present study cob(I)alamin {Cbl(I)}, a reduced form of vitamin B(12), was used for trapping of GA. Cbl(I) can react with electrophilic species, such as an epoxide, 10(5) times faster than standard nucleophiles. The trapping of GA by Cbl(I) results in the formation of an alkylcobalamin (GA-Cbl) that was used for quantitative analysis of the epoxide. The alkylcobalamin was analysed by LC-MS/MS using an electrospray ionization source in the positive ion mode. The Cbl(I) method was validated for measurement of GA in liver S9 fractions from human and rat. GA levels down to 0.01 mu M were measured in the S9 fractions, providing a sensitivity that was ca. 100 times higher than that earlier estimated by the Cbl(I) method for measurement of other (e.g. butadiene) epoxides. Compared to current analytical methods for measurement of GA, the Cbl(I) method was 10-100 times more sensitive. The method was applied to quantify GA formed from the metabolism of AA in liver S9 from human and rat.

  • 48.
    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.

  • 49. Möller, Kristina
    et al.
    Davies, Ronnie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Fred, Charlotta
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Evaluation of molecularly imprinted solid-phase extraction for a 1,2:3,4-diepoxybutane adduct to valine in haemoglobin2010In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 878, no 27, p. 2497-2501Article in journal (Refereed)
    Abstract [en]

    A molecularly imprinted polymer, MIP, was prepared and evaluated as SPE sorbent for a cyclicized adduct formed to N-terminal valine (Pyr-Val) in hemoglobin from 1,2:3,4-diepoxybutane (DEB). This metabolite plays an important role in the carcinogenesis of 1,3-butadiene. The hydrazide of Pyr-Val, formed after hydrazinolysis of hemoglobin, as well as necessary standards was synthesized. The MIP was prepared from methacrylic acid with a structure analogue to the investigated adduct as template and the method was developed for aqueous conditions. Selective desorption was achieved when the sample was washed with water after loading in 10% acetonitrile. The primary interaction with the binding sites in the imprints was most likely of ionic character. Quantification of the Pyr-Val adduct was performed with LC/ESI-MS/MS, yielding an instrumental LOD of 150 pg injected amount.

  • 50. Naruszewicz, Marek
    et al.
    Zapolska-Downar, Danuta
    Kosmider, Anita
    Nowicka, Grazyna
    Kozlowska-Wojciechowska, Malgorzata
    Vikström, Anna
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Chronic intake of potato chips in humans increases the production of reactive oxygen radicals by leukocytes and increases plasma C-reactive protein: a pilot study.2009In: Am J Clin Nutr, ISSN 0002-9165Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: Relatively high concentrations of acrylamide in commonly ingested food products, such as French fries, potato chips, or cereals, may constitute a potential risk to human health. OBJECTIVE: The objective of this pilot study was to investigate the possible connection between chronic ingestion of acrylamide-containing potato chips and oxidative stress or inflammation. DESIGN: Fourteen healthy volunteers (mean age: 35 y; 8 women and 6 smokers of >20 cigarettes/d) were given 160 g of potato chips containing 157 mg of acrylamide daily for 4 wk. RESULTS: An increase in acrylamide-hemoglobin adducts in blood was found in all the study subjects, with a mean of 43.1 pmol/L/g hemoglobin (range: 27-76; P < 0.01) in nonsmokers and 59.0 pmol . L(-1) . g(-1) hemoglobin (range: 43-132; P < 0.05) in smokers. Concurrently, a significant increase (P < 0.01) in the oxidized LDL, high-sensitivity interleukin-6, high-sensitivity C-reactive protein, and gamma-glutamyltransferase concentrations was observed in both smokers and nonsmokers. A significant increase in reactive oxygen radical production by monocytes, lymphocytes, and granulocytes and an increase in CD14 expression in macrophages (P < 0.001) were found after intake of potato chips. Twenty-eight days from the discontinuation of the experiment, the variables under study decreased to some extent. It has been shown also that acrylamide increases the production of reactive oxygen species in isolated human monocyte-macrophages in vitro and decreases the cellular glutathione concentration. CONCLUSION: These novel findings seem to indicate that chronic ingestion of acrylamide-containing products induces a proinflammatory state, a risk factor for progression of atherosclerosis.

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