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  • 1. Ali, Imran
    et al.
    Hurmerinta, Teija
    Nurmi, Tarja
    Berglund, Marika
    Rüegg, Joelle
    Poutanen, Matti
    Halldin, Krister
    Mäkelä, Sari
    Damdimopoulou, Pauliina
    From pure compounds to complex exposure: Effects of dietary cadmium and lignans on estrogen, epidermal growth factor receptor, and mitogen activated protein kinase signaling in vivo.2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 253Article in journal (Refereed)
    Abstract [en]

    Exposure to environmental endocrine active compounds correlates with altered susceptibility to disease in human populations. Chemical risk assessment is single compound based, although exposure often takes place as heterogeneous mixtures of man-made and natural substances within complex matrices like diet. Here we studied whether the effects of cadmium and enterolactone on endocrine endpoints in dietary exposure can be predicted based on pure compound effects. Ovariectomized estrogen reporter ERE-luciferase (ERE-luc) mice were maintained on diets that intrinsically contain increasing concentrations of cadmium and enterolactone precursors for three and 21 days. The activation of the ERE-luc, epidermal growth factor receptor (EGFR), mitogen activated protein kinase (MAPK)-ERK1/2, and classical estrogen responses were measured. Interactions between the diets and endogenous hormone were evaluated by challenging the animals with 17β-estradiol. Compared to animals on basal purified diet, mice consuming experimental diets were exposed to significantly higher levels of cadmium and enterolactone, yet the exposure remained comparable to typical human dietary intake. Surprisingly, we could not detect effects on endpoints regulated by pure enterolactone, such as ERE-luc activation. However, cadmium accumulation in the liver was accompanied with activation of EGFR and MAPK-ERK1/2 in line with our earlier CdCl2 studies. Further, attenuation of 17β-estradiol-induced ERE-luc response in liver by experimental diets was observed. Our findings indicate that the exposure context can have substantial effects on the activity of endocrine active compounds in vivo. Thus, whenever possible, a context that mimics human exposure should be tested along with pure compounds.

  • 2. Alvarez-Lloret, Pedro
    et al.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Nyberg, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Rodríguez-Navarro, Alejandro B
    Effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on vertebral bone mineralization and on thyroxin and vitamin D levels in Sprague-Dawley rats2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 187, no 2, p. 63-68Article in journal (Refereed)
    Abstract [en]

    The aim of the present study is to use Fourier transform infrared spectrometry (FTIR), and transmission electron microscopy (TEM) techniques, to make a more detailed description of toxic effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on bone tissue at the microstructural and at the molecular level as a result of an altered bone metabolism. We have analysed potential changes on vitamin D and thyroxin serum levels since these hormones represent endocrine endpoints that are critical for bone growth and development. For this purpose Sprague-Dawley rats were exposed (n=10) to PCB126 (i.p.) for 3 months (total dose, 384microg/kg bodyweight), while control rats (n=10) were injected with corn oil (vehicle). Results from FTIR showed that vertebrae from the exposed rats had an overall lower degree of mineralization (-8.5%; p<0.05) compared with the controls. In addition, results from peripheral quantitative computed tomography (pQCT) analyses showed significant increases in the trabecular bone mineral density (+12%; p<0.05) in the exposed group compared with the controls. The TEM analyses also showed an alteration in the crystallinity properties of vertebral bone mineral with a significant decrease in the size and crystallinity of apatite crystal forming the bone tissue in the exposed vs. non-exposed rats. Serum analysis revealed lower levels of thyroid hormones, FT4 (-42%; p<0.005), TT4 (-26%; p<0.005), and vitamin D (-21%; p<0.005) in exposed group compared to control animals. The complementary techniques (TEM and FTIR) used in this study have revealed insights into possible bone mineralization alteration due to PCB126 exposure. The lowering of both the thyroxin and vitamin D serum levels might be an underlying explanation for the observed effects on bone mineralization.

  • 3.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, SE-17176 Stockholm, Sweden.
    Banack, Sandra
    Inst Ethnomed, POB 3464, Jackson, WY 83001 USA.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. 108-114Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 4.
    Andrén, Per E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard
    AstraZeneca, Drug Safety & Metab, Cambridge, England..
    Investigating drug-induced toxicity in tissue samples using mass spectrometry imaging2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, no S, p. S42-S42Article in journal (Other academic)
  • 5. Aspenstrom-Fagerlund, Bitte
    et al.
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Oleic acid increases intestinal absorption of the BCRP/ABCG2 substrate, mitoxantrone, in mice2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 237, no 2, p. 133-139Article in journal (Refereed)
    Abstract [en]

    The efflux transporter breast cancer resistance protein (BCRP/ABCG2) decrease intestinal absorption of many food toxicants. Oleic acid increases absorption of the specific BCRP substrate mitoxantrone (MXR), and also BCRP gene expression in human intestinal Caco-2 cells, suggesting that oleic acid affect the BCRP function. Here, we investigated the effect of oleic acid on intestinal absorption of MXR in mice. Mice were orally dosed with 2.4 g oleic acid/kg b.w. and 1 mg MXR/kg b.w., and sacrificed 30, 60, 90 or 120 min after exposure, or were exposed to 0.6, 2.4 or 4.8 g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 90 min after exposure. Mice were also treated with Ko143 together with MXR and sacrificed after 60 min, as a positive control of BCRP-mediated effects on MXR absorption. Absorption of MXR increased after exposure to oleic acid at all doses, and also after exposure to Ko143. Intestinal BCRP gene expression tended to increase 120 min after oleic acid exposure. Our results in mice demonstrate that oleic acid decreases BCRP-mediated efflux, causing increased intestinal MXR absorption in mice. These findings may have implications in humans, concomitantly exposed to oleic acid and food contaminants that, similarly as MXR, are substrates of BCRP.

  • 6.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Müllerian Duct Dysgenesis: a common cause for female reproductive disorders2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no suppl., p. S184-Article in journal (Refereed)
  • 7. Bondarenko, Olesja
    et al.
    Torres, Neus Feliu
    Kupferschmidt, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Garcia-Bennett, Alfonso
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Fadeel, Bengt
    Cellular uptake of mesoporous silica particles is governed by activation state of macrophages2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S188-S188Article in journal (Refereed)
  • 8.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-induced fibril formation and protein changes in rodents2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Suppl., p. S193-193Article in journal (Other academic)
  • 9.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Developmental exposure to PBDE 209: sex, neuroprotein and neurobehavioural analyses2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no supplement, p. S90-Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardants in polymers products.Newborns and toddlers can be indirectly and directly exposed to PBDEs during a period of critical rapid brain development. The present study was undertaken to investigate neurotoxic effects after neonatal exposure to PBDE 209 on sex differences, cognitive function, neuroproteins and altered susceptibility to toxicants in adults.

     

    3-day-old NMRI mice were exposed to PBDE 209 (2,2´,3,3´,4,4´,5,5´,6,6´-decaBDE at 0, 1.4, 6.0 and 14 µmol/kg bw). At 2 months of age male mice were exposed to paraoxon (0.25 mg/kg bw, every 2nd day for 7 days) and female mice exposed to nicotine (80 µg nicotine base/kg bw). At the age of 2 and 4 months mice were observed for spontaneous behaviour, before and after adult exposure to paraoxon (male) and nicotine (female). Male mice aged 5 and 7 months were observed for memory and learning. Neuroproteins CaMKII, GAP-43, synaptophysin and tau in cerebral cortex and hippocampus from 7-months old male and female mice were analyzed.

     

    The present study shows that neonatal exposure to PBDE 209 can induce developmental neurobehavioural defects in both male and female mice. Neonatal exposure to PBDE 209 also caused increased susceptibility in adult mice to paraoxon and nicotine. All these effects were dose response related. Further, neonatal exposure to PBDE 209 caused persistent defects in memory and learning in adult male mice and increased levels of important neuroproteins e.g. tau in adult male and female mice.

  • 10.
    Carlsson, Lars
    et al.
    AstraZeneca R&D.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Boyer, Scott
    AstraZeneca R&D.
    Model building in Bioclipse Decision Support applied to open datasets2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Suppl., p. S62-Article in journal (Refereed)
    Abstract [en]

    Bioclipse Decision Support (DS) is a system capable of building predictive models of any collection of SAR data, and making them available in a simple user interface based on Bioclipse (www.bioclipse.net).

    The method is fast and uses Faulon Signatures as chemical descriptors together with a Support Vector Machine algorithm for QSAR model building. A key feature is the capability to visualize and interpret results by highlighting the substructures which contributed most to the prediction. This, together with very fast predictions, allows for editing chemical structures with instantly updated results.

    We here present the results from applying Bioclipse Decision Support to several open QSAR data sets, including endpoints from OpenTox and PubChem. The results show how to extract data from the sources and to build models which can be integrated with user specific models.

  • 11. Dach, Katharina
    et al.
    Alm, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Giersiefer, Susanne
    Fritsche, Ellen
    Of mice and men: Mechanistic studies on the developmental neurotoxicity of polybrominated diphenyl ethers (PBDES) in a 3D in vitro model2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S118-S118Article in journal (Other academic)
  • 12.
    Durling, Louise
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Svensson, Kettil
    Abramsson-Zetterberg, Lilianne
    Furan is not genotoxic in the micronucleus assay in vivo or in vitro2007In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 169, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Furan, a potential human carcinogen, is formed during heat-treatment of food. Previous studies of the genotoxicity of furan have given disparate results. Hence, there is a need for complementary data to clarify the mechanism behind the carcinogenicity of furan. In this study, we have used the flow cytometer-based micronucleus assay in mice and the cytokinesis-block micronucleus assay in human lymphocytes to investigate the genotoxic potential of furan. Three in vivo experiments were performed: intraperitoneal or subcutaneous injection of furan in male Balb/C mice (0–300 and 0–275 mg/kg body weight, respectively) and intraperitoneal injection of male CBA mice (0 and 225 mg/kg body weight). No increased level of micronucleated erythrocytes was detected in any of the in vivo experiments. In the in vitro setup, human lymphocytes from two donors were treated with furan in concentrations from 0 to 100 mM, either with or without metabolic activation (liver homogenate from rat). In parity with the in vivo results there was no significant increase in the frequency of micronucleated cells here either. As neither the in vivo nor the in vitro studies disclose any significant increase in the micronucleus frequency after treatment with furan, our results support that the carcinogenicity of furan is caused by a non-genotoxic mechanism.

  • 13. Gutleb, Arno C.
    et al.
    Arvidsson, Dan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Skaare, Janneche Utne
    Aleksandersen, Mona
    Ropstad, Erik
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Effects on bone tissue in ewes (Ovies aries) and their foetuses exposed to PCB 118 and PCB 1532010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 192, no 2, p. 126-133Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate whether low levels of mono-ortho PCB 118 and di-ortho PCB 153, affect bone composition and strength in ewes (Dala breed) and their foetuses following exposure starting at conception and ending a week before expected delivery. In male foetuses, trabecular bone mineral content at the metaphysis was almost 30% lower in the PCB 118 (49mug/kg body wt/day) group compared to the control group (corn oil) (ANCOVA, P<0.05). In female foetuses of the PCB 153 (98mug/kg body wt/day) group trabecular cross-sectional area at the metaphysis was 19% smaller than in the controls (ANCOVA, P<0.05). At the diaphysis a smaller marrow cavity area (up to 24% reduction) was observed in female and male foetuses exposed to PCB 153 compared with controls (ANCOVA, P<0.05). There were also significant differences at the mid diaphyseal measure point between the PCB 153 and the control group females (ANCOVA, P<0.05). Cortical and total bone mineral density, cortical thickness were significantly higher, endosteal circumference shorter and marrow cavity significantly smaller in the PCB 153 group (ANCOVA, P<0.05). In conclusion there were gender dependent effects on bone tissue and cortical bone was more affected than trabecular bone.

  • 14.
    Haglund, Caroline
    et al.
    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, Clinical Pharmacology.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Jacobsson, Stefan
    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.
    The FMCA-GM assays, high throughput non-clonogenic alternatives to CFU-GM in preclinical hematotoxicity testing2010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 194, no 3, p. 102-107Article in journal (Refereed)
    Abstract [en]

    One of the most common dose limiting adverse effects in cancer treatment is myelotoxicity. The aim of this study was to develop an in vitro method for measuring potential myelotoxic properties of a drug candidate in a high throughput setting. Human CD34+ progenitor cells from umbilical cord blood were plated in 384-well microplates with drugs in liquid culture, supplemented with specific cytokines for the granulocytopoietic-macrophage lineage. After 7 or 14 days of proliferation and differentiation the cells were analyzed using the automated non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). Two types of assays setups were evaluated, the FMCA-GM7 where cells were exposed to drugs directly after thawing and cytotoxicity measured on day 7 in contrast to the FMCA-GM14 where the cells were cultured 7 days prior to plating and drug exposure, with viability analysis on day 14 of differentiation. Drug sensitivity was similar in both assays and method validation was performed using 24 drugs with known myelotoxic profile (acyclovir, bortezomib, busulfan, carboplatin, chloramphenicol, chlorpromazine, cisplatin, cytarabine, clozapine, doxorubicin, erlotinib, etoposide, 5-fluorouracil, fludarabine, gefitinib, gemcitabine, hydroxyurea, imatinib, lomustine, melphalan, sorafenib, sunitinib, taxol and 6-thioguanine). The 50% inhibitory concentrations (IC50) from the FMCA-GM7 and the FMCA-GM14 correlated highly (r = 0.83) and (r = 0.82), respectively, with IC50 from the established clonogenic assay (CFU-GM), obtained from the literature. The current data suggests that the FMCA-GM could offer a simple and robust alternative to the CFU-GM assay in preclinical hematotoxicity studies.

  • 15.
    Henriksson, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Shaposhnikov, Sergey
    Oslo universitet.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Collins, Andrew
    Oslo universitet.
    Study of gene-specific DNA repair in the comet assay with padlock probes and rolling circle amplification2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 202, no 2, p. 142-147Article in journal (Refereed)
    Abstract [en]

    We used padlock probes to study the rate of gene specific repair of three genes, OGG1 (8-oxoguanine-DNA glycosylase-1), XPD (xeroderma pigmentosum group D), and HPRT (hypoxanthine-guanine phosphoribosyltransferase) in human lymphocytes, in relation to the repair rate of Alu repeats and total genomic DNA. Padlock probes offer highly specific detection of short target sequences by combining detection by ligation and signal amplification. In this approach only genes in sequences containing strand breaks, which become single-stranded in the tail, are available for hybridisation. Thus the total number of signals from the padlock probes per comet gives a direct measure of the amount of damage (strand-breaks) present and allows the repair process to be monitored. This method could provide insights on the organisation of genomic DNA in the comet tail. Alu repeat containing DNA was repaired rapidly in comparison with total genomic DNA, and the studied genes were generally repaired more rapidly than the Alu repeats.

  • 16.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jiang, Liying
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ilag, Leopold L.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

  • 17.
    Kippler, Maria
    et al.
    Institute of Environmental Medicine, Division of Metals and health, Karolinska Institutet, Stockholm, Sweden.
    Hoque, A. M. Waheedul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Raqib, Rubhana
    Öhrvik, Helena
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Vahter, Marie
    Institute of Environmental Medicine, Division of Metals and health, Karolinska Institutet, Stockholm, Sweden.
    Accumulation of cadmium in human placenta interacts with the transport of micronutrients to the fetus2010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 192, no 2, p. 162-168Article in journal (Refereed)
    Abstract [en]

    Cadmium (Cd) is a widespread, highly toxic environmental pollutant known to accumulate in human placenta. The aim of the present study was to elucidate to what extent the accumulation of Cd in human placenta interacts with the transport of micronutrients to the fetus. Cd and micronutrients were measured in placenta and umbilical cord blood from 44 non-smoking, rural Bangladeshi women, using ICPMS. Metallothionein (MT) protein expression was determined in placenta using Western blot. Cd in placenta (median 110 microg/kg dry weight, 20 microg/kg wet weight) was positively associated with maternal urinary Cd. It was also positively associated with Cd in umbilical cord blood (median 0.16 microg/kg), but negatively associated with zinc (Zn; median 3mg/kg) in umbilical cord blood. Umbilical cord blood Zn was positively associated with birth anthropometry measures, and the Cd-related impairment of Zn in umbilical cord blood seemed to decrease size at birth. In multivariate analysis, MT protein expression was associated with Cd (positively) in placenta, but not with Zn or copper (Cu) in placenta. In conclusion, the Cd concentrations in placenta were clearly elevated, which seemed to impair Zn transfer to the fetus. Induction of MT explained the placental accumulation of Cd, but not the impairment of Zn transport.

  • 18.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bladin, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala Univ, Publ Hlth & Caring Sci, Uppsala, Sweden.
    Lind, monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Adipose tissue and metabolic homeostasis in Fischer F344 rats, exposed to developmental low doses of bisphenol A, are affected in a gender specific and non-monotonic manner2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S253-S253Article in journal (Other academic)
  • 19.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Bisphenol A increases cortisol production by enhancing phosphorylation of CREB in normal human adrenocortical cells2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 20.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Induction of LINE-1 promoter hypomethylation, a hallmark of tumorigenesis, in normal human adrenocortical cells by Bisphenol A2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S149-S149Article in journal (Other academic)
  • 21.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karimullina, Elina
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jacobson Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Blumberg, Bruce
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 22.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Developmental low-dose exposure to bisphenol A results in gender-specific and non-monotonic effects on Fischer F344 rat bone2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S255-S255Article in journal (Other academic)
  • 23.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Univ Orebro, Orebro.
    Van Bavel, B.
    Univ Orebro, Orebro, Switzerland..
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of perfluorinated compounds and left ventricular geometry2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S93-S93Article in journal (Other academic)
  • 24.
    Lind, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Univ Orebro, MTM Res Ctr, Sch Sci & Technol, SE-70182 Orebro, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    van Bavel, B.
    Univ Orebro, MTM Res Ctr, Sch Sci & Technol, SE-70182 Orebro, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of perfluoroalkyl substances and biomarkers of liver function in a large population based sample of elderly men and women from Sweden2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S91-S91Article in journal (Other academic)
  • 25. Lind, Monica
    et al.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Edlund, Ulla-Britt
    Sjöblom, Linnea
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    The dioxin-like pollutant PCB 126 (3,3',4,4',5-pentachlorobiphenyl) affects risk factors for cardiovascular disease in female rats2004In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 150, no 3, p. 293-299Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies suggest that exposure to persistent organic pollutants such as organochlorines might induce cardiovascular disorders and diabetes. Some of these organochlorines, such as dioxins and some dioxin-like PCBs, have been characterised as anti-estrogenic due to their inhibition of estrogenic-induced responses. In the present pilot study, 40 female rats were subjected to either exposure to the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB 126) or vehicle, as well as ovariectomy (OVX) or sham operation in a 2 x 2 factorial design over 12 weeks to explore potential interactions between estrogen status and PCB 126 exposure on cardiovascular risk factors. PCB 126 increased heart weight and serum cholesterol levels in both groups. PCB 126 increased blood pressure in the sham-operated animals only. In conclusion, PCB 126 exposure in female rats resulted in effects on cardiovascular risk factors, such as serum cholesterol, blood pressure, and heart weight. Of these effects of PCB 126, the increase in blood pressure was dependent on estrogen status.

  • 26.
    Lundgren, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Darnerud, Per Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Polybrominated diphenyl ether exposure suppresses cytokines important in the defence to coxsackievirus B3 infection in mice2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 184, no 2, p. 107-13Article in journal (Refereed)
    Abstract [en]

    Environmental pollutants can adversely affect the immune system. The host defence during infection depends on cytokine signalling and proper function of immune cells. However, no studies have addressed how polybrominated diphenyl ethers (PBDEs) affect cytokine responses. We investigated the combined effects in Balb/c mice of human coxsackievirus B3 (CVB3) infection and exposure to PBDEs (BDE-99 or Bromkal mixture) on 21 serum cytokines. The mice were infected (i.p.) on day 0, orally treated with BDE-99 or Bromkal on day 1 (20mg/kg bw) and put to death on day 3. CVB3 was quantitatively measured in the liver and pancreas by RT-PCR. The Luminex 200 multi-analyte system was used for cytokine analysis. High numbers of viral copies were found in the liver and pancreas. Infection increased TNF-alpha, IL-6, MCP-1, IL-12p40, KC and RANTES levels. Notably, PBDE-exposure resulted in a marked decrease, or even lack, of IL-13, MIP-1beta, RANTES, IFN-gamma and KC levels in non-infected mice. However, the effects of PBDE-exposure on cytokines did not affect viral replication during early CVB3 infection. In conclusion, PBDEs causes a selective block in immune signalling pathways but the consequences of this need to be further studied in different host resistance models of infection.

  • 27. Ohlsson, Asa
    et al.
    Ullerås, Erik
    Oskarsson, Agneta
    A biphasic effect of the fungicide prochloraz on aldosterone, but not cortisol, secretion in human adrenal H295R cells--underlying mechanisms.2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 191, no 2-3, p. 174-80Article in journal (Refereed)
    Abstract [en]

    The widely used imidazole fungicide prochloraz displays anti-androgenic effects partly via inhibition of testicular steroidogenesis and testosterone secretion. Adrenal steroidogenesis and hormone secretion may also be a target of this endocrine disruptor. Herein, we demonstrate a dose-dependent inhibition of cortisol secretion and a biphasic effect on aldosterone secretion, with a 2-fold stimulation at low concentrations and a strong inhibition at high concentrations, following prochloraz treatment (0-10 microM) of human adrenocortical H295R cells. Analysis of the dose-dependent effects of prochloraz on the secretion of steroidogenic intermediates suggested that the observed effects on cortisol and aldosterone secretion might be mediated by inhibition of the steroidogenic steps catalysed by CYP17A1 and CYP21A2. The inhibition of CYP17A1 was reflected on the level of expression of steroidogenic genes as analysed by quantitative RT-PCR. In addition, analysis of enzyme activity showed a dose-dependent inhibitory effect of prochloraz on the activity of CYP17A1 and CYP21A2, but not CYP11B1. We have demonstrated specific effects of prochloraz on adrenal steroidogenic pathways and hormone secretion via inhibition of steroidogenic CYP enzymes. The disruption of adrenal hormone secretion may result in altered endocrine homeostasis and affect human health.

  • 28. Ohrvik, H
    et al.
    Ullerås, E
    Oskarsson, A
    Tallkvist, J
    Effects of cadmium on calcium transporter SPCA, calcium homeostasis and β-casein expression in the murine mammary epithelium.2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 201, no 1, p. 80-5Article in journal (Refereed)
    Abstract [en]

    Maternal cadmium (Cd) exposure during lactation causes neurobehavioral effects in the suckling offspring as well as involution like disturbances in the mammary glands of rodents. The aim of the present study was to examine Cd-induced effects in secreting mammary epithelial cells in relation to calcium (Ca) transport and β-casein expression. Reduced protein expression of secretory pathway Ca-ATPase (SPCA) was revealed in the mammary glands of lactating mice exposed to Cd during peak lactation. In concordance, SPCA gene expression was down regulated and total intracellular Ca levels reduced in murine mammary epithelial HC11 cells treated with Cd for 72 h. Cd reduced β-casein gene expression in a concentration dependent manner in the HC11 cells. Our findings on Cd-induced reduction of Ca levels, SPCA and β-casein expression in the mammary epithelium resemble the effects observed in the mammary glands as a result of forced weaning. In conclusion, maternal Cd exposure during lactation may disturb Ca regulation and decrease the levels of β-casein in milk with potential nutritional and developmental implications for the breast-fed newborn.

  • 29.
    Raqib, Rubhana
    et al.
    International Centre for Diarrhoeal Research, Bangladesh.
    Ahmed, Sultan
    International Centre for Diarrhoeal Research, Bangladesh.
    Sultana, Rokeya
    International Centre for Diarrhoeal Research, Bangladesh.
    Wagatsuma, Yukiko
    Graduate School of Comprenhensive Human Sciences, Dept. of Epidemiology, University of Tsukuba, Ibaraki, Japan.
    Mondal, Dinesh
    International Centre for Diarrhoeal Research, Bangladesh.
    Hoque, A. M. Waheedul
    International Centre for Diarrhoeal Research, Bangladesh.
    Nermell, Barbro
    Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
    Yunus, Mohammed
    International Centre for Diarrhoeal Research, Bangladesh.
    Roy, Shantonu
    International Centre for Diarrhoeal Research, Bangladesh.
    Persson, Lars-Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Arifeen, Shams El
    International Centre for Diarrhoeal Research, Bangladesh.
    Moore, Sophie
    MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London UK.
    Vahter, Marie
    Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
    Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 185, no 3, p. 197-202Article in journal (Refereed)
    Abstract [en]

    Chronic exposure to arsenic, a potent carcinogen and toxicant, via drinking water is a worldwide public health problem. Because little is known about early-life effects of arsenic on immunity, we evaluated the impact of in utero exposure on infant immune parameters and morbidity in a pilot study. Pregnant women were enrolled at 6-10 weeks of gestation in Matlab, a rural area of Bangladesh, extensively affected by arsenic contamination of tubewell water. Women (n=140) delivering at local clinics were included in the study. Anthropometry and morbidity data of the pregnant women and their children, as well as infant thymic size by sonography were collected. Maternal urine and breast milk were collected for immune marker and arsenic assessment. Maternal urinary arsenic during pregnancy showed significant negative correlation with interleukin-7 (IL-7) and lactoferrin (Ltf) in breast milk and child thymic index (TI). Urinary arsenic was also positively associated with fever and diarrhea during pregnancy and acute respiratory infections (ARI) in the infants. The effect of arsenic exposure on ARI was only evident in male children. The findings suggest that in utero arsenic exposure impaired child thymic development and enhanced morbidity, probably via immunosuppression. The effect seemed to be partially gender dependent. Arsenic exposure also affected breast milk content of trophic factors and maternal morbidity.

  • 30. Shaposhnikov, Sergey
    et al.
    Azqueta, Amaya
    Henriksson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Meier, Silja
    Gaivão, Isabel
    Huskisson, Neville H.
    Smart, Andrew
    Brunborg, Gunnar
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Collins, Andrew R.
    Twelve-gel slide format optimised for comet assay and fluorescent in situ hybridisation2010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 195, no 1, p. 31-34Article in journal (Refereed)
    Abstract [en]

    The comet assay is widely used to measure DNA damage and repair in basic research, genotoxicity testing and human biomonitoring. The conventional format has 1 or 2 gels on a microscope slide, 1 sample per slide. To increase throughput, we have designed and tested a system with 12 smaller gels on one slide, allowing incubation of individual gels with different reagents or enzymes. Thus several times more samples can be analysed with one electrophoresis run, and fewer cells and smaller volumes of test solutions are required. Applications of the modified method include treatment with genotoxic agents at different concentrations; simultaneous analysis of different lesions using a range of enzymes; analysis of cell extracts for DNA repair activity; and fluorescent in situ hybridisation (FISH) to comet DNA with specific labelled probes.

  • 31.
    Spjuth, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Willighagen, Egon
    Maastricht University.
    Hammerling, Ulf
    National Food Administration, Sweden.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grafström, Roland
    Karolinska Institutet.
    A novel infrastructure for chemical safety predictions with focus on human health2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Supplm, p. S59-Article in journal (Refereed)
    Abstract [en]

    A major objective of Computational Toxicology is to provide reliable and useful estimates in silico of (potentially) harmful actions of chemicals in humans. Predictive models are commonly based on in vitro and in vivo data, and aims at supporting risk assessment in various areas, including the environmental protection, food, and pharmaceutical sectors. The field is however hampered by the lack of standards, access to high quality data, validated predictive models, as well as means to connect toxicity data to genomics data.

    We present a framework and roadmap for a novel public infrastructure for predictive computational toxicology and chemical safety assessment, consisting of: (1) a repository capable of aggregating high quality toxicity data with gene expression data, (2) a repository where scientists can share and download predictive models for chemical safety, and (3) a user-friendly platform which makes the services and resources accessible for the scientific community. Databases under the framework will adhere to open standards and use standardized open exchange formats in order to interoperate with emerging international initiatives, such as the FP7-funded OpenTox and ToxBank projects.

    The infrastructure will strengthen and facilitate already ongoing activities within in silico toxicology, open up new possibilities for incorporating genomics data in chemicals safety modeling (toxicogenomics), as well as deepen the exploitation of signal transduction networks. The initiative will lay the foundation needed to boost decision support in risk assessment in a wide range of fields, including drug discovery, food safety, as well as agricultural and ecological safety assessment.

  • 32.
    Strömqvist, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Olsson, Jan
    Kärrman, Anna
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Role of PPARα in developmental toxicity of perfluorinated compounds in birds2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no suppl., p. S85-Article in journal (Refereed)
  • 33.
    Säfholm, Moa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Norder, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fick, Jerker
    Umeå universitet.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Environmental progestin disrupts oogenesis and Müllerian duct development  2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no suppl., p. S81-Article in journal (Refereed)
  • 34.
    Söderqvist, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Carlberg, Michael
    Hardell, Lennart
    Biomarkers in volunteers exposed to mobile phone radiation2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 235, no 2, p. 140-146Article in journal (Refereed)
    Abstract [en]

    For some time it has been investigated whether low-intensity non-thermal microwave radiation from mobile phones adversely affects the mammalian blood-brain barrier (BBB). All such studies except one have been either in vitro or experimental animal studies. The one carried out on humans showed a statistically significant increase in serum transthyretin (TTR) 60 min after finishing of a 30-min microwave exposure session. The aim of the present study was to follow up on the finding of the previous one using a better study design. Using biomarkers analyzed in blood serum before and after the exposure this single blinded randomized counterbalanced study, including 24 healthy subjects aged 18-30 years that all underwent three exposure conditions (SAR(10G) = 2 W/kg, SAR(10G) = 0.2 W/kg, sham), tested whether microwaves from an 890-MHz phone-like signal give acute effects on the integrity of brain-shielding barriers. Over time, statistically significant variations were found for two of the three biomarkers (TTR; beta-trace protein); however, no such difference was found between the different exposure conditions nor was there any interaction between exposure condition and time of blood sampling. In conclusion this study failed to show any acute clinically or statistically significant effect of short term microwave exposure on the serum levels of S100 beta, TTR and b-trace protein with a follow up limited to two hours. The study was hampered by the fact that all study persons were regular wireless phone users and thus not naive as to microwave exposure.

  • 35. Visoni, Silvia
    et al.
    Lang, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ribeiro Pinto, Felipe
    Hamster exhibits major differences in organ-specific metabolism of the esophageal carcinogen N-nitrosodiethylamine2008In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 183, no 1-3, p. 90-94Article in journal (Refereed)
    Abstract [en]

    Nitrosamines are carcinogens that require metabolic activation by CYP enzymes in order to exert their carcinogenic effect. Species differences exist in their esophageal carcinogenic potency, with the rat being the most sensitive and the Syrian hamster a resistant species. In the latter, the liver is the main target organ. This difference does not apply to directly acting N-nitroso compounds, suggesting that tissue-specific metabolic activation is involved in hamster esophageal resistance to nitrosamines. We have previously shown that Cytochrome P450 2A3 (CYP2A3) is responsible for N-nitrosodiethylamine activation in the rat esophagus. In order to find a mechanistic explanation for the resistance of hamster esophagus for nitrosamines, we have compared the metabolism of NDEA between esophagus and liver of the hamster. Hamster esophagus is capable of activating NDEA (K-m = 1.02 +/- 0.44 mu M and V-max = 1.96 +/- 0.26 nmol acetaldehyde/min/mg microsomal protein). However, the hamster liver showed a 40-fold higher catalytic efficiency (V-max/K-m) towards NDEA metabolism compared with its esophagus. Hamster esophagus expresses CYP2A8, CYP2A9 and CYP2A16, but not CYP2E1. An antibody against human CYP2A6 was able to inhibit NDEA metabolism in hamster esophageal, but not liver microsomes. Our results suggest that in the hamster esophagus, but not in the liver, most of the NDEA is metabolized by CYP2A enzymes, but with a rather poor efficiency when compared to the liver. This is in accordance with previous results showing that for the hamster, the main target organ of NDEA is the liver. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

  • 36. Willighagen, Egon
    et al.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grafström, Roland
    Computational toxicology using OpenTox & Bioclipse2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S60-S60Article in journal (Other academic)
    Abstract [en]

    Computational methods, e.g., OECD QSAR Toolbox and ToxPredict, are increasingly used to support chemicals toxicity assessment in academic settings, industry and governments. The in silico-based assessments complement experimental approaches and have potential to fill the knowledge gaps needed to broadly assess chemical hazards. We present here the interoperable Bioclipse–OpenTox platform as a novel alternative made freely and openly available.

    The interactive Bioclipse software is combined with remote computational toxicity prediction provided by services in the OpenTox network from various European institutes and SMEs. These online services apply machine learning methods for integration of a number of end points, e.g., Ames mutagenicity test in salmonella, Caco-2 cell model permeability and micronucleus assay in rodents. Coupling of such data to chemical structure assessments lead to prediction of site(s) for metabolism (using SMARTCyp), biodegradation (START), and toxicity mode prediction (Verhaar scheme). The OpenTox platform thus unifies how the services are accessed whereas the Bioclipse software provides the easy-to-use interface for interactively studying the toxic part of molecules. Additional predictive methods that are made accessible via the OpenTox network are automatically discovered by Bioclipse and models can be improved over time without any need to reinstall Bioclipse itself.

  • 37.
    Wålinder, Robert
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ernstgård, Lena
    Norbäck, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wieslander, Gunilla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Johanson, Gunnar
    Acute effects of 1-octen-3-ol, a microbial volatile organic compound (MVOC)--an experimental study2008In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 181, no 3, p. 141-7Article in journal (Refereed)
    Abstract [en]

    Acute effects were assessed from exposure to a common volatile compound of microbial origin, the aliphatic alcohol 1-octen 3-ol (octenol). Twenty-nine volunteers performed symptom reports, measurement of blink frequency by electromyography, measurement of the eye break-up time, vital staining of the eye, nasal lavage, acoustic rhinometry, transfer tests and dynamic spirometry. Subjects were during 2h in random order exposed to either 10mg/m(3) of octenol or clean air as control. During octenol exposure subjective ratings of smell and nasal irritation were increased together with higher nasal lavage biomarker levels of eosinophil cationic protein, myeloperoxidase and lysozyme. Also eye irritation and blinking frequency were increased together with throat irritation, mild dyspnoea after 1-h but not after 2-h, and a small decrease in vital capacity. Ratings of headache and nausea were also increased. Atopics did not have more reactions due to exposure, whereas females experienced more smell and mucosal irritation. Thus, there were both subjective and objective signs of mild mucosal irritation of eyes and airways together with symptoms of headache and nausea.

1 - 37 of 37
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