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  • 1.
    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.

  • 2.
    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)
  • 3.
    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.

  • 4. 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.

  • 5.
    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.

  • 6. 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.

  • 7.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Juren, Tina
    Myohanen, Kirsi
    Cornelius, Michael
    Abramsson-Zetterberg, Lilianne
    Backman, Josefin
    Menzel, Ulrike
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Kronberg, Leif
    Vahakangas, Kirsi
    Segerback, Dan
    (32)P-HPLC analysis of N1-(2-carboxy-2-hydroxyethyl)deoxyadenosine: A DNA adduct of the acrylamide-derived epoxide glycidamide2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 207, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Acrylamide (AA) is produced in many types of food products cooked or processed at high temperature. AA is metabolized to the epoxide glycidamide (GA), which can bind to deoxyguanosine and deoxyadenosine in DNA. The GA-derived N7-guanine and N3-adenine adducts are the only products which so far have been analysed in vivo. Because of previous excellent experience from analysis of adducts to N1-adenine, the aim of our study was to investigate if the N1-adenine adduct of GA could be used as a biomarker of AA exposure. A (32)P-postlabelling method was developed and tested (a) on DNA modified in vitro with GA, (b) on cells treated with GA and (c) on liver DNA from mice treated with M. The N1-adenine adduct of GA (analysed after conversion to N(6)-GA-deoxyadenosine-5'-monophosphate) was easily detected in DNA reacted with GA and in DNA from cells exposed to GA, but not in DNA from mice treated with AA. The reason for this is currently not clearly understood, but some of the possible contributing factors are discussed. The application of the method in other experimental conditions should be further pursued in order to solve this matter.

  • 8. 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.

  • 9. Pedersen, Marie
    et al.
    von Stedingk, Hans
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Botsivali, Maria
    Agramunt, Silvia
    Alexander, Jan
    Brunborg, Gunnar
    Chatzi, Leda
    Fleming, Sarah
    Fthenou, Eleni
    Granum, Berit
    Gutzkow, Kristine B.
    Hardie, Laura J.
    Knudsen, Lisbeth E.
    Kyrtopoulos, Soterios A.
    Mendez, Michelle A.
    Merlo, Domenico F.
    Nielsen, Jeanette K.
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Segerback, Dan
    Sunyer, Jordi
    Wright, John
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Kleinjans, Jos C.
    Kogevinas, Manolis
    Birth Weight, Head Circumference, and Prenatal Exposure to Acrylamide from Maternal Diet: The European Prospective Mother-Child Study (NewGeneris)2012In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 120, no 12, p. 1739-1745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. OBJECTIVES: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother child study. METHODS: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires. RESULTS: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for Factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. CONCLUSIONS: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. IF confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.

  • 10.
    Rydberg, Per
    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).
    Magnér, Jörgen
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Björklund, Jonas
    LC/MS/MS analysis of N-terminal protein adducts with improved sensitivity: A comparison of selected Edman isothiocyanate reagents.2009In: International Journal of Analytical Chemistry, ISSN 1687-8779Article in journal (Refereed)
    Abstract [en]

    This study provides a basis for a new and straightforward method for LC/MS/MS-based screening of N-terminal protein adducts. This procedure is denoted the “FIRE procedure” as fluorescein isothiocyanate (FITC) gave superior sensitivity by LC/MS/MS when measuring adducts (R) of electrophilic compounds with a modified Edman procedure. The principles of the FIRE-procedure are that adducts to N-terminal amino acids selectively are detached and measured from of proteins after derivatisation by isothiocyanate Edman reagents. In this study, FITC, 4-N,N-dimethylaminoazobenzene 4′-isothiocyanate (DABITC) and 4-dimethylamino-1-naphthyl isothiocyanate (DNITC) were used to synthesize thiohydantoin analytes from valine and N-methylvaline. The sensitivity by LC/MS/MS was enhanced by up to three orders of magnitude as compared to phenyl isothiocyanate and higher as compared to pentafluorophenyl isothiocyanate. The FITC reagent will enable measurements of low background adduct levels. Synthesized analytes were characterised with, for example, 1H NMR, 13C NMR, LC/MS/MS, and UV.

  • 11.
    von Stedingk, Hans
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Davies, Ronnie
    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).
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Methyl vinyl ketone – identification and quantification of adduct to N-terminal valine in human haemoglobin2010In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 878, no 27, p. 2491-2496Article in journal (Refereed)
    Abstract [en]

    Adducts to N-terminal valines in Hb have been shown useful as biomarkers of exposure to electrophilic compounds. Adducts from many compounds have earlier been measured with a modified Edman degradation method using a GC–MS/MS method. A recently developed method, the adduct FIRE procedure™, adopted for analysis by LC–MS/MS, has been applied in this study. With this method a fluorescein isothiocyanate (FITC) reagent is used to measure adducts (R) from electrophiles with a modified Edman procedure. By using LC–MS/MS in product ion scan mode, a new peak was identified and the obtained MS data indicated that this adduct could originate from methyl vinyl ketone (MVK). Incubation of human-, sheep- and bovine blood with MVK increased the signal of the identified peak. By comparing the LC–MS/MS data from the unknown background peak with data obtained from synthesized fluorescein thiohydantoin (FTH) standards of the MVK adduct to valine and d8-valine, the identity of this adduct was confirmed. The MVK adduct was shown present in human blood (35 pmol/g globin, n = 3) and only just above LOD in bovine blood, n = 1 (LOD = 2 pmol/g globin). MVK reacts, in similarity with acrylamide, via Michael addition. MVK is known to occur in the environment and has earlier been observed in biological samples, which means that there are possible natural and anthropogenic exposure sources. Analysis of an Hb adduct from MVK in humans has to our knowledge not been described before.

  • 12.
    von Stedingk, Hans
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Mose, Tina
    Pedersen, Marie
    Knudsen, Lisbeth
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Biomarkers of exposure- analysis of Haemoglobin adducts formed from acrylamide, glycidamide and ethylene oxide in pregnent mothers and cord blood2008In: European Environmental Mutagen Society: 38th annual meeting, 2008, p. 284-Conference paper (Other academic)
  • 13.
    von Stedingk, Hans
    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).
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    A new modified Edman procedure for analysis of N-terminal valine adducts in hemoglobin by LC-MS/MS2010In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 878, no 27, p. 2483-2490Article in journal (Refereed)
    Abstract [en]

    A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneous determination of adducts from acrylamide, glycidamide and ethylene oxide to N-terminal valines in hemoglobin (Hb) was developed. This new procedure is based on the same principles as the N-alkyl Edman procedure for analysis of adducts from electrophilic agents to N-terminal valines in Hb. The N-substituted valines can be detached, enriched and measured selectively as thiohydantoins by the use of an Edman reagent, in this case fluorescein isothiocyanate (FITC). This procedure is denoted as the "adduct FIRE procedure" as the FITC reagent is used for measurement of adducts ((R) under bar) formed from electrophilic compounds with a modified Edman procedure. In this study, fluorescein thiohydantoin (FTH) analytes of N-substituted valines from acrylamicle, glycidamide and ethylene oxide, as well as their corresponding hepta- and tri-deuterium-substituted analogues, were synthesized. These analytes (n = 8) were then characterized by LC-MS/MS (ESI, positive ion mode) and obtained product ions were interpreted. A considerable work with optimization of the FIRE procedure (TM), resulted in a procedure in which low background levels of the studied adducts could be measured from 250 mu L lyzed whole blood samples (human non-smokers). The analytes were enriched and purified with solid phase extraction columns and analyzed by LC-MS/MS with LOQ clown to 1 pmol adduct/g Hb. Compared to other procedures for determination of N-terminal Hb adducts, the introduction of FITC has led to a simplified procedure, where whole blood also can be used, giving new opportunities and reduced hand on time with increased sample throughput.

  • 14.
    von Stedingk, Hans
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Vikström, Anna
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Pedersen, Marie
    Nielsen, Jeanette K.S.
    Segerbäck, Dan
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Analysis of hemoglobin adducts from acrylamide, glycidamide and ethylene oxide in paired mother/cordblood samples from Denmark2011In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 24, no 11, p. 1957-1965Article in journal (Refereed)
    Abstract [en]

    The knowledge about fetal exposure to acrylamide/glycidamide from the maternal exposure through food is limited. Acrylamide, glycidamide, and ethylene oxide are electrophiles and form adducts with hemoglobin (Hb), which could be used for in vivo dose measurement. In this study, a method for analysis of Hb adducts by liquid chromatography–mass spectrometry, the adduct FIRE procedure, was applied to measurements of adducts from these compounds in maternal blood samples (n = 87) and umbilical cord blood samples (n = 219). The adduct levels from the three compounds, acrylamide, glycidamide, and ethylene oxide, were increased in tobacco smokers. Highly significant correlations were found between cord and maternal blood with regard to measured adduct levels of the three compounds. The mean cord/maternal hemoglobin adduct level ratios were 0.48 (range 0.27–0.86) for acrylamide, 0.38 (range 0.20–0.73) for glycidamide, and 0.43 (range 0.17–1.34) for ethylene oxide. In vitro studies with acrylamide and glycidamide showed a lower (0.38–0.48) rate of adduct formation with Hb in cord blood than with Hb in maternal blood, which is compatible with the structural differences in fetal and adult Hb. Together, these results indicate a similar life span of fetal and maternal erythrocytes. The results showed that the in vivo dose in fetal and maternal blood is about the same and that the placenta gives negligible protection of the fetus to exposure from the investigated compounds. A trend of higher levels of the measured adducts in cord blood with gestational age was observed, which may reflect the gestational age-related change of the cord blood Hb composition toward a higher content of adult Hb. The results suggest that the Hb adduct levels measured in cord blood reflect the exposure to the fetus during the third trimester. The evaluation of the new analytical method showed that it is suitable for monitoring of background exposures of the investigated electrophilic compounds in large population studies.

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