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  • 1.
    Abrahamson, Alexandra
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Gill EROD Activity in Fish: A Biomarker for Waterborne Ah-receptor Agonists2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
    Öppna denna publikation i ny flik eller fönster >>EROD activity in gill filaments from anadromous and marine fish as a biomarker of dioxin-like pollutants
    Visa övriga...
    2003 (Engelska)Ingår i: Comparative Biochemistry and Physiology Part C, Vol. 136, s. 235-243Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-95920 (URN)
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2009-04-02Bibliografiskt granskad
    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
    Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 79, nr 3, s. 226-232Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    benzo[a]pyrene, CYP1A, gill, indigo, liver, 3, 3 ', 4, 4 ', 5-pentachlorobiphenyl (PCB#126)
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95921 (URN)10.1016/j.aquatox.2006.06.006 (DOI)000240567200003 ()16872689 (PubMedID)
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
    Öppna denna publikation i ny flik eller fönster >>Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)
    Visa övriga...
    2008 (Engelska)Ingår i: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, nr 1, s. 169-175Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Atlantic cod, Biomarker, CYP1A, Crude oil, EROD, Gill, Produced water
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95922 (URN)10.1016/j.envpol.2007.07.025 (DOI)000255819300020 ()17854961 (PubMedID)
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Öppna denna publikation i ny flik eller fönster >>Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Visa övriga...
    2007 (Engelska)Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, nr 1, s. 1-8Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    fish; gill; CYP1A; EROD; monitoring
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95923 (URN)10.1016/j.aquatox.2007.07.013 (DOI)000250181300001 ()
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    Öppna denna publikation i ny flik eller fönster >>Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazole
    (Engelska)Manuskript (Övrig (populärvetenskap, debatt, mm))
    Identifikatorer
    urn:nbn:se:uu:diva-95924 (URN)
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
  • 2.
    Abrahamson, Alexandra
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Andersson, Carin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Jönsson, Maria E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fogelberg, Oscar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brunström, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters2007Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, nr 1, s. 1-8Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brunström, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Sundt, Rolf
    Jørgensen, Even
    Monitoring contaminants from oil production at sea by measuring gill EROD activity in Atlantic cod (Gadus morhua)2008Ingår i: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 153, nr 1, s. 169-175Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brunström, Björn
    Brandt, Ingvar
    Inhibition of CYP1A activity in fish detected by the gill filament EROD assay - studies on ketoconazole, bitertanol, acacetin and omeprazoleManuskript (Övrig (populärvetenskap, debatt, mm))
  • 5.
    Abramsson-Zetterberg, Lilianne
    et al.
    National Food Administration, Uppsala.
    Durling, Louise J.K.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Yang-Wallentin, Fan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för informationsvetenskap.
    Rytter, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes2006Ingår i: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 603, nr 1, s. 33-40Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Fischer, Celia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether2006Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, nr 2, s. 254-259Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Nyberg, Ingrid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    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 rats2009Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 187, nr 2, s. 63-68Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Evaluation of Biomarker Responses in Fish: with Special Emphasis on Gill EROD Activity2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
    Öppna denna publikation i ny flik eller fönster >>Gill EROD in monitoring of CYP1A inducers in fish: A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters
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    2007 (Engelska)Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, nr 1, s. 1-8Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    fish; gill; CYP1A; EROD; monitoring
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95923 (URN)10.1016/j.aquatox.2007.07.013 (DOI)000250181300001 ()
    Tillgänglig från: 2007-05-09 Skapad: 2007-05-09 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)
    Öppna denna publikation i ny flik eller fönster >>Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)
    2010 (Engelska)Ingår i: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 81, nr 2, s. 156-160Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Humic substances, Three-spined stickleback, EROD activity, Natural organic matter
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-96246 (URN)10.1016/j.chemosphere.2010.06.073 (DOI)000282155400003 ()20797764 (PubMedID)
    Tillgänglig från: 2007-09-28 Skapad: 2007-09-28 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)
    Öppna denna publikation i ny flik eller fönster >>Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)
    2007 (Engelska)Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 83, nr 1, s. 33-42Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    EROD activity, Spiggin, Vitellogenin, Three-spined stickleback, 17α-ethynylestradiol
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-96247 (URN)10.1016/j.aquatox.2007.03.008 (DOI)000246952400004 ()17445917 (PubMedID)
    Tillgänglig från: 2007-09-28 Skapad: 2007-09-28 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. A chemometrical approach to study interactions between ethynylestradiol and an AhR-agonist in stickleback (Gasterosteus aculeatus)
    Öppna denna publikation i ny flik eller fönster >>A chemometrical approach to study interactions between ethynylestradiol and an AhR-agonist in stickleback (Gasterosteus aculeatus)
    Visa övriga...
    2010 (Engelska)Ingår i: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 24, nr 11-12, s. 768-778Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Doehlert design, gill EROD activity, hepatic EROD activity, sperm motility
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-136127 (URN)10.1002/cem.1368 (DOI)000286291500016 ()
    Tillgänglig från: 2010-12-10 Skapad: 2010-12-10 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
  • 9.
    Andersson, Carin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Abrahamson, Alexandra
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Jönsson, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Otte, Jens
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brunström, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Gill filament EROD activity in the three-spined stickleback (Gasterosteus aculeatus L.) as a biomarker for exposure to Ah receptor agonists in the water2006Ingår i: Organohalogen Compounds, 2006, s. 1259-1261Konferensbidrag (Refereegranskat)
  • 10.
    Andersson, Carin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Abrahamson, Alexandra
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brunström, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Impact of humic substances on EROD activity in gill and liver of three-spined sticklebacks (Gasterosteus aculeatus)2010Ingår i: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 81, nr 2, s. 156-160Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Katsiadaki, Ioanna
    Lundstedt-Enkel, Katrin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Effects of 17α-ethynylestradiol on EROD activity, spiggin and vitellogenin in three-spined stickleback (Gasterosteus aculeatus)2007Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 83, nr 1, s. 33-42Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Norrgren, Leif
    Olsén, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    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.2001Ingår i: Arch Environ Contam Toxicol, ISSN 0090-4341, Vol. 40, nr 4, s. 519-30Artikel i tidskrift (Refereegranskat)
  • 13. Ankarberg, Emma
    et al.
    Bjerselius, Richard
    Aune, Marie
    Darnerud, Per-Ola
    Larsson, L
    Andersson, A
    Tysklind, A
    Bergek, S
    Lundstedt-Enkel, Katrin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Karlsson, L
    Törnskvist, A
    Glynn, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Study of dioxin and dioxin-like PCB levels in fatty fish from Sweden 2000-20022004Ingår i: Organohalogen compounds vol 66., 2004, s. 2035-2039Konferensbidrag (Refereegranskat)
  • 14.
    Ankarberg, Emma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Neonatal develpmental effects of nicotine in mice: Changes in brain nicotinic receptors and behavioural response to nicotine1998Ingår i: Toxicol. Lett. 95/Suppl 1, 1998Konferensbidrag (Refereegranskat)
  • 15.
    Ankarberg, Emma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Neonatal exposure to nicotine induces increased susceptibility to paraoxon exposure at adult age2004Ingår i: The Toxicologist, 2004, s. 974-Konferensbidrag (Refereegranskat)
  • 16. Ankarberg, Emma
    et al.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Neonatal exposure to nicotine induces increased suseptibility to paraoxon exposure at adult age2005Ingår i: Toxicologist 84, 2005, s. 974-Konferensbidrag (Refereegranskat)
  • 17.
    Ankarberg, Emma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Jakobsson, Eva
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Increased susceptibility to adult flame retardant exposure (PBDE 99) in mice neonatally exposed to nicotine2001Ingår i: The Second International Workshop on Brominated Flame Retardants, May 14-16, Stockholm, Sweden, 2001Konferensbidrag (Refereegranskat)
  • 18.
    Archer, Trevor
    et al.
    Department of Psychology, University of Gothenburg.
    Fredriksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Physical Exercise Attenuates MPTP-Induced Deficits in Mice2010Ingår i: Neurotoxicity research, ISSN 1029-8428, E-ISSN 1476-3524, Vol. 18, nr 3-4, s. 313-327Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

     

    Delarbeten
    1. Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
    Öppna denna publikation i ny flik eller fönster >>Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
    Visa övriga...
    2009 (Engelska)Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, nr 4, s. 389-396Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Adrenal cortex, Metabolic activation, Toxicity, Corticosterone, DDE, CYP11B1
    Nationell ämneskategori
    Biologiska vetenskaper
    Forskningsämne
    Ekotoxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-100855 (URN)10.1007/s00204-008-0342-6 (DOI)000264883800012 ()18651133 (PubMedID)
    Tillgänglig från: 2009-04-08 Skapad: 2009-04-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
    Öppna denna publikation i ny flik eller fönster >>Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
    Visa övriga...
    2007 (Engelska)Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 81, nr 11, s. 793-801Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Adrenal cortex, Cytochrome P450, Metabolic activation, Toxicity, Y-1
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-14330 (URN)10.1007/s00204-007-0206-5 (DOI)000250537400006 ()17487473 (PubMedID)
    Tillgänglig från: 2008-05-15 Skapad: 2008-05-15 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    3. Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
    Öppna denna publikation i ny flik eller fönster >>Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
    Visa övriga...
    2010 (Engelska)Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, nr 3, s. 281-289Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Adrenocorticolytic DDT metabolites, Endocrine disruption, Adrenocortical cancer (ACC), Biphasic responses, Steroidogenesis, H295R
    Nationell ämneskategori
    Farmakologi och toxikologi
    Forskningsämne
    Ekotoxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-112583 (URN)10.1016/j.taap.2009.10.018 (DOI)000273832500006 ()19900470 (PubMedID)
    Tillgänglig från: 2010-01-15 Skapad: 2010-01-15 Senast uppdaterad: 2018-01-12
    4. Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    Öppna denna publikation i ny flik eller fönster >>Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    2010 (Engelska)Ingår i: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, nr 3, s. 177-183Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Farmaceutiska vetenskaper Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-112582 (URN)10.3109/00498250903470230 (DOI)000274882900002 ()20044879 (PubMedID)
    Tillgänglig från: 2010-01-15 Skapad: 2010-01-15 Senast uppdaterad: 2018-01-12
  • 20.
    Asp, Vendela
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Cantillana, Tatiana
    Bergman, Åke
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells2010Ingår i: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, nr 3, s. 177-183Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Hermansson, Veronica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    A tiered approach to assessing adrenocortical toxicity2005Ingår i: Science for a safe chemical environment, 2005, s. 63-77Kapitel i bok, del av antologi (Refereegranskat)
  • 22.
    Asp, Vendela
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. Ekotoxikologi.
    Lindström, Veronica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. Ekotoxikologi.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. Ekotoxikologi.
    CYTOTOXICITY AND DECREASED CORTICOSTERONE PRODUCTION IN ADRENOCORTICAL CELLS BY METHYLSULPHONATED DERIVATIVES OF p,p′-DDE2007Konferensbidrag (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Lindström, Veronica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Bergström, Ulrika
    Brandt, Ingvar
    Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by o,p’-DDD and methylsulphonated derivatives of p,p’-DDEManuskript (Övrig (populärvetenskap, debatt, mm))
  • 24.
    Asp, Vendela
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Lindström, Veronica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Olsson, Jan A
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules2009Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, nr 4, s. 389-396Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Ullerås, Erik
    Lindström, Veronica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Oskarsson, Agneta
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells2010Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, nr 3, s. 281-289Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Tallkvist, Jonas
    Department of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Box 7028, SE-75007, Uppsala, Sweden.
    Ilbäck, Nils-Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Glynn, Anders W.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes2007Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 237, nr 1-3, s. 12-23Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Glynn, Anders W.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fatty acids increase paracellular absorption of aluminium across Caco-2 cell monolayers2009Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, nr 2, s. 272-278Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.