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Jönsson, Maria
Alternative names
Publications (10 of 38) Show all publications
Wincent, E., Kubota, A., Timme-Laragy, A., Jönsson, M. E., Hahn, M. E. & Stegeman, J. J. (2016). Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner. Biochemical Pharmacology, 110, 117-129
Open this publication in new window or tab >>Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner
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2016 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 110, p. 117-129Article in journal (Refereed) Published
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.

Keywords
Aryl hydrocarbon receptor; Cytochrome P4501; 6-Formylindolo[3, 2-b]carbazole; Enzyme inhibition; Zebrafish embryo toxicity; Synergistic receptor activation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-296689 (URN)10.1016/j.bcp.2016.04.012 (DOI)000377738400011 ()27112072 (PubMedID)
Funder
Swedish Research Council Formas, 2011-963 2008-1249EU, European Research Council, 634880
Available from: 2016-06-19 Created: 2016-06-19 Last updated: 2017-11-28Bibliographically approved
Jönsson, M. E., Mattsson, A., Shaik, S. & Brunström, B. (2016). Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos. Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, 179, 125-136
Open this publication in new window or tab >>Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos
2016 (English)In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 179, p. 125-136Article in journal (Refereed) Published
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.

Keywords
Formylindolo[3, 2-b]carbazole (FICZ), Cytochrome P450 1 (CYP1), Chicken, Japanese quail, Embryo toxicity, Liver necrosis
National Category
Ecology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-274425 (URN)10.1016/j.cbpc.2015.09.014 (DOI)000366873300016 ()26456929 (PubMedID)
Funder
Swedish Research Council Formas, 216-2008-1249Carl Tryggers foundation , CTS 12:227
Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2018-01-10Bibliographically approved
Gao, K., Yan, P., Tan, C.-l., Luo, Y.-h., Sun, J., Jonsson, M. E., . . . Tang, Y.-p. (2015). Application of Rainbow Trout CYP1 Gene Expression Patterns in Gill and Liver for Haihe River Bio-monitoring. Huanjing Kexue, 36(10), 3878-3883
Open this publication in new window or tab >>Application of Rainbow Trout CYP1 Gene Expression Patterns in Gill and Liver for Haihe River Bio-monitoring
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2015 (English)In: Huanjing Kexue, ISSN 0250-3301, Vol. 36, no 10, p. 3878-3883Article in journal (Refereed) Published
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.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-288997 (URN)
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-06-21Bibliographically approved
Beijer, K., Jönsson, M., Shaik, S., Behrens, D., Brunström, B. & Brandt, I. (2015). Azoles inhibit cytochrome P450 enzymes in rainbow trout involved in biotransformation and steroid hormone synthesis additively.
Open this publication in new window or tab >>Azoles inhibit cytochrome P450 enzymes in rainbow trout involved in biotransformation and steroid hormone synthesis additively
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2015 (English)Manuscript (preprint) (Other academic)
Keywords
Azole fungicide, EROD activity, cytochrome P450 (CYP), CYP1A, CYP19, aromatase, pharmaceutical, contaminant, chemical, fish, rainbow trout, gill, EROD aktivitet, cytokrom P450 (CYP), CYP1A, CYP19, aromatase, läkemedel, azol, fungicid, kemikalier, förorening, fisk, regnbågslax, gäle
National Category
Other Biological Topics
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-249010 (URN)
Available from: 2015-04-15 Created: 2015-04-10 Last updated: 2018-05-08Bibliographically approved
Wincent, E., Stegeman, J. J. & Jönsson, M. E. (2015). Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions. Toxicology and Applied Pharmacology, 284(2), 163-179
Open this publication in new window or tab >>Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions
2015 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 284, no 2, p. 163-179Article in journal (Refereed) Published
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.

Keywords
Aryl hydrocarbon receptor, Zebrafish embryo, Beta-catenin, 6-Formylindolo[3, 2-b]carbazole 3, 3 ', 4, 4 ', 5-Pentachlorobiphenyl
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-253256 (URN)10.1016/j.taap.2015.02.014 (DOI)000353864000007 ()25711857 (PubMedID)
Funder
Swedish Research Council FormasCarl Tryggers foundation
Note

Correction in: Toxicology and Applied Pharmacology, 2015, Volume: 288, Issue: 2, Pages: 280-280, DOI: 10.1016/j.taap.2015.07.021

Available from: 2015-06-12 Created: 2015-05-25 Last updated: 2018-01-11Bibliographically approved
Jönsson, M., Shaik, S., Rannug, A. & Brunström, B. (2013). Developmental effects of 6-formyl-indolo[3,2-b]carbazole in birds. In: Toxicology Letters: . Paper presented at Society of Toxicology, 52nd Annual Meeting and ToxExpo, March 10–14, 2013, San Antonio, Texas, USA (pp. 68). UK: Oxford University Press
Open this publication in new window or tab >>Developmental effects of 6-formyl-indolo[3,2-b]carbazole in birds
2013 (English)In: Toxicology Letters, UK: Oxford University Press, 2013, p. 68-Conference paper, Poster (with or without abstract) (Refereed)
Place, publisher, year, edition, pages
UK: Oxford University Press, 2013
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-215099 (URN)
Conference
Society of Toxicology, 52nd Annual Meeting and ToxExpo, March 10–14, 2013, San Antonio, Texas, USA
Available from: 2014-01-10 Created: 2014-01-10 Last updated: 2014-01-10Bibliographically approved
Beijer, K., Gao, K., Jönsson, M. E., Larsson, D. G., Brunström, B. & Brandt, I. (2013). Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish. Chemosphere, 90(3), 1149-1157
Open this publication in new window or tab >>Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish
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2013 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 90, no 3, p. 1149-1157Article in journal (Refereed) Published
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.

Keywords
CYP1, EROD, Gills, Pharmaceuticals, Three-spined stickleback, Treated wastewater, Drug products, Effluent treatment, Fish, Gene expression, Wastewater treatment, Effluents, cytochrome P450, cytochrome P450 1, cytochrome P450 1A, cytochrome P450 1B1, cytochrome P450 1C1, cytochrome P450 1C2, ethoxyresorufin deethylase, industrial effluent, messenger RNA, tap water, unclassified drug, biotransformation, concentration (composition), drug, ecological modeling, effluent, enzyme activity, manufacturing, metabolism, pollution exposure, teleost, wastewater, water treatment, animal experiment, animal tissue, article, brain, controlled study, enzyme induction, enzyme inhibition, female, Gasterosteus aculeatus, gene, genetic transcription, gill, liver, mortality, nonhuman, spiggin gene, upregulation, vitellogenin gene, waste water treatment plant, Andhra Pradesh, Hyderabad [Andhra Pradesh], India
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-192012 (URN)10.1016/j.chemosphere.2012.09.023 (DOI)000312978700035 ()
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2013-01-24 Created: 2013-01-15 Last updated: 2017-12-06Bibliographically approved
Jonsson, M. E., Kubota, A., Timme-Laragy, A. R., Woodin, B. & Stegeman, J. J. (2012). Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. Toxicology and Applied Pharmacology, 265(2), 166-174
Open this publication in new window or tab >>Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish
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2012 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-289000 (URN)
Note

Times Cited: 14

Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2017-11-30
Jönsson, M. E., Kubota, A., Timme-Laragy, A. R., Woodin, B. & Stegeman, J. J. (2012). Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.. Toxicology and Applied Pharmacology, 265(2), 166-174
Open this publication in new window or tab >>Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.
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2012 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 265, no 2, p. 166-174Article in journal (Refereed) Published
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.

National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-191201 (URN)10.1016/j.taap.2012.09.023 (DOI)000312230500003 ()23036320 (PubMedID)
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2017-12-06Bibliographically approved
Jönsson, M., Woodin, B., Stegeman, J. & Brunström, B. (2012). Cytochrome P450 1 genes in birds: evolutionary relationships and transcription profiles in chicken and japanese quail embryos. In: The Toxicologist. Paper presented at Society of Toxicology.
Open this publication in new window or tab >>Cytochrome P450 1 genes in birds: evolutionary relationships and transcription profiles in chicken and japanese quail embryos
2012 (English)In: The Toxicologist, 2012Conference paper, Published 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.

National Category
Evolutionary Biology Developmental Biology
Identifiers
urn:nbn:se:uu:diva-191230 (URN)
Conference
Society of Toxicology
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2013-02-07Bibliographically approved
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