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  • 1. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne M.
    Wikman, Anna S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rahnasto, Minna
    Juvonen, Risto O.
    Vepsalainen, Jouko
    Raunio, Hannu
    Ng, Jack C.
    Lang, Matti A.
    Metabolism of bilirubin by human cytochrome P450 2A62012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.

  • 2. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne Maioha
    Aganovic, Simona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ng, Jack C.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A52011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 257, no 1, p. 14-22Article in journal (Refereed)
    Abstract [en]

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic "BR oxidase''. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301,315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible "BR oxidase" where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced.

  • 3.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines2017In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed)
    Abstract [en]

    β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

  • 4.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Granberg, A Lizette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differential response of cultured human umbilical vein and artery endothelial cells to Ah receptor agonist treatment: CYP-dependent activation of food and environmental mutagens2000In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 169, no 1, p. 94-101Article in journal (Refereed)
    Abstract [en]

    In the present study, 7-ethoxyresorufin O-deethylase (EROD), 7,12-dimethylbenz[a]anthracene (DMBA)-hydroxylase, and covalent binding of H-3-labeled 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (H-3-Trp-P-1) and H-3-DMBA were examined in human umbilical vein endothelial cells (HUVEC) and human umbilical artery endothelial cells (HUAEC) exposed to the aryl hydrocarbon (Ah) receptor agonist beta -naphthoflavone (BNF) or vehicle only. The results revealed a marked induction of enzymatic activity in BNF-treated HUVEC compared with vehicle-treated cells, whereas no similar response was observed in BNF-treated HUAEC. EROD, DMBA hydroxylase, and covalent binding of H-3-Trp-P-1 and H-3-DMBA in BNF-treated HUVEC were reduced in the presence of the CYP1A inhibitor ellipticine. Addition of other CYP1A inhibitors ru-naphthoflavone, miconazole, 1-ethynylpyrene, 1-(1-propynyl)pyrene, or the CYP1A substrate ethoyresorufin to the incubation buffer of BNF-treated HUVEC reduced covalent binding of H-3-Trp-P-1 by 93-98%. Western blot analysis confirmed an induction of CYP1A1 in BNF-treated HUVEC, but not in BNF-treated HUAEC. CYP1A1 was, however, detected in both vehicle- and BNF-treated HUAEC. The results showed that BNF exposure induced CYP1A1 and metabolic activation of xenobiotics in HUVEC, whereas the catalytic activity remained low in BNF-treated HUAEC. Our results suggest that endothelial lining of human veins may be a target for adverse effects of xenobiotics activated into reactive metabolites by Ah receptor-regulated enzymes. Several studies have detected CYP1A1 in endothelial linings, whereas expression of CYP1A2 and CYP1B1 seems to be negligible at this site. This suggests that the metabolic activation and covalent binding of H-3-Trp-P-1 and H-3-DMBA in HUVEC are most likely mediated by CYP1A1.

  • 5. Arpiainen, Satu
    et al.
    Jarvenpaa, Sanna-Mari
    Manninen, Aki
    Viitala, Pirkko
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Pelkonen, Olavi
    Hakkola, Jukka
    Coactivator PGC-1 alpha regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes2008In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 232, no 1, p. 135-141Article in journal (Refereed)
    Abstract [en]

    The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1 alpha expression level by adenovirus mediated gene transfer increased CYP2A5 transcription, Co-transfection of Cyp2a5' promoter constructs with PGC-1 alpha expression vector demonstrated that PGC-1 alpha is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4 alpha response element in the proximal promoter of the Cyp2a5 gene. Chromartin immunoprecipitation assays showed that PGC-1 alpha binds, together with HNF-4 alpha, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1 alpha mediates the expression of Cyp2A5 induced by cAMP in mouise hepatocytes throuch coactivation of transcription factor HNF-4 alpha. This strongly suggests that PGC-1 alpha is the major factor mediating the fasting response of CYP2A5.

  • 6.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ullerås, Erik
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Oskarsson, Agneta
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, no 3, p. 281-289Article in journal (Refereed)
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.

  • 7.
    Bahrami, Fariba
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergman, Ulrika
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Persistent Olfactory Mucosal Metaplasia and Increased Olfactory Bulb Glial Fibrillary Acidic Protein Levels Following a Single Dose of Methylsulfonyl-dichlorobenzene in Mice: Comparison of the 2,5- and 2,6-Dichlorinated Isomers 2000In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 162, no 1, p. 49-59Article in journal (Refereed)
    Abstract [en]

    Histopathology was used to characterize long-term toxic effects in the olfactory system following a single ip dose (4–65 mg/kg) of methylsulfonyl-2,6-dichlorobenzene, (2,6-(diCl-MeSO2-B)), in female NMRI mice. The effects of 2,6-(diCl-MeSO2-B) and its 2,5-chlorinated isomer, (2,5-(diCl-MeSO2-B)), on the levels of glial fibrillary acidic protein (GFAP; a biomarker for neurotoxicity) in different brain regions were examined by an enzyme-linked immunosorbent assay (ELISA). The histopathologic effects of 2,6-(diCl-MeSO2-B) were dose-, time-, and tissue-dependent. At the highest doses (16–65 mg/kg), the initial effect of 2,6-(diCl-MeSO2-B) was necrosis of the Bowman's glands, followed by a sequence of secondary events including degeneration of the olfactory neuroepithelium, repopulation of the basement membrane by a ciliated respiratorylike epithelium, fibrosis and ossification in the lamina propria, formation of bilateral polyps, angiogenesis, and disappearance of nerve bundles. Remodeling was most pronounced in the dorsal meatus of the olfactory mucosa and persisted for the duration of the experiment (46 weeks). A dose-dependent induction of GFAP in the olfactory bulb of mice treated with 2,6-(diCl-MeSO2-B) was observed at all doses examined (16–65 mg/kg). GFAP levels were highest 2 weeks after treatment (eightfold induction at 65 mg/kg) and then gradually decreased to normal within 26 weeks. The 2,5-substituted isomer (65 mg/kg) did not induce GFAP in the olfactory bulb and or toxicity in the olfactory mucosa. In conclusion, a single dose of 2,6-(diCl-MeSO2-B) results in persistent metaplasia and remodeling of the olfactory mucosa, and a long-lasting but transient induction of GFAP in the olfactory bulb. It is proposed that methylsulfonyl-2,6-dichlorobenzene may serve as an experimental tool with a unique ability to produce persistent primary and/or secondary lesions in the olfactory system of mice.

  • 8.
    Castellanos, Cesilie Granum
    et al.
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Sorvik, Irene Beate
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.; Department of Pharmaceutical Biosciences, University of Oslo, Postboks 1068 Blindern, 0316 Oslo, Norway.
    Tanum, Marte Bruu
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.; The Climate and Pollution Agency (Klif), Postboks 8100 Dep, 0032 Oslo, Norway.
    Verhaegen, Steven
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ropstad, Erik
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Differential effects of the persistent DDT metabolite methylsulfonyl-DDE in nonstimulated and LH-stimulated neonatal porcine Leydig cells2013In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 267, no 3, p. 247-255Article in journal (Refereed)
    Abstract [en]

    3-Methylsulfonyl-DDE (MeSO2-DDE) is a potent adrenal toxicant formed from the persistent insecticide DDT. MeSO2-DDE is widely present in human plasma, milk and fat, and in tissues of marine mammals. In the present study, we investigated endocrine-disrupting properties of MeSO2-DDE in primary neonatal porcine Leydig cells. Unstimulated and LH-stimulated cells were exposed to MeSO2-DDE at concentrations ranging from 0.6 to 20 mu M for 48 h. Cell viability, hormone secretion and expression of steroidogenesis related genes were recorded. Secretion of testosterone and estradiol was increased in a concentration-dependent fashion in unstimulated Leydig cells, while in LH-stimulated cells, secretion of testosterone, estradiol and progesterone was decreased. The expression of important steroidogenic genes was down-regulated both in unstimulated and LH-stimulated cells. Notably, no significant impairment of cell viability occurred at any exposure except the highest concentration (20 mu M) in LH-stimulated cells. This indicated that the effects on hormone secretion and gene expression were not caused by cytotoxicity. We conclude that the adrenal toxicant MeSO2-DDE disrupts hormone secretion in a complex fashion in neonatal porcine Leydig cells. The different endocrine responses in unstimulated and LH-stimulated cells imply that the endocrine disruptive activity of MeSO2-DDE is determined by the physiological status of the Leydig cells.

  • 9. De Luca, Chiara
    et al.
    Scordo, Maria G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cesareo, Eleonora
    Pastore, Saveria
    Mariani, Serena
    Maiani, Gianluca
    Stancato, Andrea
    Loreti, Beatrice
    Valacchi, Giuseppe
    Lubrano, Carla
    Raskovic, Desanka
    De Padova, Luigia
    Genovesi, Giuseppe
    Korkina, Liudmila G.
    Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 248, no 3, p. 285-292Article in journal (Refereed)
    Abstract [en]

    Background: Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined. Objectives: We sought for genetic, immunological, and metabolic markers in MCS. Methods: We genotyped patients with diagnosis of MCS. suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1. GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined. Results: Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1. PDGFbb, and VEGF were increased. Conclusions: Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes in MCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS. (C) 2010 Elsevier Inc. All rights reserved.

  • 10.
    Gustafsson, Åsa
    et al.
    Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden..
    Agren, Lina
    Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden..
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Sandstrom, Thomas
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Bucht, Anders
    Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles2015In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 288, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.

  • 11. Hallén, I P
    et al.
    Jönsson, Siv
    Medical Products Agency.
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oskarsson, A
    Toxicokinetics of lead in lactating and nonlactating mice.1996In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 136, no 2, p. 342-7Article in journal (Refereed)
    Abstract [en]

    Toxicokinetics of lead in lactating and nonlactating mice were studied after a single intravenous injection of 0.05 mg of lead (2.5 mCi 203Pb)/kg. Lead concentrations in blood, plasma, and milk were measured for 10 days following dosing. The volume of distribution based on plasma lead was more than two times larger in lactating than in nonlactating mice, 133 and 58 liter/kg, respectively. Plasma lead clearance in lactating mice was 4.25 liter/hr/kg compared with 1.07 liter/hr/kg in nonlactating mice. However, no such pronounced difference in blood lead clearance was found between the two groups, indicating that this parameter does not reveal the kinetic characteristics during lactation. Milk was found to be an additional route of excretion for lead. About 1/3 of the administered dose of lead was excreted in milk. Accordingly, milk clearance contributed to 1/3 of the total plasma clearance in the mice. The relationships of lead in plasma to lead in whole blood as well as lead in milk to lead in whole blood were nonlinear, with a relatively higher increase in plasma and in milk lead levels at higher blood lead levels. This nonlinearity may be explained by a reduced uptake of lead in erythrocytes as the lead binding sites of these cells become saturated. In lactating mice, the maximum binding capacity of lead in red blood cells was even lower than in nonlactating mice. Similar nonlinear relationship have have also been found in human studies although at much higher levels of lead in blood. The milk:plasma concentration ratio for lead was found to be between 50 and 100 after 24 hr, demonstrating a much more efficient excretion of lead into milk than what is known from human studies. Differences in the milk composition may be one explanation for the species differences in milk excretion of lead. The present study shows that physiological changes during lactation alter the pharmacokinetics of lead in mice.

  • 12.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development2011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 250, no 2, p. 170-183Article in journal (Refereed)
  • 13.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kubota, Akira
    Timme-Laragy, Alicia R.
    Woodin, Bruce
    Stegeman, John J.
    Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish2012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed)
  • 14.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development2011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 250, no 2, p. 170-183Article in journal (Refereed)
    Abstract [en]

    The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), β-naphthoflavone (βNF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versus the control, respectively). βNF induced CYP1A and CYP1C1 (26- and 2.5-fold), while, under conditions used, indigo tended to induce only CYP1A (1.9-fold). The extent of CYP1 induction by PCB126 and βNF was positively correlated to the number of putative dioxin response elements 0-20kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1nM-10μM PCB126 at two days post-fertilization (dpf) and screened 20days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1μM PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions.

  • 15.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Kubota, Akira
    Biology Department, Woods Hole Oceanographic Institution.
    Timme-Laragy, Alicia R.
    Biology Department, Woods Hole Oceanographic Institution.
    Woodin, Bruce
    Biology Department, Woods Hole Oceanographic Institution.
    Stegeman, John J.
    Biology Department, Woods Hole Oceanographic Institution.
    Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.2012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed)
    Abstract [en]

    The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR(2)) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC(50) values of 1.4 to 2.0nM for induction of the CYP1s, 3.7 and 5.1nM (or higher) for cox-2a and cox-2b induction, and 2.5nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2nM PCB126 approximately 30% of eleutheroembryos(3) failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells.

  • 16.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Orrego, Rodrigo
    Woodin, Bruce R.
    Goldstone, Jared V.
    Stegeman, John J.
    Basal and 3,3',4,4',5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish2007In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 221, no 1, p. 29-41Article in journal (Refereed)
  • 17.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Orrego, Rodrigo
    Woodin, Bruce R.
    Goldstone, Jared V.
    Stegeman, John J.
    Basal and 3,3',4,4',5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish2007In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 221, no 1, p. 29-41Article in journal (Refereed)
    Abstract [en]

    The cytochrome P4501C (CYP1C) gene subfamily was recently discovered in fish, and zebrafish (Danio rerio) CYP1C1 transcript has been cloned. Here we cloned the paralogous CYP1C2, showing that the amino acid sequence is 78% identical to CYP1C1, and examined gene structure and expression of CYP1A, CYP1B1, CYP1C1, and CYP1C2. Xenobiotic response elements were observed upstream of the coding regions in all four genes. Zebrafish adults and embryos were exposed (24 h) to 100 nM 3,3′,4,4′,5-polychlorinated biphenyl (PCB126) or 20 ppm acetone and subsequently held in clean water for 24 h (adults) or 48 h (embryos). All adult organs examined (eye, gill, heart, liver, kidney, brain, gut, and gonads) and embryos showed basal expression of the four genes. CYP1A was most strongly expressed in liver, whereas CYP1B1, CYP1C1, and CYP1C2 were most strongly expressed in heart and eye. CYP1B1 and the CYP1C genes showed an expression pattern similar to one another and to mammalian CYP1B1. In embryos CYP1C1 and CYP1C2 tended to have a higher basal expression than CYP1A and CYP1B1. PCB126 induced CYP1A in all organs, and CYP1B1 and CYP1C1 in all organs except gonads, or gonads and brain, respectively. CYP1C2 induction was significant only in the liver. However, in embryos all four genes were induced strongly by PCB126. The results are consistent with CYP1C1 and CYP1C2, as well as CYP1A and CYP1B1, being regulated by the aryl hydrocarbon receptor. While CYP1A may have a protective role against AHR agonists in liver and gut, CYP1B1, CYP1C1, and CYP1C2 may also play endogenous roles in eye and heart and possibly other organs, as well as during development.

  • 18. Kippler, Maria
    et al.
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lönnerdal, Bo
    Goessler, Walter
    Åkesson, Agneta
    El Arifeen, Shams
    Persson, Lars-Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Vahter, Marie
    Influence of iron and zinc status on cadmium accumulation in Bangladeshi women2007In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 222, no 2, p. 221-226Article in journal (Refereed)
    Abstract [en]

    Cadmium is a widespread environmental contaminant present in food. The absorption in the intestine increases in individuals with low iron stores, but the effect of zinc deficiency is not clear. The aim of the present study was to assess the influence of iron and zinc status on cadmium accumulation in pregnant Bangladeshi women. We measured cadmium in urine from 890 women using inductively coupled plasma mass spectrometry (ICPMS). Further, we also measured ferritin and zinc in plasma. The median cadmium concentration in urine was 0.59 μg/L (adjusted to mean specific gravity of 1.012 g/mL). Analysis of covariance (ANCOVA) showed that urinary cadmium was associated with plasma ferritin and plasma zinc via a significant interaction between dichotomized plasma ferritin and plasma zinc. The analysis was adjusted for age and socioeconomic status. Women with low iron stores and adequate zinc status had significantly higher urinary cadmium compared to women with both adequate iron stores and zinc status. There was no difference in urinary cadmium between women with both low iron stores and zinc status compared to those with both adequate iron stores and zinc status. In conclusion, low iron stores were associated with increased cadmium accumulation, but only at adequate zinc status.

  • 19.
    Lee, Iwa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Eriksson, Per
    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.
    Buratovic, Sonja
    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.
    Developmental neurotoxic effects of two pesticides: behavior and biomolecular studies on chlorpyrifos and carbaryl2015In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 288, no 3, p. 429-438Article in journal (Refereed)
    Abstract [en]

    In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.

  • 20.
    Lind, Monica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Eriksen, E F
    Sahlin, L
    Edlund, M
    Örberg, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of the antiestrogenic environmental pollutant 3,3',4,4', 5-pentachlorobiphenyl (PCB #126) in rat bone and uterus: diverging effects in ovariectomized and intact animals1999In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 154, no 3, p. 236-244Article in journal (Other academic)
    Abstract [en]

    The purpose of this study was to compare effects on rat bone and uterus of estrogen depletion and exposure to the coplanar PCB-congener 3,3',4,4',5-pentachlorobiphenyl (PCB #126) which exhibits anti-estrogenic properties. Half of the rats were ovariectomized (n = 20) and the other half were sham-operated. Ten of the ovariectomized rats and ten of the sham operated were exposed to PCB #126 (ip injections) for 3 months (total dose: 384 microgram/kg body wt). The remaining control rats were injected with corn oil (vehicle). The rats were killed and the tibiae and uteri were dissected. The left tibia was used for measurements of weight, length, and bone mineral density and the right for histomorphometrical analysis. The uteri were analyzed with respect to estrogen receptor content. PCB #126 exposure did not affect bone mineral density or trabecular bone volume of tibia in sham-operated rats. In ovariectomized rats PCB #126 exposure resulted in a decreased length and an increased bone mineral density of tibia. An obvious PCB #126 induced increase in osteoid surface was observed in sham-operated rats. The cortical thickness and the organic content of the tibia were also increased in these rats. In estrogen deprived tissue like the uteri of ovariectomized rats, PCB #126 showed weak estrogen agonistic activity. The observed effects of PCB #126 on bone and uterine tissues differed between ovariectomized and sham-operated rats.

  • 21.
    Lindberg, Anna-Lena
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Rahman, Mahfuzar
    ICDDR, Dhaka, Bangladesh.
    Persson, Lars-Åke
    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, Karolinska Institutet, Stockholm, Sweden.
    The risk of arsenic induced skin lesions in Bangladeshi men and women is affected by arsenic metabolism and the age at first exposure2008In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 230, no 1, p. 9-16Article in journal (Refereed)
    Abstract [en]

    It is known that a high fraction of methylarsonate (MA) in urine is a risk modifying factor for several arsenic induced health effects, including skin lesions, and that men are more susceptible for developing skin lesions than women. Thus, we aimed at elucidating the interaction between gender and arsenic metabolism for the risk of developing skin lesions. This study is part of a population-based case-referent study concerning the risk for skin lesions in relation to arsenic exposure via drinking water carried out in Matlab, a rural area 53 km south-east of Dhaka, Bangladesh. We randomly selected 526 from 1579 referents and all 504 cases for analysis of arsenic metabolites in urine using HPLC coupled to inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). The present study confirm previous studies, with the risk for skin lesions being almost three times higher in the highest tertile of %MA (adjusted OR 2.8, 95% CI: 1.9-4.2, p < 0.001) compared to the lowest tertile. The present study is the first to show that the well documented higher risk for men to develop arsenic-related skin lesions compared to women is mainly explained by the less efficient methylation of arsenic, as defined by a higher fraction of MA and lower fraction of DMA in the urine, among men. Our previously documented lower risk for skin lesions in individuals exposed since infancy, or before, was found to be independent of the observed arsenic methylation efficiency. Thus, it can be speculated that this is due to a programming effect of arsenic in utero.

  • 22. Nihlén, Annsofi
    et al.
    Wålinder, Robert
    Löf, Agneta
    Johanson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Experimental exposure to methyl teriary-butyl ether: II. Acute effects in humans1998In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 148, no 2, p. 281-287Article in journal (Refereed)
    Abstract [en]

    Methyl tertiary-butyl ether (MTBE) is widely used in gasoline as an oxygenate and octane enhancer. Acute effects, such as headache, nausea, and nasal and ocular irritation, have been associated with the exposure to gasoline containing MTBE. The aim of this study was to assess acute health effects up to the Swedish occupational exposure limit value, both with objective methods and a questionnaire. Ten healthy male volunteers were exposed to MTBE vapor for 2 h at three levels (5, 25, and 50 ppm), during light physical work (50 W). All subjects rated the degree of irritative symptoms, discomfort, and CNS effects before, during, and after all three exposure occasions using a questionnaire. Answers were given on a 100-mm visual analog scale, graded from "not at all" to "almost unbearable." Ocular (redness, tear film break-up time, self-reported tear film break-up time, conjunctival epithelial damage, and blinking frequency) and nasal (mouth and nasal peak expiratory flow, acoustic rhinometry, biochemical inflammatory markers, and cells in nasal lavage) measurements were performed mainly at the highest exposure level. The ratings of solvent smell increased dramatically (ratings up to 50% of the scale) as the volunteers entered the chamber and declined slowly with time (p < 0.05, repeated-measures ANOVA). All other questions were rated from "not at all" to "hardly at all" (0-10% of the scale) with no significant relation to exposure. The eye measurements showed no effects of MTBE exposure. Blockage index, a measure of nasal airway resistance calculated from the peak expiratory flows, increased significantly after exposure; however, the effect was not related to exposure level. In addition, a nonsignificant tendency of decreased nasal volume was seen in the acoustic rhinometry measurements, but with no clear dose-effect relationship. In conclusion, our study suggests no or minimal acute effects of MTBE vapor upon short-term exposure at relatively high levels.

  • 23.
    Nilsson, Mats F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Skold, Anna-Carin
    Ericson, Ann-Christin
    Annas, Anita
    Villar, Rodrigo Palma
    Cebers, Gvido
    Hellmold, Heike
    Gustafson, Anne-Lee
    Webster, William S.
    Comparative effects of sodium channel blockers in short term rat whole embryo culture2013In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 272, no 2, p. 306-312Article in journal (Refereed)
    Abstract [en]

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart.

  • 24. Palminger Hallén, I
    et al.
    Jönsson, S
    Medica Products Agency.
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oskarsson, A
    Kinetic observations in neonatal mice exposed to lead via milk.1996In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 140, no 1, p. 13-8Article in journal (Refereed)
    Abstract [en]

    The absorption and disposition of lead in blood was examined in 10-day-old suckling mice exposed via milk. Lactating dams were administered a single intravenous injection of 0.05 mg Pb (2.5 mCi 203Pb)/kg body wt. Lead concentrations in blood of the suckling offspring were measured for 10 days after administration to the dams. Maximum blood lead concentrations in the pups were recorded between 50 and 74 hr after dams' administration despite the fact that the majority of the lead dose to the sucklings was delivered within 24 hr after dams' administration. Kinetic analysis of pups' blood lead data revealed a rate-limited absorption in the suckling pups with an absorption half-life of approximately 17 hr in the pups. This delayed absorption is most likely due to a retention of casein-bound lead in the ileal mucosa which has a high pinocytotic activity of dietary proteins in infant rodents. The present results also indicated that the distribution of lead to the peripheral tissues in the suckling mice was different than that of adults. The conflicting evidence on whether milk enhances or inhibits the absorption of lead in infant rodents may thus be explained by measurements of lead absorption at different time periods after administration to the animals. It is also suggested that the milk diet is one reason for the increased absorption of lead seen in immature rodents.

  • 25. Sundberg, J
    et al.
    Jönsson, S
    Medical Products Agency.
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallén, I P
    Oskarsson, A
    Kinetics of methylmercury and inorganic mercury in lactating and nonlactating mice.1998In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 151, no 2, p. 319-29Article in journal (Refereed)
    Abstract [en]

    The elimination of mercury was followed for 9 days (Days 10-19 of lactation) in milk and/or 21 days in blood and plasma of lactating and nonlactating mice administered a single iv injection of either 203Hg-labeled methylmercuric chloride or 203Hg-labeled mercuric chloride (0.5 mg Hg/kg body wt). Demethylation of methylmercury to inorganic mercury was taken into consideration by analyzing the data with a combined pharmacokinetic model based on the assumption of constant blood plasma ratios for methylmercury and inorganic mercury. A three-compartment model fitted the blood and plasma concentrations vs time profiles for both compounds. Plasma clearance and volume of distribution at steady state for methylmercury were 95. 3 ml/h/kg and 18,500 ml/kg, respectively, in lactating mice, and significantly higher than in nonlactating mice with values of 47.1 ml/h/kg and 9400 ml/kg, respectively. The terminal half-lives of methylmercury in plasma were similar, 170 h in lactating and 158 h in nonlactating mice. No differences were observed between the pharmacokinetic parameters in lactating and nonlactating mice administered inorganic mercury. The lactational transfer of mercury was more efficient following administration of inorganic mercury than after administration of methylmercury, with a five times higher peak concentration in milk, higher milk:plasma concentration ratios, and 8% of the administered dose excreted in milk compared with 4% for methylmercury. Mercury concentrations in milk following an iv dose of inorganic mercury decreased with a terminal half-life of 107 h, whereas after administration of methylmercury, the concentration of total mercury in milk remained at an almost constant level during the whole period of investigation. There was a nonlinear relationship between mercury in milk and plasma following inorganic mercury administration. It is suggested that inorganic mercury enters the mammary gland by a carrier-mediated transport system, which is saturated at high plasma levels of inorganic mercury. The present study shows that physiological changes during lactation alter the pharmacokinetics for methylmercury in mice but not for inorganic mercury.

  • 26. Sundberg, J
    et al.
    Jönsson, S
    Medical Products Agency.
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oskarsson, A
    Lactational exposure and neonatal kinetics of methylmercury and inorganic mercury in mice.1999In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 154, no 2, p. 160-9Article in journal (Refereed)
    Abstract [en]

    The concentration of mercury in milk and the distribution pattern in the sucking pup was followed over time after administration of a single iv injection of 0.5 mg/kg body wt of 203Hg-labeled methylmercuric chloride or mercuric chloride to lactating mice on Day 10 of lactation. Mercury concentrations in milk of the dams and in whole body, blood, plasma, GI-tract, liver, kidneys, and brain of the offspring were followed up to 11 days after dosing (until lactational Day 21). Following the inorganic mercury dose to the dams, most of the mercury in milk was delivered to the pups during the first 24 h, but the maximum mercury concentration in plasma and tissues of pups was not reached until 7 days after dosing, indicating a prolonged absorption of inorganic mercury in the sucking pup. Pups of dams given methylmercury were exposed to a much lower and constant mercury concentration in milk. The estimated accumulated mercury dose via milk per pup of dams given methylmercury was less than half of that estimated after the inorganic mercury dose. When the accumulated dose via milk from methylmercury-exposed dams was compared to the amount of mercury in pup's carcass (whole body minus GI-tract including content), it was revealed that almost all mercury delivered via milk was absorbed, and that the suckling pups had a very low elimination of mercury until lactational Day 17. Lactational exposure following a maternal methylmercury or inorganic mercury dose resulted in almost similar mercury concentrations in liver, kidneys, and plasma of the suckling, but higher concentrations in brain (as most 14 times) and also twice as high mercury body burden in the methylmercury group. Thus, differences in kinetics indicate that lactational exposure of methylmercury is a greater hazard for the breast-fed infant than inorganic mercury.

  • 27. Trzaska, Dominika
    et al.
    Zembek, Patrycja
    Olszewski, Maciej
    Adamczewska, Violetta
    Ullerås, Erik
    Dastych, Jarosław
    "Fluorescent Cell Chip" for immunotoxicity testing: development of the c-fos expression reporter cell lines.2005In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 207, no 2 Suppl, p. 133-41Article in journal (Refereed)
    Abstract [en]

    The Fluorescent Cell Chip for in vitro immunotoxicity testing employs cell lines derived from lymphocytes, mast cells, and monocytes-macrophages transfected with various EGFP cytokine reporter gene constructs. While cytokine expression is a valid endpoint for in vitro immunotoxicity screening, additional marker for the immediate-early response gene expression level could be of interest for further development and refinement of the Fluorescent Cell Chip. We have used BW.5147.3 murine thymoma transfected with c-fos reporter constructs to obtain reporter cell lines expressing ECFP under the control of murine c-fos promoter. These cells upon serum withdrawal and readdition and incubation with heavy metal compounds showed paralleled induction of c-Fos expression as evidenced by Real-Time PCR and ECFP fluorescence as evidenced by computer-supported fluorescence microscopy. In conclusion, we developed fluorescent reporter cell lines that could be employed in a simple and time-efficient screening assay for possible action of chemicals on c-Fos expression in lymphocytes. The evaluation of usefulness of these cells for the Fluorescent Cell Chip-based detection of immunotoxicity will require additional testing with a larger number of chemicals.

  • 28.
    Wincent, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden.
    Stegeman, John J.
    Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions2015In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 284, no 2, p. 163-179Article in journal (Refereed)
    Abstract [en]

    Wnt/beta-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between beta-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the beta-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with beta-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of p-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a beta-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonudeotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of beta-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of p-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating beta-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

  • 29. Witasp, Erika
    et al.
    Kupferschmidt, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Bengtsson, Linnéa
    Hultenby, Kjell
    Smedman, Christian
    Paulie, Staffan
    Garcia-Bennett, Alfonso E
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Fadeel, Bengt
    Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells2009In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 239, no 3, p. 306-319Article in journal (Refereed)
    Abstract [en]

    Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

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