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  • 1.
    Andersson, Helen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Garscha, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of PCB126 and 17 beta-oestradiol on endothelium-derived vasoactive factors in human endothelial cells2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 285, no 1-2, p. 46-56Article in journal (Refereed)
    Abstract [en]

    Epidemiological and experimental studies suggest an association between elevated serum levels of co-planar PCBs and hypertension, and one study indicate that this effect is dependent on the level of oestrogen. This study investigated the effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 17 beta-oestradiol (E-2) on vasoactive factors in human umbilical vein endothelial cells (HUVEC). The results reveal that PCB126 stimulated the vasoconstriction factors COX-2 and PGF(2 alpha), in HUVEC. An up-regulation of COX-2 expression was demonstrated using qRT-PCR, western blot and immunofluorescence and increased production of PGF(2 alpha), was demonstrated using LC/MS2 and enzyme immunoassay. Also. PCB126 slightly increased ROS production and decreased NO production in HUVEC. The addition of E2 enhanced PCB126-induced transcription of CYP1A1, CYP1B1 and COX-2 in HUVEC whereas an increased transcription of eNOS only occurred following combined treatment with E-2 and PCB126. Immunofluorescence demonstrated that HUVEC expressed AHR and ER beta but lacked ER alpha and the involvement of AHR and ER beta on the effects of PCB126 was examined by the addition of AHR and ER antagonists. The binding of PCB126 to AHR was critical for the effects of PCB126 whereas the role of ER beta was equivocal. In conclusion, these studies suggest that PCB126 induced changes in human endothelial cells that are characteristic for endothelial dysfunction in human hypertension and that PCB126-induced transcription of genes important for vascular function in human endothelial cells can be elevated by increased oestrogen levels. These findings may help understanding the mechanism for the association between PCB126 exposure and hypertension reported in human subjects and experimental animals.

  • 2.
    Andersson, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Demma, Jemal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells2009In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 262, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.

  • 3.
    Aspenström-Fagerlund, Bitte
    et al.
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Ring, Linda
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Tallkvist, Jonas
    Department of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Box 7028, SE-75007, Uppsala, Sweden.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 237, no 1-3, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.

  • 4. Bogdanska, Jasna
    et al.
    Borg, Daniel
    Sundström, Maria
    Bergström, Ulrika
    Halldin, Krister
    Abedi-Valugerdi, Manuchehr
    Bergman, Ake
    Nelson, Buck
    Depierre, Joseph
    Nobel, Stefan
    Tissue distribution of ³⁵S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose.2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 54-62Article in journal (Refereed)
    Abstract [en]

    The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of ³⁵S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

  • 5. Bogdanska, Jasna
    et al.
    Borg, Daniel
    Sundström, Maria
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Halldin, Krister
    Abedi-Valugerdi, Manuchehr
    Bergman, Åke
    Nelson, Buck
    DePierre, Joseph
    Nobel, Stefan
    Tissue distribution of S-35-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 54-62Article in journal (Refereed)
    Abstract [en]

    The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of S-35-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

  • 6.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Developmental neurotoxicity in neonatal mice following coexposure to PCB 153 and methyl mercury: Interaction or false positive? - Reply to the letter to the editor2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 248, no 2-3, p. 162-163Article in journal (Refereed)
  • 7.
    Fischer, Celia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Neonatal co-exposure to low doses of an ortho-PCB (PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 244, no 2-3, p. 157-165Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have shown a discrepancy between children in the Faeroe Islands and children in the Seychelles with regard to neuropsychological defects during early development. Both populations have a high consumption of MeHg-contaminated fish. The defective neuropsychological differences seen in children from the Faeroe Islands could be attributed to PCBs via the mother's dietary consumption of whale meat and blubber in addition to MeHg. We have previously reported that certain persistent environmental toxicants like PCBs, DDT and PBDEs can induce permanent developmental neurotoxic effects in mice when these agents are present during a critical period of the neonatal brain development. The present study investigates whether PCB 153 (an ortho-substituted PCB) can interact with MeHg to enhance developmental neurotoxic effects on spontaneous behavior and habituation. Neonatal NMRI male mice were exposed at 10 days of age to a single oral dose of one of the following doses: PCB 153 (1.4 μmol/kg body weight), MeHg (0.08, 0.40, or 4.0 mg/kg body weight), PCB 153 plus MeHg, or a vehicle (20% fat emulsion). Spontaneous behavior, habituation, and cognitive function were observed in 2- and 4-month-old mice. The present study demonstrates that an interaction from co-exposure to low doses of PCB 153 and MeHg enhances developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, lack of habituation, and reduced cognitive functions. These effects occur at doses within the same order of magnitude as reported for exposed children.

  • 8. Herlin, Maria
    et al.
    Kalantari, Fereshteh
    Stern, Natalia
    Sand, Salomon
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Viluksela, Matti
    Tuomisto, Jouni T.
    Tuomisto, Jouko
    Tuukkanen, Juha
    Jämsä, Timo
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Håkansson, Helen
    Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin2010In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 273, no 1-3, p. 1-11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). OBJECTIVES: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. METHODS: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000ngTCDD/kgbw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. RESULTS: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain difference for cross-sectional area of proximal tibia. CONCLUSION: The study provides novel information about TCDD-induced bone alterations at doses, which are of relevance from a health risk assessment point of view. In addition, the obtained results provide further support for a distinct role of the AhR in TCDD-induced bone alterations, and suggest that the benchmark dose modeling approach is appropriate for quantitative evaluation of bone toxicity parameters.

  • 9. Hermsen, Sanne A. B.
    et al.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Arima, Akihiro
    Muneoka, Atsunobu
    Ihara, Toshio
    Sumida, Hiroshi
    Fukusato, Toshio
    Kubota, Shunichiro
    Yasuda, Mineo
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 253, no 1-3, p. 147-152Article in journal (Refereed)
    Abstract [en]

    Bone tissue is one of the target tissues for dioxins and dioxin-like compounds. Therefore, the aim of this study was to investigate effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), oil bone tissue in rhesus monkey, the most human-like experimental model available, Pregnant rhesus monkeys (Macaca mulatta; age 4-10 years) were exposed to TCDD with a total dose of 40.5-42.0 or 405-420 ng/kg bodyweight by repeated subcutaneous injections starting at gestational day 20 and followed by injections every 30 days until 90 clays after delivery. At a mean age of 7 years the offspring were sacrificed and the femur bone dissected. Results from peripheral Quantitative Computed Tomography (pQCT) analyses of the metaphyseal part of the femur bones in female offspring showed significant increases in trabecular bone mineral content (BMC; +84.6%, p < 0.05, F-value (F)=5.9) in the low-dose treatment group compared with the controls. In the same animals, analysis of the mid-diaphyseal part revealed increases in total BMC (+21.3%. p < 0.05, F = 5.2) and cortical cross-sectional area (CSA; +16.4%. p < 0.01, F=7.4) compared with the controls. In males, changes in biomechanical properties indicating more fragile bone were observed. Displacement at failure were significantly increased in the male low-dose group compared to the controls (+38.0%, p, < 0.05, F=11). The high dose of TCDD did not induce any significant changes in bone morphology.

  • 10.
    Kippler, Maria
    et al.
    Division of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lönnerdal, Bo
    Goessler, Walter
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Arifeen, Shams El
    Vahter, Marie
    Cadmium interacts with the transport of essential micronutrients in the mammary gland: a study in rural Bangladeshi women2009In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 257, no 1-2, p. 64-69Article in journal (Refereed)
    Abstract [en]

    Although the concentrations of the toxic metal cadmium in breast milk are generally low (< 1 microg/L), experimental studies indicated neurobehavioral and endocrine effects in the suckling offspring. The aim of the present study was to elucidate how cadmium is transported to breast milk by assessing interactions with essential micronutrients. The study is nested into a food and micronutrient supplementation trial conducted among pregnant women in Matlab, a rural area in Bangladesh, where malnutrition is prevalent and the cadmium exposure is relatively high. We measured cadmium in breast milk (BM-Cd; median 0.14 microg/kg; range <0.050-1.0 microg/kg), in erythrocytes (Ery-Cd; median 1.5 microg/kg; range 0.46-4.8 microg/kg) and in urine (U-Cd; median 0.63 microg/L; range 0.050-4.5 microg/L), using inductively coupled plasma mass spectrometry (ICPMS). We found a significant positive association between Ery-Cd and BM-Cd and a breast milk-plasma ratio of approximately 3-4, indicating no barrier against cadmium transport from plasma to breast milk. BM-Cd was positively associated with manganese (r(s)=0.56; p<0.01) and iron (r(s)=0.55; p<0.01) in breast milk, but not with plasma ferritin. On the other hand, BM-Cd was negatively associated with BM-Ca (r(s)=-0.17; p=0.05), indicating that cadmium inhibits the transport of calcium to breast milk. In conclusion, the present study may indicate that cadmium shares common transporters with iron and manganese for transfer to breast milk, but inhibits secretion of calcium to breast milk.

  • 11.
    Lee, Iwa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    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 neuroprotein studies on endosulfan and cypermethrin2015In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 335, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. Exposure to these substances during early development may lead to adverse behavior effects manifested at a later phase of life. Pesticides are a wide group of chemicals which are still actively used and residues are found in the environment and in food products.

    The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5 mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.

  • 12.
    Lind, Monica
    et al.
    Karolinska Institutet, Institute of Environmental Medicine.
    Eriksen, Erik F
    Lind, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Sahlin, Lena
    Estrogen supplementation modulates effects of the endocrine disrupting pollutant PCB126 in rat bone and uterus: diverging effects in ovariectomized and intact animals.2004In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 199, no 2-3, p. 129-136Article in journal (Refereed)
    Abstract [en]

    The aims of the present study are to compare effects of estrogen depletion (OVX) and estradiol (E2) supplementation on the tissue effects of exposure to the endocrine disrupting organochlorine 3,3',4,4',5-pentachlorobiphenyl (PCB126). For this purpose two highly estrogen-dependent tissues, bone and uterus, were studied. Forty rats exposed to PCB126 (ip) for 3 months (total dose 384 microg/kg body weight (bw)) were randomized in to OVX/sham operation or E2 supplementation (ip, 23 microg/kg, 3 days weekly) per vehicle (corn oil) groups in a 2 x 2 factorial design. Sham operated rats were treated with vehicle, PCB or PCB plus E2 (sham, sham + PCB and sham + PCB + E2, n=10 per group) whereas ovariectomized were treated with vehicle, PCB or PCB plus E2(OVX, OVX + PCB and OVX + PCB + E2, n=10 per group). As control groups served OVX or sham, and OVX + E2 (n=10 in each group). In OVX rats PCB126 + E2 treatment increased trabecular bone volume (TBV) (P<0.01), whilst the opposite was found in sham-operated rats (P<0.01). In OVX animals exposed to PCB126, E2 supplementation decreased the uterine weight and increased the uterine ERbeta mRNA level, whilst no difference was found between the PCB126 and PCB126 + E2 exposed groups in the sham-operated animals. In conclusion, estrogen modulates PCB126 induced effects on trabecular bone, as well as several uterine parameters. These results further support an important role of estrogen on the toxic effects of PCB126 on bone and uterus.

  • 13.
    Lind, Monica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Larsson, S
    Johansson, S
    Melhus, H
    Wikström, M
    Lindhe, Ö
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bone tissue composition, dimensions and strength in female rats given an increased dietary level of vitamin A or exposed to 3,3',4, 4',5-pentachlorobiphenyl (PCB126) alone or in combination with vitamin C.2000In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 151, no 1-3, p. 11-23Article in journal (Refereed)
    Abstract [en]

    In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3',4,4',5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 microgram/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.

  • 14.
    Lind, Monica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Larsson, S
    Oxlund, H
    Håkansson, H
    Nyberg, K
    Eklund, T
    Örberg, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Change of bone tissue composition and impaired bone strength in rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126)2000In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 150, no 1-3, p. 41-51Article in journal (Refereed)
    Abstract [en]

    In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 μg/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600 000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.

  • 15.
    Ljunggren, S. A.
    et al.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Iggland, M.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karlsson, H.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A2016In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 347-349, p. 6-16Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25 mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

  • 16. Lundberg, Rebecca
    et al.
    Lyche, Jan L.
    Ropstad, Erik
    Aleksandersen, Mona
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Skaare, Janneche U.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Perinatal exposure to PCB 153, but not PCB 126, alters bone tissue composition in female goat offspring2006In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 228, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate if environmentally relevant doses of the putative estrogenic non dioxin-like PCB 153 and the dioxin-like PCB 126 caused changes in bone tissue in female goat offspring following perinatal exposure. Goat dams were orally dosed with PCB 153 in corn oil (98 microg/kg body wt/day) or PCB 126 (49 ng/kg body wt/day) from day 60 of gestation until delivery. The offspring were exposed to PCB in utero and through mother's milk. The suckling period lasted for 6 weeks. Offspring metacarpal bones were analysed using peripheral quantitative computed tomography (pQCT) after euthanisation at 9 months of age. The diaphyseal bone was analysed at a distance of 18% and 50% of the total bone length, and the metaphyseal bone at a distance of 9%. Also, biomechanical three-point bending of the bones was conducted, with the load being applied to the mid-diaphyseal pQCT measure point (50%). PCB 153 exposure significantly decreased the total cross-sectional area (125 mm(2)+/-4) versus non-exposed (142 mm(2)+/-5), decreased the marrow cavity (38 mm(2)+/-4) versus non-exposed (50 mm(2)+/-3) and decreased the moment of resistance (318 mm(3)+/-10) versus non-exposed (371 mm(3)+/-20) at the diaphyseal 18% measure point. At the metaphyseal measure point, the trabecular bone mineral density (121 mg/cm(3)+/-5) was increased versus non-exposed (111 mg/cm(3)+/-3). PCB 126 exposure did not produce any observable changes in bone tissue. The biomechanical testing of the bones did not show any significant changes in bone strength after PCB 153 or PCB 126 exposure. In conclusion, perinatal exposure to PCB 153, but not PCB 126, resulted in altered bone composition in female goat offspring.

  • 17.
    Lundgren, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Darnerud, Per Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lilienthal, Hellmuth
    Livsmedelsverket.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Coxsackievirus B3 infection and PBDE exposure causes organ-specific effects on CYP-gene expression in the mouse2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 242, no 1-3, p. 91-99Article in journal (Refereed)
    Abstract [en]

    Common viral infections have been shown to change the tissue distribution of xenobiotics, including polybrominated diphenyl ethers (PBDEs). In previous studies, it has been shown that CYP2B gene expression is induced after PBDE exposure whereas coxsackievirus B3 (CBV3) infection suppresses the expression of CYP-gene expression in the liver. In the present study, CVB3 adapted to Balb/c mice was used to study the combined effects of infection and exposure to pure BDE-99 or the commercial mixture Bromkal on CYP1A1 and CYP2B expression in the lungs and pancreas on day 3 of the infection. The quantitative gene expression of virus, CYP1A1 and CYP2B was measured by real-time polymerase chain reaction (RT-PCR). PBDE exposure in the non-infected mice tended to increase CYP2B expression in the lungs but not in the pancreas. Infection in both non-exposed and PBDE-exposed mice increased CYP2B expression in the lungs but was non-detectable in the pancreas. In the non-infected mice PBDE exposure left the CYP1A1 expression unaltered in both the lungs and pancreas. Infection in both non-exposed and PBDE-exposed mice tended to decrease the gene expression of CYP1A1 in the lungs but to induce it in the pancreas. A correlation between the amount of virus and the gene expression of CYP2B was found in the lungs. However, no effects of PBDE on virus replication were observed in any organ. In conclusion, viral infection affects CYP-gene expression differently in the pancreas and lungs whereas PBDE-induced effects were not obvious. The organ-specific change in gene expression could explain a changed tissue distribution of xenobiotics during infection.

  • 18.
    Lundgren, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Darnerud, Per Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lilienthal, Hellmuth
    Livsmedelsverket.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Theoretical Physics, Theoretical Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Viral infection and PBDE exposure interact on CYP gene expression and enzyme activities in the mouse liver2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 242, no 1-3, p. 100-108Article in journal (Refereed)
    Abstract [en]

    In the present study coxsackievirus B3 (CVB3) adapted to Balb/c mice was used to examine whether infection affects xenobiotic-metabolising CYP1A1 and CYP2B gene expression (measured by RT-PCR) and the corresponding enzyme activities of ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-depentylase (PROD), as observed on day 3 of infection. To study the simultaneous effects of xenobiotic exposure, mice were administered the polybrominated diphenyl ether (PBDE) compounds BDE-99 (single congener) and Bromkal 70-5 DE (commercial mixture). Serum thyroxine levels were also measured. High numbers of CVB3 were found in the livers of infected mice but no significant effects of PBDE on virus replication were observed. In infected mice gene expression and CYP activities were decreased in comparison with non-infected mice, especially for CYP2B. PBDE exposure in the non-infected mice was characterised by an increase in both CYP2B and PROD levels/activities, whereas CYP1A levels increased and EROD activity decreased. In general, PBDE exposure in the infected mice did not increase EROD and PROD activities to the same extent as in the non-infected exposed mice. Infected mice exposed to BDE-99 showed significantly higher CYP2B and PROD levels than both the infected non-exposed and Bromkal-exposed groups. T(4) levels were greatly decreased by infection and a tendency of reduced T(4) levels after PBDE exposure could be observed in non-infected mice. In conclusion, infection reduced the detoxifying capacity of the liver and the serum T(4) levels. PBDE exposure can modify these effects. Notably, in the infected mice differences between BDE-99 and Bromkal were observed on CYP2B gene expression and PROD activity.

  • 19. Ohlsson, Asa
    et al.
    Cedergreen, Nina
    Oskarsson, Agneta
    Ullerås, Erik
    Mixture effects of imidazole fungicides on cortisol and aldosterone secretion in human adrenocortical H295R cells.2010In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 275, no 1-3, p. 21-8Article in journal (Refereed)
    Abstract [en]

    Exposure to chemicals commonly occurs in the form of mixtures. Methods and models are required to analyze and predict the effect of mixtures in order to improve risk assessment. The steroidogenesis and hormone production of the adrenal gland is a sensitive target for endocrine-disrupting chemicals including imidazoles. Here, we exposed human adrenocortical H295R cells to the individual imidazole fungicides prochloraz, ketoconazole, imazalil and their mixtures and analyzed the effects on secretion of cortisol and aldosterone and the effects on steroidogenic gene expression. The individual imidazole fungicides prochloraz, ketoconazole and imazalil and their mixtures inhibited cortisol secretion in a similar monotonic dose-response pattern with an EC(50) value of approximately 0.1 microM. Aldosterone secretion, in contrast, displayed a biphasic dose-response, with low-dose stimulation of up to maximum twofold and high-dose inhibition. Biphasic dose-responses were found following prochloraz and ketoconazole exposure and their mixtures, but not following imazalil exposure. The inhibition of cortisol secretion was equally well predicted with the concentration addition (CA) and independent action (IA) models, while the biphasic aldosterone response was partially predicted by a modified CA model and not predicted well by a modified IA model. Changes in expression levels of steroidogenic genes could not conclusively explain the different effects on the two hormone endpoints or the different specificities of the imidazoles. We conclude that single imidazoles and mixtures have specific effects on adrenal hormone secretion. These effects can only partly be predicted using current models and need to be further analyzed in terms of in vivo relevance and human risk assessment.

  • 20. Ringerike, Tove
    et al.
    Ullerås, Erik
    Völker, Rene
    Verlaan, Bert
    Eikeset, Ase
    Trzaska, Dominika
    Adamczewska, Violetta
    Olszewski, Maciej
    Walczak-Drzewiecka, Aurelia
    Arkusz, Joanna
    van Loveren, Henk
    Nilsson, Gunnar
    Lovik, Martinus
    Dastych, Jarosław
    Vandebriel, Rob J
    Detection of immunotoxicity using T-cell based cytokine reporter cell lines ("Cell Chip").2005In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 206, no 2, p. 257-72Article in journal (Refereed)
    Abstract [en]

    Safety assessment of chemicals and drugs is an important regulatory issue. The evaluation of potential adverse effects of compounds on the immune system depends today on animal experiments. An increasing demand, however, exists for in vitro alternatives. Cytokine measurement is a promising tool to evaluate chemical exposure effects on the immune system. Fortunately, this type of measurement can be performed in conjunction with in vitro exposure models. We have taken these considerations as the starting point to develop an in vitro method to efficiently screen compounds for potential immunotoxicity. The T-cell lymphoma cell line EL-4 was transfected with the regulatory sequences of interleukin (IL)-2, IL-4, IL-10, interferon (IFN)-gamma or actin fused to the gene for enhanced green fluorescent protein (EGFP) in either a stabile or a destabilised form. Consequently, changes in fluorescence intensity represent changes in cytokine expression with one cell line per cytokine. We used this prototype "Cell Chip" to test, by means of flow cytometry, the immunomodulatory potential of 13 substances and were able to detect changes in cytokine expression in 12 cases (successful for cyclosporine, rapamycin, pentamidine, thalidomide, bis(tri-n-butyltin)oxide, house dust mite allergen (Der p I), 1-chloro-2,4-dinitrobenzene, benzocaine, tolylene 2,4-diisocyanate, potassium tetrachloroplatinate, sodium dodecyl sulphate and mercuric chloride; unsuccessful for penicillin G). In conclusion, this approach seems promising for in vitro screening for potential immunotoxicity, especially when additional cell lines besides T-cells are included.

  • 21. Roos, Robert
    et al.
    Andersson, Patrik L
    Halldin, Krister
    Institutet för miljömedicin, Karolinska Institutet.
    Håkansson, 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 rats.2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 42-53Article in journal (Refereed)
    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: 2.7 ng 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 1700 mg/kg b.w. PCB 180 by gavage. Increased liver weights were observed at ≥ 300 mg/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 ≥ 10 mg/kg b.w. and in females at ≥ 30 mg/kg b.w. In both genders, a significant induction of hepatic 7-ethoxyresorufin O-deethylase (EROD) activity was also observed in males at ≥ 10 mg/kg b.w. and in females at ≥ 300 mg/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 1000 mg/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 ≥ 30 mg/kg b.w. and in females at ≥ 300 mg/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 BMDL₅ 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.

  • 22.
    Rönn, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Karlsson, Helen
    Berglund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats2013In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, no 1, p. 125-132Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prenatal exposure to bisphenol A (BPA) has been shown to induce obesity in rodents. To evaluate if exposure also later in life could induce obesity or liver damage we investigated these hypothesises in an experimental rat model.

    METHODS:

    From five to fifteen weeks of age, female Fischer 344 rats were exposed to BPA via drinking water (0.025, 0.25 or 2.5mgBPA/L) containing 5% fructose. Two control groups were given either water or 5% fructose solution. Individual weight of the rats was determined once a week. At termination magnetic resonance imaging was used to assess adipose tissue amount and distribution, and liver fat content. After sacrifice the left perirenal fat pad and the liver were dissected and weighed. Apolipoprotein A-I in plasma was analyzed by western blot.

    RESULTS:

    No significant effects on body weight or the weight of the dissected fad pad were seen in rats exposed to BPA, and MRI showed no differences in total or visceral adipose tissue volumes between the groups. However, MRI showed that liver fat content was significantly higher in BPA-exposed rats than in fructose controls (p=0.04). BPA exposure also increased the apolipoprotein A-I levels in plasma (p<0.0001).

    CONCLUSION:

    We found no evidence that BPA exposure affects fat mass in juvenile fructose-fed rats. However, the finding that BPA in combination with fructose induced fat infiltration in the liver at dosages close to the current tolerable daily intake (TDI) might be of concern given the widespread use of this compound in our environment.

  • 23. Ullerås, Erik
    et al.
    Trzaska, Dominika
    Arkusz, Joanna
    Ringerike, Tove
    Adamczewska, Violetta
    Olszewski, Maciej
    Wyczółkowska, Janina
    Walczak-Drzewiecka, Aurelia
    Al-Nedawi, Khalid
    Nilsson, Gunnar
    Białek-Wyrzykowska, Urszula
    Stepnik, Maciej
    Loveren, Henk Van
    Vandebriel, Rob J
    Løvik, Martinus
    Rydzyński, Konrad
    Dastych, Jarosław
    Development of the "Cell Chip": a new in vitro alternative technique for immunotoxicity testing.2005In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 206, no 2, p. 245-56Article in journal (Refereed)
    Abstract [en]

    Predictive testing of immunotoxicity associated with chemical compounds is complicated and cannot be accomplished with a single test. As most of the existing tests for immunotoxicity employ experimental animals, there is an increasing need for alternative tests in vitro. We have developed a new system for in vitro immunotoxicity testing, which employs changes in cytokine expression observed in vitro as an endpoint indicating potential for perturbation of the immune system in vivo. This system named "fluorescent cell chip" (FCC) is based on a number of genetically modified cell lines that regulate the expression of a transgene coding for fluorescent protein enhanced green fluorescent protein (EGFP) in a similar way as they regulate expression of IL-1beta, IL-2, IL-4, IFN-gamma, IL-10, TNF-alpha, and beta-actin. Morphological and functional features of selected cell lines expressing EGFP under the control of cytokine promotors were compared with maternal cell lines and this comparison showed that critical functional features of the maternal cell lines were preserved in EGFP expressing cells. Two chemicals with known immunotoxic activities, cyclosporine A and potassium tetrachloro-platinate(II), mediated compound-specific pattern of inhibition and activation of reporter gene expression. Thus, the "fluorescent cell chip" has demonstrated potential for application as a predictive screening test for immunomodulatory activities of chemicals. The major advantage of this approach is the possibility to apply this test in high throughput screening of high number of compounds for their well defined biological activity.

  • 24.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Response to the comment on Viberg et al. (2008) "Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly" by Ching-Hung Hsu.2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 253, no 1-3, p. 154-154Article in journal (Refereed)
  • 25.
    Viberg, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 289, no 1, p. 59-65Article in journal (Refereed)
    Abstract [en]

    Flame retardants such as polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A are used as flame retardants and detected in the environmental, wildlife species and human tissues. Exposure to PBDEs during the neonatal development of the brain has been shown to affect behavior and learning and memory in adult mice, while neonatal exposure to TBBPA (another brominated flame retardant) did not affect behavioral variables in the adult. In this study, we hypothesized that the effects of these compounds could be reflected by changes in biochemical substrates and cholinergic receptors and have examined the levels of four proteins involved in maturation of the brain, neuronal growth and synaptogenesis and the densities of both muscarinic and nicotinic cholinergic receptors. We measured the levels of radioactivity in the brain after administration of (14)C-labelled TBBPA at different time points and saw that levels of TBBA peaked earlier and decreased faster than the earlier reported levels of PBDE 99. The protein analysis in the neonatal brain showed changes in the levels of calcium/calmodulin-dependent protein kinase II (CaMKII), growth associated protein-43 (GAP-43) and synaptophysin following neonatal exposure to PBDE 99 (21 mu mol/kg body weight), but not following exposure TBBPA. Furthermore, neonatal exposure to PBDE 99 and TBBPA caused a decrease in binding sites of the nicotinic ligand cytisine in frontal cortex. These results confirm earlier reported data that PBDE 99 can act as a developmental neurotoxicant, possibly due to its different uptake and retention in the brain compared to TBBPA. In addition, the changes in protein levels are interesting leads in the search for mechanisms behind the developmental neonatal neurotoxicity of PBDEs in general and PBDE 99 in particular, since also other compounds inducing similar adult behavioral disturbances as PBDE 99, affect these proteins during the period of rapid brain development.

  • 26.
    Viberg, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Dose-dependent behavioral disturbances after a single neonatal Bisphenol A dose2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 209, no 2-3, p. 188-195Article in journal (Refereed)
    Abstract [en]

    Bisphenol A is widely used in polymer products for food and beverage packaging, baby bottles, dental sealants, and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that neonatal exposure to other environmental pollutants can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. Furthermore, recent reports indicate that pre- and perinatal exposure to Bisphenol A can induce neurotoxic effects. The present study indicates that a single exposure to Bisphenol A on postnatal day 10 can alter adult spontaneous behavior and cognitive function in mice, effects that are both dose–response related and long-lasting/irreversible. Earlier studies on neonatal exposure to persistent organic pollutants (POPs) have shown the cholinergic system to be a target of neurotoxicity, but here only minor effects on the nicotine-induced behavior was seen. Furthermore, Morris swim-maze and the elevated plus-maze did not reveal any effects on spatial learning and anxiety-like behaviors. The present findings show similarities with effects earlier reported after pre- and perinatal exposure to Bisphenol A, and also with effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.

  • 27.
    Viberg, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lee, Iwa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose2013In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, p. 185-191Article in journal (Refereed)
    Abstract [en]

    Perfluoroalkyl acids, including perfluorohexane sulfonate (PFHxS), are fluorinated organic compounds used as surfactants and water and stain repellents in carpets, paper, and textiles, with characteristics to bioaccumulate and biomagnify in the food chain. PFHxS is found in umbilical cord blood, human milk and child serum from all over the world. We have recently reported that neonatal exposure to certain perfluoroalkyl acids, PFOS and PFOA, can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. The present study indicates that a single exposure to PFHxS on postnatal day 10, during a vulnerable period of brain development can alter adult spontaneous behavior and cognitive function in both male and female mice, effects that are both dose-response related and long-lasting/irreversible. PFHxS affected the cholinergic system, manifested as altered nicotine-induced behavior in adult animals. This is also in agreement with earlier studies on neonatal exposure to PFOS and PFOA. The present findings show that PFHxS, a member of the perfluoroalkyl acid group, can act as a developmental neurotoxicant and affect the cholinergic system and cognitive function and the effects show similarities with effects earlier reported after neonatal exposure to other POPs, such as bisphenol A, PBDEs and PCBs.

  • 28.
    Viberg, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Pontén, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 249, no 2-3, p. 153-9Article in journal (Refereed)
    Abstract [en]

    Ketamine, an anaesthetic agent used in newborns and toddlers, has been shown to induce neurodegeneration and alter adult behavior in mice, when administered during the neonatal period. Mammals have a marked period of rapid brain growth and development (BGS), which is postnatal in mice and rats, spanning the first 3-4 weeks of life and reaching its peak around postnatal day 10. CaMKII and GAP-43 play important roles during the BGS in mammals. In the present study, 10 days old mice were exposed to 5-25 mg ketamine/kg bw and 24 h later brains were analyzed for calcium/calmodulin-dependent protein kinase II (CaMKII) and growth associated protein-43 (GAP-43) and at an age of 2 and 4 months the animals were tested for spontaneous behavior. The protein analysis showed that CaMKII increased significantly in hippocampus, but not in cortex, in animals 24h after exposure to ketamine. GAP-43 showed a significant increase in hippocampus, but a significant decrease in cortex for the highest ketamine dose. When looking at the adult behavior it was clear that neonatal ketamine exposure affected spontaneous behavior and habituation in a dose-response-related manner and that these behavioral disturbances were not transient but still persisted 2 months later. Taken together, this shows that ketamine affects important proteins involved in normal maturation of the brain and induce functional deficits in the adult individual, which further strengthen our findings concerning ketamine as a developmental neurotoxicological agent.

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