uu.seUppsala University Publications
Change search
Refine search result
123456 1 - 50 of 278
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Abrahamson, Alexandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gill EROD Activity in Fish: A Biomarker for Waterborne Ah-receptor Agonists2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induction of the cytochrome P450(CYP)1A protein and the connected increase in 7-ethoxyresorufin O-deethylase (EROD) activity are common biomarkers in fish. Enhanced activity of this protein signals exposure to Ah-receptor agonists such as chlorinated dioxins, co-planar polychlorinated biphenyls (PCBs) and certain polycyclic aromatic hydrocarbons (PAHs). The EROD biomarker is commonly analyzed in liver microsomes. However, the gill is directly exposed to waterborne pollutants, and in this thesis the gill filament EROD assay was therefore evaluated as a monitoring tool for waterborne CYP1A inducers in fish. Originally developed in rainbow trout (Oncorhynchus mykiss), the assay was here applied in various limnic and marine species. Following exposure to low waterborne concentrations of the readily metabolized CYP1A inducers benzo(a)pyrene (BaP) and indigo, a strong EROD induction was observed in the gill but not in the liver. This likely reflected metabolic clearance of the inducers in gill and other extrahepatic tissues. The high sensitivity of the gill was confirmed in studies of fish caged in waters in urban and rural areas in Sweden where the gill consistently showed a more pronounced EROD induction compared with the liver and the kidney. Fish caged in the reference waters showed surprisingly strong gill EROD induction and CYP1A immunostaining. Consequently, there may be CYP1A inducers present in the aquatic environment that are not yet identified. The assay was further applied in Atlantic cod (Gadus morhua) as a biomarker of exposure to crude oil and produced water (PW) from oil fields in the North Sea. The assay was finally adapted to detect inhibiting compounds, and an imidazole, a triazole and a plant flavonoid turned out to be potent gill EROD inhibitors. The overall conclusion from the studies of this thesis is that the gill filament EROD assay is a practical and sensitive biomarker of exposure to waterborne CYP1A inducers in various fish species. The induction of gill EROD activity in fish also at the reference sites in the field studies calls for further studies on background contamination in Swedish waters.

    List of papers
    1. EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
    Open this publication in new window or tab >>EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
    Show others...
    2003 (English)In: Comparative Biochemistry and Physiology Part C, Vol. 136, p. 235-243Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95920 (URN)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2009-04-02Bibliographically approved
    2. Cytochrome P4501A induction in rainbow trout gills and liver following exposure to waterborne indigo, benzo(a)pyrene and 3,3',4,4',5-pentachlorobiphenyl
    Open this publication in new window or tab >>Cytochrome P4501A induction in rainbow trout gills and liver following exposure to waterborne indigo, benzo(a)pyrene and 3,3',4,4',5-pentachlorobiphenyl
    2006 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 79, no 3, p. 226-232Article in journal (Refereed) Published
    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.

    Keywords
    benzo[a]pyrene, CYP1A, gill, indigo, liver, 3, 3 ', 4, 4 ', 5-pentachlorobiphenyl (PCB#126)
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95921 (URN)10.1016/j.aquatox.2006.06.006 (DOI)000240567200003 ()16872689 (PubMedID)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    3. Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
    Open this publication in new window or tab >>Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
    Show others...
    2008 (English)In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, no 1, p. 169-175Article in journal (Refereed) Published
    Abstract [en]

    An ex vivo gill EROD assay was applied in Atlantic cod (Gadus morhua) as a biomarker for waterborne CYP1A-inducing compounds derived from oil production at sea. Exposure to nominal concentrations of 1 ppm or 10 ppm North Sea crude oil in a static water system for 24 h caused a concentration-dependent gill EROD induction. Further, exposure of cod for 14 days to environmentally relevant concentrations of produced water (PW, diluted 1:200 or 1:1000) from a platform in the North Sea using a flow-through system resulted in a concentration-dependent induction of gill EROD. Crude oil (0.2 ppm) from the same oil field also proved to induce EROD. Finally, gill EROD activity in cod caged for 6 weeks at 500-10 000 m from two platforms outside Norway was measured. The activities in these fish were very low and did not differ from those in fish caged at reference sites.

    Keywords
    Atlantic cod, Biomarker, CYP1A, Crude oil, EROD, Gill, Produced water
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95922 (URN)10.1016/j.envpol.2007.07.025 (DOI)000255819300020 ()17854961 (PubMedID)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    4. Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Open this publication in new window or tab >>Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Show others...
    2007 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was evaluated as a monitoring tool for waterborne cytochrome P4501 A (CYP1A) inducers using rainbow trout (Oncorhynchus mykiss) caged in urban area waters in Sweden. To compare the CYP1A induction response in different tissues, EROD activity was also analyzed in liver and kidney microsomes. Immunohistochemistry was used to localize CYP1A protein in gill and kidney. In two separate experiments fish were caged at sites with fairly high expected polyaromatic hydrocarbon (PAH) contamination. In the first experiment, gill EROD activities were analyzed in fish exposed for 1-21 days in a river running through Uppsala. The reference site was upstream of Uppsala. In the second, gill, liver and kidney EROD activities were analyzed in fish exposed for 1-5 days in fresh or brackish waters of Stockholm and in a reference lake 60 km north of Stockholm. Fish exposed for 5 days followed by 2 days of recovery in tap water in the laboratory were also examined. The gill consistently showed a higher EROD induction compared with the liver and the kidney. After I day of caging, gill EROD activity was markedly induced (6-17-fold) at all sites examined. Induction in gill was pronounced (5-7-fold) also in fish caged at the reference sites. In the 21-day exposure study gill EROD activity remained highly induced throughout the experiment (26-fold at most) and the induced CYP1A protein was exclusively confined to the gill secondary lamellae. In the 5-day exposure experiment, EROD activity peaked after I day and then declined in both gill and liver, while CYP1A immunostaining in the gill remained intense over the 5-day period. In the kidney, CYP1A staining was weak or absent. We conclude that gill EROD activity is a more sensitive biomarker of exposure to waterborne CYP1A inducers than EROD activity in liver and kidney.

    Keywords
    fish; gill; CYP1A; EROD; monitoring
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95923 (URN)10.1016/j.aquatox.2007.07.013 (DOI)000250181300001 ()
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    5. Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    Open this publication in new window or tab >>Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-95924 (URN)
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2010-01-14Bibliographically approved
  • 2.
    Abrahamson, Alexandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Andersson, Carin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fogelberg, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    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.
    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)
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was evaluated as a monitoring tool for waterborne cytochrome P4501 A (CYP1A) inducers using rainbow trout (Oncorhynchus mykiss) caged in urban area waters in Sweden. To compare the CYP1A induction response in different tissues, EROD activity was also analyzed in liver and kidney microsomes. Immunohistochemistry was used to localize CYP1A protein in gill and kidney. In two separate experiments fish were caged at sites with fairly high expected polyaromatic hydrocarbon (PAH) contamination. In the first experiment, gill EROD activities were analyzed in fish exposed for 1-21 days in a river running through Uppsala. The reference site was upstream of Uppsala. In the second, gill, liver and kidney EROD activities were analyzed in fish exposed for 1-5 days in fresh or brackish waters of Stockholm and in a reference lake 60 km north of Stockholm. Fish exposed for 5 days followed by 2 days of recovery in tap water in the laboratory were also examined. The gill consistently showed a higher EROD induction compared with the liver and the kidney. After I day of caging, gill EROD activity was markedly induced (6-17-fold) at all sites examined. Induction in gill was pronounced (5-7-fold) also in fish caged at the reference sites. In the 21-day exposure study gill EROD activity remained highly induced throughout the experiment (26-fold at most) and the induced CYP1A protein was exclusively confined to the gill secondary lamellae. In the 5-day exposure experiment, EROD activity peaked after I day and then declined in both gill and liver, while CYP1A immunostaining in the gill remained intense over the 5-day period. In the kidney, CYP1A staining was weak or absent. We conclude that gill EROD activity is a more sensitive biomarker of exposure to waterborne CYP1A inducers than EROD activity in liver and kidney.

  • 3.
    Abrahamson, Alexandra
    et al.
    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.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Sundt, Rolf
    Jørgensen, Even
    Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)2008In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    An ex vivo gill EROD assay was applied in Atlantic cod (Gadus morhua) as a biomarker for waterborne CYP1A-inducing compounds derived from oil production at sea. Exposure to nominal concentrations of 1 ppm or 10 ppm North Sea crude oil in a static water system for 24 h caused a concentration-dependent gill EROD induction. Further, exposure of cod for 14 days to environmentally relevant concentrations of produced water (PW, diluted 1:200 or 1:1000) from a platform in the North Sea using a flow-through system resulted in a concentration-dependent induction of gill EROD. Crude oil (0.2 ppm) from the same oil field also proved to induce EROD. Finally, gill EROD activity in cod caged for 6 weeks at 500-10 000 m from two platforms outside Norway was measured. The activities in these fish were very low and did not differ from those in fish caged at reference sites.

  • 4.
    Abrahamson, Alexandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Brandt, Ingvar
    Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazoleManuscript (Other (popular science, discussion, etc.))
  • 5.
    Abramsson-Zetterberg, Lilianne
    et al.
    National Food Administration, Uppsala.
    Durling, Louise J.K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Yang-Wallentin, Fan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science.
    Rytter, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes2006In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 603, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Folic acid has a well-documented stabilising effect on chromosomes. A correlation between folate status and chromosome stability in humans has been reported in studies that were restricted to certain subpopulations, e.g., folate-deficient persons. The goal of the present investigation was to clarify if there also is a correlation between folate status and chromosome stability among individuals without any folate deficiency.

    The method used here is the recently developed flow cytometry-based micronucleus assay in human transferrin-positive reticulocytes (MN-Trf-Ret). In a blood sample, separation of the very young reticulocytes from the mature erythrocytes makes this micronucleus assay possible.

    This investigation comprises three studies (cross-sectional, giving baseline data), two of which are connected to an intervention study. In the three cross-sectional studies (total number of subjects, 99) the frequency of MN-Trf-Ret (fMN-Trf-Ret) was measured and compared with the serum folate status. In two of the studies also serum homocysteine and Vitamin B12 were measured and compared with the baseline fMN-Trf-Ret. Combining the results from the three cross-sectional studies, a negative correlation between folate status and fMN-Trf-Ret was obtained (p < 0.05).

    The goal of the intervention studies was to clarify if different nutritional supplementations had any effect on the fMN-Trf-Ret and the cell proliferation (percentage polychromatic erythrocytes, PCE). Each of the two studies involved two groups, one placebo and one supplemented group. In one of the studies the supplementation was folic acid, 1000 μg/day during 1 week (n = 30, both sexes); in the other intervention study, folic acid (800 μg/day), B12 (20 μg/day) and B6 (4 mg/day) were taken during 1 week (n = 29, both sexes). No significant difference in %PCE or fMN-Trf-Ret between the two groups was found in either of the two intervention studies.

  • 6.
    Alm, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Fischer, Celia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether2006In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, no 2, p. 254-259Article in journal (Refereed)
    Abstract [en]

    Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.

  • 7. Alvarez-Lloret, Pedro
    et al.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Nyberg, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Rodríguez-Navarro, Alejandro B
    Effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on vertebral bone mineralization and on thyroxin and vitamin D levels in Sprague-Dawley rats2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 187, no 2, p. 63-68Article in journal (Refereed)
    Abstract [en]

    The aim of the present study is to use Fourier transform infrared spectrometry (FTIR), and transmission electron microscopy (TEM) techniques, to make a more detailed description of toxic effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on bone tissue at the microstructural and at the molecular level as a result of an altered bone metabolism. We have analysed potential changes on vitamin D and thyroxin serum levels since these hormones represent endocrine endpoints that are critical for bone growth and development. For this purpose Sprague-Dawley rats were exposed (n=10) to PCB126 (i.p.) for 3 months (total dose, 384microg/kg bodyweight), while control rats (n=10) were injected with corn oil (vehicle). Results from FTIR showed that vertebrae from the exposed rats had an overall lower degree of mineralization (-8.5%; p<0.05) compared with the controls. In addition, results from peripheral quantitative computed tomography (pQCT) analyses showed significant increases in the trabecular bone mineral density (+12%; p<0.05) in the exposed group compared with the controls. The TEM analyses also showed an alteration in the crystallinity properties of vertebral bone mineral with a significant decrease in the size and crystallinity of apatite crystal forming the bone tissue in the exposed vs. non-exposed rats. Serum analysis revealed lower levels of thyroid hormones, FT4 (-42%; p<0.005), TT4 (-26%; p<0.005), and vitamin D (-21%; p<0.005) in exposed group compared to control animals. The complementary techniques (TEM and FTIR) used in this study have revealed insights into possible bone mineralization alteration due to PCB126 exposure. The lowering of both the thyroxin and vitamin D serum levels might be an underlying explanation for the observed effects on bone mineralization.

  • 8.
    Andersson, Carin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Evaluation of Biomarker Responses in Fish: with Special Emphasis on Gill EROD Activity2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many chemicals present in the aquatic environment can interfere with physiological functions in fish. Exposure to chemicals can be revealed by the use of biomarkers. Induction of 7-ethoxyresorufin O-deethylase (EROD) activity is a commonly used biomarker for exposure to CYP1A inducers such as dioxins and polyaromatic hyrdrocarbons. Vitellogenin is a frequently used biomarker for estrogenic compounds in various fish species whereas a biomarker for androgens, spiggin, is only found in sticklebacks. The main objectives of this thesis were to evaluate gill EROD activity as a biomarker and the three-spined stickleback as a model species in ecotoxicological studies.

    EROD activities were measured in gill, liver and kidney in rainbow trout (Oncorhynchus mykiss) caged in urban areas in Sweden. EROD induction was most pronounced in the gill. Also in fish caged at reference sites, with an expected low level of known CYP1A inducers, a marked gill EROD induction was found. One suggested inducer in rural waters is humic substances (HS). To evaluate the EROD-inducing capacity of HS, three-spined sticklebacks (Gasterosteus aculeatus) were exposed to HS of natural or synthetic origin. Both kinds of HS caused significant EROD induction. Gill EROD activities were also induced in sticklebacks exposed to ethynylestradiol (EE2) and β-naphthoflavone (βNF), alone and in combinations. Production of vitellogenin was induced in sticklebacks exposed to ≥50 ng EE2/l and a significant decrease in spiggin production was observed in individuals exposed to 170 ng EE2/l.

    Results from this thesis further strengthen the contention that gill EROD activity is a very sensitive biomarker for CYP1A inducers and that the stickleback is a suitable biomonitoring species, especially for exposure to CYP1A inducers. The finding that not only classical CYP1A inducers but also HS and high EE2 concentrations stimulate gill EROD activity is of significance for the interpretation of biomonitoring data.

    List of papers
    1. Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Open this publication in new window or tab >>Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Show others...
    2007 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was evaluated as a monitoring tool for waterborne cytochrome P4501 A (CYP1A) inducers using rainbow trout (Oncorhynchus mykiss) caged in urban area waters in Sweden. To compare the CYP1A induction response in different tissues, EROD activity was also analyzed in liver and kidney microsomes. Immunohistochemistry was used to localize CYP1A protein in gill and kidney. In two separate experiments fish were caged at sites with fairly high expected polyaromatic hydrocarbon (PAH) contamination. In the first experiment, gill EROD activities were analyzed in fish exposed for 1-21 days in a river running through Uppsala. The reference site was upstream of Uppsala. In the second, gill, liver and kidney EROD activities were analyzed in fish exposed for 1-5 days in fresh or brackish waters of Stockholm and in a reference lake 60 km north of Stockholm. Fish exposed for 5 days followed by 2 days of recovery in tap water in the laboratory were also examined. The gill consistently showed a higher EROD induction compared with the liver and the kidney. After I day of caging, gill EROD activity was markedly induced (6-17-fold) at all sites examined. Induction in gill was pronounced (5-7-fold) also in fish caged at the reference sites. In the 21-day exposure study gill EROD activity remained highly induced throughout the experiment (26-fold at most) and the induced CYP1A protein was exclusively confined to the gill secondary lamellae. In the 5-day exposure experiment, EROD activity peaked after I day and then declined in both gill and liver, while CYP1A immunostaining in the gill remained intense over the 5-day period. In the kidney, CYP1A staining was weak or absent. We conclude that gill EROD activity is a more sensitive biomarker of exposure to waterborne CYP1A inducers than EROD activity in liver and kidney.

    Keywords
    fish; gill; CYP1A; EROD; monitoring
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95923 (URN)10.1016/j.aquatox.2007.07.013 (DOI)000250181300001 ()
    Available from: 2007-05-09 Created: 2007-05-09 Last updated: 2017-12-14Bibliographically approved
    2. Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)
    Open this publication in new window or tab >>Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)
    2010 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 81, no 2, p. 156-160Article in journal (Refereed) Published
    Abstract [en]

    Humic substances (HS) are ubiquitous in the environment and have been found to influence physiological functions of aquatic organisms. In the present study, three-spined sticklebacks (Gasterosteus aculeatus) were exposed to HS of different origins to evaluate effects on the  7-ethoxyresorufin O-deethylase (EROD) activity catalyzed by cytochrome   P4501A (CYP1A) in the liver and the gill. To that end, three-spined   sticklebacks were exposed for 48 h to different concentrations of synthetic humic acid (AHA), Nordic reservoir natural organic matter  (N.R.-NOM) and water from six lakes with different concentrations of   HS. EROD activity was significantly induced (3-6-fold) in the gills of   fish exposed to water from all lakes except the lake with the lowest   concentration of HS. All tested concentrations of AHA and N.R.-NOM   significantly induced gill EROD activity and the induction was   dose-dependent. AHA, but neither N.R.-NOM nor lake water, induced EROD activity in the liver. In addition, fish were exposed to the potent  CYP1A inducers benzo(a)pyrene (BaP) and PCB126 in combination with AHA.   Presence of AHA had no significant effect on EROD induction by BaP or   PCB126. The components in HS responsible for EROD induction remain to be identified. Our finding that HS of both natural and synthetic origin induce EROD activity in the gill is of significance for the   interpretation of biomonitoring data on EROD activity as well as for the choice of suitable reference waters.

    Keywords
    Humic substances, Three-spined stickleback, EROD activity, Natural organic matter
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96246 (URN)10.1016/j.chemosphere.2010.06.073 (DOI)000282155400003 ()20797764 (PubMedID)
    Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2017-12-14Bibliographically approved
    3. Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)
    Open this publication in new window or tab >>Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)
    2007 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 83, no 1, p. 33-42Article in journal (Refereed) Published
    Abstract [en]

    The three-spined stickleback (Gasterosteus aculeatus) has quantifiable biomarkers of exposure to estrogens (vitellogenin), androgens (spiggin) and aryl hydrocarbon receptor (AhR) agonists (EROD activity) and is therefore a promising test species for biomonitoring of reprotoxic chemicals in aquatic environments. In this study we evaluated the effects of 17α-ethynylestradiol (EE2) on EROD activity, induction of vitellogenin and spiggin, hepatosomatic index (HSI), ovarian somatic index (OSI) and nephrosomatic index (NSI). Adult male and female three-spined sticklebacks were exposed to concentrations of 0–170 ng EE2/l (measured concentrations) in a flow-through system for 21 days. Exposure to 170 ng EE2/l resulted in a significant 8- and 9-fold induction of gill EROD activity in males and females, respectively. In livers, EROD activity expressed in relation to microsomal protein content was suppressed due to a significant increase in microsomal protein content. Hepatic EROD activity per se expressed as picomol/min was not affected by exposure to EE2. The lowest observed effect concentration for induction of vitellogenin in males was 53.7 ng EE2/l. In females, vitellogenin levels were significantly higher in those exposed to170 ng EE2/l compared to controls. Spiggin production was significantly inhibited and NSI lower in males exposed to 170 ng EE2/l. In both females and males LSI was significantly higher in fish exposed to 170 ng EE2/l than in controls. In females exposed to 170 ng EE2/l, OSI was significantly lower and NSI higher than controls. The observed results from this study show that a synthetic estrogen can affect the well-known biomarker of exposure for dioxin-like compounds, EROD activity, and further that this response can differ between tissues. These findings are important for interpretation of biomonitoring data.

    Keywords
    EROD activity, Spiggin, Vitellogenin, Three-spined stickleback, 17α-ethynylestradiol
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96247 (URN)10.1016/j.aquatox.2007.03.008 (DOI)000246952400004 ()17445917 (PubMedID)
    Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2017-12-14Bibliographically approved
    4. A chemometrical approach to study interactions between ethynylestradiol and an AhR-agonist in stickleback (Gasterosteus aculeatus)
    Open this publication in new window or tab >>A chemometrical approach to study interactions between ethynylestradiol and an AhR-agonist in stickleback (Gasterosteus aculeatus)
    Show others...
    2010 (English)In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 24, no 11-12, p. 768-778Article in journal (Refereed) Published
    Abstract [en]

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

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

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

    Keywords
    Doehlert design, gill EROD activity, hepatic EROD activity, sperm motility
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-136127 (URN)10.1002/cem.1368 (DOI)000286291500016 ()
    Available from: 2010-12-10 Created: 2010-12-10 Last updated: 2017-12-11Bibliographically approved
  • 9.
    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)
  • 10.
    Andersson, Carin
    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.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)2010In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 81, no 2, p. 156-160Article in journal (Refereed)
    Abstract [en]

    Humic substances (HS) are ubiquitous in the environment and have been found to influence physiological functions of aquatic organisms. In the present study, three-spined sticklebacks (Gasterosteus aculeatus) were exposed to HS of different origins to evaluate effects on the  7-ethoxyresorufin O-deethylase (EROD) activity catalyzed by cytochrome   P4501A (CYP1A) in the liver and the gill. To that end, three-spined   sticklebacks were exposed for 48 h to different concentrations of synthetic humic acid (AHA), Nordic reservoir natural organic matter  (N.R.-NOM) and water from six lakes with different concentrations of   HS. EROD activity was significantly induced (3-6-fold) in the gills of   fish exposed to water from all lakes except the lake with the lowest   concentration of HS. All tested concentrations of AHA and N.R.-NOM   significantly induced gill EROD activity and the induction was   dose-dependent. AHA, but neither N.R.-NOM nor lake water, induced EROD activity in the liver. In addition, fish were exposed to the potent  CYP1A inducers benzo(a)pyrene (BaP) and PCB126 in combination with AHA.   Presence of AHA had no significant effect on EROD induction by BaP or   PCB126. The components in HS responsible for EROD induction remain to be identified. Our finding that HS of both natural and synthetic origin induce EROD activity in the gill is of significance for the   interpretation of biomonitoring data on EROD activity as well as for the choice of suitable reference waters.

  • 11.
    Andersson, Carin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Katsiadaki, Ioanna
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)2007In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 83, no 1, p. 33-42Article in journal (Refereed)
    Abstract [en]

    The three-spined stickleback (Gasterosteus aculeatus) has quantifiable biomarkers of exposure to estrogens (vitellogenin), androgens (spiggin) and aryl hydrocarbon receptor (AhR) agonists (EROD activity) and is therefore a promising test species for biomonitoring of reprotoxic chemicals in aquatic environments. In this study we evaluated the effects of 17α-ethynylestradiol (EE2) on EROD activity, induction of vitellogenin and spiggin, hepatosomatic index (HSI), ovarian somatic index (OSI) and nephrosomatic index (NSI). Adult male and female three-spined sticklebacks were exposed to concentrations of 0–170 ng EE2/l (measured concentrations) in a flow-through system for 21 days. Exposure to 170 ng EE2/l resulted in a significant 8- and 9-fold induction of gill EROD activity in males and females, respectively. In livers, EROD activity expressed in relation to microsomal protein content was suppressed due to a significant increase in microsomal protein content. Hepatic EROD activity per se expressed as picomol/min was not affected by exposure to EE2. The lowest observed effect concentration for induction of vitellogenin in males was 53.7 ng EE2/l. In females, vitellogenin levels were significantly higher in those exposed to170 ng EE2/l compared to controls. Spiggin production was significantly inhibited and NSI lower in males exposed to 170 ng EE2/l. In both females and males LSI was significantly higher in fish exposed to 170 ng EE2/l than in controls. In females exposed to 170 ng EE2/l, OSI was significantly lower and NSI higher than controls. The observed results from this study show that a synthetic estrogen can affect the well-known biomarker of exposure for dioxin-like compounds, EROD activity, and further that this response can differ between tissues. These findings are important for interpretation of biomonitoring data.

  • 12. Andersson, P L
    et al.
    Berg, A H
    Bjerselius, Rickard
    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.
    Norrgren, Leif
    Olsén, Håkan
    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.
    Olsson, P E
    Örn, S
    Tysklind, Mats
    Bioaccumulation of selected PCBs in zebrafish, three-spined stickleback, and arctic char after three different routes of exposure.2001In: Arch Environ Contam Toxicol, ISSN 0090-4341, Vol. 40, no 4, p. 519-30Article in journal (Refereed)
  • 13. Ankarberg, Emma
    et al.
    Bjerselius, Richard
    Aune, Marie
    Darnerud, Per-Ola
    Larsson, L
    Andersson, A
    Tysklind, A
    Bergek, S
    Lundstedt-Enkel, Katrin
    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.
    Karlsson, L
    Törnskvist, A
    Glynn, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Study of dioxin and dioxin-like PCB levels in fatty fish from Sweden 2000-20022004In: Organohalogen compounds vol 66., 2004, p. 2035-2039Conference paper (Refereed)
  • 14.
    Ankarberg, Emma
    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.
    Fredriksson, Anders
    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.
    Eriksson, Per
    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.
    Neonatal develpmental effects of nicotine in mice: Changes in brain nicotinic receptors and behavioural response to nicotine1998In: Toxicol. Lett. 95/Suppl 1, 1998Conference paper (Refereed)
  • 15.
    Ankarberg, Emma
    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.
    Fredriksson, Anders
    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.
    Eriksson, Per
    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.
    Neonatal exposure to nicotine induces increased susceptibility to paraoxon exposure at adult age2004In: The Toxicologist, 2004, p. 974-Conference paper (Refereed)
  • 16. Ankarberg, Emma
    et al.
    Fredriksson, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Neonatal exposure to nicotine induces increased suseptibility to paraoxon exposure at adult age2005In: Toxicologist 84, 2005, p. 974-Conference paper (Refereed)
  • 17.
    Ankarberg, Emma
    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.
    Fredriksson, Anders
    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.
    Jakobsson, Eva
    Eriksson, Per
    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.
    Increased susceptibility to adult flame retardant exposure (PBDE 99) in mice neonatally exposed to nicotine2001In: The Second International Workshop on Brominated Flame Retardants, May 14-16, Stockholm, Sweden, 2001Conference paper (Refereed)
  • 18.
    Archer, Trevor
    et al.
    Department of Psychology, University of Gothenburg.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Physical Exercise Attenuates MPTP-Induced Deficits in Mice2010In: Neurotoxicity research, ISSN 1029-8428, E-ISSN 1476-3524, Vol. 18, no 3-4, p. 313-327Article in journal (Refereed)
    Abstract [en]

    Two experiments were performed to investigate the effects of physical exercise upon the hypokinesia induced by two different types of MPTP administration to C57/BL6 mice. In the first, mice were administered either the standard MPTP dose (2 x 20 or 2 x 40 mg/kg, 24-h interval) or vehicle (saline, 5 ml/kg); and over the following 3 weeks were given daily 30-min period of wheel running exercise over five consecutive days/week or placed in a cage in close proximity to the running wheels. Spontaneous motor activity testing in motor activity test chambers indicated that exercise attenuated the hypokinesic effects of both doses of MPTP upon spontaneous activity or subthreshold l-Dopa-induced activity. In the second experiment, mice were either given wheel running activity on four consecutive days (30-min period) or placed in a cage nearby and on the fifth day, following motor activity testing over 60 min, injected with either MPTP (1 x 40 mg/kg) or vehicle. An identical procedure was maintained over the following 4 weeks with the exception that neither MPTP nor vehicle was injected after the fifth week. The animals were left alone (without either exercise or MPTP) and tested after 2- and 4-week intervals. Weekly exercise blocked, almost completely, the progressive development of severe hypokinesia in the MPTP mice and partially restored normal levels of activity after administration of subthreshold l-Dopa, despite the total absence of exercise following the fifth week. In both experiments, MPTP-induced loss of dopamine was attenuated by the respective regime of physical exercise with dopamine integrity more effectively preserved in the first experiment. The present findings are discussed in the context of physical exercise influences upon general plasticity and neuroreparative propensities as well as those specific for the nigrostriatal pathway.

  • 19.
    Asp, Vendela
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO2-DDE) is bioactivated by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of mice and forms irreversibly bound protein adducts, reduces glucocorticoid secretion, and induces cell death selectively in cortisol-producing adrenocortical cells. 3-MeSO2-DDE has therefore been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) therapy.

    The aims of this thesis were to (1) develop in vitro test systems based on murine and human adrenocortical cell lines and to (2) investigate the mechanisms behind 3-MeSO2-DDE toxicity in adrenocortical cells.

    The cytotoxic and endocrine-modulating effects of 3-MeSO2-DDE were compared to those of o,p′-DDD (mitotane), the current ACC therapy, and to those of several structurally analogous compounds in both murine and human cell lines. 3-MeSO2-DDE bioactivation and cytotoxicity proceeded in a similar manner in the murine adrenocortical Y-1 cell line as in mice in vivo. The effects were highly structure-specific. Moreover, 3-MeSO2-DDE formed irreversibly bound protein adducts and caused cell death also in the human H295R cell line, and was slightly more cytotoxic than o,p′-DDD. However, 3-MeSO2-DDE toxicity in human cells was not affected by the CYP11B1 inhibitor etomidate, suggesting that bioactivation in human cells is performed by additional/other enzyme(s) than CYP11B1. 3-MeSO2-DDE generated biphasic responses in cortisol and aldosterone secretion and in expression levels of the steroidogenic genes CYP11B1, CYP11B2, and StAR. Such hormesis-like responses were not seen for o,p′-DDD or the precursor DDT metabolite p,p′-DDE.

    In addition, the two o,p′-DDD enantiomers (R)-(+)-o,p′-DDD and (S)-(-)-o,p′-DDD exhibited slight differences in cytotoxic and endocrine-modulating activity in H295R cells.

    In conclusion, this thesis  provides  extended  knowledge  on  the  mechanisms  of  action  of 3-MeSO2-DDE and points out important differences in effects between murine and human cells. Lead optimisation studies of 3-MeSO2-DDE using the herein presented in vitro test systems are ongoing.

     

    List of papers
    1. Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
    Open this publication in new window or tab >>Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
    Show others...
    2009 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, no 4, p. 389-396Article in journal (Refereed) Published
    Abstract [en]

    The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3'(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p'-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p'-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.

    Keywords
    Adrenal cortex, Metabolic activation, Toxicity, Corticosterone, DDE, CYP11B1
    National Category
    Biological Sciences
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-100855 (URN)10.1007/s00204-008-0342-6 (DOI)000264883800012 ()18651133 (PubMedID)
    Available from: 2009-04-08 Created: 2009-04-08 Last updated: 2017-12-13Bibliographically approved
    2. Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
    Open this publication in new window or tab >>Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
    Show others...
    2007 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 81, no 11, p. 793-801Article in journal (Refereed) Published
    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.

    Keywords
    Adrenal cortex, Cytochrome P450, Metabolic activation, Toxicity, Y-1
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-14330 (URN)10.1007/s00204-007-0206-5 (DOI)000250537400006 ()17487473 (PubMedID)
    Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2017-12-11Bibliographically approved
    3. Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
    Open this publication in new window or tab >>Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
    Show others...
    2010 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, no 3, p. 281-289Article in journal (Refereed) Published
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.

    Keywords
    Adrenocorticolytic DDT metabolites, Endocrine disruption, Adrenocortical cancer (ACC), Biphasic responses, Steroidogenesis, H295R
    National Category
    Pharmacology and Toxicology
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-112583 (URN)10.1016/j.taap.2009.10.018 (DOI)000273832500006 ()19900470 (PubMedID)
    Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2018-01-12
    4. Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    Open this publication in new window or tab >>Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    2010 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 3, p. 177-183Article in journal (Refereed) Published
    Abstract [en]

    Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

    National Category
    Pharmaceutical Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-112582 (URN)10.3109/00498250903470230 (DOI)000274882900002 ()20044879 (PubMedID)
    Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2018-01-12
  • 20.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cantillana, Tatiana
    Bergman, Åke
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells2010In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

  • 21.
    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)
  • 22.
    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.

  • 23.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergström, Ulrika
    Brandt, Ingvar
    Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by o,p’-DDD and methylsulphonated derivatives of p,p’-DDEManuscript (Other (popular science, discussion, etc.))
  • 24.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Olsson, Jan A
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    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.
    Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules2009In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, no 4, p. 389-396Article in journal (Refereed)
    Abstract [en]

    The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3'(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p'-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p'-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.

  • 25.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ullerås, Erik
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Oskarsson, Agneta
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, no 3, p. 281-289Article in journal (Refereed)
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.

  • 26.
    Aspenström-Fagerlund, Bitte
    et al.
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Ring, Linda
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Tallkvist, Jonas
    Department of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Box 7028, SE-75007, Uppsala, Sweden.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 237, no 1-3, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.

  • 27. Aspenström-Fagerlund, Bitte
    et al.
    Sundström, Birgitta
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fatty acids increase paracellular absorption of aluminium across Caco-2 cell monolayers2009In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, no 2, p. 272-278Article in journal (Refereed)
    Abstract [en]

    Passive paracellular absorption, regulated by tight junctions (TJs), is the main route for absorption of poorly absorbed hydrophilic substances. Surface active substances, such as fatty acids, may enhance absorption of these substances by affecting the integrity of TJ and increasing the permeability. It has been suggested that aluminium (Al) absorption occurs mainly by the paracellular route. Herein, we investigated if physiologically relevant exposures of fully differentiated Caco-2 cell monolayers to oleic acid and docosahexaenoic acid (DHA), which are fatty acids common in food, increase absorption of Al and the paracellular marker mannitol. In an Al toxicity test, mannitol and Al absorption through Caco-2 cell monolayers were similarly modulated by Al concentrations between 1 and 30mM, suggesting that absorption of the two compounds occurred via the same pathways. Exposure of Caco-2 cell monolayers to non-toxic concentrations of Al (2mM) and (14)C-mannitol in fatty acid emulsions (15 and 30mM oleic acid, 5 and 10mM DHA) caused a decreased transepithelial electrical resistance (TEER). Concomitantly, fractional absorption of Al and mannitol, expressed as percentage of apical Al and mannitol retrieved at the basolateral side, increased with increasing dose of fatty acids. Transmission electron microscopy was applied to assess the effect of oleic acid on the morphology of TJ. It was shown that oleic acid caused a less structured morphology of TJ in Caco-2 cell monolayers. Taken together our findings indicate that fatty acids common in food increase the paracellular intestinal absorption of Al. These findings may influence future risk assessment of human Al exposure.

  • 28.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Differentiation of Brain and Reproductive Organs in Birds: Effects of Environmental Contaminants2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first objective of this thesis was to investigate effects of endocrine disruptors on the developing brain and gonads of bird embryos. The substances studied were the insecticide methoxychlor, and nine UV-filters (3-benzylidene camphor (3BC), 4 methyl benzylidene camphor (4MBC), benzophenone (BP) 1,2 and 3, 4 hydroxy benzophenone (4 HB), 4 dihydroxy benzophenone (4DHB), benzyl salicylate (BS), and ethyl-4-aminobenzoate Et-PABA)), commonly used in cosmetic products. Some of these substances have no estrogenic effect in vitro, but have been shown to be estrogenic in vivo. The PCB-mixture Clophen A50 is a well-known inducer of biotransformation enzymes and was co-administered with methoxychlor and the UV-filters 3BC and 4MBC.

    Exposure to 3BC or 4MBC caused ovotestis formation and malformations of the Müllerian ducts in Japanese quail embryos. Co-exposure to one of these compounds and Clophen A50 enhanced the effects, indicating that Clophen A50 potentiates the effects of the UV-filters. Embryonic co-exposure to Clophen A50 and methoxychlor caused a disturbed male sexual behaviour. The metabolites of methoxychlor are estrogen receptor (ER)α-selective, which indicates that the effects on behaviour following embryonic treatment were mediated by ERα.

    Another objective in this thesis was to localize estrogen receptors (ERs) in the brain of adult and embryonic Japanese quail. The ER localization provides a basis for mechanistic studies on effects of endocrine disruptors, by the identification of estrogen-responsive areas in the brain. We found that ERβ, not previously implicated in sex-differentiation of the brain, was the only ER-subtype present in a sexually dimorphic brain area during differentiation.

    In conclusion, the estrogenic effects of 3BC, 4MBC and methoxychlor were increased by co-exposure to PCB. These results raise concern since many wildlife species, as well as humans, carry large body burdens of persistent organic pollutants like PCBs, which potentially can interact and enhance the effects of other endocrine disruptors.

    List of papers
    1. Localization of estrogen receptor-alpha and -beta mRNA in brain areas controlling sexual behavior in Japanese quail
    Open this publication in new window or tab >>Localization of estrogen receptor-alpha and -beta mRNA in brain areas controlling sexual behavior in Japanese quail
    2006 (English)In: Journal of Neurobiology, Vol. 66, no 2, p. 148-54Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96943 (URN)
    Available from: 2008-03-28 Created: 2008-03-28 Last updated: 2012-02-03
    2. Expression of estrogen receptor-alpha and -beta mRNA in the brain of Japanese quail embryos
    Open this publication in new window or tab >>Expression of estrogen receptor-alpha and -beta mRNA in the brain of Japanese quail embryos
    2007 (English)In: Developmental Neurobiology, ISSN 1932-8451, Vol. 67, no 13, p. 1742-1750Article in journal (Refereed) Published
    Abstract [en]

    The present study was conducted to investigate the mRNA expression of the two estrogen receptor (ER) subtypes ERα and ERβ in the brain of Japanese quail embryos. We found expression of both ERα and ERβ mRNA in homogenate of whole head from 6-day-old embryos, and in brain homogenate from 9- and 12-day-old embryos using real-time PCR. In 9- and 12-day-old embryos the ERα expression was higher in females than in males. We used in situ hybridization to examine the localization of the ERs in sections from male and female brains on day 9 and day 17 of incubation. On day 9, ERβ mRNA was detected in the developing medial preoptic nucleus (POM), in the medial part of the bed nucleus of the striae terminalis (BSTm), and in the tuberal region of the hypothalamus. ERα signal could not be detected in the POM, the BSTm or the tuberal region in 9-day-old embryos. In 17-day-old embryos, ERβ was highly expressed in the preoptic area, the nucleus Taeniae of the Amygdala (TnA) and the BSTm. Expression of ERα mRNA was detected in parts of the preoptic area and in the telencephalic TnA. No ERα expression was found in the BSTm, an area known to be sexually dimorphic in adults. The high embryonic expression of ERβ in brain areas linked to sexual behavior indicates that ERβ plays a role in sexual differentiation of the Japanese quail brain.

    Keywords
    Japanese quail, estrogen receptors, embryo brain, real-time PCR, sexual differentiation
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-96944 (URN)10.1002/dneu.20544 (DOI)000250606300005 ()17638389 (PubMedID)
    Available from: 2008-03-28 Created: 2008-03-28 Last updated: 2012-02-03
    3. Embryonic co-exposure to methoxychlor and Clophen A50 alters sexual behavior in adult male quail
    Open this publication in new window or tab >>Embryonic co-exposure to methoxychlor and Clophen A50 alters sexual behavior in adult male quail
    2005 (English)In: Archives of Toxicology, Vol. 79, no 4, p. 237-42Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-96945 (URN)
    Available from: 2008-03-28 Created: 2008-03-28 Last updated: 2012-02-03
    4. Exposure to UV-filters leads to ovotestis formation, phocomelia and growth-inhibition of bursa fabricii in developing Japanese quail
    Open this publication in new window or tab >>Exposure to UV-filters leads to ovotestis formation, phocomelia and growth-inhibition of bursa fabricii in developing Japanese quail
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-96946 (URN)
    Available from: 2008-03-28 Created: 2008-03-28 Last updated: 2010-01-14Bibliographically approved
    5. The UV-filters 3-benzylidene camphor and 4-methylbenzylidene camphor cause mlformations of the reproductive tract and induce estrogen responsive genes in the liver of embryonic chicken
    Open this publication in new window or tab >>The UV-filters 3-benzylidene camphor and 4-methylbenzylidene camphor cause mlformations of the reproductive tract and induce estrogen responsive genes in the liver of embryonic chicken
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-96947 (URN)
    Available from: 2008-03-28 Created: 2008-03-28 Last updated: 2010-01-14Bibliographically approved
  • 29.
    Axelsson, Jeanette
    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
    Brunström, 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.
    Co-administration of PCB and methoxychlor to male quail embryos alters their adult sexual behavior2004In: Uppsala Journal of Medical Sciences: Abstracts for The 22nd Conference of European Comparative Endocrinologists, 2004, p. 13-Conference paper (Other academic)
  • 30.
    Axelsson, Jeanette
    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
    Brunström, 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.
    Expression of Estrogen Receptor -alpha and -beta mRNA in Embryonic Quail Brain2003In: Trabajos del Instituto Cajal, 2003, p. 278-Conference paper (Other academic)
  • 31.
    Axelsson, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Jan, Olsson
    Mattsson, Anna
    Brunström, Björn
    Exposure to UV-filters leads to ovotestis formation, phocomelia and growth-inhibition of bursa fabricii in developing Japanese quailManuscript (Other (popular science, discussion, etc.))
  • 32.
    Axelsson, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Mattsson, Anna
    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.
    Halldin, Krister
    Expression of estrogen receptor-alpha and -beta mRNA in the brain of Japanese quail embryos2007In: Developmental Neurobiology, ISSN 1932-8451, Vol. 67, no 13, p. 1742-1750Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to investigate the mRNA expression of the two estrogen receptor (ER) subtypes ERα and ERβ in the brain of Japanese quail embryos. We found expression of both ERα and ERβ mRNA in homogenate of whole head from 6-day-old embryos, and in brain homogenate from 9- and 12-day-old embryos using real-time PCR. In 9- and 12-day-old embryos the ERα expression was higher in females than in males. We used in situ hybridization to examine the localization of the ERs in sections from male and female brains on day 9 and day 17 of incubation. On day 9, ERβ mRNA was detected in the developing medial preoptic nucleus (POM), in the medial part of the bed nucleus of the striae terminalis (BSTm), and in the tuberal region of the hypothalamus. ERα signal could not be detected in the POM, the BSTm or the tuberal region in 9-day-old embryos. In 17-day-old embryos, ERβ was highly expressed in the preoptic area, the nucleus Taeniae of the Amygdala (TnA) and the BSTm. Expression of ERα mRNA was detected in parts of the preoptic area and in the telencephalic TnA. No ERα expression was found in the BSTm, an area known to be sexually dimorphic in adults. The high embryonic expression of ERβ in brain areas linked to sexual behavior indicates that ERβ plays a role in sexual differentiation of the Japanese quail brain.

  • 33.
    Axelsson, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Mattsson, Anna
    Jan, Olsson
    Brunström, Björn
    The UV-filters 3-benzylidene camphor and 4-methylbenzylidene camphor cause mlformations of the reproductive tract and induce estrogen responsive genes in the liver of embryonic chickenManuscript (Other (popular science, discussion, etc.))
  • 34.
    Bahrami, Fariba
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergman, Ulrika
    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 Physiology and Developmental Biology, Environmental Toxicology.
    Persistent Olfactory Mucosal Metaplasia and Increased Olfactory Bulb Glial Fibrillary Acidic Protein Levels Following a Single Dose of Methylsulfonyl-dichlorobenzene in Mice: Comparison of the 2,5- and 2,6-Dichlorinated Isomers 2000In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 162, no 1, p. 49-59Article in journal (Refereed)
    Abstract [en]

    Histopathology was used to characterize long-term toxic effects in the olfactory system following a single ip dose (4–65 mg/kg) of methylsulfonyl-2,6-dichlorobenzene, (2,6-(diCl-MeSO2-B)), in female NMRI mice. The effects of 2,6-(diCl-MeSO2-B) and its 2,5-chlorinated isomer, (2,5-(diCl-MeSO2-B)), on the levels of glial fibrillary acidic protein (GFAP; a biomarker for neurotoxicity) in different brain regions were examined by an enzyme-linked immunosorbent assay (ELISA). The histopathologic effects of 2,6-(diCl-MeSO2-B) were dose-, time-, and tissue-dependent. At the highest doses (16–65 mg/kg), the initial effect of 2,6-(diCl-MeSO2-B) was necrosis of the Bowman's glands, followed by a sequence of secondary events including degeneration of the olfactory neuroepithelium, repopulation of the basement membrane by a ciliated respiratorylike epithelium, fibrosis and ossification in the lamina propria, formation of bilateral polyps, angiogenesis, and disappearance of nerve bundles. Remodeling was most pronounced in the dorsal meatus of the olfactory mucosa and persisted for the duration of the experiment (46 weeks). A dose-dependent induction of GFAP in the olfactory bulb of mice treated with 2,6-(diCl-MeSO2-B) was observed at all doses examined (16–65 mg/kg). GFAP levels were highest 2 weeks after treatment (eightfold induction at 65 mg/kg) and then gradually decreased to normal within 26 weeks. The 2,5-substituted isomer (65 mg/kg) did not induce GFAP in the olfactory bulb and or toxicity in the olfactory mucosa. In conclusion, a single dose of 2,6-(diCl-MeSO2-B) results in persistent metaplasia and remodeling of the olfactory mucosa, and a long-lasting but transient induction of GFAP in the olfactory bulb. It is proposed that methylsulfonyl-2,6-dichlorobenzene may serve as an experimental tool with a unique ability to produce persistent primary and/or secondary lesions in the olfactory system of mice.

  • 35.
    Bahrami, Fariba
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, EB
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergman, A
    Larsson, C
    Brandt, I
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Localization and comparative toxicity of methylsulfonyl-2,5-and 2,6-dichlorobenzene in the olfactory mucosa of mice1999In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 49, no 1, p. 116-123Article in journal (Refereed)
    Abstract [en]

    Several methylsulfonyl (MeSO2) metabolites formed from chlorinated aromatic hydrocarbons have been identified in human milk, lung, and body fat, as well as in the tissues of Baltic grey seals and arctic polar bears. The tissue localization and nasal toxicity of two methylsulfonyl-substituted dichlorobenzenes (diCl-MeSO2-B), with the chlorine atoms in the 2,5-, and 2,6- positions, were investigated in female NMRI and C57B1 mice. Using tape-section autoradiography, animals dosed i.v. with 14C-labeled 2,5-, or 2,6-(diCl-MeSO2-B) showed a preferential uptake of radioactivity in the olfactory mucosa and the tracheobronchial epithelium. Histopathology showed that 2,6-(diCl-MeSO2- B) is a potent toxicant that induces necrosis in the olfactory mucosa following a single dose as low as 4 mg/kg (i.p. injection), whereas 2,5- (diCl-MeSO2-B) induced no signs of toxicity in the olfactory mucosa at doses as high as 130 mg/kg (i.p. injection). Necrosis of the Bowman's glands was the first sign of 2,6-(diCl-MeSO2-B)-induced toxicity followed by degeneration of the neuroepithelium, which implies that the Bowman's gland may be the primary site of toxicity and degeneration of the neuroepithelium may be a secondary effect. Administration of the parent compounds, 1,3-dichlorobenzene and 1,4-dichlorobenzene, or the chlorinated analog 1,2,3-trichlorobenzene (85, 85, and 105 mg/kg, respectively; i.p. injection), induced no signs of toxicity in the olfactory mucosa. These and previous results suggest that 2,6- positioned chlorine atoms and an electron withdrawing substituent in the primary position is an arrangement that predisposes for toxicity in the olfactory mucosa.

  • 36.
    Beijer, Kristina
    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.
    CYP1A inhibition in fish gill filaments: a novel assay applied on pharmaceuticals and other chemicals2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 96, no 2, p. 145-150Article in journal (Refereed)
    Abstract [en]

    The gill filament 7-ethoxyresorufin O-deethylase (EROD) assay was originally developed as a biomarker for cytochrome P4501A (CYP1A) induction by Ah-receptor agonists in water. In this study, the assay was adapted to measure inhibition of CYP1A activity in fish gill filaments ex vivo. The experiments were carried out using gill arch filaments from beta-naphthoflavone (betaNF)-exposed three-spined stickleback (Gasterosteus aculeatus). Candidate CYP1A inhibitors were added to the assay buffer. Nine selected pharmaceuticals and five known or suspected CYP1A-modulating chemicals were examined with regard to their ability to reduce EROD activity in gill filaments. Ellipticine, a well characterized CYP1A inhibitor, was the most effective inhibitor of the compounds tested. At a concentration in the assay buffer of 1 microM the antifungal azoles ketoconazole, miconazole and bitertanol, and the plant flavonoid acacetin reduced gill EROD activity by more than 50%, implying IC50 values below 1 microM. These compounds have previously been shown to inhibit EROD activity in liver microsomes from fish and mammals at similar concentrations. The proton pump inhibitor omeprazole reduced the gill EROD activity by 39% at 10 microM. It is concluded that the modified gill filament EROD assay is useful to screen for waterborne pollutants that inhibit catalytic CYP1A activity in fish gills.

  • 37.
    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)
  • 38.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gyllenhammar, Irina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Kvarnryd, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Xenopus tropicalis as a Test System for Developmental and Reproductive Toxicity2009In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 72, no 3-4, p. 219-225Article in journal (Refereed)
    Abstract [en]

    The usefulness of Xenopus tropicalis as a model species to investigate endocrine disruption and developmental reproductive toxicity was assessed. In our test system tadpoles were exposed to test substances from shortly after hatching until metamorphosis, including the period of gonadal differentiation. Effects on the sex hormone and thyroid hormone axes were evidenced as skewed sex ratios, malformations of reproductive organs, altered cytochrome (CYP19) (aromatase) activity, and gene expression in gonads and brain, as well as changed thyroid histology and time to metamorphosis. Reproductive toxicity was evaluated at sexual maturity. Male-to-female sex reversal was implied at concentrations as low as 6 pM (1.8 ng/L) ethynylestradiol (EE2), which is comparable to EE2 levels observed in the environment. EE2-exposed males that were not sex reversed had significantly reduced fertility and a reduced amount of spermatozoa in testes compared with control males. This indicates that reproduction in wild frogs might be impaired by estrogenic environmental pollutants. Aromatase activity in brain and testes of adult frogs was not affected by larval EE2 exposure. Preliminary results indicate that exposure to the environmentally relevant pharmaceutical clotrimazole modulated aromatase activity in brain and gonads during sex differentiation, which warrants further investigation. The susceptibility to estrogen-induced sex reversal of X. tropicalis was comparable to that of other frog species and fish. Similarities between the reproductive effects in X. tropicalis and those reported in fish, birds, and mammals after developmental exposure to estrogens make X. tropicalis promising model for research on endocrine disruption and developmental reproductive toxicity.

  • 39.
    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

  • 40.
    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.
    Brunström, 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.
    Effects of bisphenol A and tetrabromobisphenol A on sex organ development in quail and chicken embryos2001In: ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY, ISSN 0730-7268, Vol. 20, no 12, p. 2836-2840Article in journal (Refereed)
    Abstract [en]

    The plastic monomere bisphenol A (BPA) and the flame retardant tetrabromobisphenol A (TBBPA) were examined for estrogen-like developmental effects on the reproductive organs in avian embryos. The synthetic estrogen diethylstilbestrol (DES) was used as a p

  • 41.
    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

  • 42.
    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. Ekotoxikologi.
    Pettersson, Irina
    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.
    Ethynylestradiol Causes Female-Biased Sex-Ratios in the Frog Xenopus tropicalis2006Conference paper (Other scientific)
  • 43.
    Bergman, 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.
    Östergren, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Gustafson, Anne-Lee
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Differential effects of olfactory toxicants on olfactory regeneration.2002In: Arch Toxicol, Vol. 76, p. 104-Article in journal (Refereed)
  • 44.
    Bergström, Ulrika
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Ekotoxikologi. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Franzén, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Catarina
    Lindh, Christian
    Brittebo, Eva B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Drug targeting to the brain: Transfer of picolinic acid along the olfactory pathways2002In: J Drug Target, Vol. 10, p. 469-Article in journal (Refereed)
  • 45.
    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.
    Fredriksson, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Long-term effects in the olfactory mucosa and bulb following systemic exposure to chemicals2002In: Toxicology Letters 135, Suppl 1, 2002, p. 139-Conference paper (Other scientific)
  • 46.
    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.
    Giovanetti, Anna
    Piras, Elena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Methimazole-induced damage in the olfactory mucosa: effects on ultrastructure and glutathione levels.2003In: Toxicol Pathol, ISSN 0192-6233, Vol. 31, no 4, p. 379-87Article in journal (Refereed)
  • 47.
    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)
  • 48.
    Bergström, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Olsson, Jan A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Hvidsten, Torgeir R
    Komorowski, Jan
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Differential gene expression in the olfactory bulb following exposure to the olfactory toxicant 2,6-dichlorophenyl methylsulphone and its 2,5-dichlorinated isomer in mice2007In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 28, no 6, p. 1120-1128Article in journal (Refereed)
    Abstract [en]

    2,6-Dichlorophenyl methylsulphone and a number of structurally related chemicals are CYP-activated toxicants in the olfactory mucosa in mice and rats. This toxicity involves both the olfactory neuroepithelium and its subepithelial nerves. In addition, 2,6-dichlorophenyl methylsulphone, induces glial acidic fibrillary protein expression (Gfap, a biomarker for gliosis) in the olfactory bulb, as well as long-lasting learning deficits and changes in spontaneous behavior in mice and rats. So far the 2,5-dichlorinated isomer has not been reported to cause toxicity in the olfactory system, although it gives rise to transient changes in spontaneous behavior. In the present study we used 15k cDNA gene arrays and real-time RTPCR to determine 2,6-dichlorophenyl methylsulphone-induced effects on gene expression in the olfactory bulb in mice. Seven days following a single ip dose of 2,6-dichlorophenyl methylsulphone, 56 genes were found to be differentially expressed in the olfactory bulb. Forty-one of these genes clustered into specific processes regulating, for instance, cell differentiation, cell migration and apoptosis. The genes selected for real-time RT-PCR were chosen to cover the range of B-values in the cDNA array analysis. Altered expression of Gfap, mt-Rnr2, Ncor1 and Olfml3 was confirmed. The expression of these genes was measured also in mice dosed with 2,5-dichlorophenyl methylsulphone, and mt-Rnr2 and Olfml3 were found to be altered also by this isomer. Combined with previous data, the results support the possibility that the persistent neurotoxicity induced by 2,6-dichlorophenyl methylsulphone in mice represents both an indirect and a direct effect on the brain. The 2,5-dichlorinated isomer, negative with regard to CYP-catalyzed toxicity in the olfactory mucosa, may prove useful to resolve this issue.

  • 49.
    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. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. ekotoxikologi.
    Olsson, 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. 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
    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. ekotoxikologi.
    Neurotoxicity of the Olfactory toxicant 2,6-Dichlorophenyl Methylsulphone in Olfactory bulb:Impaired expression of genes relating to neurodegenerative disease2007In: DIOXIN2007, 2007, p. 1841-1844Conference paper (Refereed)
  • 50.
    Bernabó, Ilaria
    et al.
    Department of Animal Biology, University of Calabria, Italy.
    Brunelli, Elivra
    Department of Animal Biology, University of Calabria, Italy.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bonacci, Antonella
    Department of Animal Biology, University of Calabria, Italy.
    Tripepi, Sandro
    Department of Animal Biology, University of Calabria, Italy.
    Endosulfan acute toxicity in Bufo bufo gills: ultrastructural changes and nitric oxide synthase localization2008In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 86, no 3, p. 447-456Article in journal (Refereed)
    Abstract [en]

    Endosulfan is an organochlorine pesticide used in agriculture for a wide range of crops. Endosulfan concentrations of up to 0.7 mg/L can be found in ponds and streams near sprayed agricultural fields. We investigated the short-term toxicity of endosulfan in common toad (Bufo bufo) tadpoles after 24, 48, and 96 h of exposure. Acute toxicity was evaluated at nominal concentrations ranging from 0.01 to 0.6 mg/L: concentrations that could be found after the application of pesticide. Our results show that 0.43 mg/L of endosulfan caused 50% mortality (LC(50)). The effects of a sublethal endosulfan concentration (0.2mg/L) on gill apparatus morphology were evaluated by scanning and transmission electron microscopy. Immunohistochemical methods were also applied to detect the expression pattern of the inducible isoform of nitric oxide synthase (iNOS) in the gills using the confocal laser scanner microscope. Exposure to 0.2mg/L of endosulfan caused an apparent increase in mucus production, the occurrence of secretory vesicles and lamellar bodies, a widening of intercellular spaces and additionally there was evidence of an inflammatory response in the gill apparatus. The morphological alterations occurred after 24h and were more pronounced after 48 and 96 h of exposure. Altered morphology and increased mucus secretion indicate impaired gas exchange and osmoregulation in the gills. In addition, there was an increase of iNOS expression after 24 and 48 h which may reflect hypoxia and inflammation in the gill epithelium. Our results clearly indicate that short-term exposure to a sublethal concentration of endosulfan, near the high end of the environmental range, disrupts gill morphology and function in B. bufo tadpoles.

123456 1 - 50 of 278
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf