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  • 1.
    Abuabaid, Hanan
    et al.
    Örebro University, School of Science and Technology.
    Karlsson, Mattias
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Probiotic Lactobacillus rhamnosus alters inflammatory responses of bladder epithelial and macrophage-like cells in co-cultureManuscript (preprint) (Other academic)
  • 2.
    Asnake, Solomon
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Banjop-Kharlyngdoh, Joubert
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH)-mediated steroid hormone receptor activation and gene regulation in chicken LMH cells2014In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 33, no 4, 891-899 p.Article in journal (Refereed)
    Abstract [en]

    The incorporation of brominated flame retardants into industrial and household appliances has increased their occurrence in the environment, resulting in deleterious effects on wildlife. With the increasing restraints on available compounds, there has been a shift to using brominated flame retardants that has seen the production of alternative brominated flame retardants such as 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH), which has been detected in the environment. In previous in silico and in vitro studies the authors have shown that TBECH can activate both the human androgen receptor (hAR) and the zebrafish AR (zAR) suggesting that it is a potential endocrine disruptor. The present study was aimed at determining the interaction of TBECH with the chicken AR (cAR). In the present study, TBECH bound to cAR, but in vitro activation assay studies using the chicken LMH cell line showed it had a potency of only 15% compared with testosterone. Sequence difference between ARs from different species may contribute to the different responses to TBECH. Further quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis showed that TBECH interacted with and altered the expression of both thyroid receptors and estrogen receptors. In addition, the qRT-PCR analysis showed that TBECH altered the transcription pattern of genes involved in inflammatory, apoptotic, proliferative, DNA methylation, and drug-metabolizing pathways. This demonstrates that TBECH, apart from activating cAR, can also influence multiple biological pathways in the chicken.

  • 3.
    Asnake, Solomon
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and act as potential endocrine disrupters in chicken LMH cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 8, 1993-2000 p.Article in journal (Refereed)
    Abstract [en]

    Increased exposure of birds to endocrine disrupting compounds has resulted in developmental and reproductive dysfunctions. We have recently identified the flame retardants, ally1-2,4,6-tribromophenyl ether (TBP-AE), 2-3-dibromopropy1-2,4,6-tribromophenyl ether (TBP-DBPE) and the TBP-DBPE metabolite 2-bromoallyI-2,4,6-tribromophenyl ether (TBP-BAE) as antagonists to both the human androgen receptor (AR) and the zebrafish AR. In the present study, we aimed at determining whether these compounds also interact with the chicken AR. In silico modeling studies showed that TBP-AE, TBP-BAE and TBP-DBPE were able to dock into to the chicken AR ligand-binding pocket. In vitro transfection assays revealed that all three brominated compounds acted as chicken AR antagonists, inhibiting testosterone induced AR activation. In addition, qRT-PCR studies confirmed that they act as AR antagonists and demonstrated that they also alter gene expression patterns of apoptotic, anti-apoptotic, drug metabolizing and amino acid transporter genes. These studies, using chicken LMH cells, suggest that TBP-AE, TBP-BAE and TBP-DBPE are potential endocrine disrupters in chicken.

  • 4.
    Asnake, Solomon
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and alter gene expression in chicken LMH cellsManuscript (preprint) (Other academic)
  • 5.
    Banjop Kharlyngdoh, Joubert
    et al.
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Combination effects on human cell lines following exposure to brominated flame-retardants that interact with the androgen receptorManuscript (preprint) (Other academic)
  • 6.
    Banjop Kharlyngdoh, Joubert
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Androgen receptor mutations associated with prostate cancer lead to differential activation by DBE-DBCH diastereomersManuscript (preprint) (Other academic)
  • 7.
    Banjop-Kharlygdoh, Joubert
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Walstad, Anders
    Örebro University, School of Science and Technology.
    Ivarsson, Per
    ALS Laboratory Group, Analytical Chemistry & Testing Services, Stockholm, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 74, 60-70 p.Article in journal (Refereed)
    Abstract [en]

    Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5. α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5. α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.

  • 8.
    Berg, A. H.
    et al.
    Örebro University, School of Science and Technology.
    Westerlund, L.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Regulation of Arctic char (Salvelinus alpinus) egg shell proteins and vitellogenin during reproduction and in response to 17beta-estradiol and cortisol2004In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 135, no 3, 276-285 p.Article in journal (Refereed)
    Abstract [en]

    Estrogens induce both vitellogenin (Vtg) and egg shell (zona pellucida; ZP) protein synthesis in salmonids. However, while Vtg is strictly under estrogenic control, recent reports suggest that additional mechanisms are involved in ZP protein synthesis. During sexual maturation both estrogen and glucocorticoid levels increase in the circulation of female fish. As glucocorticoids have been shown to interfere with Vtg induction in fish we investigated whether cortisol (F) had similar effects on ZP regulation. In the present study we determined both the natural variation in Vtg and ZP during an annual reproductive cycle in female Arctic char (Salvelinus alpinus), and the effect of co-treatment of juvenile Arctic char with 17beta-estradiol (E2) and F. During sexual maturation the expression of Vtg and ZP correlated to plasma levels of E2 and F. Determination of Vtg and ZP protein levels following co-treatment with E2 and F showed that F antagonized E2 induction of Vtg. However, F was observed to potentiate the expression of ZP protein in the same fish. These results indicate that in Arctic char Vtg and ZP proteins are not regulated by the same mechanisms and suggest that ZP protein expression does not necessarily imply exposure to estrogenic compounds alone, and may thus not be ideally suited as a biomarker of exposure to estrogenic compounds.

  • 9.
    Berg, A. Håkan
    et al.
    Örebro University, Department of Natural Sciences.
    Thomas, Peter
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Biochemical characterization of the Arctic char (Salvelinus alpinus) ovarian progestin membrane receptor2005In: Reproductive Biology and Endocrinology, ISSN 1477-7827, Vol. 3, 64- p.Article in journal (Refereed)
    Abstract [en]

    Membrane progestin receptors are involved in oocyte maturation in teleosts. However, the maturation-inducing steroid (MIS) does not appear to be conserved among species and several progestins may fulfill this function. So far, complete biochemical characterization has only been performed on a few species. In the present study we have characterized the membrane progestin receptor in Arctic char (Salvelinus alpinus) and show that the 17,20beta-dihydroxy-4-pregnen-3-one (17,20beta-P) receptor also binds several xenobiotics, thus rendering oocyte maturation sensitive to environmental pollutants. We identified a single class of high affinity (Kd, 13.8 +/- 1.1 nM), low capacity (Bmax, 1.6 +/- 0.6 pmol/g ovary) binding sites by saturation and Scatchard analyses. Receptor binding displayed rapid association and dissociation kinetics typical of steroid membrane receptors, with t1/2 s of less than 1 minute. The 17,20beta-P binding also displayed tissue specificity with high, saturable, and specific 17,20beta-P binding detected in ovaries, heart and gills while no specific binding was observed in muscle, brain or liver. Changes in 17,20beta-P binding during oocyte maturation were consistent with its identity as the oocyte MIS membrane receptor. Incubation of fully-grown ovarian follicles with gonadotropin induced oocyte maturation, which was accompanied by a five-fold increase in 17,20beta-P receptor binding. In addition, competition studies with a variety of steroids revealed that receptor binding is highly specific for 17,20beta-P, the likely maturation-inducing steroid (MIS) in Arctic char. The relative-binding affinities of all the other progestogens and steroids tested were less than 5% of that of 17,20beta-P for the receptor. Several ortho, para derivatives of DDT also showed weak binding affinity for the 17,20beta-P receptor supporting the hypothesis that xenobiotics may bind steroid receptors on the oocyte's surface and might thereby interfere with oocyte growth and maturation.

  • 10.
    Berg, Håkan
    et al.
    Örebro University, School of Science and Technology.
    Modig, Carina
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    17beta-estradiol induced vitellogenesis is inhibited by cortisol at the post-transcriptional level in Arctic char (Salvelinus alpinus)2004In: Reproductive biology and endocrinology, ISSN 1477-7827, Vol. 2, 62- p.Article in journal (Refereed)
    Abstract [en]

    This study was performed to investigate stress effects on the synthesis of egg yolk precursor, vitellogenin (Vtg) in Arctic char (Salvelinus alpinus). In particular the effect of cortisol (F) was determined since this stress hormone has been suggested to interfere with vitellogenesis and is upregulated during sexual maturation in teleosts. Arctic char Vtg was purified and polyclonal antibodies were produced in order to develop tools to study regulation of vitellogenesis. The Vtg antibodies were used to develop an enzyme-linked immunosorbent assay. The corresponding Vtg cDNA was cloned from a hepatic cDNA library in order to obtain DNA probes to measure Vtg mRNA expression. Analysis of plasma from juvenile Arctic char, of both sexes, exposed to different steroids showed that production of Vtg was induced in a dose dependent fashion by 17beta-estradiol (E2), estrone and estriol. Apart from estrogens a high dose of F also upregulated Vtg. In addition, F, progesterone (P) and tamoxifen were tested to determine these compounds ability to modulate E2 induced Vtg synthesis at both the mRNA and protein level. Tamoxifen was found to inhibit E2 induced Vtg mRNA and protein upregulation. P did not alter the Vtg induction while F reduced the Vtg protein levels without affecting the Vtg mRNA levels. Furthermore the inhibition of Vtg protein was found to be dose dependent. Thus, the inhibitory effect of F on Vtg appears to be mediated at the post-transcriptional level.

  • 11.
    Berg, Håkan
    et al.
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Liimatta, Harri
    Örebro University, School of Science and Technology.
    Hoffmann, Erik
    Karlsson, Johnny
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Characterization of antibodies for quantitative determination of spiggin protein levels in male and female three-spined stickleback (Gasterosteus aculeatus)2009In: Reproductive Biology and Endocrinology, ISSN 1477-7827, E-ISSN 1477-7827, Vol. 7, no 1, 46Article in journal (Refereed)
    Abstract [en]

    Spiggin is an adhesive glycoprotein produced in the kidney of sticklebacks during the breeding season and is subsequently secreted into the urinary bladder from where it is employed for nest building. Since the production of the protein has been shown to be under androgenic control, spiggin has been suggested to be a useful biomarker for androgenic substances in the environment. In this study, two polyclonal spiggin antibodies based on synthetic peptides and one polyclonal antibody directed against native spiggin have been characterized. The antibodies ability to identify spiggin was investigated by quantitative immunoassay. For both peptide antibodies the quantification range was determined to be between 1 and 80 ng spiggin and determination of renal spiggin levels from immature and mature males displayed a 15-fold increase in total spiggin content of the kidney resulting in a 6-fold increase in male kidney weight due to hypertrophy. The kidney somatic index (KSI) was found to correlate well with the total renal spiggin content and therefore it appears that KSI in sticklebacks could be used as an initial method to identify substances displaying androgenic effects. Furthermore, western blot analysis revealed that the polyclonal antibodies recognize different spiggin isoforms and that spiggin can be detected in the urinary bladder and kidney of both males and female sticklebacks. In order to develop a quantitative detection method for native spiggin it is necessary to produce a standard that can be used in a bioassay. Due to the adhesive and polymerization characteristics of spiggin the protein is difficult to use as a standard in bioassays. So far spiggin has been shown to exist in at least 14 isoforms, all of which contain polymerization domains. To overcome the solubility problem we have produced recombinant spiggin gamma, with only one polymerization domain, that can be expressed in E. coli. Western blot analysis demonstrated that the polyclonal antibodies were able to detect recombinant spiggin gamma protein in bacterial cell lysate, suggesting that it may be developed into a useful source of standard spiggin to be used for quantitative determination of androgen induced spiggin production in sticklebacks.

  • 12.
    Björkblom, Carina
    et al.
    Laboratory of Aquatic Pathobiology, Åbo Akademi University, Turku, Finland.
    Högfors, Eva
    Laboratory of Aquatic Pathobiology, Åbo Akademi University, Turku, Finland.
    Salste, Lotta
    Laboratory of Organic Chemistry, Åbo Akademi University, Turku, Finland.
    Bergelin, Eija
    Laboratory of Wood and Paper Chemistry, Åbo Akademi University, Turku, Finland.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Katsiadaki, Ioanna
    Cefas Weymouth Laboratory, Weymouth, United Kingdom.
    Wiklund, Tom
    Laboratory of Aquatic Pathobiology, Åbo Akademi University, Turku, Finland.
    Estrogenic and androgenic effects of municipal wastewater effluent on reproductive endpoint biomarkers in three-spined stickleback (Gasterosteus aculeatus)2009In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 28, no 5, 1063-1071 p.Article in journal (Refereed)
    Abstract [en]

    Municipal wastewater treatment plants have been associated with the release of endocrine-disrupting chemicals, which consequently lead to alterations of reproductive function in aquatic organisms. The three-spined stickleback (Gasterosteus aculeatus) has quantifiable biomarkers for assessment of both estrogen (vitellogenin) and androgen (spiggin) activity, which makes this species very valuable in the research of endocrine disruption. The estrogenic and androgenic biomarkers were used for evaluating exposure effects of municipal wastewater effluent. We evaluated the effects of 17alpha-ethinylestradiol (EE2), 17alpha-methyltestosterone (MT), and wastewater effluents on induction of vitellogenin and spiggin production, gonadosomatic index, hepatosomatic index, nephrosomatic index, plasma steroid levels, and histopathology. Adult female and male sticklebacks were exposed to 20 ng/L of EE2, 10 microg/L of MT, and wastewater effluent (10, 50, and 80% of original concentration) in a flow-through system for an exposure of one week and an extended exposure of four weeks. Chemical analyses of the steroids were done for verification of exposure concentrations and presence in the used wastewater. Our results show that municipal wastewater effluent exerts estrogenic action on three-spined stickleback as observed by elevated vitellogenin levels in exposed fish, corresponding to the effect seen in fish exposed to EE2. Furthermore, wastewater and EE2 exerted similar histopathological effects on testis of exposed fish. Although domestic effluent is suspected to have a high content of natural androgens, no obvious androgenic effect of wastewater was observed in the present study.

  • 13. Björkblom, Carina
    et al.
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Katsiadaki, I
    Wiklund, T
    Estrogen- and androgen-sensitive bioassays based on primary cell and tissue slice cultures from three-spined stickleback (Gasterosteus aculeatus)2007In: Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, ISSN 1532-0456, Vol. 146, no 3, 431-442 p.Article in journal (Refereed)
    Abstract [en]

    Endocrine disrupting compounds are chemicals that may interfere with the endocrine system causing severe effects in organisms. The three-spined stickleback (Gasterosteus aculeatus L.) offers a potential for the assessment of endocrine disruption caused by a) estrogenic xenobiotics through the estrogen-dependent protein vitellogenin and b) androgenic xenobiotics through the androgen-dependent protein spiggin. The stickleback is presently the only known fish species with a quantifiable androgen and anti-androgen biomarker endpoint. In the current study, hepatocyte and kidney primary cell cultures and liver and kidney tissue slice cultures were prepared and used for detecting estrogenic or androgenic activity in vitro through the action of hormones or municipal sewage water. The results indicate that stickleback male hepatocyte cultures are suitable in detecting estrogenic activity and stickleback female kidney tissue slice cultures in detecting androgenic activity. The tested sewage water showed high estrogenic activity but no significant androgenic activity. Primary cell and tissue slice cultures isolated from the three-spined stickleback will allow simultaneously screening in vitro for potential estrogenic and androgenic activity of complex samples.

  • 14.
    Björkbom, Carina
    et al.
    Laboratory of Aquatic Pathobiology, Environmental and Marine Biology, Department of Biosciences, Åbo Akademi University, Turku, Finland.
    Mustamäki, Noora
    Laboratory of Aquatic Pathobiology, Environmental and Marine Biology, Department of Biosciences, Åbo Akademi University, Turku, Finland.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Katsiadaki, Ioanna
    Cefas Weymouth Laboratory, Weymouth, United Kingdom .
    Wiklund, Tom
    Laboratory of Aquatic Pathobiology, Environmental and Marine Biology, Department of Biosciences, Åbo Akademi University, Turku, Finland.
    Assessment of reproductive biomarkers in three-spined stickleback (Gasterosteus aculeatus) from sewage effluent recipients2013In: Environmental Toxicology, ISSN 1520-4081, E-ISSN 1522-7278, Vol. 28, no 4, 229-237 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine the occurrence of endocrine disruption close to sewage treatment plant effluent discharges along the Finnish Baltic Sea coast using a set of reproductive biomarkers present in adult three-spined stickleback (Gasterosteus aculeatus). Possible variation and sensitivity of the biomarkers during an entire reproductive period were also examined. The analysis of vitellogenin (VTG) for estrogenic activity and spiggin for androgenic activity, together with histopathological analysis indicated that sticklebacks were exposed to estrogenic loads sufficient to cause inappropriate production of VTG and to disrupt normal testicular structure in adult male sticklebacks. No androgenic disruption was observed. The results emphasize the need of a combination of several reproductive biomarkers in fish and repeated sampling for the detection of potential endocrine modulating substances under field condition

  • 15.
    Carvalho, Raquel N.
    et al.
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Italy.
    Arukwe, Augustine
    Norwegian University of Science & Technology, Trondheim, Norway.
    Ait-Aissa, Selim
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Bado-Nilles, Anne
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France Reims University, France.
    Balzamo, Stefania
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Baun, Anders
    Department of Environmental Engineering,Technical University of Denmark, Kgs Lyngby, Denmark.
    Belkin, Shimshon
    Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
    Blaha, Ludek
    Faculty of Science, Masaryk University, RECETOX, Brno, Czech Republic.
    Brion, Francois
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Conti, Daniela
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Creusot, Nicolas
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Essig, Yona
    Analytical and Environmental Sciences Division, King's College London, UK.
    Ferrero, Valentina E. V.
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Italy.
    Flander-Putrle, Vesna
    Marine Biology Station Piran, National Institute of Biology, Slovenia.
    Furhacker, Maria
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Grillari-Voglauer, Regina
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Hogstrand, Christer
    Diabetes and Nutritional Sciences Division, King's College London, UK.
    Jonas, Adam
    Faculty of Science, Masaryk University, RECETOX, Brno, Czech Republic.
    Kharlyngdoh, Joubert B.
    Örebro University, School of Science and Technology.
    Loos, Robert
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Italy.
    Lundebye, Anne-Katrine
    National Institute of Nutrition and Seafood Research, Bergen, Norway.
    Modig, Carina
    Örebro University, School of Science and Technology. Life Science Center, Örebro University, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology. Life Science Center, Örebro University, Sweden.
    Pillai, Smitha
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Polak, Natasa
    Analytical and Environmental Sciences Division, King's College London, UK.
    Potalivo, Monica
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Sanchez, Wilfried
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Schifferli, Andrea
    Swiss Centre for Applied Ecotoxicology, Eawag-EPFL, Dübendorf, Switzerland.
    Schirmer, Kristin
    Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland; ETH Zürich, Department of Environmental Systems Science, Swiss Federal Institute of Technology, Zürich, Switzerland; EPF Lausanne, School of Architecture, Civil and Environmental Engineering, Lausanne, Switzerland.
    Sforzini, Susanna
    Department of Environmental and Life Sciences, Università del Piemonte Orientale Vercelli Novara Alessandria, Alessandria, Italy.
    Sturzenbaum, Stephen R.
    Analytical and Environmental Sciences Division, King's College London, UK.
    Søfteland, Liv
    National Institute of Nutrition and Seafood Research, Bergen, Norway.
    Turk, Valentina
    Marine Biology Station Piran, National Institute of Biology, Slovenia.
    Viarengo, Aldo
    Department of Environmental and Life Sciences, Università del Piemonte Orientale Vercelli Novara Alessandria, Alessandria, Italy.
    Werner, Inge
    Swiss Centre for Applied Ecotoxicology, Eawag-EPFL, Dübendorf, Switzerland.
    Yagur-Kroll, Sharon
    Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
    Zounkova, Radka
    Faculty of Science, Masaryk University, RECETOX, Brno, Czech Republic.
    Lettieri, Teresa
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Italy.
    Mixtures of chemical pollutants at European legislation safety concentrations: how safe are they?2014In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 141, no 1, 218-233 p.Article in journal (Refereed)
    Abstract [en]

    The risk posed by complex chemical mixtures in the environment to wildlife and humans is increasingly debated, but has been rarely tested under environmentally relevant scenarios. To address this issue, two mixtures of 14 or 19 substances of concern (pesticides, pharmaceuticals, heavy metals, polyaromatic hydrocarbons, a surfactant, and a plasticizer), each present at its safety limit concentration imposed by the European legislation, were prepared and tested for their toxic effects. The effects of the mixtures were assessed in 35 bioassays, based on 11 organisms representing different trophic levels. A consortium of 16 laboratories was involved in performing the bioassays. The mixtures elicited quantifiable toxic effects on some of the test systems employed, including i) changes in marine microbial composition, ii) microalgae toxicity, iii) immobilization in the crustacean Daphnia magna, iv) fish embryo toxicity, v) impaired frog embryo development, and vi) increased expression on oxidative stress-linked reporter genes. Estrogenic activity close to regulatory safety limit concentrations was uncovered by receptor-binding assays. The results highlight the need of precautionary actions on the assessment of chemical mixtures even in cases where individual toxicants are present at seemingly harmless concentrations.

  • 16.
    Caspillo, Nasim Reyhanian
    et al.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden; Univ Örebro, Örebro Life Sci Ctr, Sch Sci & Technol, Örebro, Sweden.
    Volkova, Kristina
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden; Univ Örebro, Örebro Life Sci Ctr, Sch Sci & Technol, Örebro, Sweden.
    Hallgren, Stefan
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, Huddinge, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Porsch-Hällström, Inger
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, Huddinge, Sweden.
    Short-term treatment of adult male zebrafish (Danio Rerio) with 17α-ethinyl estradiol affects the transcription of genes involved in development and male sex differentiation.2014In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 164, 35-42 p.Article in journal (Refereed)
    Abstract [en]

    The synthetic estrogen 17α-ethinyl estradiol (EE2) disturbs reproduction and causes gonadal malformation in fish. Effects on the transcription of genes involved in gonad development and function that could serve as sensitive biomarkers of reproductive effects in the field is, however, not well known. We have studied mRNA expression in testes and liver of adult zebrafish (Danio rerio) males treated with 0, 5 or 25ng/L EE2for 14days. qPCR analysis showed that the mRNA expression of four genes linked to zebrafish male sex determination and differentiation, Anti-Mullerian Hormone, Double sex and mab-related protein, Sry-related HMG box-9a and Nuclear receptor subfamily 5 group number 1b were significantly decreased by 25ng/L, but not 5ng/L EE2 compared with the levels in untreated fish. The decreased transcription was correlated with a previously shown spawning failure in these males (Reyhanian et al., 2011. Aquat Toxicol 105, 41-48), suggesting that decreased mRNA expression of genes regulating male sexual function could be involved in the functional sterility. The mRNA level of Cytochrome P-45019a, involved in female reproductive development, was unaffected by hormone treatment. The transcription of the female-specific Vitellogenin was significantly induced in testes. While testicular Androgen Receptor and the Estrogen Receptor-alpha mRNA levels were unchanged, Estrogen receptor-beta was significantly decreased by 25ng/L EE2. Hepatic Estrogen Receptor-alpha mRNA was significantly increased by both exposure concentrations, while Estrogen Receptor-beta transcription was unaltered. The decreased transcription of male-predominant genes supports a demasculinization of testes by EE2 and might reflect reproductive disturbances in the environment.

  • 17.
    El Marghani, Ahmed
    et al.
    Örebro University, School of Science and Technology.
    Kjellén, Peter
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Involvement of TOM1L1 in cytokine regulation in THP-1 cellsManuscript (preprint) (Other academic)
  • 18.
    El Marghani, Ahmed M.
    et al.
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Immune cell activation by sewage treatment plant effluents and inland waters in SwedenManuscript (preprint) (Other academic)
  • 19.
    Elmarghani, Ahmed
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Seyoum, Asmerom
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Science and Technology.
    Ros, Torbjön
    Pelagia Miljokonsult AB, Umeå, Sweden.
    Forsberg, Lars-Håkan
    Mälarenergi AB, Vasterås, Sweden.
    Nermark, Tomas
    Karlskoga Energi MO AB, Karlskoga, Sweden.
    Osterman, Lisa
    Skebäcks Reningsverk, Örebro, Sweden.
    Wiklund, Ulf
    Tyrens AB, Umeå, Sweden.
    Ivarsson, Per
    ALS Scandinavia AB, Täby, Sweden.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Contribution of pharmaceuticals, fecal bacteria and endotoxin to the inflammatory responses to inland waters2014In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 488-489, 228-235 p.Article in journal (Refereed)
    Abstract [en]

    The increasing contamination of freshwater with pharmaceuticals, surfactants, pesticides and other organic compounds are of major concern. As these contaminants are detected at trace levels in the environment it is important to determine if they elicit biological responses at the observed levels. In addition to chemical pollutants, there is also a concern for increasing levels of bacteria and other microorganisms in freshwater systems. In an earlier study, we observed the activation of inflammatory systems downstream of a wastewater treatment plant (WWTP) in southern Sweden. We also observed that the water contained unidentified components that were pro-inflammatory and potentiated the immune response in human urinary bladder epithelial cells. In order to determine if these effects were unique for the studied site or represent a common response in Swedish water, we have now performed a study on three WWTPs and their recipient waters in central Sweden. Analysis of immune responses in urinary bladder epithelial cells, monocyte-like cells and blood mononuclear cells confirm that these waters activate the immune system as well as induce pro-inflammatory responses. The results indicate that the cytokine profiles correlate to the endotoxin load of the waters rather than to the levels of pharmaceuticals or culturable bacteria load, suggesting that measurements of endotoxin levels and immune responses would be a valuable addition to the analysis of inland waters.

  • 20.
    Elmarghani, Ebraheem [Ibrahim] Daabag
    et al.
    Örebro University, School of Science and Technology.
    Poonlapthawee, Sirirat
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Antibiotic resistance in fecal indicator bacteria in Hjälmaren lake systemManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Increasing levels of multi-antibiotic resistant bacteria are ound in the environment, causing serious concerns for treatment of infectious diseases. his increase is believed to be due to release of antibiotic resistant bacteria and election pressure resulting from pharmaceuticals in the environment.

    Objectives: We evaluated the presence of multi-antibiotic resistant fecal ndicator bacteria from the surface waters of a recipient river and lake downstream of he wastewater treatment plant (WWTP) in Sweden.

    Methods: Surface waters from Svartån river and Hjälmaren lake in Sweden were ampled in 2010 and 2011. The waters were analyzed for fecal indicator bacteria Escherichia coli, enterococci) by membrane filtration and selective agar plating. E. coli nd enterococci were evaluated by Etest for resistance to tetracycline, chloramphenicol, alidixic acid, trimethoprim-sulfamethoxazole, ciprofloxacin, cefotaxime, ceftazidime, eropenem, imipenem, ampicillin, vancomycin, gentamycin and streptomycin.

    Results: The highest concentration of E. coli and enterococci were found in vartån river at Naturens Hus closest site downstream of the WWTP. Tetracycline resistance as the most prominent in both fecal indicator bacteria. Over the two years, there was 42% (13/31) and 24% (7/29) multi-antibiotic resistant (≥2 antibiotics) E. coli and nterococci, respectively. Furthermore, we identified one ESBL and one AmpC hyperproducing . coli in 2010 and vancomycin (vanA) resistant E. faecium in 2011.

    Conclusions: The presence, of multi-antibiotic resistant strains of fecal ndicator organisms in regions considered predominantly clean, is of great concern. While t currently may not be a major threat in the region, it is demonstrating the accelerating incidence and spread of antibiotic resistance worldwide.

  • 21.
    Elmarghani, Ibrahim [Ebraheem]
    et al.
    Örebro University, School of Science and Technology.
    Elmarghani, Ahmed
    Biotechnology research center Tripoli, Libya PO Box 3310.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    The impact of environmental waters on cellular response in human and bacterial cellsManuscript (preprint) (Other academic)
    Abstract [en]

    The escalating frequency of pharmaceutical and antibiotic use contributes to the increasing amounts of these substances being released into the environment. While wastewater treatment plants (WWTP) effectively remove substantial amounts of contaminating substances, some are persistent and are released into the environment. It is not possible to identify all of the potentially bioactive substances released into the environment, therefore it is more rational to explore the biological effects of the waters to determine prospective health hazards. The present study evaluates the cellular response of human and bacterial cells (Enterococcus faecalis) to environmental waters upstream anddownstream of the WWTP near the  city of Örebro, Sweden. Water samples werecollected from 4 sites during May 2011. These included a site upstream in Svartån at Tekniska Kvarn, downstream at Naturens Hus near the WWTP, in the recipient Hjälmaren lake and in Ånnaboda lake (control site). THP-1 monocytes exhibited a significant increase in secretion of pro-inflammatory cytokines TNF-α and IL-β when treated with waters from Svartån at Naturens Hus, justdownstream of the WWTP outlet. Water from this site was thereafter tested using an environmental E. faecalis isolate and the stress response, virulence and antibiotic gene expression was evaluated by qPCR. There was no statistically significant effect observed on the selected genes in E. faecalis when treated with the environmental waters compared to MQ water. Thus the waters contained substances that influence inflammatory response in human cells in vitro but did not affect fecal indicator enterococci.

  • 22.
    Hoffmann, Erik
    et al.
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Walstad, Anders
    Örebro University, School of Science and Technology.
    Karlsson, Johnny
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Borg, Bertil
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Androgen receptor-beta mRNA levels in different tissues in breeding and post-breeding male and female sticklebacks, Gasterosteus aculeatus2012In: Reproductive Biology and Endocrinology, ISSN 1477-7827, E-ISSN 1477-7827, Vol. 10, 23Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Androgens induce male characters by activating androgen receptors (AR). Previous quantitative studies on AR in fishes have been limited to few tissues and/or a single season/reproductive state. The aim of this investigation was to study the possible role of AR-beta expression levels in the control of male traits in the three-spined stickleback. To that end, AR-beta expression levels in major tissues in breeding and post-breeding male and female sticklebacks were examined.

    METHODS: AR-beta mRNA levels were quantified in ten tissues; eye, liver, axial muscle, heart, brain, intestine, ovary, testis, kidney and pectoral muscle in six breeding and post-breeding males and females using reverse transcription quantitative PCR.

    RESULTS: Breeding in contrast to post-breeding males built nests and showed secondary sexual characters (e.g. kidney hypertrophy) and elevated androgen levels. Post-breeding females had lower ovarian weights and testosterone levels than breeding females. AR-beta was expressed in all studied tissues in both sexes and reproductive states with the highest expression in the gonads and in the kidneys. The kidney is an androgen target organ in sticklebacks, from which breeding males produce the protein spiggin, which is used in nest-building. There was also high AR-beta expression in the intestine, an organ that appears to take over hyperosmo-regulation in fresh water when the kidney hypertrophies in mature males and largely loses this function. The only tissue that showed effects of sex or reproductive state on AR-beta mRNA levels was the kidneys, where post-breeding males displayed higher AR-beta mRNA levels than breeding males.

    CONCLUSION: The results indicate that changes in AR-beta mRNA levels play no or little role in changes in androgen dependent traits in the male stickleback.

  • 23. Hossain, Mohammad Sorowar
    et al.
    Larsson, Anders
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Orban, Laszlo
    Zebrafish androgen receptor: isolation, molecular, and biochemical characterization2008In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 78, no 2, 361-369 p.Article in journal (Refereed)
    Abstract [en]

    Androgens play an important role in male sexual differentiation and development. They exert their function by binding to and activating the androgen receptor (Ar), a member of the steroid hormone receptor superfamily. Here, we report on the isolation and characterization of zebrafish Ar. The complete transcript of zebrafish ar is 5.3 kb long encoding a putative polypeptide of 868 amino acids. Our experimental and bioinformatic analysis has found a single ar locus in zebrafish. Phylogenetic analysis using the ligand-binding domain showed that the zebrafish Ar clustered with its cyprinid orthologs to form a separate group, which was closer to the beta clade than to the alpha clade. Tissue-specific expression analysis revealed that the ar mRNA was expressed ubiquitously in all adult tissues tested, with sexually dimorphic expression in the gonad and muscle. While the ar transcript was maternally deposited into the embryo, signs of zygotic expression could be detected as early as 24 h after fertilization, and the expression level increased substantially afterwards. When analyzed during gonad development, the expression level of ar mRNA at 4 wk after fertilization was similar in both developing gonads but later became higher in the transforming testis, suggesting a potential role during male gonad differentiation. We also combined theoretical modeling with in vitro experiments to show that the zebrafish Ar is preferentially activated by 11-ketotestosterone.

  • 24.
    Karlsson, Mattias
    et al.
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-κB activity in Escherichia coli-stimulated urinary bladder cells2012In: FEMS Immunology and Medical Microbiology, ISSN 0928-8244, E-ISSN 1574-695X, Vol. 66, no 2, 147-156 p.Article in journal (Refereed)
    Abstract [en]

    Lactobacillus rhamnosus GR-1 is a probiotic bacterium used to maintain urogenital health. The putative mechanism for its probiotic effect is by modulating the host immunity. Urinary tract infections (UTI) are often caused by uropathogenic Escherichia coli that frequently evade or suppress immune responses in the bladder and can target pathways, including nuclear factor-kappaB (NF-κB). We evaluated the role of L. rhamnosus GR-1 on NF-κB activation in E. coli-stimulated bladder cells. Viable L. rhamnosus GR-1 was found to potentiate NF-κB activity in E. coli-stimulated T24 bladder cells, whereas heat-killed lactobacilli demonstrated a marginal increase in NF-κB activity. Surface components released by trypsin- or LiCl treatment, or the resultant heat-killed shaved lactobacilli, had no effect on NF-κB activity. Isolation of released products from L. rhamnosus GR-1 demonstrated that the induction of NF-κB activity was owing to released product(s) with a relatively large native size. Several putative immunomodulatory proteins were identified, namely GroEL, elongation factor Tu and NLP/P60. GroEL and elongation factor Tu have previously been shown to elicit immune responses from human cells. Isolating and using immune-augmenting substances produced by lactobacilli is a novel strategy for the prevention or treatment of UTI caused by immune-evading E. coli.

  • 25.
    Khalaf, Hazem
    et al.
    Örebro University, School of Health and Medical Sciences.
    Jass, Jana
    Örebro University, School of Science and Technology. Univ Western Ontario, Lawson Hlth Res Inst, London, ON N6A 4V2, Canada; Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 4V2, Canada.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Differential cytokine regulation by NF-κB and AP-1 in Jurkat T-cells2010In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 11, 26Article in journal (Refereed)
    Abstract [en]

    Background: Activator protein (AP)-1 and nuclear factor (NF)-κB largely control T-cell activation, following binding offoreign antigens to the T-cell receptor leading to cytokine secretion. Elevated levels of pro-inflammatory cytokines andchemokines such as TNF, IL-6 and CXCL8 are associated with several human diseases including cystic fibrosis, pulmonary fibrosis and AIDS. The aim of this study was to investigate the role of the transcription factors, AP-1 and NF-κB, in IL-6 and CXCL8 regulation in Jurkat T-cells.

    Results: Phorbol myristate acetate (PMA) exposure resulted in an up-regulation of AP-1 and down-regulation of NF-κBactivity, however, exposure to heat killed (HK) Escherichia. coli MG1655 resulted in a dose-dependent increase in NF-κBactivity without affecting AP-1. The cytokine profile revealed an up-regulation of the chemokine CXCL8 and the pro-inflammatory cytokines TNF, IL-2 and IL-6 following treatment with both PMA and HK E. coli, while the levels of the anti-inflammatory cytokine IL-10 were not affected by PMA but were significantly down-regulated by HK E. coli. AP-1activation was significantly increased 2 h after PMA exposure and continued to increase thereafter. In contrast, NF-κBresponded to PMA exposure by a rapid up-regulation followed by a subsequent down-regulation. Increased intracellular Ca2+ concentrations countered the down-regulation of NF-κB by PMA, while similar treatment with calcium ionophore resulted in a reduced NF-κB activity following induction with HK E. coli. In order to further study NF-κB activation, we considered two up-stream signalling proteins, PKC and Bcl10. Phosphorylated-PKC levels increased inresponse to PMA and HK E. coli, while Bcl10 levels significantly decreased following PMA treatment. Using an NF-κBactivation inhibitor, we observed complete inhibition of IL-6 expression while CXCL8 levels only decreased by 40% atthe highest concentration. Treatment of Jurkat T-cells with PMA in the presence of JNK-inhibitor suppressed both CXCL8 and IL-6 while PKC-inhibitor primarily decreased CXCL8 expression.

    Conclusion: The present study shows that NF-κB regulated IL-6 but not CXCL8. This complex regulation of CXCL8suggests that there is a need to further evaluate the signalling pathways in order to develop new treatment fordiseases with elevated CXCL8 levels, such as AIDS and autoimmune diseases.

  • 26.
    Khalaf, Hazem
    et al.
    Örebro University, School of Health and Medical Sciences.
    Jass, Jana
    Örebro University, School of Health and Medical Sciences.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Influence of growth conditions on in vitro regulation of NF-κB activity in Jurkat T-cells2010Manuscript (preprint) (Other academic)
  • 27.
    Khalaf, Hazem
    et al.
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The role of calcium, NF-κB and NFAT in the regulation of CXCL8 and IL-6 expression in Jurkat T-cells2013In: International Journal of Biochemistry and Molecular Biology, ISSN 2152-4114, Vol. 4, no 3, 150-156 p.Article in journal (Refereed)
    Abstract [en]

    T-cells play an important role in host immunity against invading pathogens. Determining the underlying regulatory mechanisms will provide a better understanding of T-cell-derived immune responses. In this study, we have shown the differential regulation of IL-6 and CXCL8 by NF-κB and NFAT in Jurkat T-cells, in response to PMA, heat killed Escherichia coli and calcium. CXCL8 was closely associated with the activation pattern of NFAT, while IL-6 expression was associated with NF-κB. Furthermore, increasing the intracellular Ca(2+) concentration by calcium ionophore treatment of the cells resulted in NFAT induction without affecting the NF-κB activity. Interestingly, NF-κB activation by heat killed E. coli, as well as CXCL8 and IL-6 expression was significantly suppressed following addition of the calcium ionophore. This indicates that calcium plays an important role in regulating protein trafficking and T-cell signalling, and the subsequent inflammatory gene expression infers an involvement of NFAT in CXCL8 regulation.Understanding these regulatory patterns provide clarification of conditions that involve altered intracellular signalling leading to T-cell-derived cytokine expression.

  • 28.
    Khalaf, Hazem
    et al.
    Örebro University, School of Science and Technology.
    Larsson, Anders
    Örebro University, School of Science and Technology.
    Berg, Håkan
    Örebro University, School of Science and Technology.
    McCrindle, Robert
    Wellington Laboratories Inc., Research Division, Guelph, Ontario, Canada.
    Arsenault, Gilles
    Wellington Laboratories Inc., Research Division, Guelph, Ontario, Canada.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Diastereomers of the Brominated Flame Retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane Induce Androgen Receptor Activation in the HepG2 Hepatocellular Carcinoma Cell Line and the LNCaP Prostate Cancer Cell Line2009In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 117, no 12, 1853-1859 p.Article in journal (Refereed)
    Abstract [en]

    Background: Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohex​ane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to be maternally transferred in zebrafish.

    Objectives: In the present study we investigated interaction energies between TBECH diastereomers (α, β, γ, and δ) and the hAR, and their ability to activate the receptor and induce prostate-specific antigen (PSA) expression in vitro.

    Methods: We performed computational modeling to determine interaction energies between the ligand and the AR ligand-binding site, and measured in vitro competitive binding assays for AR by polarization fluorometry analysis. We used enzyme-linked immunosorbent assays to determine PSA activity in LNCaP and HepG2 cells.

    Results: We found the γ and δ diastereomers to be more potent activators of hAR than the α and β diastereomers, which was confirmed in receptor binding studies. All TBECH diastereomers induced PSA expression in LNCaP cells even though the AR present in these cells is mutated (T877A). Modeling studies of LNCaP AR revealed that TBECH diastereomers bound to the receptor with a closer distance to the key amino acids in the ligand-binding domain, indicating stronger binding to the mutated receptor.

    Conclusions: The present study demonstrates the ability of TBECH to activate the hAR, indicating that it is a potential endocrine disruptor.

  • 29.
    Khalaf, Hazem
    et al.
    Örebro University, School of Science and Technology.
    Ochsner, Scott A.
    Koskinen, Jarno
    Karlsson, Marie
    Karlsson, Jesper
    Sreenivasan, Rajini
    McKenna, Neil J.
    Orban, Laszlo
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Zebrafish feminization in response to heat killed bacterial exposure suggests a function for anti-apoptotic genes in oocyte maintenanceManuscript (preprint) (Other academic)
  • 30.
    Khalaf, Hazem
    et al.
    Örebro University, School of Health and Medical Sciences.
    Salste, Lotta
    Karlsson, Patrik
    Ivarsson, Per
    Jass, Jana
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    In vitro analysis of inflammatory responses following environmental exposure to pharmaceuticals and inland waters2009In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 407, no 4, 1452-1460 p.Article in journal (Refereed)
    Abstract [en]

    Pharmaceuticals are regularly released into the environment; in particular non-steroidalanti-inflammatory drugs (NSAIDs) and antibiotics. Erythromycin, naproxen, furosemideand atenolol are reported to be stable for up to 1 year in the environment, which increasesthe risk for accumulation. In the present study we have measured the occurrence andconcentration of pharmaceuticals in river Viskan (Jössabron) downstream of a sewagetreatment plant in Borås, Sweden. Pharmaceuticals and water samples were tested forpotential human risk by evaluating inflammatory responses (NF-κB and AP-1) using humanT24 bladder epithelial cells and Jurkat T-cells. NF-κB activity in T24 cells was significantlyreduced by all NSAIDs analysed (diclofenac, ketoprofen, naproxen, ibuprophen anddextropropoxyphene), but also by trimethoprim, using environmentally relevantconcentrations. NF-κB and AP-1 activation was further analysed in response to watersamples collected from different locations in Sweden. Dose-dependent down-regulation ofAP-1 activity in Jurkat cells was observed at all locations. At two locations (Jössabron andAlmenäs) down-regulation of NF-κB was observed. In contrast, the NF-κB response waspotentiated by exposure to water from both locations following activation of NF-κB bytreatment with heat-killed Escherichia coli. To determine the involvement ofpharmaceuticals in the responses, T24 cells were exposed to the pharmaceutical mixture,based on the determined levels at Jössabron. This resulted in reduction of the NF-κBresponse following exposure to the pharmaceutical mixture alone while no potentiationwas observed when cells were co-exposed to heat killed E. coli and pharmaceuticals. Theobtained results demonstrate that the identified pharmaceuticals affect the inflammatoryresponses and furthermore indicate the presence of unknown substance(s) with the abilityto potentiate inflammatory responses

  • 31.
    Kharlyngdoh, Joubert Banjop
    et al.
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer2016In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 307, 91-101 p.Article in journal (Refereed)
    Abstract [en]

    Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.

  • 32.
    Kling, Peter
    et al.
    Göteborg University.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Mujahed, Huthayfa
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Science and Technology.
    von Hofsten, Jonas
    Umeå University.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Differential regulation of the rainbow trout (Oncorhynchus mykiss) MT-A gene by nuclear factor interleukin-6 and activator protein-12013In: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 14, no 1, 28- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previously we have identified a distal region of the rainbow trout (Oncorhynchus mykiss) metallothionein-A (rtMT-A) enhancer region, being essential for free radical activation of the rtMT-A gene. The distal promoter region included four activator protein 1 (AP1) cis-acting elements and a single nuclear factor interleukin-6 (NF-IL6) element. In the present study we used the rainbow trout hepatoma (RTH-149) cell line to further examine the involvement of NF-IL6 and AP1 in rtMT-A gene expression following exposure to oxidative stress and tumour promotion.

    RESULTS: Using enhancer deletion studies we observed strong paraquat (PQ)-induced rtMT-A activation via NF-IL6 while the AP1 cis-elements showed a weak but significant activation. In contrast to mammals the metal responsive elements were not activated by oxidative stress. Electrophoretic mobility shift assay (EMSA) mutation analysis revealed that the two most proximal AP1 elements, AP11,2, exhibited strong binding to the AP1 consensus sequence, while the more distal AP1 elements, AP13,4 were ineffective. Phorbol-12-myristate-13-acetate (PMA), a known tumor promoter, resulted in a robust induction of rtMT-A via the AP1 elements alone. To determine the conservation of regulatory functions we transfected human HepG2 cells with the rtMT-A enhancer constructs and were able to demonstrate that the cis-elements were functionally conserved. The importance of NF-IL6 in regulation of teleost MT is supported by the conservation of these elements in MT genes from different teleosts. In addition, PMA and PQ injection of rainbow trout resulted in increased hepatic rtMT-A mRNA levels.

    CONCLUSIONS: These studies suggest that AP1 primarily is involved in PMA regulation of the rtMT-A gene while NF-IL6 is involved in free radical regulation. Taken together this study demonstrates the functionality of the NF-IL6 and AP-1 elements and suggests an involvement of MT in protection during pathological processes such as inflammation and cancer.

  • 33.
    Koskinen, Jarno
    et al.
    Örebro University, School of Science and Technology.
    Karlsson, Johnny
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Sox9a regulation of ff1a in zebrafish (Danio rerio) suggests an involvement of ff1a in cartilage development2009In: Comparative Biochemistry and Physiology A, ISSN 1095-6433, E-ISSN 1531-4332, Vol. 153, no 1, 39-43 p.Article in journal (Refereed)
    Abstract [en]

    The NR5A family of orphan nuclear receptors has been implicated in development of the vertebrate embryo, but their exact role remains largely unknown. To evaluate the regulation and developmental role for ff1a (NR5A2) in zebrafish (Danio rerio), we performed morpholino knockdown to block translation of the ff1a gene and the upstream located sox9a gene during embryogenesis. Using a newly developed antibody against Ff1a we could show that the ff1a morpholinos were functional and that a reduction in the expression of Ff1a correlated to altered phenotypes. The role of Sox9a in ff1a gene regulation and function was studied using sox9a morpholinos. Knock-down of sox9a resulted in abolished ff1a signals in the somites, mandibular arches and pharyngeal arches, while the pectoral fin signal remained. The reduction in Ff1a levels correlated to truncated tails and cranio-facial malformation. As Sox9a is involved in chondrocyte development we analysed for cartilage formation and found that blocking translation of either sox9a or ff1a also blocked cartilage formation. In light of the results, the present study suggests a novel function of ff1a in chondrocyte development.

  • 34.
    Kumar, Ranjeet
    et al.
    School of Science and Technology, The Life Science Center-Biology, Örebro University, Örebro, Sweden.
    Pradhan, Ajay
    School of Science and Technology, The Life Science Center-Biology, Örebro University, Örebro, Sweden.
    Khan, Faisal Ahmad
    Örebro University, School of Science and Technology.
    Lindström, Pia
    Boliden Mineral AB, Boliden, Sweden.
    Ragnvaldsson, Daniel
    Envix Nord AB, Umeå , Sweden.
    Ivarsson, Per
    ALS Scandinavia AB, Täby, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Comparative analysis of stress induced gene expression in caenorhabditis elegans following exposure to environmental and lab reconstituted complex metal mixture2015In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 7, e0132896Article in journal (Refereed)
    Abstract [en]

    Metals are essential for many physiological processes and are ubiquitously present in the environment. However, high metal concentrations can be harmful to organisms and lead to physiological stress and diseases. The accumulation of transition metals in the environment due to either natural processes or anthropogenic activities such as mining results in the contamination of water and soil environments. The present study used Caenorhabditis elegans to evaluate gene expression as an indicator of physiological response, following exposure to water collected from three different locations downstream of a Swedish mining site and a lab reconstituted metal mixture. Our results indicated that the reconstituted metal mixture exerted a direct stress response in C. elegans whereas the environmental waters elicited either a diminished or abrogated response. This suggests that it is not sufficient to use the biological effects observed from laboratory mixtures to extrapolate the effects observed in complex aquatic environments and apply this to risk assessment and intervention.

  • 35.
    Larsson, Anders
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Andersson, Patrik L.
    Ivarson, Per
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist2006In: Journal of medicinal chemistry, ISSN 0022-2623, Vol. 49, no 25, 7366-7372 p.Article in journal (Refereed)
    Abstract [en]

    To investigate androgen receptor (AR) activation by exogenous compounds, we used a combination of experimental analysis and theoretical modeling to compare a set of brominated flame retardants (BFRs) to dihydrotestosterone (DHT) with regard to ligand docking, AR binding, and AR activation in human hepatocellular liver carcinoma cells, as well as interacting energy analysis. Modeling of receptor docking was found to be a useful first step in predicting the potential to translocate to the ligand pocket of the receptor, and the computed interaction energy was found to correlate with the observed binding affinity. Flexible alignment studies of the BFR compounds demonstrated that 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (BCH) closely overlap DHT. Combining the theoretical modeling with in vitro ligand-binding and receptor-activation assays, we show that BCH binds to and activates the human AR. The remaining BFRs did not successfully interact with the ligand pocket, were not able to replace a synthetic androgen from the receptor, and failed to activate the receptor.

  • 36. Mayer, Gregory D.
    et al.
    Leach, Allan
    Kling, Peter
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Hogstrand, Christer
    Activation of the rainbow trout metallothionein-A promoter by silver and zinc2003In: Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology, ISSN 1096-4959, E-ISSN 1879-1107, Vol. 134, no 1, 181-188 p.Article in journal (Refereed)
    Abstract [en]

    In fish, the synthesis of metallothionein (MT) is increased by a number of heavy metals. The rainbow trout MT-A gene promoter region contains six known metal responsive elements (MREs), that mediate promoter activation by metals. In the present study, two fish cell lines differing in their ability to produce MT, RTG-2 (produce MT protein) and CHSE-214 (produce no detectable MT protein), were used to help elucidate the roles of Zn, Ag and MT in the activation of the MT promoter. The hypothesis tested was that Ag activates the MT-A promoter indirectly by displacing Zn from pre-existing Zn-MT and that this liberated Zn subsequently induces MT synthesis. Both cell lines were transfected with a luciferase reporter gene construct containing the rainbow trout MT-A promoter, exposed to various concentrations of Zn or Ag, and assayed for luciferase activity. CHSE-214 cells showed five times greater production of luciferase than RTG-2 cells when exposed to identical concentrations of Ag. Thus, Ag can likely induce MT transcription without displacing Zn from pre-existing Zn-MT. Furthermore, Ag activated the MT promoter at concentrations 100-fold lower than those required for Zn to initiate transcription, suggesting that zinc displaced from other sites by such low concentrations of Ag would not be sufficient to initiate MT transcription. This interpretation was further supported by radiotracer studies indicating that Ag did not cause a redistribution of 65Zn within either of the two cell types. These combined results indicate that Ag may be a direct inducer of MT.

  • 37.
    Modig, Carina
    et al.
    Örebro University, Department of Natural Sciences.
    Modesto, Teresa
    Canario, Adelino
    Cerdà, Joan
    von Hofsten, Jonas
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Molecular characterization and expression pattern of zona pellucida proteins in gilthead seabream (Sparus aurata)2006In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 75, no 5, 717-725 p.Article in journal (Refereed)
    Abstract [en]

    The developing oocyte is surrounded by an acellular envelope that is composed of 2-4 isoforms of zona pellucida (ZP) proteins. The ZP proteins comprise the ZP1, ZP2, ZP3, and ZPX isoforms. While ZP1 (ZPB) and ZP3 (ZPC) are present in all species, ZP2 (ZPA) is not found in teleost fish and ZPX is not found in mammals. In the present study, we identify and characterize the ZP1, ZP3 and ZPX isoforms of gilthead seabream. Furthermore, by analyzing the conserved domains, which include the external hydrophobic patch and the internal hydrophobic patch, we show that ZP2 and ZPX are closely related isoforms. ZP proteins are synthesized in either the liver or ovary of most teleosts. Only in rainbow trout has it been shown that zp3 has dual transcription sites. In gilthead seabream, all four mRNA isoforms are transcribed in both the liver and ovary, with zp1a, zp1b, and zp3 being highly expressed in the liver, and zpx being primarily expressed in the ovary. However, determination of the ZP proteins in plasma showed high levels of ZP1b, ZP3, and ZPX, with low or non-detectable levels of ZP1a. In similarity to other teleost ZPs, the hepatic transcription of all four ZP isoforms is under estrogenic control. Previously, we have shown that cortisol can potentiate estrogen-induced ZP synthesis in salmonids, and now we show that this is not the case in the gilthead seabream. The present study shows for the first time the endocrine regulation of a teleost ZPX isoform, and demonstrates the dual-organ transcriptional activities of all the ZP proteins in one species.

  • 38.
    Modig, Carina
    et al.
    Örebro University, School of Science and Technology.
    Raldúa, Demetrio
    Cerdà, Joan
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Analysis of vitelline envelope synthesis and composition during early oocyte development in gilthead seabream (Sparus aurata)2008In: Molecular Reproduction and Development, ISSN 1040-452X, E-ISSN 1098-2795, Vol. 75, no 8, 1351-1360 p.Article in journal (Refereed)
    Abstract [en]

    The oocyte vitelline envelope (VE) of gilthead seabream is composed of four known zona pellucida (ZP) proteins, ZPBa, ZPBb, ZPC, and ZPX. We have previously shown that the gilthead seabream ZP proteins are differentially transcribed in liver and ovary, with the expression in liver being under estrogenic control. However, although mRNA was found in both liver and ovary, only low ZPBa protein levels were detected in liver and plasma. Using isoform-specific ZP antibodies we show that ZPBa and ZPX translation products are present in the cytosol of stage I and II oocytes. In addition, the zpBa and zpX mRNAs were detected in early developing oocytes. During oocyte growth (vitellogenesis), the VE increased in thickness (>10 µm), and we show that the four ZP isoforms are present in different regions of the VE. ZPX was detected closest to the oocyte plasma membrane while the intermediate region was composed of ZPBa, ZPBb, and ZPC. At the outer layer, only ZPC was detected. When oocytes reach the fully grown stage they resume meiosis and hydration. As the oocyte expands, thinning to 4 µm, the VE acquire a striped and compact appearance at the electron microscopy level. This study provides further evidence for the oocyte origin of some ZP proteins in the gilthead seabream and suggests that the ZP proteins are differentially distributed within the VE. Mol. Reprod. Dev. 75: 1351-1360, 2008.

  • 39.
    Olsson, Per-Erik
    et al.
    Örebro University, Department of Natural Sciences.
    Berg, A. Håkan
    von Hofsten, Jonas
    Grahn, Birgitta
    Hellqvist, Anna
    Larsson, Anders
    Örebro University, Department of Natural Sciences.
    Karlsson, Johnny
    Örebro University, Department of Natural Sciences.
    Modig, Carina
    Örebro University, Department of Natural Sciences.
    Borg, Bertil
    Thomas, Peter
    Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone2005In: Reproductive biology and endocrinology, ISSN 1477-7827, Vol. 3:37Article in journal (Refereed)
    Abstract [en]

    Although 11-ketotestosterone is a potent androgen and induces male secondary sex characteristics in many teleosts, androgen receptors with high binding affinity for 11-ketotestosterone or preferential activation by 11-ketotestosterone have not been identified. So, the mechanism by which 11-ketotestosterone exhibits such high potency remains unclear. Recently we cloned the cDNA of an 11-ketotestosterone regulated protein, spiggin, from three-spined stickleback renal tissue. As spiggin is the only identified gene product regulated by 11-ketotestosterone, the stickleback kidney is ideal for determination of the mechanism of 11-ketotestosterone gene regulation. A single androgen receptor gene with two splicing variants, belonging to the androgen receptor-beta subfamily was cloned from stickleback kidney. A high affinity, saturable, single class of androgen specific binding sites, with the characteristics of an androgen receptor, was identified in renal cytosolic and nuclear fractions. Measurement of ligand binding moieties in the cytosolic and nuclear fractions as well as to the recombinant receptor revealed lower affinity for 11-ketotestosterone than for dihydrotestosterone. Treatment with different androgens did not up-regulate androgen receptor mRNA level or increase receptor abundance, suggesting that auto-regulation is not involved in differential ligand activation. However, comparison of the trans-activation potential of the stickleback androgen receptor with the human androgen receptor, in both human HepG2 cells and zebrafish ZFL cells, revealed preferential activation by 11-ketotestosterone of the stickleback receptor, but not of the human receptor. These findings demonstrate the presence of a receptor preferentially activated by 11-ketotestosterone in the three-spined stickleback, so far the only one known in any animal.

  • 40.
    Olsson, Per-Erik
    et al.
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    CXCL8 regulation and function in HIV infections and potential treatment strategies2011In: HIV and AIDS: updates on biology, immunology, epidemiology and treatment strategies / [ed] Nancy Dumais, InTech, 2011, 327-344 p.Chapter in book (Refereed)
  • 41. Orban, Laszlo
    et al.
    Sreenivasan, Rajini
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Long and winding roads: testis differentiation in zebrafish2009In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 312, no 1-2, 35-41 p.Article in journal (Refereed)
    Abstract [en]

    Zebrafish sex determination, gonad differentiation and reproduction are far from being fully understood. Although the mode of sex determination is still being disputed, most experimental data point towards the lack of sex chromosomes and a multigenic sex determination system. Secondary effects from the environment and/or (xeno)hormones may influence the process, resulting in biased sex ratios. The exact time point of sex determination is unknown. Gonad differentiation involves a compulsory 'juvenile ovary' stage with subsequent transformation of the gonad into a testis in males. As the latter is a late event, there is a delay between sex determination and testis differentiation in zebrafish, in contrast to mammals. Information on the expression of several candidate genes thought to be involved in these processes has been supplemented with data from large-scale gonadal transcriptomic studies. New approaches and methodologies provide hope that answers to a number of important questions will be deciphered in the future.

  • 42. Ostrakhovitch, Elena A.
    et al.
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Jiang, Sean
    Cherian, M. George
    Interaction of metallothionein with tumor suppressor p53 protein2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 5, 1235-1238 p.Article in journal (Refereed)
    Abstract [en]

    Previous reports have shown that metallothionein (MT) may modulate p53 activity through zinc exchange. However, little is known on a direct interaction between MT and p53 in cells. The results demonstrate an interaction between MT and p53 can occur in vitro. The complex between MT and p53 was observed in breast cancer epithelial cells with both wild and inactive type of p53. Furthermore, it was shown that wt-p53 was preferentially associated with Apo-MT. Our data suggest that co-expression of MT and p53 and their complex formation in tumor cells may be involved in regulation of apoptosis in these cells.

  • 43. Ostrakhovitch, Elena A
    et al.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    von Hofsten, Jonas
    Cherian, M. George
    P53 mediated regulation of metallothionein transcription in breast cancer cells2007In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 102, no 6, 1571-1583 p.Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that only breast cancer epithelial cells with intact p53 can induce metallothionein (MT) synthesis after exposure to metals. In this study, the potential role of p53 on regulation of MT was investigated. Results demonstrate that zinc and copper increased metal response elements (MREs) activity and MTF-1 expression in p53 positive MN1 and parental MCF7 cells. However, inactivation of p53 by treatment with pifithrin- or the presence of inactive p53 inhibited MRE-dependent reporter gene expression in response to metals. MTF-1 levels remained unchanged after treatment with zinc in cells with nonfunctional p53. The introduction of wild-type p53 in MDD2 cells, containing nonfunctional p53, enhanced the ability of zinc to increase MRE-dependent reporter gene expression. The cellular level of p21Cip1/WAF1 was increased in MDD2 cells after p53 transfection, confirming the presence of active p53. The treatment of MN1 and parental MCF7 with trichostatin A led to a sixfold increase in the MRE activity in response to zinc. On the contrary, MRE activity remained unaltered in MDD2 cells with inactive p53. The above results demonstrate that activation of p53 is an important factor in metal regulation of MT. J. Cell. Biochem. 102: 1571-1583, 2007.

  • 44. O'Toole, Ronan
    et al.
    von Hofsten, Jonas
    Rosqvist, Roland
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Wolf-Watz, Hans
    Visualisation of zebrafish infection by GFP-labelled Vibrio anguillarum2004In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 37, no 1, 41-46 p.Article in journal (Refereed)
    Abstract [en]

    Vibrio anguillarum is an invasive pathogen of fish causing a septicaemia called vibriosis. In this work, transparent zebrafish were immersed in water containing green fluorescent protein labelled V. anguillarum. The infection was visualised at the whole fish and single bacterium levels using microscopy. The gastrointestinal tract was the first site where the pathogen was detected. This enteric localisation occurred independently of the flagellum or motility. On the other hand, chemotactic motility was essential for association of the pathogen with the fish surface. In conclusion, the zebrafish infection model provides evidence that the intestine and skin represent sites of infection by V. anguillarum and suggests a host site where chemotaxis may function in virulence.

  • 45.
    Poonlapthawee, Sirirat
    et al.
    Örebro University, School of Science and Technology.
    Kahn, Faisal Ahmad
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Gene expression in Escherichia coli CFT073 grown in sub-MIC tetracycline and environmental watersManuscript (preprint) (Other academic)
    Abstract [en]

    We examined the prevalence of fecal indicator bacteria (coliform E. coli and enterococci) for water quality (World Health Organization, 2011, European Enviroment Agency, 2012) and antibiotic resistant E. coli in lake Mälaren from surface water in Björnö Island at Vinterviken bay and in untreated incoming water to Mälarenergi, drinking water treatment plant (DWTP) in Västerås, Sweden. Our studies have demonstrated that the water quality of environmental water was ‘excellent‘ in both surface water at Bjornö in Vinterviken bay and in the untreated incoming water to the DWTP. However, one multi-antibiotic resistant and one antibiotic resistant strain were isolated from the surface waters. Hence antibiotic resistant strains can persist even in low population of fecal bacterial contamination in the waters. Pharmaceutical compounds in the environment are believed to provide a selective pressure for the development of antibiotic resistance in bacteria (Tenover, 2006, Alekshun and Levy, 2007, Mazumdar et al., 2006). Our study demonstrated that pharmaceutical compounds persisted in lake waters with detectable concentrations as others have shown (Godfrey et al., 2007, Loos et al., 2009). Caffeine, naproxen, hydrochlorothiazide, metoprolol and tramadol were present at detectable levels. To study the effect of contaminants on microorganisms, qPCR method was chosen due to its rapid, sensitive and quantitative analyses of gene expression. Thus a qPCR array was designed, to determine the effect of environmental waters on E. coli isolates. Specific genes that were responsible for antibiotic resistance, virulence factors and stress responses were selected. E. coli CFT073 was treated with either sub-MIC levels (0.1 μg/ml) of tetracycline in LB medium or incoming untreated waters to DWTP in LB medium and compared to controls. Gene expression was determined using qPCR. No significant difference in gene response was observed after treatment with sub-MIC of tetracycline or environmental waters. Pharmaceutical compounds which contaminated the water did not appear to exert a significant gene response in the pathogenic E. coli. Pharmaceutical contamination in the water can promote human and animal health risks however the effect of long-term exposure is yet unknown (European Environment Agency, 2011, Wennmalm and Gunnarsson, 2005, Triebskorn et al., 2007). The antibiotic resistant strains likely originated from the WWTP rather than the selective pressure due to pharmaceutical pollutants in the water. 

  • 46.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafishManuscript (preprint) (Other academic)
  • 47.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 233, 35-45 p.Article in journal (Refereed)
    Abstract [en]

    The brominated flame retardants (BFRs) 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH or DBE-DCBH) and allyl 2,4,6-tribromophenyl ether (ATE or TBP-AE) are alternative BFRs that have been introduced to replace banned BFRs. TBECH is a potential endocrine disrupter in human, chicken and zebrafish and in a recent study we showed that ATE, along with the structurally similar BFR 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE or TBP-DBPE) and its metabolite 2-bromoallyl 2,4,6-tribromophenyl ether (BATE or TBP-BAE) are potential endocrine and neuronal disrupters in human. In this study we analyzed ATE, BATE and DPTE for zebrafish androgen receptor (zAR) modulating properties. In silico analysis with two softwares, Molecular Operating Environment (MOE) and Internal Coordinate Mechanics (ICM), showed that ATE, BATE and DPTE bind to zAR. In vitro AR activation assay revealed that these three BFRs down-regulate 11-ketotestosterone (KT) mediated zAR activation. Exposure to 10 mu M DPTE resulted in reduced hatching success and like TBECH, BATE and DPTE at 10 mu M also had teratogenic properties with 20% and 50% back-bone curvature respectively. Gene transcription analysis in zebrafish embryos as well as in juveniles showed down-regulation of the androgen receptor and androgen response genes, which further support that these BFRs are androgen antagonists and potential endocrine disrupting compounds. Genes involved in steroidogenesis were also down-regulated by these BFRs. In view of this, the impact of these BFRs on humans and wildlife needs further analysis.

  • 48.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Ivarsson, Per
    Örebro University, School of Science and Technology. BioImpakt AB, Örebro, Sweden.
    Ragnvaldsson, Daniel
    Envix Nord AB, Umeå, Sweden.
    Berg, Håkan
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Transcriptional responses of zebrafish to complex metal mixtures in laboratory studies overestimates the responses observed with environmental water2017In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 584-585, 1138-1146 p.Article in journal (Refereed)
    Abstract [en]

    Metals released into the environment continue to be of concern for human health. However, risk assessment of metal exposure is often based on total metal levels and usually does not take bioavailability data, metal speciation or matrix effects into consideration. The continued development of biological endpoint analyses are therefore of high importance for improved eco-toxicological risk analyses. While there is an on-going debate concerning synergistic or additive effects of low-level mixed exposures there is little environmental data confirming the observations obtained from laboratory experiments. In the present study we utilized qRT-PCR analysis to identify key metal response genes to develop a method for biomonitoring and risk-assessment of metal pollution. The gene expression patterns were determined for juvenile zebrafish exposed to waters from sites down-stream of a closed mining operation. Genes representing different physiological processes including stress response, inflammation, apoptosis, drug metabolism, ion channels and receptors, and genotoxicity were analyzed. The gene expression patterns of zebrafish exposed to laboratory prepared metal mixes were compared to the patterns obtained with fish exposed to the environmental samples with the same metal composition and concentrations. Exposure to environmental samples resulted in fewer alterations in gene expression compared to laboratory mixes. A biotic ligand model (BLM) was used to approximate the bioavailability of the metals in the environmental setting. However, the BLM results were not in agreement with the experimental data, suggesting that the BLM may be overestimating the risk in the environment. The present study therefore supports the inclusion of site-specific biological analyses to complement the present chemical based assays used for environmental risk-assessment.

  • 49.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ochsner, Scott A.
    Baylor College of Medicine, Houston, USA.
    Sreenivasan, Rajini
    Temasek Life Sciences Laboratory, Singapore.
    Koskinen, Jarno
    Örebro University, School of Science and Technology.
    Karlsson, Marie
    Örebro University, School of Science and Technology.
    Karlsson, Jesper
    Örebro University, School of Science and Technology.
    McKenna, Neil J.
    Baylor College of Medicine, Houston, USA.
    Orban, Laszlo
    Temasek Life Sciences Laboratory, Singapore; National University of Singapore; University of Pannonia, Keszthely, Hungary.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Activation of NF-kappa B Protein Prevents the Transition from Juvenile Ovary to Testis and Promotes Ovarian Development in Zebrafish2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 45, 37926-37938 p.Article in journal (Refereed)
    Abstract [en]

    Testis differentiation in zebrafish involves juvenile ovary to testis transformation initiated by an apoptotic wave. The molecular regulation of this transformation process is not fully understood. NF-kappa B is activated at an early stage of development and has been shown to interact with steroidogenic factor-1 in mammals, leading to the suppression of anti-Mullerian hormone (Amh) gene expression. Because steroidogenic factor-1 and Amh are important for proper testis development, NF-kappa B-mediated induction of anti-apoptotic genes could, therefore, also play a role in zebrafish gonad differentiation. The aim of this study was to examine the potential role of NF-kappa B in zebrafish gonad differentiation. Exposure of juvenile zebrafish to heat-killed Escherichia coli activated the NF-kappa B pathways and resulted in an increased ratio of females from 30 to 85%. Microarray and quantitative real-time-PCR analysis of gonads showed elevated expression of NF-kappa B-regulated genes. To confirm the involvement of NF-kappa B-induced anti-apoptotic effects, zebrafish were treated with sodium deoxycholate, a known inducer of NF-kappa B or NF-kappa B activation inhibitor (NAI). Sodium deoxycholate treatment mimicked the effect of heat-killed bacteria and resulted in an increased proportion of females from 25 to 45%, whereas the inhibition of NF-kappa B using NAI resulted in a decrease in females from 45 to 20%. This study provides proof for an essential role of NF-kappa B in gonadal differentiation of zebrafish and represents an important step toward the complete understanding of the complicated process of sex differentiation in this species and possibly other cyprinid teleosts as well.

  • 50.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances2013In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 142, 63-72 p.Article in journal (Refereed)
    Abstract [en]

    Tetrabromoethylcyclohexane (TBECH) is a brominated flame retardant that has been shown to be a potent agonist to the human androgen receptor (AR). However, while it is present in the environment, it is not known if it interacts with AR from aquatic species. The present study was therefore aimed at improving our understanding of how TBECH affects aquatic animals using zebrafish as a model organism. In silica modeling demonstrated that TBECH diastereomers bind to the zebrafish androgen receptor (zAR) and in vitro and in vivo data showed that TBECH has androgenic properties. Deleterious effects of TBECH were studied on embryonic and juvenile zebrafish and qRT-PCR analysis in vitro and in vivo was performed to determine TBECH effects on gene regulation. TBECH was found to delay hatching at 1 mu M and 10 mu M doses while morphological abnormalities and juvenile mortality was observed at 10 mu M. The qRT-PCR analysis showed alterations of multiple genes involved in chondrogenesis (cartilage development), metabolism and stress response. Thus, TBECH induces androgenic activity and has negative effects on zebrafish physiology and therefore its impact on the environment should be carefully monitored. (C) 2013 Elsevier B.V. All rights reserved.

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