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  • 1.
    Andersson, Carin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Katsiadaki, Ioanna
    Holt, William V
    Van Look, Katrien J W
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    A chemometrical approach to study interactions between ethynylestradiol and an AhR-agonist in stickleback (Gasterosteus aculeatus)2010In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 24, no 11-12, p. 768-778Article in journal (Refereed)
    Abstract [en]

    Quantifiable responses in fish, such as induction of certain proteins, can be used as indicators of chemical contamination of waterways. In order to evaluate differences in ethoxyresorufin-O-deethylase (EROD) induction capacity of the gill and the liver and effects on organs and biomarker proteins, e.g. gill and liver EROD, hepatosomatic index (HSI), nephrosomatic index (NSI), gonadosomatic index (GSI), spiggin, vitellogenin and sperm motility were analysed in male three-spined sticklebacks (Gasterosteus aculeatus) exposed for 21 days to β-naphthoflavone (βNF) alone (Exp 1) or in combination with 17α-ethynylestradiol (EE2) (Exp 2). The sperm motility variables were studied using computer-assisted sperm analysis (CASA).

    Exp 1: Gill EROD activity was significantly induced in fish exposed to ≥1.2 µg/l and hepatic EROD activity in fish exposed to ≥6 µg/l. No significant effect of ßNF on the production of spiggin or vitellogenin or on sperm variables was found.

    Exp 2: A significant additative effect of EE2 + βNF was shown for gill EROD. A significant antagonistic effect of the two compounds was found on NSI where an increased EE2 concentration led to an increase in NSI while an increased concentration of βNF led to a decreased NSI. Interestingly, the results showed that exposure to intermediate concentrations of EE2 and ßNF led to a significant increase in the sperm variables. In the aquatic environment mixtures of numerous chemicals with oestrogenic activity are present, so if the capacity to induce gill EROD activity is a general property of oestrogen-acting chemicals, our findings are important.

  • 2.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Granberg, A Lizette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differential response of cultured human umbilical vein and artery endothelial cells to Ah receptor agonist treatment: CYP-dependent activation of food and environmental mutagens2000In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 169, no 1, p. 94-101Article in journal (Refereed)
    Abstract [en]

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

  • 3. Aspenstrom-Fagerlund, Bitte
    et al.
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Oleic acid increases intestinal absorption of the BCRP/ABCG2 substrate, mitoxantrone, in mice2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 237, no 2, p. 133-139Article in journal (Refereed)
    Abstract [en]

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

  • 4. Aspenström-Fagerlund, Bitte
    et al.
    Tallkvist, Jonas
    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 Organismal Biology, Environmental Toxicology.
    Oleic acid decreases BCRP mediated efflux of mitoxantrone in Caco-2 cell monolayers2012In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 50, no 10, p. 3635-3645Article in journal (Refereed)
    Abstract [en]

    Breast cancer resistance protein (BCRP) efflux restricts intestinal absorption of substances like heterocyclic amines, mycotoxins and certain human and veterinary drugs. Fat rich meals seem to increase absorption of drugs which are BCRP substrates or inhibitors. We therefore hypothesize that absorption of toxicants normally effluxed by BCRP are increased by fatty acids in food. Transport across and accumulation of H-3-Mitoxantrone (MXR) in Caco-2 cell monolayers were measured after 60 min exposure to emulsions of H-3-MXR (1 mu M) and oleic acid (0.5-5 mM). In addition, BCRP gene expression (RT-PCR) and the amount of BCRP protein (Western blot) were measured in oleic acid exposed Caco-2 cells. Oleic acid increased transport of MXR in a concentration dependent manner and 2 mM oleic acid or higher increased accumulation of MXR in cells, without any signs of cytotoxicity. Gene expression of BCRP was increased after exposure to oleic acid for 6 h, but the amount of BCRP protein was not increased. In conclusion, oleic acid clearly induced BCRP gene expression and reduced BCRP mediated efflux, although the amount of BCRP in cells was not affected. Consequently, effects of fatty acids on BCRP mediated efflux are important to consider in risk assessment of toxicants in food.

  • 5.
    Behrendt, Lars
    et al.
    Woods Hole Oceanographic Institution.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Goldstone, Jared V.
    Woods Hole Oceanographic Institution.
    Stegeman, John J.
    Woods Hole Oceanographic Institution.
    Induction of cytochrome P450 1 genes and stress response genes in developing zebrafish exposed to ultraviolet radiation2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 1, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Ultraviolet (UV) radiation damages cell molecules, and has been suggested to up-regulate mammalian cytochrome P4501 (CYP1) genes through an aryl hydrocarbon receptor (AHR) mediated mechanism. In this study, embryos and larvae of zebrafish (Danio rerio) were exposed to UV to determine the effects on expression of CYP1 and stress response genes in vivo in these fish. Zebrafish embryos were exposed for varying times to UV on two consecutive days, with exposure beginning at 24 and 48h post-fertilization (hpf). Embryos exposed for 2, 4 or 6h twice over 2 days to UVB (0.62 W/m(2); 8.9-26.7 kJ/m(2)) plus UVA (2.05 W/m(2); 29.5-144.6 kJ/m(2)) had moderately (2.4+/-0.8-fold) but significantly up-regulated levels of CYP1A. UVA alone had no effect on CYP1A expression. Proliferating cellular nuclear antigen (PCNA) and Cu-Zn superoxide dismutase (SOD1) transcript levels were induced (2.1+/-0.2 and 2.3+/-0.5-fold, respectively) in embryos exposed to two 6-h pulses of 0.62 W/m(2) UVB (26.8 kJ/m(2)). CYP1A was induced also in embryos exposed to higher intensity UVB (0.93 W/m(2)) for two 3-h or two 4-h pulses (20.1 or 26.8 kJ/m(2)). CYP1B1, SOD1 and PCNA expression was induced by the two 3-h pulses of the higher intensity UVB, but not after two 4-h pulses of the higher intensity UVB, possibly due to impaired condition of surviving embryos, reflected in a mortality of 34% at that UVB dose. A single 8-h long exposure of zebrafish larvae (8dpf) to UVB at 0.93 W/m(2) (26.8 kJ/m(2)) significantly induced CYP1A and CYP1B1 expression, but other CYP1 genes (CYP1C1, CYP1C2 and CYP1D1) showed no significant increase. The results show that UVB can induce expression of CYP1 genes as well stress response genes in developing zebrafish, and that UVB intensity and duration influence the responses.

  • 6.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    An Amphibian Model for Studies of Developmental Reproductive Toxicity2012In: Developmental Toxicology: Methods and Protocols / [ed] Craig Harris, Jason M Hansen, Humana Press , 2012, p. 73-83Chapter in book (Other academic)
  • 7.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Progestins in the environment – a threat to reproduction in amphibians?2013Conference paper (Other academic)
  • 8.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    The Frog Test System2010In: Towards Sustainable Pharmaceuticals in a Healthy Society: MistraPharma Research / [ed] Christina Rudén, Karin Liljelund, Helene Hagerman, Stockholm: MistraPharma , 2010, p. 46-56Chapter in book (Other academic)
  • 9.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Müllerian Duct Dysgenesis: a common cause for female reproductive disorders2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no suppl., p. S184-Article in journal (Refereed)
  • 10.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Lundstedt-Enkel, KatrinUppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.Malmsten, JonasSLU.Persson, SaraSLU.
    Reproductive Disorders in Baltic Vertebrate Wildlife (BALTREP 2011): What is the status of, and the threats to reproductive health in Baltic region wildlife?2011Conference proceedings (editor) (Other academic)
  • 11.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Progestins: potent endocrine disrupters of the female reproductive system2012In: Abstract book: Part 2, 2012, p. 179-179Conference paper (Refereed)
  • 12.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fick, Jerker
    Umeå universitet.
    Norder, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Environmental progestin concentrations disrupt oogenesis in amphibians2012In: Abstract book: part 1, 2012Conference paper (Refereed)
  • 13.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Jansson, Erika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Olsson, A. Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fick, Jerker
    Umeå universitet.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Combined Exposure to Progestin and Estrogen Mixtures: effects on vitellogenin and hormone receptor mRNA expression2012In: Comparative Biochemistry and Physiology A, ISSN 1095-6433, E-ISSN 1531-4332, Vol. 163, no suppl., p. S56-S57Article in journal (Refereed)
  • 14. 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.

  • 15.
    Borg, Daniel
    et al.
    Karolinska Institutet.
    Bogdanska, Jasna
    Stockholms Universitet.
    Sundström, Maria
    Stockholms Universitet.
    Nobel, Stefan
    Stockholms Universitet.
    Håkansson, Helen
    Karolinska Institutet.
    Bergman, Åke
    Stockholms Universitet.
    Depierre, Jospeh W
    Stockholms Universitet.
    Halldin, Krister
    Karolinska Institutet.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Tissue distribution of (35)S-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival. Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to (35)S-PFOS (12.5mg/kg), we determined the distribution in dams, fetuses (GD18 and GD20) and pups (postnatal day 1, PND1) employing whole-body autoradiography and liquid scintillation counting. In dams, levels were highest in liver and lungs. After placental transfer, (35)S-PFOS was present on GD18 at 2-3 times higher levels in lungs, liver and kidneys than in maternal blood. In PND1 pups, levels in lungs were significantly higher than in GD18 fetuses. A heterogeneous distribution of (35)S-PFOS was observed in brains of fetuses and pups, with levels higher than in maternal brain. This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.

  • 16.
    Brandt, Ingvar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Laboratory vs Field Studies to Assess Environmental Hazards and Risks Posed by Pharmaceuticals for Human Use2010In: Towards Sustainable Pharmaceuticals in a Healthy Society: MistraPharma Research / [ed] Christina Rudén, Karin Liljelund, Helene Hagerman, MistraPharma , 2010, p. 72-79Chapter in book (Other academic)
  • 17.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Helén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Monica
    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.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells2012In: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm), 2012Conference paper (Refereed)
    Abstract [en]

    Introduction

    Recent epidemiological studies reveal associations between exposure to environmental pollutants and cardiovascular disorders in humans. Elevated serum concentrations of polychlorinated biphenyls (PCBs) have for instance been associated with cardiovascular risk factors such as hypertension (1-3). Exposure to the carbonate plastic monomer bisphenol A (BPA) has been associated with an increased incidence of cardiovascular disease and atherogenic changes in the vascular wall (4-6). The contention that the human cardiovascular system is a sensitive target for toxic chemicals gain support from our earlier and recent experimental studies in rodents, birds and fish, as well as in cultured human primary endothelial cells. It is also compatible with earlier observations that certain polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens that may also contribute to atherosclerosis in mice and birds (7,8).

    In this presentation we will briefly discuss effects of Ah receptor (AhR) agonists (e.g. the coplanar PCB126 or BNF, ß-naphthoflavone) on the expression of cytochrome P450 (CYP)1 enzymes in various endothelia in rodents in vivo or ex vivo, as well as in cultured human umbilical vein endothelial cells (HUVEC). The CYP1-dependent bioactivation and irreversible binding of prototype polyaromatic hydrocarbons (PAH) and heterocyclic amines such as benzo(a)pyrene (BaP), 7,12-dimethyl- benz(a)anthracene (DMBA) and 3-amino-1,4-dimethyl-5H-pyrido- [4,3-b]indole (Trp-P1) in these endothelia will be reviewed. We will also report how PCB126 affects vasoactive factors in HUVEC, and how these effects are modulated by physiological 17ß-oestradiol concentrations. Some effects of PCB126, 1-nitropyrene (1-NP) and bisphenol A (BPA) on biomarkers for endothelial dysfunction, cell stress and DNA damage in HUVEC will finally be presented.

    Material and methods

    Human umbilical vein endothelial cells (HUVEC) were purchased from Science Cell Research laboratories, Carlsbad, CA. C57Bl mice and Wistar or Sprague Dawley rats were purchased from various suppliers. All animal experiments were approved by the Local Ethical Committee for Research on Animals in Uppsala and the studies followed the guidelines laid down by the Swedish and European Union legislation on animal experimentation. Rodents, tissue-slices and cultured cells were treated with model chemicals as previously described. Tape section and light microscopy autoradiographic imaging using 3H-labelled BaP, DMBA and Trp-P-1 and immunohistochemistry was performed as previously described (9-19). Precision-cut tissue slices for in vitro autoradiography were prepared as described in (14) and the slices were incubated with various 3H-labelled chemicals. HUVEC were exposed to various compounds and the detection of biomarkers of endothelial dysfunction, DNA damage were performed as described (20-22). Finally, female Fischer rats were exposed to BPA (0.025, 0.25 and 2.5 mg/l) and fructose (50 g/l) in the drinking water from 5 to 15 weeks of age to mimic human exposure (unpublished data).

    Results and discussion

    Co-localization of CYP1A1 expression and BaP, DMBA and Trp-P-1 adduct formation in endothelial linings As demonstrated by immunohistochemistry, a high CYP1A immunoreactivity occurred in capillaries of the heart, skeletal muscle, uterus and in blood-brain interfaces such as the leptomeninges and plexus choroideus, whereas no expression was observed for instance in cerebral capillary endothelial cells of mice treated with AhR agonists (9-11). No, or very low constitutive immunoreactivities were observed in these endothelia in vehicle-treated animals. No basal or induced CYP1B1 expression was observed in endothelial cells, while a weak CYP1B1 immunostaining was detected in the muscle layer of small arteries. It should be noted that in subcellular preparations of whole organs, e.g. heart and brain, the CYP1A1 in endothelial cells is diluted due to cells that do not express high levels of CYP1A1, for examples myocytes or neurons, in excess. A cell-specific metabolism in endothelial cells may therefore remain undetected due to the presence of metabolically inactive cells. In order to detect minor sites of bioactivation such as endothelial linings we employed light microscopic autoradiographic imaging to examine the bioactivation and subsequent irreversible binding of the radiolabelled prototype toxicants in tissues of animals pretreated with AhR-agonists. As determined by light microscopic autoradiography of AhR-agonist-treated mice exposed to 3H-labelled BaP, DMBA or Trp-P-1 and birds exposed to 3H-Trp-P-1 a significant accumulation of non-extractable radioactivity occurred in endothelial linings (9-18). The bound radioactivity occurred in the nuclei and the perinuclear cytoplasm, suggesting that the autoradiograms depict both DNA- and protein-bound adducts. Since the binding sites of 3H-labelled BaP, DMBA or Trp-P-1 corresponded with the sites of CYP1A1 induction, we concluded that rodents express a constitutively low but highly inducible and functional CYP1A1 in endothelial cells. The binding of reactive metabolites in endothelial cells exceeded the binding in all other cell types in AhR-agonist treated mice and was abolished by pretreatment with the CYP1A1 inhibitor ellipticine, supporting a CYP1A1-catalysed metabolic activation in situ to a reactive species (9, 10,12). These findings imply that there is a preferential CYP1A1-catalysed formation of reactive metabolites from all three carcinogens in endothelial cells expressing high CYP1A1 levels. Interestingly, however, carcinogenesis in endothelial cells is a relative rare finding, suggesting that degenerative lesions and cell death may be more prevalent responses to metabolism-activated carcinogens/mutagens in these cells. Experiments with 3H-DMBA and 3H-Trp-P-1 in HUVEC confirmed that AhR-agonists induced an increased bioactivation, suggesting that also human endothelial cells should be targets for toxicity of reactive intermediates formed from CYP1A1- activated carcinogens/mutagens (17-18). This conclusion is supported by immunohistochemical studies on the heavily vascularized human endometrium demonstrating an expression of CYP1A1 and CYP1B1 protein in and around human endometrial blood vessels, although a large interindividual

    variation was observed (19). None of the endometrial biopsy samples displayed vascular expression of CYP2A6, CYP2B6, CYP2C8/2C9/2C19, CYP2D6, or CYP3A4/5 protein.

    Effects of PCB 126, 1-NP, and BPA on biomarkers of endothelial dysfunction and cell stress in endothelial cells In vitro studies demonstrated that PCB126 increased the levels of vasoconstriction factors and decreased the levels of vasodilating factors in cultured HUVEC in a fashion that is characteristic for endothelial dysfunction related to human hypertension. The study showed that the co-planar PCB126 induced expression of the endothelium-derived vasoconstriction factor COX-2 and stimulated formation of the vasoconstrictor prostaglandin PGF2 via the AhR in HUVEC (20). COX-2 is known to play a role in hypertension by catalysing the formation of vasoconstriction prostaglandins and by stimulating reactive oxygen species (ROS) production. Further studies demonstrated that PCB126 increased the production of the vasoconstriction prostaglandin PGF2 and ROS in HUVEC. The relationship between increased ROS production and human hypertension is well established, ROS promotes vasoconstriction by stimulating the production of vasoconstriction prostaglandins and by reducing bioavailability of the vasorelaxing factor NO. Indeed, exposure to PCB126 slightly reduced the production of NO in HUVEC. Furthermore, the PCB126-induced mRNA expressions of CYP1A1, CYP1B1 and COX-2 in HUVEC were enhanced in the presence of physiological levels of 17- estradiol. This suggests that increased levels of oestrogen stimulate AhR-dependent transcription of genes previously associated with endothelial dysfunction and hypertension.

    In another study we have examined the effects of a nitrated PAH, 1-nitropyrene, that is abundant in diesel exhausts (21). The results revealed that 1-NP induced DNA damage, increased levels of ROS and increased protein expression of the endoplasmic reticulum stress chaperone GRP78 in cultured HUVEC. Induction of CYP1A1 by PCB126 as well as 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 and not by CYP1-dependent bioactivation to reactive intermediates.

    Recent in vitro studies demonstrated that bisphenol A increased the mRNA expression of genes that regulate vasoconstriction and angiogenesis in HUVEC (eNOS, VEGF, VEGFR2, connexin 43 and ACE1) and in human cardiomyocytes (eNOS and ACE1) (22). The results also showed that BPA increased the expression of P-eNOS(ser1177) and the production of NO in HUVEC. NO is the main effector molecule in angiogenesis downstream of VEGF. Based on the findings that BPA increase the expression of proangiogenic factors we investigated whether BPA could stimulate in vitro angiogenesis in HUVEC using the endothelial tube formation assay. The results demonstrated that BPA increased HUVEC tube formation suggesting that BPA can act directly on the endothelium and stimulate angiogenesis. Long-term exposure in rats revealed that environmentally relevant levels of BPA, increased the cardiac mRNA expression of genes that regulate vasoconstriction and angiogenesis. Ten weeks exposure of rats from preadolescence to adulthood to BPA in the drinking water increased the

    expression of eNOS, VEGF, VEGFR2 and ACE1 in the heart. Taken together, the genes that were upregulated in rat cardiac tissues in vivo were also upregulated in human endothelial cells and cardiomyocytes in vitro. The heart is a heavily vascularized tissue that consists mainly of cardiac endothelial cells and cardiomyocytes and although cardiomyocytes dominate the volume of the myocardium the number of endothelial cells exceeds the number of cardiomyocytes by approximately three to one. Thus, the effects of BPA on eNOS VEGF, VEGFR2 and ACE1 mRNA expression in rat cardiac tissues are most likely to be related to an effect of BPA on endothelial cells but may also involve cardiomyocytes.

    We conclude that endothelial cells may be targets for bioactivation and toxicity of environmental pollutants. The immunohistochemical and autoradiographic data demonstrated a differential expression of CYP1 enzymes and metabolic activation of pollutants in various endothelial linings suggesting that some but not all endothelial linings may be targets for xenobiotics metabolised by AhR-regulated enzymes. Studies on the effects of PCB126, 1-nitropyrene and BPA in cultured human primary endothelial cells demonstrated up-regulation of various biomarkers for endothelial dysfunction and cell stress suggesting that the human endothelium may be a sensitive target for these pollutants. The bioactivation and effects of environmental pollutants in endothelial cells should be further studied in order to unravel the role of these chemicals in human cardiovascular disease.

  • 18.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Crofton, Kevin
    Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. EPA, Research Triangle Park, USA.
    Viberg, Henrik
    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.
    Comparison of single and repeated exposure to low doses of pyrethroids, permethrin and bioallethrin, during neonatal brain development on adult spontaneous behaviour2012Conference paper (Refereed)
    Abstract [en]

    Permethrin and bioallethrin belong to the Type 1 class of pyrethroid pesticides. The primary mechanism of action is interference with nerve membrane sodium channels that results in increased neuronal activity. We have earlier reported on developmental neurotoxic effects after repeated, PND 10 to PND16, neonatal exposure to pyrethroids. The effects were manifested as altered spontaneous behavior, hyperactivity and reduced cognitive function and changes in cholinergic muscarinic/nicotinic receptors in the cerebral cortex of neonatal and adult mice. The present study was undertaken to compare repeated and single exposure to permethrin and bioallethrin during the neonatal brain growth spurt (BGS) on adult spontaneous behavior in a novel home environment. Neonatal NMRI male mice were given permethrin, orally (0.55; 3.3; 6.6 mg/kg bw/day) on PND 10-14, or just a single oral dose of 6.6 mg/kg bw on PND 10. Bioallethrin was given as a single oral dose of 0.7 mg/kg bw on PND 10, and compared to earlier published data on repeated exposure. Mice serving as controls received the 20 % fat emulsion vehicle. Spontaneous behavior test (locomotion, rearing, total activity) in 2-month-old mice revealed a significant higher activity in mice exposed to repeated doses of 6.6 mg permethrin, as well in mice just receiving a single 6.6 mg dose of permethrin. No significant difference was observed between repeated and single exposure.  A single dose of 0.7 mg bioallethrin on PND 10 caused the same effects as a repeated dose of 0.7 mg between PND 10 to PND 16. This demonstrates that a single dose of these pyrethroids can cause the same developmental neurotoxic effects as that seen following repeated doses over one week during the neonatal BGS period in mouse. This research provides is consistent with previous findings that exposure during the BGS can result in persistent behavioral defects.

  • 19.
    Buratovic, Sonja
    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. 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.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Developmental exposure to PBDE 209 alters adult susceptibility to paraoxon and nicotine: gender and neurobehavioural analysis2011Conference paper (Refereed)
    Abstract [en]

    Newborns, infants and children can be indirectly and directly exposed to PBDEs. This exposure coincides with a period of rapid brain development. Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardants in polymers, especially in electric appliances.A concern is that these compounds are present at a higher level in newborns and toddlers than in the average adult individual, especially the highly brominated PBDEs. We have earlier reported that neonatal exposure to toxicants can lead to an increased susceptibility of the cholinergic system at adult age. The present study was undertaken to investigate whether neonatal exposure of male and female mice to PBDE 209 alters the adult susceptibility to the organophosphorous compound, paraoxon, and to nicotine, respectively.. Neonatal, 3-day-old, NMRI mice were exposed to PBDE 209 (2,2´,3,3´,4,4´,5,5´,6,6´-decaBDE at 1.4, 6.0 and 14 µmol/kg bw). At two months of age male mice were exposed to paraoxon (0.25 mg/kg bw, every 2nd day for 7 days) and female mice exposed to nicotine. At the age of 2 months male and female mice were observed for spontaneous behaviour in a novel home environment, before and after adult exposure to paraoxon and nicotine, respectively. Adult male and female mice neonatally exposed to PBDE 209 showed significant impaired spontaneous behaviour. Male mice neonatally exposed to PBDE 209 and to paraoxon as adults developed additional defect spontaneous behaviour and lack of habituation. Female mice neonatally exposed to PBDE 209 showed an increased susceptibility to nicotine, where PBDE 209 exposed mice responded with a decrease in activity to nicotine whereas control mice responded with increased activity. The present study shows that PBDE 209 can induce developmental neurobehavioural defects in both male and female mice. Neonatal exposure to PBDE 209 caused also increased susceptibility in adult mice to paraoxon and nicotine. All these effects were dose response related.

  • 20.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Exposure to a single dose of ionising radiation during brain development can cause cognitive defects and increased levels of tau in mice2012Conference paper (Refereed)
    Abstract [en]

    Ionising radiation (IR) is widely used in the medical field for treating tumours, including tumours in the central nervous system, and for imaging techniques such as computed tomography (CT). There is a lack of knowledge and increasing concern about effects and consequences from low dose exposure during critical phases of perinatal and/or neonatal brain development compared to prenatal irradiation. It is known that IR causes neurotoxicological and neurobehavioural defects in mammals. Further, an epidemiological study has suggested that low doses of IR to the human brain during infancy can have a negative effect on cognitive abilities in adulthood. The rapid brain growth spurt (BGS) occurs in humans as well as mice. In humans the BGS starts during the third trimester of pregnancy and continues throughout the first two years of life. In mouse and rat the BGS is neonatal, spanning the first 3-4 weeks of life. The BGS is characterized by maturation of axonal and dendritic outgrowth, establishment of neural connections and acquisition of many new motor and sensory abilities. By using the neonatal mouse as an animal model we are able to study the effect of IR during early periods of brain development and which consequences it has for the adult animal. Disturbances in development caused by nicotine, MeHg, PCBs and PBDEs have previously been shown to alter adult spontaneous behaviour and/or neuroprotein levels in mice.

    Neonatal NMRI male mice were irradiated (0; 0.35 and 0.5 Gy) at one single occasion on postnatal day 10. Mice serving as controls were placed in plastic dishes for a time-period corresponding to the irradiation. Spontaneous behaviour was tested in a novel home environment at 2- and 4-months of age and parameters observed were locomotion, rearing and total activity. Analyses of important neuroprotein levels were performed on 6-month-old control and 0.5 Gy irradiated mice.

    Spontaneous behaviour test (locomotion, rearing, total activity revealed a significantly deranged behaviour in 2- and 4-month old mice irradiated with 0.35 or 0.5 Gy in a dose-response related manner, when compared to controls. The behavioural alterations were manifested as a reduced activity during at the beginning of the observational period and a higher activity at the end of the observational period. Analyses of the neuroprotein tau, which in human medicine is used as a biomarker for Alzheimer’s disease, showed a significantly higher level in mice irradiated with 0.5 Gy compared to controls. This demonstrates that a single dose of gamma radiation, given at a defined critical time period during brain development, is sufficient to cause persistently reduced cognitive functions and increased levels of tau in mice.   

  • 21.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Developmental exposure to PBDE 209: sex, neuroprotein and neurobehavioural analyses2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no supplement, p. S90-Article in journal (Refereed)
    Abstract [en]

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

     

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

     

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

  • 22.
    Dahlbom, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lagman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Sundström, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Boldness predicts social status in zebrafish (Danio rerio)2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, article id e23565Article in journal (Refereed)
    Abstract [en]

    This study explored if boldness could be used to predict social status. First, boldness was assessed by monitoring individual zebrafish behaviour in (1) an unfamiliar barren environment with no shelter (open field), (2) the same environment when a roof was introduced as a shelter, and (3) when the roof was removed and an unfamiliar object (Lego® brick) was introduced. Next, after a resting period of minimum one week, social status of the fish was determined in a dyadic contest and dominant/subordinate individuals were determined as the winner/loser of two consecutive contests. Multivariate data analyses showed that males were bolder than females and that the behaviours expressed by the fish during the boldness tests could be used to predict which fish would later become dominant and subordinate in the ensuing dyadic contest. We conclude that bold behaviour is positively correlated to dominance in zebrafish and that boldness is not solely a consequence of social dominance.

  • 23.
    Dahlbom, S. Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Backström, Tobias
    Sveriges lantbruksuniversitet, Institutionen för vilt, fisk och miljö .
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Aggression and monoamines: Effects of sex and social rank in zebrafish (Danio rerio)2012In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 228, no 2, p. 333-338Article in journal (Refereed)
    Abstract [en]

    Social defeat is a common model for studies on depression. However, such models are most often used to study aggression in males and sex differences in depression may therefore be overseen. This study investigated the potential of the zebrafish (Danio rerio) as a model for male and female aggression. In addition, effects on the brain serotonergic and dopaminergic neurotransmitter systems after agonistic interaction are well studied in many species, but not in zebrafish. We wanted to explore whether the zebrafish follows the same patterns as many other species. Therefore, the effects of agonistic interaction on brain monoaminergic activity were studied in adult male and female wild-type zebrafish. The fish interacted in pairs with one of the same sex for five days during which agonistic behaviour was quantified daily. Clear dominant/subordinate relationships developed in all pairs, both in males and females. The frequency of aggressive acts increased over time but did not differ between male and female pairs. Further, we found that dyadic agonistic interaction resulted in elevated brain serotonergic activity in subordinate zebrafish, as indicated by elevated hindbrain 5-hydroxyindoleacetic acid to serotonin ratios (5-hydroxyindolacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios). We also observed a sex difference in forebrain dopamine levels and forebrain 5-HIAA/5-HT ratios, with females displaying higher concentrations of dopamine but lower 5-HIAA/5-HT ratios than males. These results suggest that zebrafish is a suitable model for studies on female aggression and sex differences in brain monoaminergic neurotransmission.

  • 24.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Fischer, Celia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Sundell-Bergman, Synnöve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Interaction of gamma-radiation and methyl mercury during a  critical phase of neonatal brain development in mice  exacerbates developmental neurobehavioral effects2010In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 31, no 2, p. 223-229Article in journal (Refereed)
    Abstract [en]

    In our environment, mammals (including humans) are exposed to various types of ionizing radiation and both persistent and non-persistent toxic chemicals. It is known that ionizing radiation, as well as methyl mercury, can induce neurotoxicological and neurobehavioural effects in mammals. These developmental neurotoxic effects can be seen following exposure during gestation. There is a lack of knowledge concerning the effects and consequences of low-dose exposure during critical phases of pen natal and/or neonatal brain development, and of the combination of ionizing radiation and environmental chemicals. A recent study has indicated that low doses of ionizing radiation to the human brain during infancy influence cognitive ability in adulthood. In the present study, 10-day old neonatal male NMRI mice were exposed to a single oral dose of MeHg (0.40 or 4.0 mg/kg bw). Four hours after the MeHg exposure the mice were subjected to Co-60 gamma-radiation on one occasion at doses of 0.2 and 0.5 Gy. The animals were then subjected to a spontaneous behaviour test at 2 and 4 months, and a water maze test at the age of 5 months. Neither the single dose of MeHg (0.4 mg/kg bw) nor the radiation dose of 0.2 Gy affected their spontaneous behaviour, whereas the co-exposure to external gamma-radiation and MeHg caused developmental neurotoxic effects. The study shows that gamma-radiation and MeHg can interact and significantly exacerbate developmental neurotoxic effects, as manifested by disrupted spontaneous behaviour, lack of habituation, and impaired learning and memory functions.

  • 25.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Ionizing radiation and environmental toxicants can interact during brain development to exacerbate cognitive defects in mice2012Conference paper (Other academic)
  • 26.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Co-exposure to radiation and environmental toxicants (PBDE 99 and MeHg) during a defined critical phase of neonatal brain development enhances cognitive defects in adult mice2011Conference paper (Refereed)
  • 27.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö, .
    Co-exposure to radiation and environmental toxicants (PBDE 99 and MeHg) during a defined critical phase of neonatal brain development enhances cognitive defects in adult mice2011Conference paper (Refereed)
  • 28.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö, .
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Developmental co-exposure to low doses of ionising radiation and environmental toxicants during a critical period of brain development exacerbate cognitive defects in adult mice.2011Conference paper (Refereed)
  • 29.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Developmental exposure to PBDEs and environmental toxicants: Effects effects and functional consequences later in life2010In: Organohalogen Compounds, ISSN 1026-4892, Vol. 72Article in journal (Refereed)
  • 30.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Johansson, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Luo, Flora
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Neonatal low dose exposure of  female  mice to nicotine alters adult susceptability to paraoxon mannifeested as persistent neurobehavioral defects and  increased levels of protein tau2010In: The Toxicologist, ISSN 1096-6080, Vol. 114, no 1, suppl., p. 38-38Article in journal (Refereed)
  • 31.
    Gao, Kai
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Goldstone, Jared V.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Cytochrome P450 1A, 1B, and 1C mRNA induction patterns in three-spined stickleback exposed to a transient and a persistent inducer2011In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 154, no 1, p. 42-55Article in journal (Refereed)
    Abstract [en]

    Cytochrome P450 1 (CYP1) mRNA induction patterns in three-spined stickleback (Gasterosteus aculeatus) were explored for use in environmental monitoring of aryl hydrocarbon receptor (AHR) agonists. The cDNAs of stickleback CYP1A, CYP1B1, CYP1C1, and CYP1C2 were cloned and their basal and induced expression patterns were determined in the brain, gill, liver and kidney. Also, their induction time courses were compared after waterborne exposure to a transient (indigo) or a persistent (3,3',4,4',5-pentacholorbiphenyl PCB 126) AHR agonist. The cloned stickleback CYP1s exhibited a high amino acid sequence identity compared with their zebrafish orthologs and their constitutive tissue distribution patterns largely agreed with those reported in other species. PCB 126 (100 nM) induced different CYP1 expression patterns in the four tissues, suggesting tissue-specific regulation. Both indigo (1 nM) and PCB 126 (10 nM) induced a strong CYP1 expression in gills. However, while PCB 126 gave rise to a high and persistent induction in gills and liver, induction by indigo was transient in both organs. The number of putative dioxin response elements found in each CYP1 gene promoter roughly reflected the induction levels of the genes. The high responsiveness of CYP1A,CYP1B1, and CYP1C1 observed in several organs suggests that three-spined stickleback is suitable for monitoring of pollution with AHR agonists.

  • 32.
    Glynn, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Larsdotter, Maria
    Aune, Marie
    Darnerud, Per Ola
    Bjerselius, Rickard
    Bergman, Åke
    Changes in serum concentrations of polychlorinated biphenyls (PCBs), hydroxylated PCB metabolites and pentachlorophenol during pregnancy2011In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 83, no 2, p. 144-151Article in journal (Refereed)
    Abstract [en]

    We studied pregnancy-related changes in serum concentrations of five polychlorinated biphenyls (PCBs, CB 118, CB 138, CB 153, CB 156, CB 180), three hydroxylated PCB metabolites (4-OH-CB107, 4-OH-CB146, 4-OH-CB187), and pentachlorophenol (PCP). Median serum lipid content increased 2-fold between early (weeks 9-13) and late pregnancy (weeks 35-36) (N = 10). whereas median PCB levels in serum lipids decreased 20-46%, suggesting a dilution of PCB concentrations in serum lipids. Nevertheless, strong positive intra-individual correlations (Spearman's r = 0.61-0.99) were seen for PCBs during the whole study period. Thus, if samples have been collected within the same relative narrow time window during pregnancy, PCB results from one single sampling occasion can be used in assessment of relative differences in body burdens during the whole pregnancy period. Concentrations of OH-PCBs in blood serum tended to decline as pregnancy progressed, although among some women the concentrations increased at the end of pregnancy. Positive intra-individual correlations (r = 0.66-0.99) between OH-PCB concentrations were observed during the first and second trimester, whereas correlations with third trimester concentrations were more diverging (r = -0.70-0.85). No decline in PCP concentrations was observed during pregnancy and no significant correlations were found between concentrations at different sampling periods. Our results suggest that for both OH-PCBs and PCP, sampling has to be more specifically timed depending on the time period during pregnancy that is of interest. The differences in patterns of intra- and inter-individual variability of the studied compounds may be due to a combination of factors, including lipid solubility, persistence of the compounds, distribution in blood, metabolic formation, and pregnancy-related changes in body composition and physiological processes.

  • 33. Goldstone, Jared V.
    et al.
    McArthur, Andrew G.
    Kubota, Akira
    Zanette, Juliano
    Parente, Thiago
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Nelson, David R.
    Stegeman, John J.
    Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 1, p. 643-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development.

    RESULTS: Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters.

    CONCLUSIONS: Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.

  • 34.
    Johansson, Niclas
    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.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) affect developmental marker proteins, CaMKII, GAP-43, and synaptophysin levels in the mouse brain2008Conference paper (Refereed)
  • 35.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development2011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 250, no 2, p. 170-183Article in journal (Refereed)
    Abstract [en]

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

  • 36.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Gao, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Olsson, Jan A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Goldstone, Jared V
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Induction patterns of new CYP1 genes in environmentally exposed rainbow trout2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 4, p. 311-321Article in journal (Refereed)
    Abstract [en]

    The cytochrome P4501 (CYP1) gene family comprises four subfamilies in fish: CYP1A, CYP1B, CYP1C, and CYP1D. Only two CYP1 genes, CYP1A1 and CYP1A3, are so far known in rainbow trout (Oncorhynchus mykiss). The present study aimed to identify other CYP1 subfamily genes in rainbow trout, to establish methods for quantitative mRNA expression analysis of these genes, and to determine their basal and induced mRNA expression in gills and liver. Another goal was to examine their mRNA expression in environmentally exposed fish. We cloned four new transcripts, denoted rbCYP1B1, rbCYP1C1, rbCYP1C2, and rbCYP1C3. Levels of these and the previously known rbCYP1A transcripts were determined by real-time PCR in unexposed fish, fish exposed to the potent aryl hydrocarbon receptor (AhR) agonist 3,3',4,4',5-pentachlorobiphenyl (PCB126), and fish caged in various waters in the Uppsala region (Sweden). The mRNA expression patterns observed in unexposed rainbow trout (basal levels) were markedly similar to those reported for orthologous genes in other species. All six transcripts were induced by PCB126 in gills and liver, suggesting all genes to be AhR regulated. The caged fish showed clear rbCYP1 induction in gills at all monitoring sites (up to 70-fold the basal level), whereas the liver responses were weak; induction (up to 5-fold) was recorded only at the Uppsala municipal sewage treatment plant outlet. Gill filament EROD activity was induced at all caging sites. Most interestingly, the rbCYP1 gene response patterns in gills differed among caging sites and among subfamilies. The EROD induction seemed to only reflect induction of rbCYP1A transcription. Response patterns of multiple CYP1 genes in gills and liver could provide an improved monitoring strategy. Such patterns could be used to characterize complex mixtures of AhR agonists and antagonists in aquatic environments.

  • 37.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Kubota, Akira
    Biology Department, Woods Hole Oceanographic Institution.
    Timme-Laragy, Alicia R.
    Biology Department, Woods Hole Oceanographic Institution.
    Woodin, Bruce
    Biology Department, Woods Hole Oceanographic Institution.
    Stegeman, John J.
    Biology Department, Woods Hole Oceanographic Institution.
    Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.2012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed)
    Abstract [en]

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

  • 38.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Woodin, Bruce
    Biology Department, Woods Hole Oceanographic Institution.
    Stegeman, John
    Biology Department, Woods Hole Oceanographic Institution.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Cytochrome P450 1 genes in birds: evolutionary relationships and transcription profiles in chicken and japanese quail embryos2012In: The Toxicologist, 2012Conference paper (Other academic)
    Abstract [en]

    Cytochrome P450 1 (CYP1) genes are biomarkers for aryl hydrocarbon receptor (AHR) agonists and may be involved in their toxic effects. Susceptibility to AHR-mediated toxicity varies among species; e.g., Japanese quail is less sensitive than chicken to halogenated AHR agonists. CYP1s other than the CYP1As are poorly studied in birds. Here we characterize CYP1B and CYP1C genes in birds and examine mRNA expression of the complete CYP1 complement and AHR1, comparing basal and induced levels in chicken and quail embryos. We cloned cDNAs of chicken CYP1C1 and quail CYP1B1 and AHR1. CYP1Cs occur in several bird genomes, but we found no CYP1C gene in quail. The CYP1C genomic region was found to be highly conserved among many vertebrates. It also shared some synteny with the CYP1Bregion, suggesting CYP1B and CYP1C genes derive from duplication of a common ancestor gene. Quantitative PCR analysis revealed similar tissue distribution patterns for CYP1A4, CYP1A5, CYP1B1, and AHR1 mRNA in chicken and quail embryos, with the highest expression of CYP1As in liver, and of CYP1B1 in eye, brain, and heart. Our results suggest the basal transcript levels are considerably higher for CYP1A in quail than in chicken, but roughly similar for CYP1B1 and AHR1 in the two species. Chicken CYP1C1 was most highly expressed in eye and heart. Tissue distribution of CYP1B and CYP1C transcripts in birds resembles that previously found in zebrafish, which may imply that these genes serve similar functions in diverse vertebrates. 3,3’,4,5,5’-Pentachlorobiphenyl induced all four CYP1s in chicken; in quail a 1000-foldhigher dose induced the CYP1As, but not CYP1B1. The apparent absence of CYP1C1 in quail, and weak expression and induction of CYP1C1 in chicken suggest that CYP1Cs have diminishing roles in tetrapods, which may be met by CYP1B1. Determining catalytic functions of CYP1s in different species should indicate the evolving roles of these duplicated genes in physiological and toxicological processes.

  • 39.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Woodin, Bruce
    Biology, Woods Hole Oceanographic Institution.
    Stegeman, John
    Biology, Woods Hole Oceanographic Institution.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Cytochrome P450 1 Genes in Birds: Evolutionary Relationships and Transcription Profiles in Chicken and Japanese Quail Embryos2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, article id e28257Article in journal (Refereed)
    Abstract [en]

    Background: Cytochrome P450 1 (CYP1) genes are biomarkers for aryl hydrocarbon receptor (AHR) agonists and may beinvolved in some of their toxic effects. CYP1s other than the CYP1As are poorly studied in birds. Here we characterize avianCYP1B and CYP1C genes and the expression of the identified CYP1 genes and AHR1, comparing basal and induced levels inchicken and quail embryos.

    Methodology/Principal Findings: We cloned cDNAs of chicken CYP1C1 and quail CYP1B1 and AHR1. CYP1Cs occur in severalbird genomes, but we found no CYP1C gene in quail. The CYP1C genomic region is highly conserved among vertebrates.This region also shares some synteny with the CYP1B region, consistent with CYP1B and CYP1C genes deriving fromduplication of a common ancestor gene. Real-time RT-PCR analyses revealed similar tissue distribution patterns for CYP1A4,CYP1A5, CYP1B1, and AHR1 mRNA in chicken and quail embryos, with the highest basal expression of the CYP1As in liver,and of CYP1B1 in eye, brain, and heart. Chicken CYP1C1 mRNA levels were appreciable in eye and heart but relatively low inother organs. Basal transcript levels of the CYP1As were higher in quail than in chicken, while CYP1B1 levels were similar inthe two species. 3,39,4,5,59-Pentachlorobiphenyl induced all CYP1s in chicken; in quail a 1000-fold higher dose induced theCYP1As, but not CYP1B1.

    Conclusions/Significance: The apparent absence of CYP1C1 in quail, and weak expression and induction of CYP1C1 inchicken suggest that CYP1Cs have diminishing roles in tetrapods; similar tissue expression suggests that such roles may bemet by CYP1B1. Tissue distribution of CYP1B and CYP1C transcripts in birds resembles that previously found in zebrafish,suggesting that these genes serve similar functions in diverse vertebrates. Determining CYP1 catalytic functions in differentspecies should indicate the evolving roles of these duplicated genes in physiological and toxicological processes.

  • 40.
    Kvarnryd, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    The Frog as a Model for Studies on Reproductive Toxicity of Progestagenic Environmental Pollutants2011Licentiate thesis, comprehensive summary (Other academic)
    List of papers
    1. Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs
    Open this publication in new window or tab >>Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs
    2011 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 103, no 1-2, p. 18-24Article in journal (Refereed) Published
    Abstract [en]

    Levonorgestrel (LNG) is a commonly used pharmaceutical progestin found in the environment. Information on the long-term toxicity of progestins following early life exposure is scant. We investigated the effects of developmental LNG exposure on sex differentiation, reproductive organ development and fertility in the model frog Xenopus tropicalis. Tadpoles were exposed to 0, 0.06 or 0.5 nM LNG via the water from hatching until metamorphosis. At metamorphosis effects on gonadal differentiation were evaluated using a subsample of frogs. Remaining animals were held unexposed for nine months, at which time reproductive organ structure, function and fertility were determined. LNG exposure severely impaired oviduct and ovary development and fertility. All adult females in the 0.5 nM group (n = 10) completely lacked oviducts. They also displayed a significantly larger fraction of immature oocytes, arrested in meiotic prophase, than control females. Upon mating with unexposed males, only one of 11 LNG-exposed females laid eggs, whereas all control females did. No effects on testicular development, sperm count or male fertility were observed. At metamorphosis, no effects on sex ratio or gonadal histology were evident. The effects on ovarian and oviductal development were detected at adult age but not at metamorphosis, emphasising the importance of investigating the long-term consequences of developmental exposure. This is the first developmental reproductive toxicity study of a progestin in an aquatic vertebrate. Considering that several progestins are present in contaminated surface waters, further investigation into the sensitivity of frogs to progestins is warranted to understand the risk such compounds may pose to wild frog populations.

    Keywords
    Endocrine disruption, Developmental reproductive toxicity, Levonorgestrel, Oogenesis, Oviduct, Sex differentiation
    National Category
    Biological Sciences
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-153282 (URN)10.1016/j.aquatox.2011.02.003 (DOI)000290502000003 ()21392492 (PubMedID)
    Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2017-12-11Bibliographically approved
    2. Inhibited oogenesis in Xenopus tropicalis frogs after exposure to levonorgestrel
    Open this publication in new window or tab >>Inhibited oogenesis in Xenopus tropicalis frogs after exposure to levonorgestrel
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-153327 (URN)
    Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2011-07-19
  • 41.
    Kvarnryd, Moa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Grabic, Roman
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs2011In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 103, no 1-2, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Levonorgestrel (LNG) is a commonly used pharmaceutical progestin found in the environment. Information on the long-term toxicity of progestins following early life exposure is scant. We investigated the effects of developmental LNG exposure on sex differentiation, reproductive organ development and fertility in the model frog Xenopus tropicalis. Tadpoles were exposed to 0, 0.06 or 0.5 nM LNG via the water from hatching until metamorphosis. At metamorphosis effects on gonadal differentiation were evaluated using a subsample of frogs. Remaining animals were held unexposed for nine months, at which time reproductive organ structure, function and fertility were determined. LNG exposure severely impaired oviduct and ovary development and fertility. All adult females in the 0.5 nM group (n = 10) completely lacked oviducts. They also displayed a significantly larger fraction of immature oocytes, arrested in meiotic prophase, than control females. Upon mating with unexposed males, only one of 11 LNG-exposed females laid eggs, whereas all control females did. No effects on testicular development, sperm count or male fertility were observed. At metamorphosis, no effects on sex ratio or gonadal histology were evident. The effects on ovarian and oviductal development were detected at adult age but not at metamorphosis, emphasising the importance of investigating the long-term consequences of developmental exposure. This is the first developmental reproductive toxicity study of a progestin in an aquatic vertebrate. Considering that several progestins are present in contaminated surface waters, further investigation into the sensitivity of frogs to progestins is warranted to understand the risk such compounds may pose to wild frog populations.

  • 42.
    Kvarnryd, Moa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Norder, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fick, Jerker
    Department of Chemistry, Umeå University.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Inhibited oogenesis in Xenopus tropicalis frogs after exposure to levonorgestrelManuscript (preprint) (Other academic)
  • 43.
    Lee, Iwa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Quantification of p53-expressing cells and neurodegenerative cells in neonatal mouse brain after exposure to PBDE 99, TBBPA or ketamine2011Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 44.
    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.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    A single neonatal exposure to bisphenol A alters the levels of important neuroproteins in mice2012Conference paper (Refereed)
  • 45.
    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.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Neonatal exposure to perfluorohexane sulfonate in mice affects neuroprotein levels important for the developing brain2013Conference paper (Refereed)
  • 46.
    Lee, Iwa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Neonatal exposure to perfluoroxane sulfonate (PFHxS) in mice alters neuroprotein levels essential for the developing brain2013Conference paper (Refereed)
  • 47.
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Comments on "Levels of PCDD/F and dioxin-like PCB in Baltic fish of different age and gender" by M. Pandelova, B. Henkelmann, O. Roots, M. Simm, L Jarv, E. Benfenati and K.-W. Schramm [Chemosphere 71(2) (2008) 369-378]2011In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 82, no 5, p. 786-786Article in journal (Refereed)
  • 48.
    Lundstedt-Enkel, Katrin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Bjerselius, Rickard
    Asplund, Lillemor
    Nylund, Kerstin
    Liu, Yang
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Södervall, Mathias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Modeling Relationships between Baltic Sea Herring (Clupea harengus) Biology and Contaminant Concentrations Using Multivariate Data Analysis2010In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 44, no 23, p. 9018-9023Article in journal (Refereed)
    Abstract [en]

    Baltic Sea herring (Clupea harengus) is a pelagic, zoo-planktivorous fish and young (2-5 years old) individuals of this species are sampled annually in the Swedish marine monitoring program. This study determined concentrations of organochlorines (OCs) and brominated flame retardants (BFRs) in dorsal muscle from herring (n = 60) of varying age (2-13 years), weight (25-200 g), and body length (16-29 cm) caught at three locations in the Swedish part of the Baltic Proper. In order to ensure that the fish biclogy was as varied as possible, though still similar from all sampling sites, the fish to be chemically analyzed were selected from a large number of fish with determined biology using Multivariate Design. In statistical evaluation of the data, univariate and multivariate data analysis techniques, e.g. principal components analysis (PCA), partial least-squares regression (PLS), and orthogonal PLS (OPLS), were used. The results showed that the fish are exposed to a cocktail of contaminants and levels are presented. Significant OPLS models were found for all biological variables versus concentrations of OCs and BFRs, showing that fish biology covaries with fish contaminant concentrations. Correlation coefficients were as high as 0.98 for e.g. beta HCH concentration (wet weight) versus the lipid content. Lastly, the DC concentrations in herring muscle were modeled against the BFR concentrations to determine whether concentrations of either could be used to predict the other. It was found that OPLS models allowed BFR concentrations to be predicted from OC concentrations with high, but varying, accuracy (R-2 Ys between 0.93 to 0.75). Thus, fish biology and contaminant concentrations are interwoven, and fish biological parameters can be used to calculate (predict) contaminant concentrations. It is also possible to predict the BFR concentrations in an individual fish from its concentrations of OCs with very high accuracy.

  • 49.
    Lundstedt-Enkel, Katrin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Karlsson, Daniel
    Darnerud, Per Ola
    Interaction study with rats given two flame retardants: polybrominated diphenyl ethers (Bromkal 70-5 DE) and chlorinated paraffins (Cereclor 70L)2010In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 24, no 11-12, p. 710-718Article in journal (Refereed)
    Abstract [en]

    This study explored possible interaction effects on animal liver microsomal enzymes and thyroid hormones of two flame retardants: Bromkal 70-5 DE, a mixture of polybrominated diphenyl ethers (hereafter called PBDE); and Cereclor 70L, a mixture of chlorinated paraffins (hereafter called CP). Female Sprague-Dawley rats were exposed to these compounds in dose ranges of 1.3–18.7 mg/kg bw/day (PBDE) and 1–55 mg/kg bw/day (CP), by gavage for 14 days. Biological responses were measured on liver somatic index (LSI) and hepatic enzyme activity of (a) ethoxyresorufin-O-deethylase (EROD) (indicating CYP1A1 activity), (b) pentoxyresorufin-O-depentylase (PROD) (indicating CYP2B activity) and (c) the phase II conjugation enzyme uridine diphosphoglucuronosyl transferase (UDP-GT). The levels of total and free thyroxine hormone in rat plasma (TT4 and FT4, respectively) were also measured. In the experimental work, a Doehlert uniform shell design was used in order to select the combination of concentrations of PBDE and CP administered to the rats. Eight different combinations were used, including a control. The measured responses were modelled with multiple linear regression (MLR), giving response surface plots. The results showed strong synergism between the two flame retardants at one particular exposure combination, resulting in increased hepatic microsomal enzyme responses and decreased serum T4 concentrations. Notably, the exposure combination causing the most marked effects represented intermediate doses of both substances. The mechanisms behind the observed effects are unknown, but may involve induction or inhibition of enzyme systems.