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  • 1.
    Ekstrand-Hammarström, Barbro
    et al.
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Wigenstam, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue2011Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 280, nr 3, s. 88-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Low-dose exposure of alkylating mustard gas causes long-term respiratory complications characterized by bronchitis and lung fibrosis. In this study, we utilized a mouse model for lung exposure of the nitrogen mustard melphalan, in order to define early and late events in the pathogenesis such as expression of pro-inflammatory cytokines, recruitment of inflammatory cells to airways and late-phase fibrosis. We investigated the roles of different T lymphocyte subsets on the inflammatory response by using knockout mice lacking either the genes expressing T cell receptor (TCR)αβ or TCRγδ, and compared the responsiveness with that of wild type mice and double knockout mice completely deficient in T cells. Exposure to melphalan induced an early burst of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-23 in airways, followed by extensive infiltration of neutrophils in the lung tissue and airways within 24h. The acute phase was followed by a sustained lymphocytic response that persisted for at least 14 days with resulting lung fibrosis. Engagement of T lymphocytes, particularly the γδ T cell subset, was crucial both for the acute cytokine and neutrophil response and for the late-phase lung fibrosis as indicated by the lack of response in γδ T cell deficient mice. Our data demonstrate that T lymphocytes play a prominent role in the pathogenesis of long-term lung injuries caused by strong alkylating agents.

  • 2.
    Gunnarsson, David
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Nordberg, Gunnar
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin.
    Lundgren, Per
    Umeå universitet, Medicinsk fakultet, Klinisk vetenskap.
    Selstam, Gunnar
    Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten).
    Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats2003Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 183, nr (1-3), s. 57-63Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cadmium (Cd) is a widespread environmental pollutant, characterized by its ability to affect various organs. Adverse effect of Cd on the testis including decreased testosterone production are well-known phenomena, but the cellular events explaining these effects have not yet been established. In the present study the initial steps of gonadotropin mediated testosterone biosynthesis were examined in vivo in rats, in relation to Cd dose and time after injection. In the dose–response experiment Male Sprague–Dawley rats received a single subcutaneous (sc) injection of CdCl2 (1, 5 or 10 μmol/kg body weight) and were sacrificed 48 h after injection. A statistically significant decrease in luteinizing hormone (LH) receptor mRNA level in the testicular tissue was demonstrated at the highest dose (10 μmol/kg). In the temporal–response experiment rats were given 10 μmol/kg of CdCl2 sc and sacrificed 0.48, 4.8, 48 or 144 h after injection. LH receptor mRNA levels as well as cyclic adenosine monophosphate (cAMP) levels were found to be significantly lowered at 48 and 144 h. These observations of the mechanisms whereby Cd exerts its effect on the initial steps of testosterone biosynthesis are the first from in vivo experiments.

  • 3.
    Gunnarsson, David
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Svensson, Mona
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Selstam, Gunnar
    Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten).
    Nordberg, Gunnar
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Pronounced induction of testicular PGF2alpha and suppression of testosterone by cadmium: prevention by zinc2004Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 200, nr 1, s. 49-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(PGF) production, adult male Sprague–Dawley rats were exposed to CdCl2 by subcutaneous injections. Dose–response as well as temporal–response experiments were performed, and PGF levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 μmol/kg) caused a dramatic elevation of testicular PGF, which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 μmol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF synthesis (22.3-fold) detected after exposure to 20 μmol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

  • 4.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Jonasson, Sofia
    FOI.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lorentzen, Johnny
    KI, IMM.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles2014Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 326, s. 74-85Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    This study examines the immunological responses in rats following inhalation to titanium dioxide nanoparticles (TiO2 NPs), in naïve rats and in rats with induced allergic airway disease. The responses of two different inbred rat strains were compared: the Dark Aguoti (DA), susceptible to chronic inflammatory disorders, and the Brown Norwegian (BN), susceptible to atopic allergic inflammation. Naïve rats were exposed to an aerosol of TiO2 NPs once daily for 10 days. Another subset of rats was sensitized to the allergen ovalbumin (OVA) in order to induce airway inflammation. These sensitized rats were exposed to TiO2 NPs before and during the allergen challenge. Naïve rats exposed to TiO2 NPs developed an increase of neutrophils and lymphocytes in both rat strains. Airway hyperreactivity and production of inflammatory mediators typical of a T helper 1 type immune response were significantly increased, only in DA rats. Sensitization of the rats induced a prominent OVA-specific-IgE and IgG response in the BN rat while DA rats only showed an increased IgG response. Sensitized rats of both strains developed airway eosinophilia following allergen challenge, which declined upon exposure to TiO2 NPs. The level of neutrophils and lymphocytes increased upon exposure to TiO2 NPs in the airways of DA rats but remained unchanged in the airways of BN rats. In conclusion, the responses to TiO2 NPs were strain-dependent, indicating that genetics play a role in both immune and airway reactivity. DA rats were found to be higher responder compared to BN rats, both when it comes to responses in naïve and sensitized rats. The impact of genetically determined factors influencing the inflammatory reactions pinpoints the complexity of assessing health risks associated with nanoparticle exposures.

  • 5. Jonasson, S.
    et al.
    Koch, B.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Inhalation of chlorine causes long-standing lung inflammation and airway hyperresponsiveness in a murine model of chemical-induced lung injury2013Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, s. 34-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chlorine is highly irritating when inhaled, and is a common toxic industrial gas causing tissue damage in the airways followed by an acute inflammatory response. In this study, we investigated mechanisms by which chlorine exposure may cause reactive airways dysfunction syndrome (RADS) and we examined the dose-dependency of the development of symptoms. Mice were exposed to 50 or 200ppm Cl2 during a single 15min exposure in a nose-only container. The experiment terminated 2, 6, 12, 24, 48, 72h and 7, 14, 28 and 90 days post exposure. Inflammatory cell counts in bronchoalveolar lavage (BAL), secretion of inflammatory mediators in BAL, occurrence of lung edema and histopathological changes in lung tissue was analyzed at each time-point. Airway hyperresponsiveness (AHR) was studied after 24 and 48h and 7, 14, 28 and 90 days. The results showed a marked acute response at 6h (50ppm) and 12h (200ppm) post exposure as indicated by induced lung edema, increased airway reactivity in both central and peripheral airways, and an airway inflammation dominated by macrophages and neutrophils. The inflammatory response declined rapidly in airways, being normalized after 48h, but inflammatory cells were sustained in lung tissue for at least seven days. In addition, a sustained AHR was observed for at least 28 days. In summary, this mouse model of chlorine exposure shows delayed symptoms of hyperreactive airways similar to human RADS. We conclude that the model can be used for studies aimed at improved understanding of adverse long-term responses following inhalation of chlorine.

  • 6. Lilienthal, Hellmuth
    et al.
    Heikkinen, Päivi
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Viluksela, Matti
    Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats2013Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 311, nr 1-2, s. 52-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000mg/kg body wt) or PCB180 (6 dose groups, total dose of 0-1000mg/kg body wt). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760μMol/kg body wt, corresponding to 229mg/kg or 248mg/kg body wt of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs.

  • 7. Lilienthal, Hellmuth
    et al.
    Korkalainen, Merja
    Andersson, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Viluksela, Matti
    Developmental exposure to purity-controlled polychlorinated biphenyl congeners (PCB74 and PCB95) in rats: Effects on brainstem auditory evoked potentials and catalepsy2015Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 327, s. 22-31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Whereas the effects of dioxin-like polychlorinated biphenyls (DL-PCBs) are well described, less is known about non-dioxin-like PCBs (NDL-PCBs), including influences on the nervous system and related behavioral effects after developmental exposure. Following the examination of the highly purified NDL congeners PCB52 and PCB180, we report here the results of experiments with PCB74 and PCB95. Rat dams were orally exposed to equimolar doses of either congener (40 mu mol/kg bw - 11.68 mg PCB74/kg bw or 13.06 mg PCB95/kg bw) from gestational day (GD) 10 to postnatal day (PND) 7. Control dams were given the vehicle. Adult offspring were tested for cataleptic behavior after induction with haloperidol, a classical neuroleptic drug, and brainstem auditory evoked potentials (BAEPs), using clicks and tone pips of different frequencies for stimulation. Results revealed slight effects on latencies to movement onset in female offspring exposed to PCB74, whereas PCB74 males and offspring exposed to PCB95 were not affected. Pronounced changes were observed in BAEPs at low frequencies in PCB74 offspring, with elevated thresholds in both sexes. PCB95 increased thresholds in males, but not females. Small effects were detected on latency of the late wave IV in both sexes after developmental exposure to PCB74 or PCB95. Compared with the other NDL-PCB congeners tested, PCB74 caused the most pronounced effects on BAEPs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

  • 8. Rocksén, David
    et al.
    Elfsmark, Daniel
    Heldestad, Victoria
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Wallgren, Karin
    Cassel, Gudrun
    Göransson Nyberg, Ann
    An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.2008Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 250, nr 1, s. 32-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  • 9. Rocksén, David
    et al.
    Elfsmark, Daniel
    Heldestad, Victoria
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Wallgren, Karin
    Cassel, Gudrun
    Göransson Nyberg, Ann
    An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.2008Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 250, nr 1, s. 32-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  • 10. Roos, Robert
    et al.
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Halldin, Krister
    Hǻkansson, Helen
    Westerholm, Emma
    Hamers, Timo
    Hamscher, Gerd
    Heikkinen, Päivi
    Korkalainen, Merja
    Leslie, Heather A
    Niittynen, Marjo
    Sankari, Satu
    Schmitz, Hans-Joachim
    van der Ven, Leo T M
    Viluksela, Matti
    Schrenk, Dieter
    Hepatic effects of a highly purified 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in male and female rats2011Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, nr 1-3, s. 42-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PCB 180 (2,2',3,4,4',5,5'-heptachlorobiphenyl) is a persistent and accumulating polychlorinated biphenyl abundantly present in food and the environment. In this study, we used highly purified PCB 180 (dioxinlike impurities: 2.7ng TEQ(WHO)/g PCB 180) in a 28-day toxicity study in young adult Sprague-Dawley rats. Male and female rats were given total doses of 3, 10, 30, 100, 300, 1000 or 1700mg/kg b.w. PCB 180 by gavage. Increased liver weights were observed at ≥300mg/kg b.w. in males and females. No increases in serum ALT or ALP activities were found. A significant increase in liver pentoxyresorufin O-dealkylase (PROD) activity was found in males at ≥10mg/kg b.w. and in females at ≥30mg/kg b.w. In both genders, a significant induction of hepatic 7-ethoxyresorufin O-deethylase (EROD) activity was also observed in males at ≥10mg/kg b.w. and in females at ≥300mg/kg b.w. Western blotting showed that mainly cytochromes P450 (CYPs) 2B1/2 and 3A1 were induced while slight effects were seen on CYP1A1, CYP1A2 and CYP1B1. However, no induction of CYP1A1, 1A2 and 1B1 was found on the mRNA level, except for a slight effect in females at 1000mg/kg b.w. Furthermore, hepatic UDP-glucuronosyltransferases (UGTs) 1A1 and 1A6 were markedly induced in males and slightly induced in females. The hepatic concentrations of apolar retinoids were decreased in males at ≥30mg/kg b.w. and in females at ≥300mg/kg b.w. Taken together our findings show that pure PCB 180 leads to hepatic changes in a dose range which did not cause CYP1A1 induction but causes centrilobular liver hypertrophy, affects drug-metabolizing enzymes involved in the metabolism of exogenous and endogenous substrates and leads to changes in liver retinoid levels. A benchmark dose (BMD) approach is presented in order to model lowest effective dose levels for these effects. Comparison of PCB 180 liver level related to BMDL(5) for hepatic hypertrophy in rats with human data on 'total' hepatic PCB levels in individuals without history of specific exposure suggests a relatively small margin of tissue burden in the range of 37-fold. Our results show that the highly pure non dioxin-like PCB 180 exerted strong effects different to dioxin-like compounds and that the low TEQ contamination allowed a characterization of the PCB as non-dioxinlike.

  • 11. Strapáčová, Simona
    et al.
    Brenerová, Petra
    Krčmář, Pavel
    Andersson, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van Ede, Karin, I
    van Duursen, Majorie B. M.
    van den Berg, Martin
    Vondráček, Jan
    Machala, Miroslav
    Relative effective potencies of dioxin-like compounds in rodent and human lung cell models2018Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 404–405, s. 33-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.

  • 12. Wigenstam, Elisabeth
    et al.
    Elfsmark, Linda
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Jonasson, Sofia
    Inhaled sulfur dioxide causes pulmonary and systemic inflammation leading to fibrotic respiratory disease in a rat model of chemical-induced lung injury2016Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 368, s. 28-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inhalation of high concentrations of sulfur dioxide (SO2) affects the lungs and can be immediately dangerous to life. We examined the development of acute and long-term effects after exposure of SO2 in Sprague-Dawley rats, in particular inflammatory responses, airway hyperresponsiveness (AHR) and lung fibrosis. Animals were subjected to a single exposure of 2200 ppm SO2 during 10 min and treated with a single dose of the anti-inflammatory corticosteroid dexamethasone 1 h following exposure. Exposed rats showed labored breathing, decreased body-weight and an acute inflammation with neutrophil and macrophage airway infiltrates 5 h post exposure. The acute effects were characterized by bronchial damage restricted to the larger bronchi with widespread injured mucosal epithelial lining. Rats displayed hyperreactive airways 24 h after exposure as indicated by increased methacholine-induced respiratory resistance. The inflammatory infiltrates remained in lung tissue for at least 14 days but at the late time-point the dominating granulocyte types had changed from neutrophils to eosinophils. Analysis of immunoregulatory and pro-inflammatory cytokines in serum and airways implicated mixed macrophage phenotypes (M-1/M-2) and T helper cell activation of both T(H)1 and T(H)2 subtypes. Increased expression of the pro-fibrotic cytokine TGF beta 1 was detected in airways 24 h post exposure and remained increased at the late time-points (14 and 28 days). The histopathology analysis confirmed a significant collagen deposition 14 days post exposure. Treatment with dexamethasone significantly counteracted the acute inflammatory response but was insufficient for complete protection against SO2-induced adverse effects, i.e. treatment only provided partial protection against AHR and the long-term fibrosis.

  • 13.
    Wigenstam, Elisabeth
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Jonasson, Sofia
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Koch, Bo
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation2012Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 301, nr 1-3, s. 66-71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. Methods: C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1,2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Results: Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Conclusion: Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 14. Wigenstam, Elisabeth
    et al.
    Koch, Bo
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Jonasson, Sofia
    N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury2015Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, s. 40-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chlorine (Cl-2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1 h after Cl-2-exposure could improve protection against acute lung injury in Cl-2-exposed mice. BALB/c mice were exposed to 300 ppm Cl-2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24 h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.

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