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  • 1.
    Andersson, Carin
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Abrahamson, Alexandra
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Jönsson, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Otte, Jens
    Örberg, Jan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gill filament EROD activity in the three-spined stickleback (Gasterosteus aculeatus L.) as a biomarker for exposure to Ah receptor agonists in the water2006In: Organohalogen Compounds, 2006, p. 1259-1261Conference paper (Refereed)
  • 2.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines2017In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, article id e78133Article in journal (Refereed)
  • 4.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e78133-Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease and proposed to be biomagnified in terrestrial and aquatic food chains. We have previously shown that the neonatal period in rats, which in humans corresponds to the last trimester of pregnancy and the first few years of age, is a particularly sensitive period for exposure to BMAA. The present study aimed to examine the secretion of C-14-labeled L-and D-BMAA into milk in lactating mice and the subsequent transfer of BMAA into the developing brain. The results suggest that secretion into milk is an important elimination pathway of BMAA in lactating mothers and an efficient exposure route predominantly for L-BMAA but also for D-BMAA in suckling mice. Following secretion of [C-14] L-BMAA into milk, the levels of [C-14] L-BMAA in the brains of the suckling neonatal mice significantly exceeded the levels in the maternal brains. In vitro studies using the mouse mammary epithelial HC11 cell line confirmed a more efficient influx and efflux of L-BMAA than of D-BMAA in cells, suggesting enantiomer-selective transport. Competition experiments with other amino acids and a low sodium dependency of the influx suggests that the amino acid transporters LAT1 and LAT2 are involved in the transport of L-BMAA into milk. Given the persistent neurodevelopmental toxicity following injection of L-BMAA to neonatal rodent pups, the current results highlight the need to determine whether BMAA is enriched mother's and cow's milk.

  • 5.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs2018In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 147, p. 720-724Article in journal (Refereed)
    Abstract [en]

    C-carboxyl-labeled BMAA were compared. The results revealed a pronounced incorporation of radioactivity in the eggs, predominantly in the yolk but also in the albumen. Imaging analysis showed that the concentrations of radioactivity in the liver decreased about seven times between the 24h and the 72h time points, while the concentrations in egg yolk remained largely unchanged. At 72h the egg yolk contained about five times the concentration of radioactivity in the liver. Both BMAA preparations gave rise to similar distribution pattern in the bird tissues and in the eggs, indicating metabolic stability of the labeled groups. The demonstrated deposition into eggs warrants studies of BMAAs effects on bird development. Moreover, birds' eggs may be a source of human BMAA exposure, provided that the laying birds are exposed to BMAA via their diet.

  • 6.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Induction of ethoxyresorufin O-deethylase (EROD) and endothelial activation of the heterocyclic amine Trp-P-1 in bird embryo hearts1998In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 72, no 7, p. 402-410Article in journal (Refereed)
    Abstract [en]

    The xenobiotic-metabolizing activity of avian heart was investigated in chicken and Eider duck embryos exposed to aryl hydrocarbon (Ah) receptor agonists in ovo. Both beta-naphthoflavone (BNF) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) induced 7-ethoxyresorufin O-deethylase (EROD) activities in chicken embryo hearts whereas Eider duck embryos only responded to BNF. The differential responses of chicken and Eider duck embryos were used to examine the involvement of Ah receptor-mediated enzyme induction in the activation of the environmental and food mutagen 3-amino- 1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1). As determined by light microscopic autoradiography, there was a highly selective binding of non-extractable 3H-Trp-P-1-derived radioactivity in endothelial cells of large vessels and capillaries in hearts of BNF- and PCB 126-treated chicken embryos. No binding occurred at these sites in vehicle-treated controls. There was also a strong endothelial binding of 3H-Trp-P-1 in hearts of BNF-treated Eider duck embryos whereas no binding occurred in hearts of PCB 126-treated Eider duck embryos. A positive correlation between induction of EROD activity and covalent binding of 3H-Trp-P-1 to protein in heart homogenates from BNF- and PCB 126-treated chicken and Eider duck embryos was also observed. The results suggest a cytochrome P450 1A (CYP1A)-mediated activation of Trp-P-1 in avian heart endothelial cells although involvement of other Ah receptor-regulated enzymes is also possible. We propose that heart endothelial cells may be targets for bioactivation and toxicity of environmental contaminants in birds exposed to Ah receptor agonists.

  • 7.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granberg, Lena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Strandberg, William
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Basal and induced EROD activity in the chorioallantoic membrane during chicken embryo development1999In: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 8, no 1, p. 49-52Article in journal (Other academic)
    Abstract [en]

    The chorioallantoic membrane (CAM) is a highly vascularized tissue that takes part in the respiratory exchange of gases through the eggshell. Although the CAM may be exposed to environmental contaminants, its response to pollutants has not been studied. We examined the cytochrome P4501A (CYP1A)-catalyzed deethylation of 7-ethoxyresorufin (EROD) in the CAM during chicken embryo development. EROD was constitutively present and was inducible by the aryl hydrocarbon (Ah) receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Our results suggest the CAM as a first line of defence of the avian embryo against toxic compounds, but also as a target for CYP1A-activated chemicals.

  • 8.
    Asp, Vendela
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Hermansson, Veronica
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    A tiered approach to assessing adrenocortical toxicity2005In: Science for a safe chemical environment, 2005, p. 63-77Chapter in book (Refereed)
  • 9.
    Asp, Vendela
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Lindström, Veronica
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Bergström, Ulrika
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    CYTOTOXICITY AND DECREASED CORTICOSTERONE PRODUCTION IN ADRENOCORTICAL CELLS BY METHYLSULPHONATED DERIVATIVES OF p,p′-DDE2007Conference paper (Refereed)
    Abstract [en]

    3-methylsulphonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo. The activated compound induces cell death in the adrenocortical zona fasciculata and decreases glucocorticoid production. We have in the present study reproduced both the cytotoxicity and the decreased hormone production in vitro using the mouse adrenocortical cell line Y-1. Cytotoxicity was inhibited by the CYP11-inhibitor etomidate, confirming that CYP11-dependent bioactivation takes place also in vitro. Moreover, 3-MeSO2-DDE decreased corticosterone production in a concentration-dependent manner both in cells that had been induced with forskolin and in non-induced cells. In addition, we have investigated the effects on cell viability and corticosterone production of three structurally related compounds. 2-MeSO2-DDE and 3,3′(bis)-MeSO2-DDE induced cytotoxicity, although to a lower degree than 3-MeSO2-DDE. In contrast, the parent compound p,p′-DDE was not cytotoxic, indicating that the methylsulphonyl moieties are required for biological activity. This study shows that by using the basic structures of 3-MeSO2-DDE in drug design we can easily screen for biologically active compounds in the development of new adrenocorticolytic drugs for adrenocortical cancer and Cushing’s syndrome. We consider the Y-1 and other adrenocortical cell lines to be useful tools in overcoming the gap between animal studies and estimation of potential therapeutic effects and/or risks in humans.

  • 10.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Björlenius, Berndt
    Royal Inst Technol KTH, Albanova Univ Ctr, Sch Biotechnol, SE-10691 Stockholm, Sweden..
    Shaik, Siraz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. IUF Leibniz Res Inst Environm Med, Hennekamp 50, D-40225 Dusseldorf, Germany..
    Lindberg, Richard H.
    Umea Univ, Dept Chem, KBC 6A Linnaeus Vag 6, SE-90187 Umea, Sweden..
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Removal of pharmaceuticals and unspecified contaminants in sewage treatment effluents by activated carbon filtration and ozonation: Evaluation using biomarker responses and chemical analysis2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 176, p. 342-351Article in journal (Refereed)
    Abstract [en]

    Traces of active pharmaceutical ingredients (APIs) and other chemicals are demonstrated in effluents from sewage treatment plants (STPs) and they may affect quality of surface water and eventually drinking water. Treatment of effluents with granular activated carbon (GAC) or ozone to improve removal of APIs and other contaminants was evaluated at two Swedish STPs, Kappala and Uppsala (88 and 103 APIs analyzed). Biomarker responses in rainbow trout exposed to regular and additionally treated effluents were determined. GAC and ozone treatment removed 87-95% of the total concentrations of APIs detected. In Kappala, GAC removed 20 and ozonation (7 g O-3/m(3)) 21 of 24 APIs detected in regular effluent. In Uppsala, GAC removed 25 and ozonation (5.4 g O-3/m(3)) 15 of 25 APIs detected in effluent. GAC and ozonation also reduced biomarker responses caused by unidentified pollutants in STP effluent water. Elevated ethoxyresorufin-O-deethylase (EROD) activity in gills was observed in fish exposed to effluent in both STPs. Gene expression analysis carried out in Kappala showed increased concentrations of cytochrome P450 (CYP1A5 and CYP1C3) transcripts in gills and of CYP1As in liver of fish exposed to effluent. In fish exposed to GAC- or ozone-treated effluent water, gill EROD activity and expression of CYP1As and CYP1C3 in gills and liver were generally equal to or below levels in fish held in tap water. The joint application of chemical analysis and sensitive biomarkers proved useful for evaluating contaminant removal in STPs with new technologies.

  • 11.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Gao, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Larsson, D. G. J.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish2013In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 90, no 3, p. 1149-1157Article in journal (Refereed)
    Abstract [en]

    We have previously reported very high concentrations of pharmaceuticals in the effluent from a treatment plant receiving wastewater from about 90 bulk drug manufacturers near Hyderabad, India. The main objective of the present study was to examine how high dilutions of this effluent affect mRNA expression of cytochrome P450 (CYP) 1 family genes and ethoxyresorufin O-deethylase (EROD) activity in exposed wildlife, using the three-spined stickleback (Gasterosteus aculeatus) as a model. In gill filaments exposed to diluted effluent ex vivo, EROD activity was strongly inhibited in a concentration-dependent manner. In a subsequent in vivo study, groups of fish were exposed (24. h) to three concentrations of effluent, 0.8%, 1.6% or 3.2%. In this experiment, EROD in gills was induced 27-, 52- or 60-fold, respectively. Accordingly, CYP1A mRNA was markedly up-regulated in gill, liver and brain of fish exposed to all three effluent concentrations. Expression of mRNA for CYP1B1 and CYP1C1 was induced in gills at all concentrations while effects on these genes in liver and brain were weak or absent. The results of a time course study suggested that most CYP1-inducing substances in the effluent were readily metabolised or excreted, because the induced EROD activity and mRNA expression decreased when the fish were transferred to clean water. Considering that CYP1 enzymes play important roles in biotransformation of endogenous and foreign compounds, the observed dual effect of the effluent on CYP1 catalytic activity and mRNA expression suggests that multiple physiological functions could be affected in exposed wildlife.

  • 12.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jönsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Shaik, Siraz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Behrens, Daphné
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)2018In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 198, p. 73-81Article in journal (Refereed)
    Abstract [en]

    Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes.

    We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo. The advantage of this method is that both induction and inhibition of EROD are performed ex vivo. Among thirteen azoles studied, the five that caused the strongest inhibition of gill EROD activity at a concentration of 5 μM were selected for concentration–response assessment. These compounds (bifonazole, clotrimazole, imazalil, miconazole, and prochloraz) showed IC50 values ranging from 0.1 to 1.5 μM. CYP19 (aromatase) inhibition was measured using microsomes from rainbow trout brains. Concentration-response curves for CYP19 inhibition were determined for letrozole, bifonazole, clotrimazole, imazalil, miconazole and prochloraz, which gave IC50 values ranging from 0.02 to 3.3 μM. It was further found that mixtures of the five most potent azoles reduced both CYP1 and 19 catalytic activity in an additive fashion (IC50 = 0.7 μM and 0.6 μM, in the respective assay). Bifonazole (IC50 = 0.1 μM) is not previously known to inhibit CYP1 activity.

    The additive inhibition of CYP1 and CYP19 catalytic activity is an important finding of the present study. We conclude that this additive action of azoles could mediate adverse impacts on CYP regulated physiological functions in environmentally exposed fish.

  • 13.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Backström, Tobias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lindberg, Richard
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental Exposure to Fluoxetine Modulates the Serotonin System in Hypothalamus2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e55053-Article in journal (Refereed)
    Abstract [en]

    The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLU, Prozac (R)) is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured)) on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks) until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation) of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.

  • 14.
    Berg, Cecilia
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Avd för ekotoxikologi.
    Blomqvist, Alexandra
    Holm, Lena
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Avd för ekotoxikologi.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Avd för ekotoxikologi.
    Ridderstråle, Yvonne
    Embryonic exposure to oestrogen causes eggshell thinning and altered shell gland carbonic anhydrase expression in the domestic hen.2004In: Reproduction, ISSN 1470-1626, Vol. 128, no 4, p. 455-61Article in journal (Refereed)
  • 15.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Müllerian Duct Dysgenesis: a common cause for female reproductive disorders2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no suppl., p. S184-Article in journal (Refereed)
  • 16.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunstrom, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Methods for studying xenoestrogenic effects in birds1998In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 103, p. 671-676Article in journal (Other academic)
    Abstract [en]

    The embryonated bird egg provides a simple whole organism test system that allows examination of xenoestrogenic effects at different levels of biological organisation. Test compounds are injected into the yolk, the albumen or the air chamber at defined st

  • 17.
    Berg, Cecilia
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holm, Lena
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Anatomical and histological changes in the oviducts of Japanese quail, Coturnix japonica, after embryonic exposure to ethynyloestradiol2001In: REPRODUCTION, ISSN 1470-1626, Vol. 121, no 1, p. 155-165Article in journal (Refereed)
    Abstract [en]

    Oestrogen is needed for normal oviductal development in female birds, but excessive early exposure to oestrogen can cause oviductal abnormalities and impair egg-laying ability. In this study, the anatomical and histological effects of in ovo exposure to t

  • 18.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jansson, Erika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Umeå universitet.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effects of Progestin and Estrogen Mixtures: a partial life cycle study on sex differentiation2013Conference paper (Other academic)
  • 19.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Jansson, Erika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Olsson, A. Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Fick, Jerker
    Umeå universitet.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Combined Exposure to Progestin and Estrogen Mixtures: effects on vitellogenin and hormone receptor mRNA expression2012In: Comparative Biochemistry and Physiology A, ISSN 1095-6433, E-ISSN 1531-4332, Vol. 163, no suppl., p. S56-S57Article in journal (Refereed)
  • 20. Bergman, Ake
    et al.
    Andersson, Anna-Maria
    Becher, Georg
    van den Berg, Martin
    Blumberg, Bruce
    Bjerregaard, Poul
    Bornehag, Carl-Gustaf
    Bornman, Riana
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brian, Jayne V.
    Casey, Stephanie C.
    Fowler, Paul A.
    Frouin, Heloise
    Giudice, Linda C.
    Iguchi, Taisen
    Hass, Ulla
    Jobling, Susan
    Juul, Anders
    Kidd, Karen A.
    Kortenkamp, Andreas
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Martin, Olwenn V.
    Muir, Derek
    Ochieng, Roseline
    Olea, Nicolas
    Norrgren, Leif
    Ropstad, Erik
    Ross, Peter S.
    Ruden, Christina
    Scheringer, Martin
    Skakkebaek, Niels Erik
    Soder, Olle
    Sonnenschein, Carlos
    Soto, Ana
    Swan, Shanna
    Toppari, Jorma
    Tyler, Charles R.
    Vandenberg, Laura N.
    Vinggaard, Anne Marie
    Wiberg, Karin
    Zoeller, R. Thomas
    Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors2013In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, p. 69-Article in journal (Other academic)
    Abstract [en]

    The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.

  • 21. Bergman, Ake
    et al.
    Heindel, Jerrold J.
    Kasten, Tim
    Kidd, Karen A.
    Jobling, Susan
    Neira, Maria
    Zoeller, R. Thomas
    Becher, Georg
    Bjerregaard, Poul
    Bornman, Riana
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kortenkamp, Andreas
    Muir, Derek
    Drisse, Marie-Noel Brune
    Ochieng, Roseline
    Skakkebaek, Niels E.
    Bylehn, Agneta Sunden
    Iguchi, Taisen
    Toppari, Jorma
    Woodruff, Tracey J.
    The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 4, p. A104-A106Article in journal (Other academic)
  • 22.
    Bergman, Åke
    et al.
    Swedish Toxicol Sci Res Ctr Swetox, Sodertalje, Sweden..
    Becher, Georg
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Blumberg, Bruce
    Univ Calif Irvine, Irvine, CA USA..
    Bjerregaard, Poul
    Univ Southern Denmark, Odense, Denmark..
    Bornman, Riana
    Univ Pretoria, Sch Hlth Syst & Publ Hlth, ZA-0002 Pretoria, South Africa..
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Casey, Stephanie C.
    Univ Calif Irvine, Irvine, CA USA..
    Frouin, Heloise
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Giudice, Linda C.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Heindel, Jerrold J.
    Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA..
    Iguchi, Taisen
    Natl Inst Basic Biol, Okazaki, Aichi 444, Japan..
    Jobling, Susan
    Brunel Univ London, Uxbridge, Middx, England..
    Kidd, Karen A.
    Univ New Brunswick, New Brunswick, NJ USA..
    Kortenkamp, Andreas
    Brunel Univ London, Uxbridge, Middx, England..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Muir, Derek
    Environm Canada, Burlington, ON L7R 4A6, Canada..
    Ochieng, Roseline
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Ropstad, Erik
    Norwegian Univ Life Sci, Oslo, Norway..
    Ross, Peter S.
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Skakkebaek, Niels Erik
    Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Toppari, Jorma
    Univ Turku, Turku, Finland..
    Vandenberg, Laura N.
    Univ Massachusetts, Amherst, MA 01003 USA..
    Woodruff, Tracey J.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Zoeller, R. Thomas
    Univ Massachusetts, Amherst, MA 01003 USA..
    Manufacturing doubt about endocrine disrupter science - A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"2015In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 73, no 3, p. 1007-1017Article in journal (Other academic)
    Abstract [en]

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.

  • 23.
    Bergström, Ulrika
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Olsson, Jan A
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Hvidsten, Torgeir R
    Komorowski, Jan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Ekotoxikologi.
    Altered gene expression in the olfactory bulb following exposure to 2,6-dichlorophenyl methylsulfone2005In: Toxicology Letters 158 Supp 1., 2005, p. 61-Conference paper (Other scientific)
  • 24. Blomqvist, Alexandra
    et al.
    Berg, Cecilia
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holm, Lena
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Defective reproductive organ morphology and function in domestic rooster embryonically exposed to o,p'-DDT or ethynylestradiol.2006In: Biol Reprod, ISSN 0006-3363, Vol. 74, no 3, p. 481-6Article in journal (Refereed)
  • 25. Blomqvist, Alexandra
    et al.
    Holm, Lena
    Berg, Cecilia
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Progesterone receptor in the reproductive organs of domestic rooster2004In: Uppsala Journal of Medical Sciences: Abstracts for The 22nd Conference of European Comparative Endocrinologists, 2004, p. 16-Conference paper (Other scientific)
  • 26.
    Brandt, Ingvar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Laboratory vs Field Studies to Assess Environmental Hazards and Risks Posed by Pharmaceuticals for Human Use2010In: Towards Sustainable Pharmaceuticals in a Healthy Society: MistraPharma Research / [ed] Christina Rudén, Karin Liljelund, Helene Hagerman, MistraPharma , 2010, p. 72-79Chapter in book (Other academic)
  • 27.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Helén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells2012In: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm), 2012Conference paper (Refereed)
    Abstract [en]

    Introduction

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

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

    Material and methods

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

    Results and discussion

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

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

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

    In another study we have examined the effects of a nitrated PAH, 1-nitropyrene, that is abundant in diesel exhausts (21). The results revealed that 1-NP induced DNA damage, increased levels of ROS and increased protein expression of the endoplasmic reticulum stress chaperone GRP78 in cultured HUVEC. Induction of CYP1A1 by PCB126 as well as inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction and not by CYP1-dependent bioactivation to reactive intermediates.

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

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

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

  • 28.
    Carlsson, Carina
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bahrami, Fariba
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice.2002In: Arch Toxicol, ISSN 0340-5761, Vol. 76, no 8, p. 474-83Article in journal (Refereed)
  • 29.
    Carlsson, Carina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, no 4, p. 156-168Article in journal (Refereed)
    Abstract [en]

    2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.

  • 30. Carlsson, Carina
    et al.
    Harju, Mikael
    Bahrami, Fariba
    Cantillana, Tatiana
    Tysklind, Mats
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. Avd för ekotoxikologi.
    Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives.2004In: Arch Toxicol, ISSN 0340-5761, Vol. 78, no 12, p. 706-15Article in journal (Refereed)
  • 31.
    Castellanos, Cesilie Granum
    et al.
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Sorvik, Irene Beate
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.; Department of Pharmaceutical Biosciences, University of Oslo, Postboks 1068 Blindern, 0316 Oslo, Norway.
    Tanum, Marte Bruu
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.; The Climate and Pollution Agency (Klif), Postboks 8100 Dep, 0032 Oslo, Norway.
    Verhaegen, Steven
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ropstad, Erik
    Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Postboks 8146 Dep, 0033 Oslo, Norway.
    Differential effects of the persistent DDT metabolite methylsulfonyl-DDE in nonstimulated and LH-stimulated neonatal porcine Leydig cells2013In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 267, no 3, p. 247-255Article in journal (Refereed)
    Abstract [en]

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

  • 32. Gao, Kai
    et al.
    Yan, Pei
    Tan, Cui-ling
    Luo, Yan-he
    Sun, Jing
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Tang, Yun-ping
    Application of Rainbow Trout CYP1 Gene Expression Patterns in Gill and Liver for Haihe River Bio-monitoring2015In: Huanjing Kexue, ISSN 0250-3301, Vol. 36, no 10, p. 3878-3883Article in journal (Refereed)
    Abstract [en]

    CYP1 subfamily genes in gills and liver of rainbow trout as biomarkers were studied to establish methods for quantitative mRNA expression analysis of these genes and to determine their expression pattern. Fish caged in various waters in the Haihe River (Tianjin) were analyzed. The mRNA expression patterns observed in Machangjian River and estuary site of Haihe River were markedly similar but at different levels, reflecting that those sites shared the similar pollution components but with different local pollution load. CYP1C1 and 1C3 were only induced at Gegu site and estuary site of Haihe River, indicating different types of CYP1 agonists in Machangjian River. Response patterns of multiple CYP1 genes in gills and liver could be applied in the monitoring strategy. The response patterns of CYP1 genes could be used for better understanding the relationship between complex mixtures of pollutants and biological response of organisms in aquatic environments.

  • 33.
    Granberg, Lizette
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Formation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene adducts in vascular endothelia of cytochrome P4501A-induced chicken embryos.2003In: Environ Toxicol Chem, ISSN 0730-7268, Vol. 22, no 10, p. 2393-9Article in journal (Refereed)
  • 34.
    Granberg, Lizette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Östergren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells.2003In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 31, no 3, p. 259-265Article in journal (Refereed)
    Abstract [en]

    Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.

  • 35. Halldin, K
    et al.
    Berg, C
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, I
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunstrom, B
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Sexual behavior in Japanese quail as a test end point for endocrine disruption: Effects of in Ovo exposure to ethinylestradiol and diethylstilbestrol1999In: ENVIRONMENTAL HEALTH PERSPECTIVES, ISSN 0091-6765, Vol. 107, no 11, p. 861-866Article in journal (Other scientific)
    Abstract [en]

    Chemicals having a capacity to disturb the endocrine system have attracted considerable interest during recent years. There is a shortage of well-characterized in vivo tests with which to study such disturbances in different classes of vertebrates. In the

  • 36. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Developmental toxicity in Japanese quail exposed to hydroxylated metabolites pf PCBs in ovo.2005In: Avian and Poultry Biology Reviews, no 16, p. 11-17Article in journal (Refereed)
  • 37.
    Halldin, Krister
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergman, Åke
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Distribution of bisphenol A and tetrabromobisphenol A in quail eggs, embryos and laying birds and studies on reproduction variables in adults following in ovo exposure2001In: ARCHIVES OF TOXICOLOGY, ISSN 0340-5761, Vol. 75, no 10, p. 597-603Article in journal (Refereed)
    Abstract [en]

    In a previous study, we showed that bisphenol A (BPA) had oestrogen-like effects in bird embryos, causing malformations of the oviducts in Japanese quail (Coturnix japonica) and feminisation of the left testis in chicken (Gallus domesticus). In this study

  • 38.
    Hermansson, Veronica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Asp, Vendela
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergman, Åke
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells2007In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 81, no 11, p. 793-801Article in journal (Refereed)
    Abstract [en]

    The environmental pollutant 3-MeSO2–DDE [2-(3-methylsulfonyl-4-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethene] is an adrenocortical toxicant in mice, specifically in the glucocorticoid-producing zona fasciculata, due to a cytochrome P450 11B1 (CYP11B1)-catalysed bioactivation and formation of covalently bound protein adducts. o,p′-DDD [2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane] is toxic and inhibits steroidogenesis in the human adrenal cortex after bioactivation by unidentified CYPs, but does not exert any toxic effects on the mouse adrenal. As a step towards determining in vitro/in vivo relationships for the CYP-catalysed binding and toxicity of 3-MeSO2–DDE and o,p′-DDD, we have investigated the irreversible protein binding of these two toxicants in the murine adrenocortical cell line Y-1. The irreversible binding of 3-MeSO2–DDE previously demonstrated in vivo was successfully reproduced and could be inhibited by the CYP-inhibitors etomidate, ketoconazole and metyrapone. Surprisingly, o,p′-DDD reached similar levels of binding as 3-MeSO2–DDE. The binding of o,p′-DDD was sensitive to etomidate and ketoconazole, but not to metyrapone. Moreover, GSH depletion increased the binding of 3-MeSO2–DDE, but not of o,p′-DDD, indicating an important role of GSH conjugation in the detoxification of the 3-MeSO2–DDE-derived reactive metabolite. In addition, the specificity of CYP11B1 in activating 3-MeSO2–DDE was investigated using structurally analogous compounds. None of the analogues produced histopathological lesions in the mouse adrenal in vivo following a single i.p. injection of 100 mg/kg body weight, but two of the compounds were able to decrease the irreversible binding of 3-MeSO2–DDE to Y-1 cells. These results indicate that the bioactivation of 3-MeSO2–DDE by CYP11B1 is highly structure-dependent. In conclusion, both 3-MeSO2–DDE and o,p′-DDD bind irreversibly to Y-1 cells despite differences in binding and adrenotoxicity in mice in vivo. This reveals a notable in vitro/in vivo discrepancy, the contributing factors of which remain unexplained. We consider the Y-1 cell line as appropriate for studies of the cellular mechanisms behind the adrenocortical toxicity of these substances.

  • 39.
    Hermansson, Veronica
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Asp, Vendela
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergström, Ulrika
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Chemical-induced cell death in the adrenal cortex: Mechanisms of action of 3-MeSO2-DDE.2005In: Drug Metabolism Reviews 37, 2005, p. 262-Conference paper (Other scientific)
  • 40.
    Hermansson, Veronica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cantillana, Tatiana
    Hovander, Lotta
    Bergman, Åke
    Ljungvall, Karl
    Magnusson, Ulf
    Törneke, Karolina
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p′-DDD (mitotane) in Minipigs2008In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 61, no 2, p. 267-274Article in journal (Refereed)
    Abstract [en]

    The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO2-DDE) and the anticancer drug o,p′-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO2-DDE or o,p′-DDD as single oral doses (30 mg/kg). Concentrations in plasma and subcutaneous fat were measured by gas chromatography at different time points during 180 days. Maximal plasma concentrations appeared within 24 h for both compounds, but were about 2 times higher for 3-MeSO2-DDE. o,p′-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO2-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO2-DDE reached about 25-fold higher levels than o,p′-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO2-DDE liver concentrations were about 18-fold higher than those in plasma at 180 days. In contrast, o,p′-DDD liver and plasma levels were about equal at 180 days. o,p′-DDD had roughly 45 times larger CL/F than 3-MeSO2-DDE, confirming that the elimination of this compound was more rapid. Both compounds were characterised by their localisation and retention in fat tissue, and the individual size of the fat stores clearly determined the plasma concentrations. It is concluded that although 3-MeSO 2-DDE is an interesting candidate for therapeutic use due to its potential characteristics to specifically target adrenocortical tumour cells the slow elimination of the compound might make it challenging to design appropriate dosage regimes.

  • 41. Holm, Lena
    et al.
    Berg, Cecilia
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Altered localization of carbonic anhydrase in the quail shell gland following in ovo exposure to ethynylestradiol2001In: Hormones in the Environment and Animal Production - A Public Health Concern?: Proceedings from a symposium at the Ultuna Campus, Uppsala, March 13, 2001, 2001Conference paper (Other scientific)
  • 42. Holm, Lena
    et al.
    Berg, Cecilia
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstrale, Yvonne
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Disrupted carbonic anhydrase distribution in the avian shell gland following in ovo exposure to estrogen2001In: ARCHIVES OF TOXICOLOGY, ISSN 0340-5761, Vol. 75, no 6, p. 362-368Article in journal (Refereed)
    Abstract [en]

    Eggshell thinning among wild birds has been an environmental concern for almost half a century and the underlying mechanisms are still not fully understood. Previously we showed that exposure of quail embryos to ethynylestradiol (EE2) caused disorganizati

  • 43. Holm, Lena
    et al.
    Blomqvist, Alexandra
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Embryonic exposure to o,p'-DDT causes eggshell thinning and altered shell gland carbonic anhydrase expression in the domestic hen2006In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 25, no 10, p. 2787-2793Article in journal (Refereed)
    Abstract [en]

    The mechanism for contaminant-induced eggshell thinning in wild birds remains to be clarified. It is generally assumed, however, that it results from exposure of the adult laying female. We have reported that embryonic exposure to the synthetic estrogen ethynylestradiol (EE2) results in eggshell thinning in the domestic hen. The objective of this study was to investigate whether eggshell thinning can be induced following in ovo exposure to a bioaccumulating estrogenic environmental contaminant, o,p '-DDT. Ethynylestradiol was used as a positive control. Domestic hens exposed in ovo to o,p '-DDT (37 or 75 mu g/g egg) or EE2 (60 ng/g egg) laid eggs with thinner shells than the control birds. The hens from these exposure groups also had a significantly reduced frequency of shell gland capillaries with carbonic anhydrase (CA) activity, a key enzyme in eggshell formation. The decreased number of capillaries with CA activity suggests that a developmentally induced disruption of CA expression in the shell gland was involved in the eggshell thinning found in this study. Egg laying was not affected in hens exposed embryonically to 37 or 75 mu g o,p '-DDT/g egg, whereas it was inhibited in hens exposed to higher doses. Decreased lengths of the left oviduct and its infundibulum were seen after embryonic treatment with o,p '-DDT or EE2. In addition, o,p '-DDT exposure resulted in right oviduct retention. The results support our hypothesis that eggshell thinning in avian wildlife can result from a functional malformation in the shell gland, induced by embryonic exposure to estrogenic substances.

  • 44.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Abrahamson, Alexandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cytochrome P4501A induction in rainbow trout gills and liver following exposure to waterborne indigo, benzo(a)pyrene and 3,3',4,4',5-pentachlorobiphenyl2006In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 79, no 3, p. 226-232Article in journal (Refereed)
    Abstract [en]

    We have developed a gill-filament based ethoxyresorufin O-deethylase (EROD) assay to be used as a tool to monitor cytochrome P4501A (CYP1A) induction in caged fish. The present study aimed to compare temporal patterns of EROD induction in gills and liver of rainbow trout (Oncorhynchus mykiss) exposed in the laboratory to readily metabolized and persistent CYP1A inducers, i.e. indigo, benzo[a]pyrene (BaP), and 3,3',4,4',5-pentachlorobiphenyl (PCB#126). Branchial and hepatic EROD activities were examined in fish exposed for 6, 12, or 24h and in fish exposed for 24h and then held in clean water for 2 or 14 days. Furthermore, branchial CYP1A protein expression was localized by immunohistochemistry. All compounds strongly induced branchial EROD activity within 6 h. The highest EROD inductions observed for indigo, BaP, and PCB#126 were roughly similar in gills (52-, 76-, and 74-fold), but differed considerably in liver (11-, 78-, and 200-fold). In indigo- and BaP-exposed fish, both hepatic and branchial EROD activities decreased rapidly in clean water. In PCB#126-exposed fish, decreased branchial and increased hepatic EROD activities were observed following transfer to clean water. The substances gave rise to immunostaining for CYP1A at different cellular sites. All inducers increased the CYP1A-immunostaining in the gill filament secondary lamellae, but PCB#126 also induced a pronounced CYP1A immunoreactivity in cells near the basal membrane of the epithelium of the primary lamellae. The observation that the low BaP and indigo concentrations induced EROD activity markedly in the gills but only slightly or not at all in the liver, supports the contention that readily metabolized AhR agonists may escape detection when hepatic EROD activity is used for environmental monitoring. The results show that gill filament EROD activity is a sensitive biomarker both for persistent and readily metabolized AhR agonists in polluted water.

  • 45.
    Jönsson, Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Abrahamson, Alexandra
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ingebrigtsen, Kristian
    Jørgensen, Even H
    EROD activity in gill filaments of anadromous and marine fish as a biomarker of dioxin-like pollutants.2003In: Comp Biochem Physiol C Toxicol Pharmacol, ISSN 1532-0456, Vol. 136, no 3, p. 235-43Article in journal (Refereed)
  • 46.
    Jönsson, Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    A gill filament-based EROD assay for monitoring waterborne dioxin-like pollutants in fish.2002In: Environmental Science and Technology, Vol. 36, p. 3340-3344Article in journal (Refereed)
  • 47.
    Kalayou, Shewit
    et al.
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway.;Mekelle Univ, Coll Vet Med, Mekelle, Ethiopia..
    Granum, Cesilie
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway..
    Berntsen, Hanne Friis
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway..
    Groseth, Per Kristian
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway..
    Verhaegen, Steven
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway..
    Connolly, Lisa
    Queens Univ Belfast, Inst Global Food Secur, Sch Biol Sci, Belfast BT7 1NN, Antrim, North Ireland..
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    de Souza, Gustavo Antonio
    Univ Oslo, Oslo Univ Hosp, Dept Immunol, Rikshosp, POB 4950, N-0424 Oslo, Norway..
    Ropstad, Erik
    Norwegian Univ Life Sci, Sect Expt Biomed, Oslo, Norway..
    Label-free based quantitative proteomics analysis of primary neonatal porcine Leydig cells exposed to the persistent contaminant 3-methylsulfonyl-DDE2016In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 137, p. 68-82Article in journal (Refereed)
    Abstract [en]

    Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cell function may have ultimate consequences. 3-Methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed the endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE on viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue (TM) assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and Luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10 mu M) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 6804 proteins were identified in which the abundance of 86 proteins in unstimulated Leydig cells and 145 proteins in LH-stimulated Leydig cells was found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathione-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.

  • 48.
    Lindhe, Orjan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Christiansen, Jørgen Schou
    Ingebrigtsen, Kristian
    Irreversible binding of o,p'-DDD in interrenal cells of Atlantic cod (Gadus morhua).2003In: Chemosphere, ISSN 0045-6535, Vol. 50, no 9, p. 1249-53Article in journal (Refereed)
  • 49.
    Lindhe, Örjan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Granberg, Lizette
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cytochrome P450-catalysed irreversible binding examined in precision-cut adrenal slice culture.2001In: Adv Exp Med Biol, ISSN 0065-2598, Vol. 500, p. 531-4Article in journal (Refereed)
  • 50.
    Lindhe, Örjan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Granberg, Lizette
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Target cells for cytochrome p450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands.2002In: Arch Toxicol, ISSN 0340-5761, Vol. 76, no 8, p. 460-6Article in journal (Refereed)
12 1 - 50 of 64
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