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  • 1.
    Andersson, Britta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Janson, Veronica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.2006In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 6, p. 986-994Article in journal (Refereed)
  • 2.
    Andersson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evaluation of catechol-induced DNA damage in human lymphocytes: A comparison between freshly isolated lymphocytes and T-lymphocytes from extended-term cultures2007In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 21, no 4, p. 716-722Article in journal (Refereed)
    Abstract [en]

    Extended-term cultures of proliferating human T-lymphocytes (ETC) may be a practical alternative to freshly isolated non-proliferating peripheral blood lymphocytes (PBL) when studying genotoxicity in vitro. To investigate if the pattern of DNA damage differs between the two in vitro systems, catechol-induced DNA damage was evaluated in PBL and ETC derived from the same blood sample, using three different donors. DNA damage was monitored using the comet assay. Whereas 3 h of exposure to 0.5 mM catechol was found to be without DNA damaging effects, 3 mM was found to induce significant damage both in the PBL and the ETC (the latter being clearly less sensitive). The level of reactive oxygen species (ROS) was also measured in the ETC using the fluorescent probe carboxy-H2DCFA. ROS was found to be considerably increased both at 0.5 and 3 mM catechol. The demonstrated difference in sensitivity towards catechol-induced DNA damage between PBL and ETC may be due to their different proliferative status, but despite this difference both in vitro systems were able to identify catechol as a DNA damaging agent at the same concentration.

  • 3.
    Andres, M I
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, A
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Walum, E
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Polygodial-induced noradrenaline release in human neuroblastoma SH-SY5Y cells.1997In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 11, no 5, p. 509-11Article in journal (Refereed)
    Abstract [en]

    Polygodial is a natural sesquiterpene which exhibits pronounced pungency and a powerful antifeedant activity. At low concentrations, which do not alter general cell membrane permeability, polygodial increases the intracellular concentration of free calcium ([Ca(2+)](i)). Sensory neurotransmission depends on noradrenaline (NA) release, and vesicular exocytosis, in turn, is dependent on an increase in [Ca(2+)](i). The nociceptive response induced by polygodial could therefore be directly linked to intracellular calcium levels. Consequently, the objective of this work was to investigate the effect of polygodial on NA release. The human neuroblastoma cell line SH-SY5Y was selected as an in vitro model for sensory neurones. Semiconfluent cells were preloaded with tritiated NA ([(3)H]NA). After 3 min exposure of polygodial to the cells, released and unreleased radioactivity were measured. Polygodial induced a significant [(3)H]NA release at concentrations between 0.1 and 0.5 mug/ml with a maximum effect at 0.2 mug/ml (40% increased release of [(3)H]NA as compared with unstimulated control cells). No polygodial-induced transmitter release was seen at 3.5 and 5 mug/ml. For comparison, carbachol (1 rim) increased [(3)H]NA release by 10% and the KCl-induced (100 mm) [(3)H]NA release increased by 8% as compared with unstimulated SH-SY5Y cells. In conclusion polygodial, at the concentrations 0.1-0.5 mug/ml (equal to 0.4-2 mum), induces NA release which is dependent on polygodial-induced increase in [Ca(2+)](i).

  • 4.
    Asnake, Solomon
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and act as potential endocrine disrupters in chicken LMH cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 8, p. 1993-2000Article in journal (Refereed)
    Abstract [en]

    Increased exposure of birds to endocrine disrupting compounds has resulted in developmental and reproductive dysfunctions. We have recently identified the flame retardants, ally1-2,4,6-tribromophenyl ether (TBP-AE), 2-3-dibromopropy1-2,4,6-tribromophenyl ether (TBP-DBPE) and the TBP-DBPE metabolite 2-bromoallyI-2,4,6-tribromophenyl ether (TBP-BAE) as antagonists to both the human androgen receptor (AR) and the zebrafish AR. In the present study, we aimed at determining whether these compounds also interact with the chicken AR. In silico modeling studies showed that TBP-AE, TBP-BAE and TBP-DBPE were able to dock into to the chicken AR ligand-binding pocket. In vitro transfection assays revealed that all three brominated compounds acted as chicken AR antagonists, inhibiting testosterone induced AR activation. In addition, qRT-PCR studies confirmed that they act as AR antagonists and demonstrated that they also alter gene expression patterns of apoptotic, anti-apoptotic, drug metabolizing and amino acid transporter genes. These studies, using chicken LMH cells, suggest that TBP-AE, TBP-BAE and TBP-DBPE are potential endocrine disrupters in chicken.

  • 5.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, S.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm Univ, Dept Neurochem, S-10691 Stockholm, Sweden.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 35, p. 100-111Article in journal (Refereed)
    Abstract [en]

    Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10 fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10 pM. Acrylamide significantly reduced the number of neurons starting at 1 mu M and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide.

  • 6.
    Bergquist, Jonas
    et al.
    Unité INSERM 303, BP no. 3, 06230 Villefranche-sur-Mer, France.
    Strandberg, C
    Unité INSERM 303, BP no. 3, 06230 Villefranche-sur-Mer, France.
    Andersson, M
    Unité INSERM 303, BP no. 3, 06230 Villefranche-sur-Mer, France.
    Sterner, O
    Department of Organic Chemistry 2, Chemical Center, University of Lund.
    Pesando, D
    Unité INSERM 303, BP no. 3, 06230 Villefranche-sur-Mer, France.
    Girard, J P
    Laboratoire de Physiologie Cellulaire et Comparée, URA CNRS 651, Faculté des Sciences, France.
    Structure-activity relationships for unsaturated dialdehydes 8( *). Comparative effects of 10 sesquiterpenoids on the sea urchin gamete fertilization.1993In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 7, no 3, p. 205-12Article in journal (Refereed)
    Abstract [en]

    The effects of 10 sesquiterpenoids with unsaturated dialdehyde functionalities were studied on fertilization, first cleavage, and calcium permeability of egg membranes of sea urchin gametes. Fertilization was inhibited by nine compounds when sperm was exposed and by five compounds when eggs were exposed (50 mug/ml for 5 min). All compounds except one (9alpha-hydroxymerulidial) inhibited the first cleavage in a dose-response manner. Only one compound (velleral) increased the Ca(2+) permeability of egg membranes at 20 mug/ml. All compounds reduced to a varying extent the ATP-driven Ca(2+) sequestration by non-mitochondrial intracellular compartments. In general, when hydroxylated and non-hydroxylated derivatives of the compounds are compared, the hydroxylated ones present a lower toxicity when measuring fertilization and cleavage inhibition, and reduction of intracellular Ca(2+) sequestration.

  • 7.
    De Jong, Wim H.
    et al.
    RIVM National Institute for Public Health and the Environment, The Netherlands.
    Hoffmann, Sebastian
    Seh consulting + services, Germany.
    Lee, Michelle
    Nelson Laboratories Inc., USA.
    Kandárová, Helena
    MatVitro Life Science Laboratories, Slovakia.
    Pellevoisin, Christian
    EPISKIN, France.
    Haishima, Yuji
    NIHS National Institute of Health Sciences, Japan.
    Rollins, Beau
    Arthrex Inc., USA.
    Zdawczyk, Austin
    NAMSA, USA.
    Willoughby, Jamin
    Cyprotex US LCC, USA.
    Bachelor, Michael
    MatTek Corporation, USA.
    Schatz, Timothy
    American Preclinical Services LLC, USA.
    Skoog, Shelby
    US Food and Drug Administration, USA.
    Parker, Sherry
    WuXi AppTec, USA.
    Sawyer, Anita
    Becton Dickinson, USA.
    Pescio, Paolo
    Eurofins Biolab Srl., Italy.
    Fant, Kristina
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Kim, Kwang-Mahn
    Yonsei University, South Korea.
    Kwon, Jae Sung
    Yonsei University, South Korea.
    Gehrke, Helge
    Eurofins Biopharma, Germany.
    Hofman-Hüther, Hana
    Eurofins Biopharma, Germany.
    Meloni, Morisa
    VitroScreen, Italy.
    Julius, Conrad
    Envigo CRS GmbH, Germany.
    Briotet, Damien
    NAMSA, France.
    Letasiova, Silvia
    MatTek In Vitro Life Science Laboratories, Slovakia.
    Kato, Reiko
    NIHS National Institute of Health Sciences, Japan.
    Miyajima, Atsuko
    NIHS National Institute of Health Sciences, Japan.
    De La Fonteyne, Liset J. J.
    RIVM National Institute for Public Health and the Environment, The Netherlands.
    Videau, Christelle
    EPISKIN, France.
    Tornier, Carine
    EPISKIN, France.
    Turley, Audrey P.
    Nelson Laboratories Inc., USA.
    Christiano, Nicholas
    Arthrex Inc., USA.
    Rollins, Thor S.
    Nelson Laboratories Inc., USA.
    Coleman, Kelly P.
    Medtronic plc, USA.
    Round robin study to evaluate the reconstructed human epidermis (RhE) model as an in vitro skin irritation test for detection of irritant activity in medical device extracts2018In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 50, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Assessment of skin irritation is an essential component of the safety evaluation of medical devices. OECD Test Guideline 439 describes the use of reconstructed human epidermis (RhE) as an in vitro test system for classification of skin irritation by neat chemicals. An international round robin study was conducted to evaluate the RhE method for determination of skin irritant potential of medical device extracts. Four irritant polymers and three non-irritant controls were obtained or developed that had demonstrated their suitability to act as positive or negative test samples. The RhE tissues (EpiDerm™ and SkinEthic™ RHE) were dosed with 100 μL aliquots of either saline or sesame oil extract. Incubation times were 18 h (EpiDerm™) and 24 h (SkinEthic™ RHE). Cell viability reduction > 50% was indicative of skin irritation. Both the EpiDerm™ and SkinEthic™ RHE tissues were able to correctly identify virtually all of the irritant polymer samples either in the saline, sesame oil or both solvent extracts. Our results indicate that RhE tissue models can detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts. Therefore, these models may be suitable replacements for the rabbit skin irritation test to support the biological evaluation of medical devices.

  • 8. Dejongh, J
    et al.
    Forsby, A
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Houston, J B
    Beckman, M
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Combes, R
    Blaauboer, B J
    An Integrated Approach to the Prediction of Systemic Toxicity using Computer-based Biokinetic Models and Biological In vitro Test Methods: Overview of a Prevalidation Study Based on the ECITTS Project.1999In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 13, no 4-5, p. 549-54Article in journal (Refereed)
    Abstract [en]

    Chemical toxicity was estimated by integrating in vitro study results with physiologically-based biokinetic models for eight neurotoxic compounds (benzene, toluene, lindane, acrylamide, parathion/oxon, caffeine, diazepam and phenytoin). In vitro studies on general and specific neurotoxicity were performed and biotransformation and tissue-blood distribution studies were used in modelling the biokinetic behaviour of the compounds. Subsequently, neurotoxicity was estimated from the integrated in vitro and kinetic studies. These results were compared with in vivo data from the literature on minimal neurotoxicity for these compounds, such as lowest-observed-effect levels (LOELs). The discrepancy between estimated and experimental LOELs ranged from 2- to 10-fold. LOEL estimates for compounds with a relatively low toxicity were more accurate than for compounds with a relatively high toxicity. LOELs for the most active compounds could only be established after consideration of additional in vitro results from the literature. The present study has generated encouraging results on the risk assessment of chemicals from in vitro studies and computer simulations and has identified some key directions for future research.

  • 9.
    Demma, Jemal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Genotoxicity of plumbagin and its effects on catechol and NQNO-induced DNA damage in mouse lymphoma cells2009In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 23, no 2, p. 266-271Article in journal (Refereed)
    Abstract [en]

    Plumbagin, a naphtoquinone present in the roots of Plumbago zeylanica, has been reported to have many beneficial effects such as antibacterial, antifungal, anticancer, antimutagenic and antioxidant effects, but this compound has also been reported to have many side   effects. Given the wide use of P. zeylanica in traditional medicine and the various potential therapeutic uses of plumbagin, the present study was carried out to further elucidate the potential genotoxicity and antigenotoxicity of plumbagin in mouse lymphoma L5178Y cells, using the comet assay. Without affecting the cell viability, plumbagin itself was found to induce significant DNA damage at concentrations as low as 0.25 ng/ml. When the cells were exposed to non-DNA damaging concentrations of plumbagin, together with NQNO (known to interact with DNA in many different ways) or catechol (known to induce oxidative DNA damage), plumbagin was found to significantly reduce the catechol-induced DNA   damage, but to be without protective effect against the NQNO-induced damage. The fact that non-DNA damaging concentrations of plumbagin diminished the DNA damage induced by catechol, provides further support for the idea that plumbagin may act as an antioxidative agent at low concentrations.

  • 10. Ekstrand-Hammarström, Barbro
    et al.
    Magnusson, Roger
    Österlund, Camilla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Andersson, Britt M.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Wingfors, Håkan
    Oxidative stress and cytokine expression in respiratory epithelial cells exposed to well-characterized aerosols from Kabul, Afghanistan2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 825-833Article in journal (Refereed)
    Abstract [en]

    In this study aerosol samples collected in an Asian mega-city (Kabul, Afghanistan) were compared to PM samples collected in a European location with traffic (Umea, Sweden) and a reference urban dust material (SRM 1649b). The toxicity of each sample towards normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) was tested along with their ability to induce reactive oxygen species (ROS) formation and inflammatory responses. The extracts' morphology and elemental composition was studied by SEM-EDXRF, and filter samples were analyzed for metals and organic compounds. The PM from Kabul contained a larger fraction of fine particles, 19 times more polyaromatic hydrocarbons (PAH) and 37 times more oxygenated PAH (oxy-PAH) compared to samples from timed. The PM-samples from Kabul and the reference material (SRM 1649b) induced significantly stronger oxidative stress responses than the samples from Umea. Furthermore, samples collected in Kabul induced significantly higher secretion of the cytokines IL-6, IL-8 and GM-CSF while SRM1649b induced a cytokine pattern more similar to samples collected in Umea. Several properties of the particles could potentially explain these differences, including differences in their size distribution and contents of PAH and oxy-PAH, possibly in combination with their relative transition metal contents. 

  • 11.
    Folch, Jaume
    et al.
    Unitat de Bioquimica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Tarragona, Spain.
    Alvira, Daniel
    Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
    López-Querol, Marta
    Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Tarragona, Spain.
    Tajes, Marta
    Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
    Sureda, Francesc X
    Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Tarragona, Spain.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Rimbau, Víctor
    Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
    Camins, Antoni
    Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
    Pallàs, Mercè
    Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
    Evaluation of transcriptional activity of caspase-3 gene as a marker of acute neurotoxicity in rat cerebellar granular cells2010In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 24, no 2, p. 465-471Article in journal (Refereed)
    Abstract [en]

    Caspase-3 is a key protein involved in the classical apoptosis mechanism in neurons, as in many other cells types. In the present research, we describe the transcriptional activity of caspase-3 gene as a marker of acute toxicity in a primary culture model of rat cerebellar granule neurons (CGNs). CGNs were incubated for 16h in complete medium containing the chemicals at three concentrations (10, 100 μM and 1 mM). A total of 48 different compounds were tested. Gene transcriptional activity was determined by low-density array assays, and by single Taqman caspase-3 assays. Results from the PCR arrays showed that the caspase-3 gene was up-regulated when CGNs were exposed to neurotoxic chemicals. Significative correlations were found between the transcriptional activity of caspase-3 and the activity of some other genes related to apoptosis, cell-cycle and ROS detoxification. In our experiments, acute exposure of CGNs to well-documented pro-apoptotic xenobiotics modulated significantly caspase-3 gene expression, whereas chemicals not related to apoptosis did not modify caspase-3 gene expression. In conclusion, acute exposure of CGNs to neurotoxic compounds modulates the transcriptional activity of genes involved in the classical apoptotic pathway, oxidative stress and cell-cycle control. Transcriptional activity of caspase-3 correlates significantly with these changes and it could be a good indicator of acute neurotoxicity.

  • 12. Forreryd, Andy
    et al.
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Karolinska Institutet, Sweden.
    Lindberg, Tim
    Lindstedt, Malin
    Predicting skin sensitizers with confidence - Using conformal prediction to determine applicability domain of GARD2018In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 48, p. 179-187Article in journal (Refereed)
    Abstract [en]

    GARD - Genomic Allergen Rapid Detection is a cell based alternative to animal testing for identification of skin sensitizers. The assay is based on a biomarker signature comprising 200 genes measured in an in vitro model of dendritic cells following chemical stimulations, and consistently reports predictive performances similar to 90% for classification of external test sets. Within the field of in vitro skin sensitization testing, definition of applicability domain is often neglected by test developers, and assays are often considered applicable across the entire chemical space. This study complements previous assessments of model performance with an estimate of confidence in individual classifications, as well as a statistically valid determination of the applicability domain for the GARD assay. Conformal prediction was implemented into current GARD protocols, and a large external test dataset (n = 70) was classified at a confidence level of 85%, to generate a valid model with a balanced accuracy of 88%, with none of the tested chemical reactivity domains identified as outside the applicability domain of the assay. In conclusion, results presented in this study complement previously reported predictive performances of GARD with a statistically valid assessment of uncertainty in each individual prediction, thus allowing for classification of skin sensitizers with confidence.

  • 13.
    Hackett, JM
    et al.
    Ottawa Hosp, Res Inst, Ottawa, ON K1H 8L6 Canada.
    Ferguson, C
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    Dare, E
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    McLaughlin, CR
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Optimal neural differentiation and extension of hybrid neuroblastoma cells (NDC) for nerve-target evaluations using a multifactorial approach2010In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 24, no 2, p. 567-577Article in journal (Refereed)
    Abstract [en]

    In vitro models of tissues, such as the cornea, represent systems for modeling cell-to-cell interactions and tissue function. The objective of this study was to develop an optimized nerve differentiation medium to incorporate into a 3D in vitro model to study innervation and cell targeting. A hybrid neuroblastoma cell line (NDC) was examined for its ability to differentiate into neurons, produce neurites, and functionally contact target cells. Neuronal differentiation of NDCs was optimized through a combinatorial approach which involved culturing cells in the presence of various extracellular matrices and soluble factors. A serum-free medium containing nerve growth factor (NGF), dimethyl sulfoxide (DMSO), or dexamethasone resulted in the greatest proportion of NDCs demonstrating a neuronal morphology. Similarly, with supplementation of cyclic AMP (cAMP) or NGF, neurite extension was optimized. Combining these factors generated an optimized differentiation and extension medium, relative to the individual components alone. In co-culture with epithelial cells, NDC neurites generated in the optimized medium formed contacts with epithelial targets and produced substance P. Similarly, NDCs seeded into a collagen matrix produced neurites that projected through the matrix to target epithelial cells, promoted epithelial stratification, and increased the rate of epithelial wound healing. As well, differentiated NDCs could target and alter acetylcholine receptor clustering in mouse C2C12 myotubes, demonstrating synaptic plasticity. Our data supports the use of NDCs, in combination with optimized medium, for generating an innervated in vitro model. (C) 2009 Elsevier Ltd. All rights reserved.

  • 14. Hamm, Jon
    et al.
    Sullivan, Kristie
    Clippinger, Amy J.
    Strickland, Judy
    Bell, Shannon
    Bhhatarai, Barun
    Blaauboer, Bas
    Casey, Warren
    Dorman, David
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry. Swedish Toxicology Sciences Research Center (Swetox), Sweden.
    Garcia-Reyero, Natàlia
    Gehen, Sean
    Graepel, Rabea
    Hotchkiss, Jon
    Lowit, Anna
    Matheson, Joanna
    Reaves, Elissa
    Scarano, Louis
    Sprankle, Catherine
    Tunkel, Jay
    Wilson, Dan
    Xia, Menghang
    Zhu, Hao
    Allen, David
    Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing2017In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 41, p. 245-259Article, review/survey (Refereed)
    Abstract [en]

    Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants.

  • 15.
    Hassan, Saadia B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity2007In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 21, no 6, p. 1174-1181Article in journal (Refereed)
    Abstract [en]

    Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50–300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.

  • 16.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca Gothenburg, CVMD GMed, GMD, Mölndal, Sweden.
    MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 34, p. 26-34Article in journal (Refereed)
    Abstract [en]

    Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity.

  • 17.
    Johansson, M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Sanderson, J. T.
    Lund, B-O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line2002In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 16, no 2, p. 113-121Article in journal (Refereed)
    Abstract [en]

    The formation of steroids in the H295R human adrenocortical carcinoma cell line was analysed by HPLC or RIA, and based on these data the apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in this cell line were calculated. The environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP) inhibitors ketoconazole, metyrapone and aminoglutethimide were studied for their effects on the steroid formation. Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM). Aminoglutethimide was examined only for effects on CYP11A activity and was shown to inhibit pregnenolone formation (20 microM: 61 +/- 4% of control). The possibility of studying all CYP enzymes in the corticosteroidogenesis makes this cell line a valuable test system to examine effects of chemicals, such as suspected endocrine disruptors, on the human glucocorticoid hormone synthesis. The inhibition of cortisol formation by 3-MeSO2-DDE supports an interaction with the active site of CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In mice, this interaction led to metabolic activation and a high adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity of 3-MeSO2-DDE in humans are needed.

  • 18.
    Kotova, N.
    et al.
    Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden..
    Hebert, N.
    Univ Paris 06, UMR CDR St Antoine Proliferat & Differentiat Cell, Paris, France.;INSERM, UMR Proliferat & Differentiat Cellules Souches S9, Paris, France.;Etab Francais Sang Ile France, Ivry, France..
    Harnwall, E-L
    Vare, D.
    Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden..
    Mazurier, C.
    Univ Paris 06, UMR CDR St Antoine Proliferat & Differentiat Cell, Paris, France.;INSERM, UMR Proliferat & Differentiat Cellules Souches S9, Paris, France.;Etab Francais Sang Ile France, Ivry, France..
    Douay, L.
    Univ Paris 06, UMR CDR St Antoine Proliferat & Differentiat Cell, Paris, France.;INSERM, UMR Proliferat & Differentiat Cellules Souches S9, Paris, France.;Etab Francais Sang Ile France, Ivry, France.;Hop St Antoine, AP HP, Serv Hematol Biol, F-75571 Paris, France..
    Jenssen, D.
    Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden..
    Grawé, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    A novel micronucleus in vitro assay utilizing human hematopoietic stem cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 7, p. 1897-1905Article in journal (Refereed)
    Abstract [en]

    The induction of micronucleated reticulocytes in the bone marrow is a sensitive indicator of chromosomal damage. Therefore, the micronucleus assay in rodents is widely used in genotoxicity and carcinogenicity testing. A test system based on cultured human primary cells could potentially provide better prediction compared to animal tests, increasing patient safety while also implementing the 3Rs principle, i.e. replace, reduce and refine. Hereby, we describe the development of an in vitro micronucleus assay based on animal-free ex vivo culture of human red blood cells from hematopoietic stem cells. To validate the method, five clastogens with direct action, three clastogens requiring metabolic activation, four aneugenic and three non-genotoxic compounds have been tested. Also, different metabolic systems have been applied. Flow cytometry was used for detection and enumeration of micronuclei. Altogether, the results were in agreement with the published data and indicated that a sensitive and cost effective in vitro assay to assess genotoxicity with a potential to high-throughput screening has been developed. (C) 2015 The Authors. Published by Elsevier Ltd.

  • 19.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hebert, N.
    Härnwall, Eva-Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mazurier, C.
    Douay, L.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Grawe, J.
    A novel micronucleus in vitro assay utilizing human hematopoietic stem cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 7, p. 1897-1905Article in journal (Refereed)
    Abstract [en]

    The induction of micronucleated reticulocytes in the bone marrow is a sensitive indicator of chromosomal damage. Therefore, the micronucleus assay in rodents is widely used in genotoxicity and carcinogenicity testing. A test system based on cultured human primary cells could potentially provide better prediction compared to animal tests, increasing patient safety while also implementing the 3Rs principle, i.e. replace, reduce and refine. Hereby, we describe the development of an in vitro micronucleus assay based on animal-free ex vivo culture of human red blood cells from hematopoietic stem cells. To validate the method, five clastogens with direct action, three clastogens requiring metabolic activation, four aneugenic and three non-genotoxic compounds have been tested. Also, different metabolic systems have been applied. Flow cytometry was used for detection and enumeration of micronuclei. Altogether, the results were in agreement with the published data and indicated that a sensitive and cost effective in vitro assay to assess genotoxicity with a potential to high-throughput screening has been developed.

  • 20.
    Lindegren, H.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Mogren, H.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    EL Andaloussi-Lilja, J.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, J.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, A.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Anionic linear aliphatic surfactants activate TRPV1: a possible endpoint for estimation of detergent induced eye nociception?2009In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 23, no 8, p. 1472-1476Article in journal (Refereed)
    Abstract [en]

    The transient receptor potential vanilloid type 1 (TRPV1) has been reported as one of the key components in the pain pathway. Activation of the receptor causes a Ca2+ influx in sensory C-fibres with secondary effects leading to neurogenic inflammation in the surrounding tissue. We have earlier reported specific activation of TRPV1 by surfactant-containing hygiene products. We have continued this project by investigating activation of the TRPV1 by shampoo and soap ingredients in low concentrations measured as intracellular Ca2+ influxes in stably TRPV1-expressing neuroblastoma SH-SY5Y cells. As a TRPV1 specific control, the TRPV1 antagonist capsazepine was used. The response was quantified as the product induced Ca2+ influx during 2 min in relation to the maximum response induced by the TRPV1 agonist capsaicin. The results show that anionic alkyl linear surfactant ingredients such as sodium lauryl sulphate, sodium laureth sulphate, ammonium lauryl sulphate, sodium C12-15 pareth sulphate and N-lauroylsarcosine concentration-dependently induced Ca2+ influx that could be addressed to TRPV1. The cationic surfactants benzalkonium chloride and cetylpyridinium chloride induced a Ca2+ influx that was not TRPV1 mediated as well as the zwitterionic surfactant cocamidopropyl betaine, the non-linear anionic surfactant sodium deoxycholate and the non-ionic surfactant Triton-X. These results reveal a new mechanistic pathway for surfactant-induced nociception.

  • 21.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-938Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent.

    The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets.

    None of the metabolites cotinine, cotinine-N-oxide, nicotine-1′-N-oxide or trans-3′-hydroxycotinine (0.1–10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3′-hydroxycotinine (0.1 μM) and nicotine-1′-N-oxide (1–10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor.

    Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 22.
    Ljungberg, Liza U.
    et al.
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Karin
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Eriksson, Andreas C
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Green, Henrik
    Faculty of Health Sciences, Linköping University, Linköping, Sweden; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden.
    Whiss, Per A
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-8Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 μM) and nicotine-1'-N-oxide (1-10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 23. Ljungberg, Liza U.
    et al.
    Persson, Karin
    Eriksson, Andreas C.
    Green, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Whiss, Per A.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-938Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 mu M) affected platelet aggregation or P-selectin expression. Nicotine (10 mu M) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 mu M) and nicotine-1'-N-oxide (1-10 mu M) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 24.
    Lundqvist, Jessica
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    EL Andaloussi-Lilja, Johanna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Svensson, Christina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson Dorfh, Helena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Optimisation of culture conditions for differentiation of C17.2 neural stem cells to be used for in vitro toxicity tests2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 5, p. 1565-1569Article in journal (Refereed)
    Abstract [en]

    Here we present a multipotent neuronal progenitor cell line for toxicity testing as an alternative to primary cultures of mixed cell types from brain tissue. The v-myc immortalised C17.2 cell line, originally cloned from mouse cerebellar neural stem cells, were maintained as monolayer in cell culture dishes in DMEM supplemented with fetal calf serum, horse serum and antibiotics. Different media and exposure scenarios were used to induce differentiation. The optimal condition which generated mixed cultures of neurons and astrocytes included serum-free DMEM:F12 medium with N2 supplements, brain-derived neurotrophic factor and nerve growth factor. The medium was changed every 3rd or 4th day to fresh N2 medium with supplements. After 7days, the culture contained two different morphological cell types, assumed to be neurons and glia cells. The presence of astrocytes and neurons in the culture was confirmed by RT-PCR and Western blot analyses, indicating increased mRNA and protein levels of the specific biomarkers glial fibrillary acidic protein (GFAP) and βIII-tubulin, respectively. Concomitantly, the expression of the neural progenitor cell marker nestin was down-regulated.

  • 25. Marcusson, JA
    et al.
    Cederbrant, K
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Gunnarsson, L-G
    Serotonin production in lymphocytes and mercury intolerance.2000In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 14, p. 133-137Article in journal (Refereed)
  • 26.
    Nordin-Andersson, M
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, A
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Heldring, N
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Dejongh, J
    Kjellstrand, P
    Walum, E
    Neurite degeneration in differentiated human neuroblastoma cells.1998In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 12, no 5, p. 557-60Article in journal (Refereed)
    Abstract [en]

    We have studied neurite degeneration in differentiated human neuroblastoma (SH-SY5Y) cells. The axonopathy-inducing potency in vitro of caffeine, diazepam, methylmercury chloride (MeHg), triethyltin chloride (TET) and acrylamide (ACR) was elucidated. After 72 hours of exposure the neurite degeneration was determined (by morphological quantification) as well as the total protein content (general cytotoxicity). The concentrations that caused 20% reduction of number of neurites (ND(20)) for ACR (250+/-36 mum) and TET (0.097+/-0.03 mum) was significantly lower, 63% and 35%, respectively (P</=0.005), as compared to corresponding inhibition of general cytotoxicity (IC(20)). The effects of TET on the neurites may be related to the disturbance in Ca(2+)-signalling, and thus a secondary event. The ND(20)s for caffeine and diazepam, which are compounds without a known neurite degenerative potency in vivo, were higher as compared with the IC(20). For MeHg which is an extremely cyto- and neurotoxic compound the ND(20) was not statistically different from the IC(20), indicating that degeneration of the neurites is not a primary effect. This study indicates that the SH-SY5Y-neurite degeneration model is useful for the identification of axonopathy-inducing substances.

  • 27.
    Popova, Dina
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig O. P.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    A fluorescence microplate screen assay for the detection of neurite outgrowth and neurotoxicity using an antibody against βIII-tubulin2014In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 28, no 3, p. 411-418Article in journal (Refereed)
    Abstract [en]

    The majority of environmental and commercial chemicals have not been evaluated for their potential to cause neurotoxicity. We have investigated if neuron specific anti-βIII-tubulin antibodies are useful in a microplate assay of neurite outgrowth of retinoic acid-induced neurons from mouse P19 embryonal carcinoma cells. By incubating the P19-derived neurons with the primary anti-βIII-tubulin antibody and a secondary Alexa Fluor 488-conjugated antibody, followed by measuring the fluorescence in a microplate reader, a time-dependent increase in anti-βIII-tubulin immunofluorescence was observed. The relative fluorescence units increased by 4.3-fold from 2 to 10 days in culture. The results corresponded well with those obtained by semi-automatic tracing of neurites in fluorescence microscopy images of βIII-tubulin-labeled neurons. The sensitivity of the neurite outgrowth assay using a microplate reader to detect neurotoxicity produced by nocodazole, methyl mercury chloride and okadaic acid was significantly higher than for a cell viability assay measuring intracellular fluorescence of calcein-AM. The microplate-based method to measure toxicity targeting neurites using anti-βIII-tubulin antibodies is however less sensitive than the extracellular lactate dehydrogenase activity assay to detect general cytotoxicity produced by high concentrations of clomipramine, or glutamate-induced excitotoxicity. In conclusion, the fluorescence microplate assay for the detection of neurite outgrowth by measuring changes in βIII-tubulin immunoreactivity is a rapid and sensitive method to assess chemical- or toxin-induced neurite toxicity.

  • 28. Prieto, P.
    et al.
    Kinsner-Ovaskainen, A.
    Stanzel, S.
    Albella, B.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Campillo, N.
    Cecchelli, R.
    Cerrato, L.
    Diaz, L.
    Di Consiglio, E.
    Guerra, A.
    Gombau, L.
    Herrera, G.
    Honegger, P.
    Landry, C.
    O'Connor, J. E.
    Paez, J. A.
    Quintas, G.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Turco, L.
    Zurich, M. G.
    Zurbano, M. J.
    Kopp-Schneider, A.
    The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: Results from the European Project ACuteTox2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 4, p. 1357-1376Article in journal (Refereed)
    Abstract [en]

    ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6 months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50 > 2000 mg/kg b.w.).

  • 29. Rodhe, Ylva
    et al.
    Skoglund, Sara
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Wallinder, Inger Odnevall
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Potacova, Zuzana
    Moller, Lennart
    Copper-based nanoparticles induce high toxicity in leukemic HL60 cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 7, p. 1711-1719Article in journal (Refereed)
    Abstract [en]

    From the increasing societal use of nanoparticles (NPs) follows the necessity to understand their potential toxic effects. This requires an in-depth understanding of the relationship between their physicochemical properties and their toxicological behavior. The aim of the present work was to study the toxicity of Cu and CuO NPs toward the leukemic cell line HL60. The toxicity was explored in terms of mitochondrial damage, DNA damage, oxidative DNA damage, cell death and reactive oxygen species (ROS) formation. Particle characteristics and copper release were specifically investigated in order to gain an improved understanding of prevailing toxic mechanisms. The Cu NPs revealed higher toxicity compared with both CuO NPs and dissolved copper (CuCl2), as well as a more rapid copper release compared with CuO NPs. Mitochondrial damage was induced by Cu NPs already after 2 h exposure. Cu NPs induced oxidation at high levels in an acellular ROS assay, and a small increase of intracellular ROS was observed. The increase of DNA damage was limited. CuO NPs did not induce any mitochondrial damage up to 6 h of exposure. No acellular ROS was induced by the CuO NPs, and the levels of intracellular ROS and DNA damage were limited after 2 h exposure. Necrosis was the main type of cell death observed after 18 h exposure to CuO NP and dissolved copper.

  • 30. Thors, L.
    et al.
    Koch, B.
    Koch, M.
    Hägglund, L.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden b Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University.
    In vitro human skin penetration model for organophosphorus compounds with different physicochemical properties2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 32, p. 198-204Article in journal (Refereed)
    Abstract [en]

    A flow-through diffusion cell was validated for in vitro human epidermal penetration studies of organophosphorus compounds (OPCs) applied by infinite dosing. By testing OPCs with similar molecular weight but different physicochemical properties, it was shown that hydrophilic and lipophilic properties are major determinants for the penetration rate. Lipophilic OPCs displayed maximum cumulative penetration in the 20-75% agent concentration range whereas the hydrophilic OPCs displayed maximum cumulative penetration at 10 or 20% agent concentration. Low penetration was observed for all agents at 1% agent concentration or when applied as neat agents. The impact of the receptor solution composition was evaluated by comparing the penetration using receptor solutions of different ratios of ethanol and water. For diluted OPCs, a high concentration of ethanol in the receptor solution significantly increased the penetration compared to lower concentrations. When OPCs were applied as neat agents, the composition of the receptor solution only affected the penetration for one of four tested compounds. In conclusion, the flow-through diffusion cell was useful for examining the penetration of OPCs through the epidermal membrane. It was also demonstrated that the penetration rates of OPCs are strongly influenced by dilution in water and the receptor fluid composition.

  • 31.
    Törmä, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Geijer, Sophia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Gester, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    Alpholm, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    Lindberg, Magnus
    Variations in the mRNA expression of inflammatory mediators, markers of differentiation and lipid-metabolizing enzymes caused by sodium lauryl sulphate in cultured human keratinocytes2006In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 4, p. 472-479Article in journal (Refereed)
    Abstract [en]

    Detergents are well known irritants. Effects of the detergent sodium lauryl sulphate (SLS) on cell toxicity using the XTT assay and mRNA expression of inflammatory mediators, markers of keratinocyte differentiation and enzymes synthesizing barrier lipids using real-time PCR were studied in cultured differentiated keratinocytes. After exposure for 24 h to SLS concentrations at 0.002% or above, toxic effects were observed. When a lower SLS concentration (0.00075%) was used the mRNA expression of inflammatory mediators peaked around 4-8 h. The expression of enzymes involved in the synthesis of cholesterol, fatty acids and ceramides and markers of keratinocyte differentiation also increased but after 24 h. In cells exposed to 0.000125-0.0015% SLS, a concentration-dependent induction of the expression of inflammatory mediators was found after 4 h. Similar changes were found after 24 h for involucrin and enzymes involved in ceramide synthesis. The mRNA expression of HMG-CoA synthase and reductase, long-chain acyl-CoA synthase and transglutaminase also peaked after 24 h, but maximal induction was observed already at 0.00075% SLS. In conclusion, SLS induces an inflammatory response in keratinocytes and alters the mRNA expression of important barrier lipid enzymes and markers of keratinocyte differentiation, of possible importance for the irritant properties of SLS.

  • 32.
    Vicente Carrillo, Alejandro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Edebert, I.
    Karlbergsvägen 83 B, Stockholm, Sweden.
    Garside, H.
    AstraZeneca Research and Dev, England.
    Cotgreave, I.
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Rigler, R.
    Karolinska Institute, Sweden.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Boar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 3, p. 582-591Article in journal (Refereed)
    Abstract [en]

    Replacement of animal testing by in vitro methods (3-R principles) requires validation of suitable cell models, preferably obtained non-invasively, defying traditional use of explants. Ejaculated spermatozoa are highly dependent on mitochondrial production and consumption of ATP for their metabolism, including motility display, thus becoming a suitable model for capturing multiple modes of action of drugs and other chemicals acting via mitochondrial disturbance. In this study, a hypothesis was tested that the boar spermatozoon is a suitable cell type for toxicity assessment, providing a protocol for 3R-replacement of animals for research and drug-testing. Boar sperm kinetics was challenged with a wide variety of known frank mito-toxic chemicals with previously shown mitochondrial effects, using a semi-automated motility analyser allied with real-time fluorescent probing of mitochondrial potential (MitoTracker and JC-1). Output of this sperm assay (obtained after 30 min) was compared to cell viability (ATP-content, data obtained after 24-48 h) of a hepatome-cell line (HepG2). Results of compound effects significantly correlated (P less than 0.01) for all sperm variables and for most variables in (HepG2). Dose-dependent decreases of relative ATP content in HepG2 cells correlated to sperm speed (r= 0.559) and proportions of motile (r = 0.55) or progressively motile (r = 0.53) spermatozoa. The significance of the study relies on the objectivity of computerized testing of sperm motility inhibition which is comparable albeit of faster output than somatic cell culture models. Sperm suspensions, easily and painlessly obtained from breeding boars, are confirmed as suitable biosensors for preclinical toxicology screening and ranking of lead compounds in the drug development processes.

  • 33.
    Wei, Tianling
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Geijer, Sophia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindberg, Magnus
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Detergents with different chemical properties induce variable degree of cytotoxicity and mRNA expression of lipid-metabolizing enzymes and differentiation markers in cultured keratinocytes2006In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 8, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    The knowledge how detergents with different chemical properties influence epidermal keratinocytes is sparse. In the present study, the effects of five detergents were examined with respect to cell-toxicity and mRNA expression of key-enzymes in barrier lipid production and keratinocyte differentiation markers. First, the LD(50) for each detergent were determined. Secondly, keratinocytes were exposed to sub-toxic concentrations and the mRNA expression was analysed by real-time PCR after 24 h exposure to the detergents. SLS and CAPB induced a concentration-dependent increase in the expression of enzymes producing cholesterol and ceramides, while transcripts of enzymes producing fatty acids were unaffected. SLES and cocoglucoside increased the expression of certain enzymes involved in cholesterol and fatty acid synthesis while sodium cocoamphoacetate (SCAA) stimulated expression of transcripts involved in fatty acid synthesis. The expression of differentiation markers were increased by SLS, SLES and CAPB, while SCAA and cocoglucoside exhibited no effect. The present findings show that detergents have variable effects on lipid synthesis and keratinocyte differentiation, which could partly explain their barrier destruction potential in vivo.

  • 34.
    Yin, Xiaoqin
    et al.
    Nanjing Univ, Peoples R China.
    Ma, Tan
    Nanjing Univ, Peoples R China.
    Han, Ruitong
    Nanjing Univ, Peoples R China.
    Ding, Jie
    Nanjing Univ, Peoples R China.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Han, Xiaodong
    Nanjing Univ, Peoples R China.
    Li, Dongmei
    Nanjing Univ, Peoples R China.
    MiR-301b-3p/3584-5p enhances low-dose mono-n-butyl phthalate (MBP) induced proliferation by targeting Rasd1 in Sertoli cells2018In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 47, p. 79-88Article in journal (Refereed)
    Abstract [en]

    To investigate the possible molecular mechanism of low concentration plasticizer mono-n-butyl phthalate (MBP)-induced juvenile Sertoli cells (SCs) proliferation, we evaluated global alterations of miRNA and mRNA expression in rat SCs treated with 0.1 mM MBP. Microarray analysis revealed that miR-3584-5p and miR-301b-3p were up-regulated and their common target gene Dexamethasone-induced Ras-related protein 1 (Rasd1) was down-regulated. Further work suggested that SCs proliferation induced by low concentration MBP in vitro might be mediated by Rasd1 regulating ERK1/2 signaling pathway. The present study is first to investigate the effect of low-dose MBP on SCs proliferation and may enhance our understanding on the modes of action of low concentration MBP on male reproductive system. We hope the results will contribute to explain the causes of precocious puberty and testicular tumors induced by exogenous chemicals.

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