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  • 1. DeJongh, J
    et al.
    Nordin-Andersson, M
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ploeger, B A
    Forsby, A
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Estimation of systemic toxicity of acrylamide by integration of in vitro toxicity data with kinetic simulations.1999In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 158, no 3, p. 261-268Article in journal (Refereed)
    Abstract [en]

    Neurodegenerative properties of acrylamide were studied in vitro by exposure of differentiated SH-SY5Y human neuroblastoma cells for 72 h. The number of neurites per cell and the total cellular protein content were determined every 24 h throughout the exposure and the subsequent 96-h recovery period. Using kinetic data on the metabolism of acrylamide in rat, a biokinetic model was constructed in which the in vitro toxicity data were integrated. Using this model, we estimated the acute and subchronic toxicity of acrylamide for the rat in vivo. These estimations were compared to experimentally derived lowest observed effect doses (LOEDs) for daily intraperitoneal exposure (1, 10, 30, and 90 days) to acrylamide. The estimated LOEDs differed maximally twofold from the experimental LOEDs, and the nonlinear response to acrylamide exposure over time was simulated correctly. It is concluded that the integration of the present in vitro toxicity data with kinetic data gives adequate estimates of acute and subchronic neurotoxicity resulting from acrylamide exposure.

  • 2.
    Gustafsson, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lindegren, Heléne
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Axelsson, Viktoria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Neurofunctional endpoints assessed in human neuroblastoma SH-SY5Y cells for estimation of acute systemic toxicity2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 245, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    The objective of the EU-funded integrated project ACuteTox is to develop a strategy in which general cytotoxicity, together with organ-specific toxicity and biokinetic features, are used for the estimation of human acute systemic toxicity. Our role in the project is to characterise the effect of reference chemicals with regard to neurotoxicity. We studied cell membrane potential (CMP), noradrenalin (NA) uptake, acetylcholine esterase (AChE) activity, acetylcholine receptor (AChR) signalling and voltage-operated calcium channel (VOCC) function in human neuroblastoma SH-SY5Y cells after exposure to 23 pharmaceuticals, pesticides or industrial chemicals. Neurotoxic alert chemicals were identified by comparing the obtained data with cytotoxicity data from the neutral red uptake assay in 3T3 mouse fibroblasts. Furthermore, neurotoxic concentrations were correlated with estimated human lethal blood concentrations (LC50). The CMP assay was the most sensitive assay, identifying eight chemicals as neurotoxic alerts and improving the LC50 correlation for nicotine, lindane, atropine and methadone. The NA uptake assay identified five neurotoxic alert chemicals and improved the LC50 correlation for atropine, diazepam, verapamil and methadone. The AChE, AChR and VOCC assays showed limited potential for detection of acute toxicity. The CMP assay was further evaluated by testing 36 additional reference chemicals. Five neurotoxic alert chemicals were generated and orphendrine and amitriptyline showed improved LC50 correlation. Due to the high sensitivity and the simplicity of the test protocol, the CMP assay constitutes a good candidate assay to be included in an in vitro test strategy for prediction of acute systemic toxicity.

  • 3. 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.

  • 4.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Kinsner-Ovaskainen, Agnieszka
    In vitro toxicology unit.
    Hartung, Thomas
    Traceability, Risk and Vulnerability Assessment.
    Coecke, Sandra
    In vitro toxicology unit.
    Bal-Price, Anna
    In vitro toxicology unit.
    Gene expression as a sensitive endpoint to evaluate cell differentiation andmaturation of the developing central nervous system in primary cultures of ratcerebellar granule cells (CGCs) exposed to pesticides2009In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 235, p. 268-286Article in journal (Refereed)
    Abstract [en]

    The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides signi different stages of neuronal and/or glial cell development and maturation. The most signi observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA expression of NF-68 and GABA as signi astrocyte marker (S100 multiple pathways of neurodevelopment can be identi in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity. A receptors), proliferation and differentiation of astrocytes (GFAP and S100β) as well as theficantly modified the expression of selected genes, related to theficant changes wereA receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNAA receptors) whereas cycloheximide had an effect on neurons and astrocytes,ficant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and theβ) were observed. Our results suggest that toxicity induced by pesticides that targetfied by studying expression of genes that are involved

  • 5. Jarvis, Ian W. H.
    et al.
    Bergvall, Christoffer
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bottai, Matteo
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Stenius, Ulla
    Dreij, Kristian
    Persistent activation of DNA damage signaling in response to complex mixtures of PAHs in air particulate matter2013In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 266, no 3, p. 408-418Article in journal (Refereed)
    Abstract [en]

    Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are present in air particulate matter (PM) and have been associated with many adverse human health effects including cancer and respiratory disease. However, due to their complexity, the risk of exposure to mixtures is difficult to estimate. In the present study the effects of binary mixtures of benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and complex mixtures of PAHs in urban air PM extracts on DNA damage signaling was investigated. Applying a statistical model to the data we observed a more than additive response for binary mixtures of BP and DBP on activation of DNA damage signaling. Persistent activation of checkpoint kinase 1 (Chk1) was observed at significantly lower BP equivalent concentrations in air PM extracts than BP alone. Activation of DNA damage signaling was also more persistent in air PM fractions containing PAHs with more than four aromatic rings suggesting larger PAHs contribute a greater risk to human health. Altogether our data suggests that human health risk assessment based on additivity such as toxicity equivalency factor scales may significantly underestimate the risk of exposure to complex mixtures of PAHs. The data confirms our previous findings with PAH-contaminated soil (Niziolek-Kierecka et al., 2012) and suggests a possible role for Chk1 Ser317 phosphorylation as a biological marker for future analyses of complex mixtures of PAHs.

  • 6.
    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)
  • 7.
    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.

  • 8. Noaksson, Erik
    et al.
    Gustavsson, Bodil
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Linderoth, Maria
    Zebühr, Yngve
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Broman, Dag
    Balk, Lennart
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Gonad development and plasma steroid profiles by HRGC/HRMS during one reproductive cycle in reference and leachate-exposed female perch (Perca fluviatilis)2004In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 195, no 2, p. 247-261Article in journal (Refereed)
    Abstract [en]

    Endocrine processes were studied in reference female perch (Perca fluviatilis) from Lake Djursjön and in leachate-exposed females from Lake Molnbyggen during one reproductive cycle. A high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) technique enabled the analysis of circulating sex steroids [progesterone (P), 17α-hydroxyprogesterone (17α-OHP), androstenedione (A), testosterone (T), estrone (E1), and 17β-estradiol (E2)], the maturation-inducing hormone (MIH) 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-P), and glucocorticoids [11-deoxycortisol (11-DC) and cortisol]. Body and organ measurements, ratio of sexually mature (SM) females, and frequencies of body lesions, were also recorded. High frequencies of body lesions and a low ratio of SM females were generally found in Molnbyggen. These females also had lower gonadosomatic index (GSI) and liver-somatic index (LSI) in the early stages of vitellogenesis, indicating either a delayed onset of oogenesis or an impaired vitellogenesis. Non-reproducing females from both lakes showed a similar LSI cycle as SM females. Increasing T and A levels in SM females from Djursjön coincided with the GSI peak at the time of spawning. These two androgens were on several occasions lower in SM females from Molnbyggen, possibly the result of a disrupted 17,20-lyase activity of the P450 17α enzyme because only minor effects were observed on circulating P and 17α-OHP levels. E2 and E1 levels increased during vitellogenesis in females from both lakes, with E1 levels more closely resembling the peaks of A and GSI. Peak levels of 17α,20β-P at the time of spawning confirmed its function as the MIH in perch, while the simultaneous peak of 11-DC suggests that it also may be involved in final maturation of the oocytes.

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