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  • 1. Abrahamson, Alexandra
    et al.
    Andersson, Carin
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fogelberg, Oscar
    Orberg, Jan
    Brunstrom, Bjorn
    Brandt, Ingvar
    Gill EROD in monitoring of CYP1A inducers in fish - A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters2007In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed)
  • 2.
    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)
  • 3. Behrendt, Lars
    et al.
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    Induction of cytochrome P450 1 genes and stress response genes in developing zebrafish exposed to ultraviolet radiation2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 1, p. 74-82Article in journal (Refereed)
  • 4.
    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.

  • 5.
    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.

  • 6.
    Gao, Kai
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Goldstone, Jared V.
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Cytochrome P450 1A, 1B, and 1C mRNA induction patterns in three-spined stickleback exposed to a transient and a persistent inducer2011In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 154, no 1, p. 42-55Article in journal (Refereed)
  • 7. 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.

  • 8. Goldstone, J. V.
    et al.
    Jönsson, M. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Behrendt, L.
    Woodin, B. R.
    Jenny, M. J.
    Nelson, D. R.
    Stegeman, J. J.
    Cytochrome P450 1D1: A novel CYP1A-related gene that is not transcriptionally activated by PCB126 or TCDD2009In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 482, no 1-2, p. 7-16Article in journal (Refereed)
  • 9. Goldstone, J. V.
    et al.
    Jönsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Behrendt, L.
    Woodin, B. R.
    Jenny, M. J.
    Nelson, D. R.
    Stegeman, J. J.
    Cytochrome P450 1D1: A novel CYP1A-related gene that is not transcriptionally activated by PCB126 or TCDD2009In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 482, no 1-2, p. 7-16Article in journal (Refereed)
    Abstract [en]

    Enzymes in the cytochrome P450 1 family oxidize many common environmental toxicants. We identified a new CYP1, termed CYP1D1, in zebrafish. Phylogenetically, CYP1D1 is paralogous to CYP1A and the two share 45% amino acid identity and similar gene structure. In adult zebrafish, CYP1D1 is most highlyexpressed in liver and is relatively highly expressed in brain. CYP1D1 transcript levels were higher at 9 h post-fertilization than at later developmental times. Treatment of zebrafish with potent aryl hydrocarbon receptor (AHR) agonists (3,3',4,4',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin) did not induce CYP1D1 transcript expression. Morpholino oligonucleotide knockdown of AHR2, which mediates induction of other CYP1s, did not affect CYP1D1 expression. Zebrafish CYP1D1 heterologously expressed in yeast exhibited ethoxyresorufin- and methoxyresorufin-O-dealkylase activities. Antibodies against a CYP1D1 peptide specifically detected a single electrophoretically-resolved protein band in zebrafish liver microsomes, distinct from CYP1A. CYP1D1 in zebrafish is a CYP1A-like gene that could have metabolic functions targeting endogenous compounds.

  • 10. Goldstone, Jared V.
    et al.
    McArthur, Andrew G.
    Kubota, Akira
    Zanette, Juliano
    Parente, Thiago
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Nelson, David R.
    Stegeman, John J.
    Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11Article in journal (Refereed)
  • 11.
    Jonsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Brunstrom, Bjorn
    A gill filament-based EROD assay to monitor waterborne dioxin-like pollutants2002In: Marine Environmental Research, ISSN 0141-1136, E-ISSN 1879-0291, Vol. 54, no 3-5, p. 841-841Article in journal (Refereed)
  • 12.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development2011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 250, no 2, p. 170-183Article in journal (Refereed)
  • 13.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunstrom, Bjorn
    Brandt, Ingvar
    The zebrafish gill model: Induction of CYP1A, EROD and PAH adduct formation2009In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 91, no 1, p. 62-70Article in journal (Refereed)
  • 14.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kubota, Akira
    Timme-Laragy, Alicia R.
    Woodin, Bruce
    Stegeman, John J.
    Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish2012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed)
  • 15.
    Jonsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Woodin, Bruce R.
    Stegeman, John J.
    Brunstrom, Bjorn
    Cytochrome P450 1 Genes in Birds: Evolutionary Relationships and Transcription Profiles in Chicken and Japanese Quail Embryos2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12Article in journal (Refereed)
  • 16.
    Jönsson, M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Abrahamson, A.
    Brunstrom, B.
    Brandt, I.
    Ingebrigtsen, K.
    Jorgensen, E. H.
    EROD activity in gill filaments of anadromous and marine fish as a biomarker of dioxin-like pollutants2003In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 136, no 3, p. 235-243Article in journal (Refereed)
  • 17.
    Jönsson, M. E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunstrom, B.
    Ingebrigtsen, K.
    Brandt, I.
    Cell-specific CYP1A expression and benzo a pyrene adduct formation in gills of rainbow trout (Oncorhynchus mykiss) following CYP1A induction in the laboratory and in the field2004In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 23, no 4, p. 874-882Article in journal (Refereed)
  • 18.
    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)
  • 19.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunstrom, Bjorn
    Brandt, Ingvar
    CYP1A induction and PAH adduct formation in zebrafish and rainbow trout gills2006In: Marine Environmental Research, ISSN 0141-1136, E-ISSN 1879-0291, Vol. 62, p. S313-S313Article in journal (Refereed)
  • 20.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunstrom, Bjorn
    Ingebrigtsen, Kristian
    Brandt, Ingvar
    Cell specific CYP1A expression and EROD activity in gills of rainbow trout following 1 to 28 days of exposure to the aryl hydrocarbon receptor agonist eta-naphthoflavone2004In: Marine Environmental Research, ISSN 0141-1136, E-ISSN 1879-0291, Vol. 58, no 2-5, p. 537-538Article in journal (Refereed)
  • 21.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Carlsson, Carina
    Smith, Richard W.
    Part, Peter
    Effects of copper on CYP1A activity and epithelial barrier properties in the rainbow trout gill2006In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 79, no 1, p. 78-86Article in journal (Refereed)
  • 22.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Franks, Diana G.
    Woodin, Bruce R.
    Jenny, Matthew J.
    Garrick, Rita A.
    Behrendt, Lars
    Hahn, Mark E.
    Stegeman, John J.
    The tryptophan photoproduct 6-formylindolo 3,2-b carbazole (FICZ) binds multiple AHRs and induces multiple CYP1 genes via AHR2 in zebrafish2009In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, no 3, p. 447-454Article in journal (Refereed)
  • 23.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Gao, Kai
    Olsson, Jan A.
    Goldstone, Jared V.
    Brandt, Ingvar
    Induction patterns of new CYP1 genes in environmentally exposed rainbow trout2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 4, p. 311-321Article in journal (Refereed)
  • 24.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Gao, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Olsson, Jan A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Goldstone, Jared V
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Induction patterns of new CYP1 genes in environmentally exposed rainbow trout2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 4, p. 311-321Article in journal (Refereed)
    Abstract [en]

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

  • 25.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jenny, Matthew J.
    Woodin, Bruce R.
    Hahn, Mark E.
    Stegeman, John J.
    Role of AHR2 in the expression of cytochrome P450 1 family genes, cell cycle genes, and morphological defects in developing zebrafish exposed to 3,3 ',4,4 ',5-pentachlorobiphenyl2008In: Marine Environmental Research, ISSN 0141-1136, E-ISSN 1879-0291, Vol. 66, no 1, p. 33-34Article in journal (Refereed)
  • 26.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jenny, Matthew J.
    Woodin, Bruce R.
    Hahn, Mark E.
    Stegeman, John J.
    Role of AHR2 in the expression of novel cytochrome p450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3 ',4,4 ',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin2007In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 100, no 1, p. 180-193Article in journal (Refereed)
  • 27.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Kubota, Akira
    Biology Department, Woods Hole Oceanographic Institution.
    Timme-Laragy, Alicia R.
    Biology Department, Woods Hole Oceanographic Institution.
    Woodin, Bruce
    Biology Department, Woods Hole Oceanographic Institution.
    Stegeman, John J.
    Biology Department, Woods Hole Oceanographic Institution.
    Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.2012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed)
    Abstract [en]

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

  • 28.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Mattsson, Anna
    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.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos2016In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 179, p. 125-136Article in journal (Refereed)
    Abstract [en]

    The tryptophan derivative formylindolo[3,2-b]carbazole (FICZ) binds with high ligand affinity to the aryl hydrocarbon receptor (AHR) and is readily degraded by AHR-regulated cytochrome P450 family 1 (CYP1) enzymes. Whether in vivo exposure to FICZ can result in toxic effects has not been examined and the main objective of this study was to determine if FICZ is embryotoxic in birds. We examined toxicity and CYP1 mRNA induction of FICZ in embryos from chicken (Gallus domesticus) and Japanese quail (Coturnix japonica) exposed to FICZ (2200 jag kg(-1)) by yolk and air sac injections. FICZ caused liver toxicity, embryo mortality, and CYP1A4 and CYP1A5 induction in both species with similar potency. This is in stark contrast to the very large difference in sensitivity of these species to halogenated AHR agonists. We also exposed chicken embryos to a low dose of FICZ (4 mu g kg(-1)) in combination with a CYP inhibitor, ketoconazole (KCZ). The mixture of FICZ and KCZ was lethal while FICZ alone had no effect at 4 mu g kg(-1). Furthermore, mixed exposure to FICZ and KCZ caused stronger and more long-lasting hepatic CYP1A4 induction than exposure to each compound alone. These findings indicate reduced biotransformation of FICZ by co-treatment with KCZ as a cause for the enhanced effects although additive AHR activation is also possible. To conclude, FICZ is toxic to bird embryos and it seems reasonable that the toxicity by FICZ involves AHR activation. However, the molecular targets and biological events leading to hepatic damage and mortality are unknown.

  • 29.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Orrego, Rodrigo
    Woodin, Bruce R.
    Goldstone, Jared V.
    Stegeman, John J.
    Basal and 3,3',4,4',5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish2007In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 221, no 1, p. 29-41Article in journal (Refereed)
  • 30.
    Jönsson, Maria
    et al.
    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.
    Rannug, Agneta
    Karolinska University, IMM.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental effects of 6-formyl-indolo[3,2-b]carbazole in birds2013In: Toxicology Letters, UK: Oxford University Press, 2013, p. 68-Conference paper (Refereed)
  • 31.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Woodin, Bruce
    Biology Department, Woods Hole Oceanographic Institution.
    Stegeman, John
    Biology Department, Woods Hole Oceanographic Institution.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Cytochrome P450 1 genes in birds: evolutionary relationships and transcription profiles in chicken and japanese quail embryos2012In: The Toxicologist, 2012Conference paper (Other academic)
    Abstract [en]

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

  • 32.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Woodin, Bruce
    Biology, Woods Hole Oceanographic Institution.
    Stegeman, John
    Biology, Woods Hole Oceanographic Institution.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Cytochrome P450 1 Genes in Birds: Evolutionary Relationships and Transcription Profiles in Chicken and Japanese Quail Embryos2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, article id e28257Article in journal (Refereed)
    Abstract [en]

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

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

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

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  • 33.
    Mentor, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    Bornehag, Carl-Gustaf
    Karlstad Univ, Publ Hlth Sci, Karlstad, Sweden;Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
    Jönsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    A suggested bisphenol A metabolite (MBP) interfered with reproductive organdevelopment in the chicken embryo while a human-relevant mixture ofphthalate monoesters had no such effects2020In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 83, no 2, p. 66-81Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) and phthalate diesters are ubiquitous environmental contaminants. While thesecompounds have been reported as reproductive toxicants, their effects may partially be attributedto metabolites. The aim of this study was to examine reproductive organ development in chickenembryos exposed to the BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP;100 μg/g egg) or a human-relevant mixture of 4 phthalate monoesters (85 μg/g egg). The mixturewas designed within the EU project EDC-MixRisk based upon a negative association with anogenitaldistance in boys at 21 months of age in a Swedish pregnancy cohort. Chicken embryoswere exposed in ovo from an initial stage of gonad differentiation (embryonic day 4) anddissected two days prior to anticipated hatching (embryonic day 19). No discernible effectswere noted on reproductive organs in embryos exposed to the mixture. MBP-treated malesexhibited retention of Müllerian ducts and feminization of the left testicle, while MBPadministeredfemales displayed a diminished the left ovary. In the left testicle of MBP-treatedmales, mRNA expression of female-associated genes was upregulated while the testicular markergene SOX9 was downregulated, corroborating a feminizing effect by MBP. Our results demonstratethat MBP, but not the phthalate monoester mixture, disrupts both male and femalereproductive organ development in an avian embryo model.

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  • 34.
    Mentor, Anna
    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.
    Mattsson, Anna
    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.
    Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio)2020In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 238, article id 124584Article in journal (Refereed)
    Abstract [en]

    Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfiuorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3 h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.

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  • 35.
    Mentor, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    Bornehag, Carl-Gustaf
    Public Health Sciences, Karlstad University.
    Brunström, Björn
    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.
    Metabolic disruption by a human-relevant chemical mixture, triclosan, and tributyltin in larval zebrafish (Danio rerio)Manuscript (preprint) (Other academic)
    Abstract [en]

    Exposure to metabolism disrupting compounds during development may have short- and long-term health consequences. We have studied the effects of a mixture that consists of perfluoroalkyl acids, phthalate monoesters, and triclosan (TCS) on metabolic endpoints in developing zebrafish (Danio rerio). The mixture has previously been negatively associated with birth weight in the Swedish pregnancy cohort SELMA. We also studied one of the mixture components (TCS) and the known obesogen tributyltin (TBT). Water concentrations of the mixture and TCS corresponded to 1, 20, 60, and 100 times the geometrical mean of the gestational week 10 serum concentration in the SELMA women. The fish were exposed from 3 hours post fertilization and effects on metabolic rate were assessed at 2-5 days post fertilization (dpf) and lipid content in the blood, whole-body neutral lipid content, and adiposity were determined at 7 dpf. Exposure to the mixture and TCS altered metabolic rate. The mixture and both single compounds reduced lipid levels in whole-body samples and in the blood. A higher proportion of fish in the mixture- and TBT-exposed groups had visible adipocytes at 7 dpf compared with the control group and a similar tendency was observed in TCS-exposed fish. Our results demonstrate metabolism disrupting properties of the mixture and its component TCS that were similar to those of TBT. The results further indicate that TCS contributes to, but is not solely responsible for, the effect by the mixture.

  • 36.
    Smirnova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Mentor, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ranefall, Petter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.
    Bornehag, Carl-Gustaf
    Public Health Sciences, Karlstad University.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    Jönsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Increased apoptosis, reduced Wnt/β-catenin signaling, and altered tail development in zebrafish embryos exposed to a chemical mixture that has been inversely associated with birth weight in humansManuscript (preprint) (Other academic)
    Abstract [en]

    A wide variety of anthropogenic chemicals is detected in humans and wildlife and the health effects of such exposure are not well understood. The early developmental period is generally most susceptible to chemical disruption and early-life exposure is a suggested cause for disease in adulthood. Two developmentally important signaling networks that can be targeted by pollutants are those of apoptosis and Wnt/β-catenin signaling. We used zebrafish embryo models to determine effects of a mixture of chemicals that was defined within the EU-project EDC-MixRisk based on its inverse association with birth weight in a human pregnancy cohort (SELMA). The mixture (Mixture G) was composed of five phthalate monoesters, triclosan, and three perfluoroalkyl acids. We recently showed that developmental exposure to Mixture G leads to increased formation of adipocytes in zebrafish larvae. Here we determined its effects on apoptosis and Wnt/β-catenin signaling in zebrafish embryos. Apoptosis was assayed by TUNEL, caspase-3 activity, and acridine orange staining while Wnt/β-catenin signaling was studied using a transgenic zebrafish line expressing an EGFP reporter in response to Tcf/Lef-mediated Wnt/ß-catenin signaling. We found that Mixture G increased the incidence of apoptosis and suppressed Wnt/β-catenin signaling in the caudal fin at human-relevant concentrations (20 or 100 times the geometric mean serum levels in the cohort). Furthermore, caudal fin shape was altered in Mixture G-exposed embryos. These results suggest that chemicals that human embryos/fetuses are exposed to can induce morphological and/or physiological alterations, effects that could result in adverse health effects.

  • 37.
    Smith, R. W.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Blaney, S. C.
    Dowling, K.
    Sturm, A.
    Jonsson, M.
    Houlihan, D. F.
    Protein synthesis costs could account for the tissue-specific effects of sub-lethal copper on protein synthesis in rainbow trout (Oncorhynchus mykiss)2001In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 53, no 3-4, p. 265-277Article in journal (Refereed)
  • 38.
    Smith, RW
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Jonsson, M
    Department of Physiology and Developmental Biology.
    Houlihan, DF
    Part, P
    Department of Physiology and Developmental Biology.
    Minimising aerobic respiratory demands could form the basis to sub-lethal copper tolerance by rainbow trout gill epithelial cells in vitro2001In: FISH PHYSIOLOGY AND BIOCHEMISTRY, ISSN 0920-1742, Vol. 24, no 2, p. 157-169Article in journal (Refereed)
    Abstract [en]

    Mechanisms of Cu tolerance were investigated in respiratory epithelial cell cultures, from rainbow trout gills, by studying O-2 consumption and protein synthesis rates, intracellular Na concentration and TER. The lowest concentration found to reduce O-2 c

  • 39. Stegeman, J. J.
    et al.
    Goldstone, J. V.
    Jonsson, M. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kubota, A.
    Lemaire, B.
    Evolutionary history and functional diversity of the cytochrome P450 1 gene family2012In: Comparative Biochemistry and Physiology A, ISSN 1095-6433, E-ISSN 1531-4332, Vol. 163, no 1, p. S28-S28Article in journal (Refereed)
  • 40. Stegeman, John J.
    et al.
    Goldstone, Jared V.
    Jonsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Woodin, Bruce
    Oxidative xenobiotic metabolism in zebrafish: The cytochrome P450 gene complement, regulation, and function2007In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 20, no 12, p. 1990-1990Article in journal (Refereed)
  • 41.
    Wincent, Emma
    et al.
    Swetox.
    Kubota, Akira
    Woods Hole Oceanographic Institution.
    Timme-Laragy, Alicia
    Woods Hole Oceanographic Institution.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Hahn, Mark E
    Woods Hole Oceanographic Institution.
    Stegeman, John J
    Woods Hole Oceanographic Institution.
    Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner2016In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 110, p. 117-129Article in journal (Refereed)
    Abstract [en]

    6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.

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  • 42.
    Wincent, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden.
    Stegeman, John J.
    Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions2015In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 284, no 2, p. 163-179Article in journal (Refereed)
    Abstract [en]

    Wnt/beta-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between beta-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the beta-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with beta-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of p-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a beta-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonudeotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of beta-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of p-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating beta-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

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