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  • 1. Abrahamson, Alexandra
    et al.
    Andersson, Carin
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fogelberg, Oscar
    Orberg, Jan
    Brunstrom, Bjorn
    Brandt, Ingvar
    Gill EROD in monitoring of CYP1A inducers in fish - A study in rainbow trout (Oncorhynchus mykiss) caged in Stockholm and Uppsala waters2007In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 85, no 1, p. 1-8Article in journal (Refereed)
  • 2. Agerstrand, Marlene
    et al.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bjorlenius, Berndt
    Breitholtz, Magnus
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Gunnarsson, Lina
    Larsson, D. G. Joakim
    Sumpter, John P.
    Tysklind, Mats
    Ruden, Christina
    Improving Environmental Risk Assessment of Human Pharmaceuticals2015In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 49, no 9, p. 5336-5345Article in journal (Refereed)
    Abstract [en]

    This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

  • 3.
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Cellular transport and secretion of the cyanobacterial neurotoxin BMAA into milk and egg: Implications for developmental neurotoxicity2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA) is a neurotoxin implicated in the etiology of neurodegenerative diseases. Cyanobacteria are cosmopolitan organisms present in various environments. BMAA can cause long-term neurodegenerative alterations in rats exposed during the neonatal period, a period that corresponds to the last trimester and the first few years of life in humans. As BMAA has been reported to be bioaccumulated in the aquatic food chain and detected in mussels, crayfish and fish used for human consumption, the main aim of this thesis has been to investigate the final step in the mammalian food-chain, i.e. the transfer of BMAA into breast milk.

    Autoradiographic imaging and mass spectrometry analysis showed an enantiomer-selective uptake of BMAA and that the neurotoxin was transferred from lactating mice and rat, via the milk, to the brain of the nursed pups. The results show that transport of BMAA may be disproportional to dose. In addition, BMAA was found present both as free amino acid and tightly associated to proteins in rat brains. Surprisingly, however, no association to milk proteins was found. In vitro studies of murine (HC11) and human (MCF7) mammary epithelial cells suggest that BMAA can pass the human mammary epithelium into milk. Additional transport studies on human intestinal, glioblastoma and neuroblastoma cells showed that L-BMAA was consistently favored over D-BMAA and that the transport was mediated by several amino acid transporters. We also demonstrated that egg-laying quail transfer BMAA to its offspring by deposition in the eggs, particularly in the yolk but also in the albumen. Furthermore, comparative analysis of carboxyl- and methyl-labeled [14C]-BMAA suggested that BMAA was not metabolized to a large degree.

    Altogether, the results indicate that BMAA can be transferred from mothers, via the milk, to the brain of nursed human infants. Determinations of BMAA in mothers’ milk and cows’ milk are therefore warranted. We also propose that birds’ eggs could be an additional source of BMAA exposure in humans. It might therefore be of concern that mussels are increasingly used as feed in commercial egg production.

    List of papers
    1. Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring
    Open this publication in new window or tab >>Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e78133-Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-211448 (URN)10.1371/journal.pone.0078133 (DOI)000326037000089 ()
    Available from: 2013-11-27 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
    2. Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis
    Open this publication in new window or tab >>Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis
    2016 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. 108-114Article in journal (Refereed) Published
    Abstract [en]

    The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

    Keywords
    BMAA; Cyanobacterial neurotoxin, kinetics; Milk secretion; Developmental neurotoxicity; Mother-to-offspring transfer
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-265847 (URN)10.1016/j.toxlet.2016.06.015 (DOI)000381648300012 ()27320960 (PubMedID)
    Projects
    Milk, secretion, BMAA, beta-N-methylamino-L-alanine, autoradiography, mass spectrometry
    Funder
    Swedish Research Council Formas
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-05-12Bibliographically approved
    3. Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines
    Open this publication in new window or tab >>Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines
    2017 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keywords
    BMAA, Cellular transport, Amino acid transporters, Breast milk, Neurodegeneration
    National Category
    Cell Biology Developmental Biology
    Research subject
    Biology with specialization in Environmental Toxicology
    Identifiers
    urn:nbn:se:uu:diva-265857 (URN)10.1016/j.taap.2017.02.004 (DOI)000396798200006 ()28174119 (PubMedID)
    Funder
    Swedish Research Council Formas
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-05-02Bibliographically approved
    4. Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats
    Open this publication in new window or tab >>Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats
    Show others...
    2014 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed) Published
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

    Keywords
    ALS/PDC, Cyanobacteria, Autoradiography, Mass spectrometry, Misincorporation, N-(2-aminoethyl) glycine
    National Category
    Medical and Health Sciences Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-222718 (URN)10.1016/j.toxlet.2014.01.027 (DOI)000332409000001 ()24472610 (PubMedID)
    Funder
    Swedish Research Council Formas
    Available from: 2014-04-17 Created: 2014-04-14 Last updated: 2017-06-30Bibliographically approved
    5. Deposition of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (L-BMAA) in birds' egg: A potential source of BMAA exposure in humans
    Open this publication in new window or tab >>Deposition of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (L-BMAA) in birds' egg: A potential source of BMAA exposure in humans
    (English)Manuscript (preprint) (Other academic)
    Keywords
    BMAA, beta-N-methylamino-L-alanine, quail, metabolism, autoradiography
    National Category
    Developmental Biology
    Research subject
    Biology with specialization in Environmental Toxicology
    Identifiers
    urn:nbn:se:uu:diva-265859 (URN)
    Funder
    Swedish Research Council Formas
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2016-01-13
  • 4.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines2017In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, SE-17176 Stockholm, Sweden.
    Banack, Sandra
    Inst Ethnomed, POB 3464, Jackson, WY 83001 USA.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. 108-114Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 6.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, article id e78133Article in journal (Refereed)
  • 7.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e78133-Article in journal (Refereed)
    Abstract [en]

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

  • 8.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Deposition of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (L-BMAA) in birds' egg: A potential source of BMAA exposure in humansManuscript (preprint) (Other academic)
  • 9.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs2018In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 147, p. 720-724Article in journal (Refereed)
    Abstract [en]

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

  • 10. Bakshi, Mayur V
    et al.
    Barjaktarovic, Zarko
    Azimzadeh, Omid
    Kempf, Stefan J.
    Merl, Juliane
    Hauck, Stefanie M.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Atkinson, Michael J.
    Tapio, Soile
    Total body exposure to low-dose ionizing radiation induces long term alterations to the liver proteome of neonatally exposed mice2015In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 14, no 1, p. 366-373Article in journal (Refereed)
    Abstract [en]

    Tens of thousands of people are being exposed daily toenvironmental low-dose gamma radiation. Epidemiological data indicate thatsuch low radiation doses may negatively affect liver function and result in thedevelopment of liver disease. However, the biological mechanisms behindthese adverse effects are unknown. The aim of this study was to investigateradiation-induced damage in the liver after low radiation doses. Neonatal maleNMRI mice were exposed to total body irradiation on postnatal day 10 usingacute single doses ranging from 0.02 to 1.0 Gy. Early (1 day) and late (7months) changes in the liver proteome were tracked using isotope-codedprotein label technology and quantitative mass spectrometry. Our dataindicate that low and moderate radiation doses induce an immediateinhibition of the glycolysis pathway and pyruvate dehydrogenase availability inthe liver. Furthermore, they lead to significant long-term alterations in lipidmetabolism and increased liver inflammation accompanying inactivation of thetranscription factor peroxisome proliferator-activated receptor alpha. This study contributes to the understanding of the potentialrisk of liver damage in populations environmentally exposed to ionizing radiation.

  • 11. Bakshi, Mayur V.
    et al.
    Barjaktarovic, Zarko
    Azimzadeh, Omid
    Kempf, Stefan J.
    Merl, Juliane
    Hauck, Stefanie M.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Atkinson, Michael J.
    Tapio, Soile
    Long-term effects of acute low-dose ionizing radiation on the neonatal mouse heart: a proteomic study2013In: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 52, no 4, p. 451-461Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies establish that children and young adults are especially susceptible to radiation-induced cardiovascular disease (CVD). The biological mechanisms behind the elevated CVD risk following exposure at young age remain unknown. The present study aims to elucidate the long-term effects of ionizing radiation by studying the murine cardiac proteome after exposure to low and moderate radiation doses. NMRI mice received single doses of total body Co-60 gamma-irradiation on postnatal day 10 and were sacrificed 7 months later. Changes in cardiac protein expression were quantified using isotope-coded protein label and tandem mass spectrometry. We identified 32, 31, 66, and 34 significantly deregulated proteins after doses of 0.02, 0.1, 0.5, and 1.0 Gy, respectively. The four doses shared 9 deregulated proteins. Bioinformatics analysis showed that most of the deregulated proteins belonged to a limited set of biological categories, including metabolic processes, inflammatory response, and cytoskeletal structure. The transcription factor peroxisome proliferator-activated receptor alpha was predicted as a common upstream regulator of several deregulated proteins. This study indicates that both adaptive and maladaptive responses to the initial radiation damage persist well into adulthood. It will contribute to the understanding of the long-term consequences of radiation-induced injury and developmental alterations in the neonatal heart.

  • 12. Behrendt, Lars
    et al.
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Goldstone, Jared V.
    Stegeman, John J.
    Induction of cytochrome P450 1 genes and stress response genes in developing zebrafish exposed to ultraviolet radiation2010In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 98, no 1, p. 74-82Article in journal (Refereed)
  • 13.
    Beijer, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Azoles and Contaminants in Treated Effluents Interact with CYP1 and CYP19 in Fish: 2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Numerous contaminants are present in mixtures in the aquatic environment. Among these are the azoles, a group of chemicals that includes both pharmaceuticals and pesticides. Azole fungicides are designed to inhibit lanosterol 14-demethylase (cytochrome P450 (CYP) 51), while other azoles are intended to inhibit aromatase (CYP19), i.e. the enzyme catalyzing biosynthesis of estrogens. In fish, a variety of CYP enzymes are involved in biotransformation of waterborne contaminants, and in metabolism of endogenous compounds including steroidal hormones. The induction of CYP1A protein and 7-ethoxyresorufin O-deethylase (EROD) activity are common biomarkers for exposure to aryl hydrocarbon receptor (AhR) agonists in fish. We developed an assay to measure inhibition of CYP1A activity (EROD) in three-spined stickleback and rainbow trout gill tissue ex vivo. Several azole fungicides were found to be potent inhibitors of CYP1A activity. A wastewater effluent containing high concentrations of pharmaceuticals was also shown to inhibit CYP1A activity. Further, several azoles inhibited CYP19 activity in rainbow trout brain microsomes in vitro. Azole mixtures reduced both CYP1A and CYP19 activity monotonically and in an additive way. Given the additive action of the azoles, studies to determine adverse effects of azole mixtures on CYP-regulated physiological functions in fish are needed. Induction of EROD and of gene expression of CYP1 in several organs was observed in an in vivo exposure with the same effluent shown to inhibit EROD. This finding could imply that there was a mixture of AhR agonists and CYP1A inhibitors in the effluent. Finally, wastewater treatment technologies were evaluated using biomarker responses in rainbow trout exposed to effluents of different treatments. The results from chemical analysis together with the biomarker results show that ozone and granulated active carbon treatment removed most pharmaceuticals, as well as AhR agonists and other chemicals present in the regular effluent. This part of the thesis demonstrates that biomarkers in fish such as induction of CYP1 gene expression are applicable to evaluate the efficiency of different treatment technologies for wastewater.

    List of papers
    1. CYP1A inhibition in fish gill filaments: a novel assay applied on pharmaceuticals and other chemicals
    Open this publication in new window or tab >>CYP1A inhibition in fish gill filaments: a novel assay applied on pharmaceuticals and other chemicals
    2010 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 96, no 2, p. 145-150Article in journal (Refereed) Published
    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.

    Keywords
    Gill filament assay, CYP inhibition, Pharmaceuticals, Antifungal azoles, Three-spined stickleback, EROD activity
    National Category
    Pharmacology and Toxicology Biological Sciences
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-120904 (URN)10.1016/j.aquatox.2009.10.018 (DOI)000274978500009 ()19913926 (PubMedID)
    Available from: 2010-03-17 Created: 2010-03-17 Last updated: 2018-01-12Bibliographically approved
    2. Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)
    Open this publication in new window or tab >>Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)
    Show others...
    2018 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 198, p. 73-81Article in journal (Refereed) Published
    Abstract [en]

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

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

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

    Keywords
    Azole fungicide, EROD activity, cytochrome P450 (CYP), CYP1A, CYP19, aromatase, pharmaceutical, contaminant, chemical, fish, rainbow trout, gill, EROD aktivitet, cytokrom P450 (CYP), CYP1A, CYP19, aromatase, läkemedel, azol, fungicid, kemikalier, förorening, fisk, regnbågslax, gäle
    National Category
    Other Biological Topics
    Research subject
    Biology with specialization in Environmental Toxicology
    Identifiers
    urn:nbn:se:uu:diva-249010 (URN)10.1016/j.aquatox.2018.02.016 (DOI)000430630100008 ()
    Funder
    Mistra - The Swedish Foundation for Strategic Environmental Research
    Available from: 2015-04-15 Created: 2015-04-10 Last updated: 2018-08-07Bibliographically approved
    3. Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish
    Open this publication in new window or tab >>Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish
    Show others...
    2013 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 90, no 3, p. 1149-1157Article in journal (Refereed) Published
    Abstract [en]

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

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

    De två första författarna delar förstaförfattarskapet.

    Available from: 2013-01-24 Created: 2013-01-15 Last updated: 2017-12-06Bibliographically approved
    4. Reduction of pharmaceuticals and other contaminants in sewage treatment effluents by active carbon filtration and ozonation: Evaluation using biomarker responses in fish and chemical analysis
    Open this publication in new window or tab >>Reduction of pharmaceuticals and other contaminants in sewage treatment effluents by active carbon filtration and ozonation: Evaluation using biomarker responses in fish and chemical analysis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    effluent, STP, wastewater, active carbon, ozonation, rainbow trout
    National Category
    Other Biological Topics
    Research subject
    Biology with specialization in Environmental Toxicology
    Identifiers
    urn:nbn:se:uu:diva-251294 (URN)
    Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2015-07-07
  • 14.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Björlenius, Berndt
    Royal Inst Technol KTH, Albanova Univ Ctr, Sch Biotechnol, SE-10691 Stockholm, Sweden..
    Shaik, Siraz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. IUF Leibniz Res Inst Environm Med, Hennekamp 50, D-40225 Dusseldorf, Germany..
    Lindberg, Richard H.
    Umea Univ, Dept Chem, KBC 6A Linnaeus Vag 6, SE-90187 Umea, Sweden..
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Removal of pharmaceuticals and unspecified contaminants in sewage treatment effluents by activated carbon filtration and ozonation: Evaluation using biomarker responses and chemical analysis2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 176, p. 342-351Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Gao, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Larsson, D. G. J.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effluent from drug manufacturing affects cytochrome P450 1 regulation and function in fish2013In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 90, no 3, p. 1149-1157Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jönsson, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Shaik, Siraz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Behrens, Daphné
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)2018In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 198, p. 73-81Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 17.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Nilsson, Peter M.
    SUS Malmo, Dept Clin Sci, Malmo, Sweden..
    Elmstahl, Solve
    Lund Univ, Div Geriatr Med, Dept Hlth Sci, Malmo Univ Hosp, Malmo, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Interaction between physical activity and television time on blood pressure level: cross-sectional data from 45000 individuals2018In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, no 5, p. 1041-1050Article in journal (Refereed)
    Abstract [en]

    Objectives:The aim was to investigate if there is an interaction between sitting time and leisure time physical activity on blood pressure and if there are age differences and sex differences in this respect.

    Methods:Linear regression analysis on cross-sectional data was performed in more than 45000 men and women from two Swedish cohort studies, EpiHealth (45-75 years) and LifeGene (18-45 years). Self-reported leisure time physical activity was given in five levels from low (level 1) to vigorous physical activity (level 5) and television time was used as a proxy measure of sitting time.

    Results:High physical activity was associated with lower DBP (P=0.001), but not SBP. Active middle-aged men had lower DBP (-1.1mmHg; 95% CI -1.7 to -0.4) compared with inactive participants. Prolonged television time was associated with higher SBP (P<0.001) and DBP (P=0.011) in both sexes and in most age groups. Watching 3h instead of 1h television per day was associated with higher SBP in middle-aged women (SBP: 1.1mmHg; 95% CI 0.7-1.4) and men (SBP: 1.2mmHg; 95% CI 0.8-1.6). Only in young men, a high physical activity (level 4 instead of level 1) could compensate for a prolonged television time (3h per day) in terms of DBP.

    Conclusion:Prolonged television time was associated with higher SBP and DBP in both sexes and at most ages, whereas an increased physical activity was mainly associated with a lower DBP. Only in young men, a high physical activity could compensate for prolonged television time regarding DBP.

  • 18.
    Beijer, kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Shaik, Siraz
    Berndt, Björlenius
    KTH.
    Lindberg, Richard
    Umeå Universitet.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Reduction of pharmaceuticals and other contaminants in sewage treatment effluents by active carbon filtration and ozonation: Evaluation using biomarker responses in fish and chemical analysisManuscript (preprint) (Other academic)
  • 19.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Müllerian duct differentiation: a sensitive target for endocrine disrupters in amphibians2013Conference paper (Other academic)
  • 20.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Backström, Tobias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lindberg, Richard
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental Exposure to Fluoxetine Modulates the Serotonin System in Hypothalamus2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e55053-Article in journal (Refereed)
    Abstract [en]

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

  • 21.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lundstedt-Enkel, KatrinUppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.Olovsson, MattsUppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.Persson, SaraSveriges lantbruksuniversitet, Institutionen för kliniska vetenskaper.
    Female Reproduction and Endocrine Disrupting Chemicals (FEMREP 2013)2013Conference proceedings (editor) (Other academic)
  • 22.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Environmental concentrations of norethindrone and progesteroneinhibit egg development in amphibians2013Conference paper (Other academic)
  • 23.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Reproductive toxicity of progestogens: norethindrone and progesterone inhibit vitellogenesis2013Conference paper (Other academic)
  • 24.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Säfholm, Moa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jansson, Erika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Umeå universitet.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effects of Progestin and Estrogen Mixtures: a partial life cycle study on sex differentiation2013Conference paper (Other academic)
  • 25. Bergman, Ake
    et al.
    Andersson, Anna-Maria
    Becher, Georg
    van den Berg, Martin
    Blumberg, Bruce
    Bjerregaard, Poul
    Bornehag, Carl-Gustaf
    Bornman, Riana
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brian, Jayne V.
    Casey, Stephanie C.
    Fowler, Paul A.
    Frouin, Heloise
    Giudice, Linda C.
    Iguchi, Taisen
    Hass, Ulla
    Jobling, Susan
    Juul, Anders
    Kidd, Karen A.
    Kortenkamp, Andreas
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Martin, Olwenn V.
    Muir, Derek
    Ochieng, Roseline
    Olea, Nicolas
    Norrgren, Leif
    Ropstad, Erik
    Ross, Peter S.
    Ruden, Christina
    Scheringer, Martin
    Skakkebaek, Niels Erik
    Soder, Olle
    Sonnenschein, Carlos
    Soto, Ana
    Swan, Shanna
    Toppari, Jorma
    Tyler, Charles R.
    Vandenberg, Laura N.
    Vinggaard, Anne Marie
    Wiberg, Karin
    Zoeller, R. Thomas
    Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors2013In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, p. 69-Article in journal (Other academic)
    Abstract [en]

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

  • 26. Bergman, Ake
    et al.
    Heindel, Jerrold J.
    Kasten, Tim
    Kidd, Karen A.
    Jobling, Susan
    Neira, Maria
    Zoeller, R. Thomas
    Becher, Georg
    Bjerregaard, Poul
    Bornman, Riana
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kortenkamp, Andreas
    Muir, Derek
    Drisse, Marie-Noel Brune
    Ochieng, Roseline
    Skakkebaek, Niels E.
    Bylehn, Agneta Sunden
    Iguchi, Taisen
    Toppari, Jorma
    Woodruff, Tracey J.
    The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 4, p. A104-A106Article in journal (Other academic)
  • 27.
    Bergman, Åke
    et al.
    Swedish Toxicol Sci Res Ctr Swetox, Sodertalje, Sweden..
    Becher, Georg
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Blumberg, Bruce
    Univ Calif Irvine, Irvine, CA USA..
    Bjerregaard, Poul
    Univ Southern Denmark, Odense, Denmark..
    Bornman, Riana
    Univ Pretoria, Sch Hlth Syst & Publ Hlth, ZA-0002 Pretoria, South Africa..
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Casey, Stephanie C.
    Univ Calif Irvine, Irvine, CA USA..
    Frouin, Heloise
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Giudice, Linda C.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Heindel, Jerrold J.
    Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA..
    Iguchi, Taisen
    Natl Inst Basic Biol, Okazaki, Aichi 444, Japan..
    Jobling, Susan
    Brunel Univ London, Uxbridge, Middx, England..
    Kidd, Karen A.
    Univ New Brunswick, New Brunswick, NJ USA..
    Kortenkamp, Andreas
    Brunel Univ London, Uxbridge, Middx, England..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Muir, Derek
    Environm Canada, Burlington, ON L7R 4A6, Canada..
    Ochieng, Roseline
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Ropstad, Erik
    Norwegian Univ Life Sci, Oslo, Norway..
    Ross, Peter S.
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Skakkebaek, Niels Erik
    Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Toppari, Jorma
    Univ Turku, Turku, Finland..
    Vandenberg, Laura N.
    Univ Massachusetts, Amherst, MA 01003 USA..
    Woodruff, Tracey J.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Zoeller, R. Thomas
    Univ Massachusetts, Amherst, MA 01003 USA..
    Manufacturing doubt about endocrine disrupter science - A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"2015In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 73, no 3, p. 1007-1017Article in journal (Other academic)
    Abstract [en]

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

  • 28.
    Bladin, Emelie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effects of low-dose developmental exposure to Bisphenol A: Hepatic gene expression and hepatic lipid accumulation in juvenile Fischer 344 rats2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background: The endocrine-disrupting chemical bisphenol A (BPA) is suggested to have a potential role in the development of obesity and metabolic disorders. Human exposure occurs worldwide and the developmental period seems to be particularly sensitive, even to very low doses. In January 2015 the European Food Safety Authority (EFSA) lowered the tolerable daily intake (TDI) from 50 μg/kg bw/day to 4 μg/kg bw/day. Ingestion of BPA-contaminated food is the main route of exposure and biotransformation occurs in the liver. Little is known about the effects of BPA exposure on basal metabolic rate and hepatic homeostasis.

    Objectives: This study aimed to investigate potential alterations on hepatic gene expression and hepatic lipid accumulation due to low-dose perinatal BPA developmental exposure.

    Methods: Pregnant Fischer 344 rats were exposed to a lower dose (0.5 μg/kg bw/day) and a higher dose (50 μg/kg bw/day) of BPA via their drinking water during gestation and lactation until weaning. The offspring were exposed in utero and during lactation. They were sacrificed at five weeks of age. Liver mRNA gene expression was measured using qPCR and potential lipid accumulation in the liver was examined using image analysis (ImageJ) of micrographs of tissue sections.

    Results: Perinatal exposure to BPA altered the mRNA expression in males. The mRNA levels of the pro adipogenic transcription factor CCAAT/enhancer binding protein, alpha (C/EBP-α), were 26% lower in higher-dose exposed males compared to controls (p=0.05). No significant effects on mRNA expression were seen in females. Liver lipid accumulation was not significantly altered by BPA exposure.

    Conclusion: Perinatal low-dose BPA exposure (0.5 and 50 μg/kg bw/day), altered hepatic expression of one gene involved in adipogenic transcription in the juvenile male offspring. The results support the potential role of low-dose BPA exposure on metabolic homeostasis and it might be of concern with regard to the currently allowed TDI and the ubiquitous exposure among humans

  • 29. Bogdanska, Jasna
    et al.
    Sundstrom, Maria
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Borg, Daniel
    Abedi-Valugerdi, Manuchehr
    Bergman, Ake
    DePierre, Joseph
    Nobel, Stefan
    Tissue distribution of S-35-labelled perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days2014In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 98, p. 28-36Article in journal (Refereed)
    Abstract [en]

    Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1,3 or 5 d to 16 mg S-35-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5 d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.

  • 30.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Low-Dose Ionizing Radiation Induces Neurotoxicity in the Neonate: Acute or fractionated doses and interaction with xenobiotics in mice2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis examines the developmental neurotoxic effects of exposure to low-dose ionizing radiation (IR), alone or together with xenobiotics, during a critical period of neonatal brain development in mice.

    During mammalian brain development there is a period called the brain growth spurt (BGS), which involves extensive growth and maturation of the brain. It is known that neonatal exposure during the BGS to xenobiotics can have a negative impact on neonatal brain development, resulting in impaired cognitive function in the adult mouse. In humans, the BGS starts during the third trimester of pregnancy and continues for approximately 2 years in the child.  

    The present thesis has identified a defined critical period, during the BGS, when IR can induce developmental neurotoxicity in mice. The observed neurotoxicity was not dependent on sex or strain and manifested as altered neurobehaviour in the adult mouse. Furthermore, fractionated dose exposures appear to be as potent as a higher acute dose. The cholinergic system can be a target system for developmental neurotoxicity of IR, since alterations in adult mouse cholinergic system susceptibility were observed. Co-exposure to IR and nicotine exacerbated the behavioural disturbances and cholinergic system dysfunction. Furthermore, co-exposure with the environmental agent paraquat has indicated that the dopaminergic system can be a potential target.  

    In this thesis, clinically relevant doses of IR and a sedative/anesthetic agent (ketamine) were shown to interact and exacerbate defects in adult mouse neurobehaviour, learning and memory, following neonatal exposure, at doses where the single agents did not have any impact on the measured variables. This indicates a shift in the dose-response curve for IR, towards lower doses, if exposure occurs during the neonatal brain development. In addition, co-exposed mice, showing cognitive defects, expressed elevated levels of tau protein in the cerebral cortex. Furthermore, exacerbation of neurochemical deviations were observed following co-exposure compared to irradiation alone.

    Further investigations of neurotoxic effects following fractionated or acute low-dose IR, modelling the clinical situation during repeated CT scans or levels of radiation deposited in non-target tissue during radiotherapy, and possible interaction effects with xenobiotics, is of great importance in the field of radioprotection. 

    List of papers
    1. Neonatal exposure to whole body ionizing radiation induces adult neurobehavioural defects: Critical period, dose-response effects and strain and sex comparison
    Open this publication in new window or tab >>Neonatal exposure to whole body ionizing radiation induces adult neurobehavioural defects: Critical period, dose-response effects and strain and sex comparison
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    2016 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 304, p. 11-19Article in journal (Refereed) Published
    Abstract [en]

    Development of the brain includes periods which can be critical for its normal maturation. The present study investigates specifically vulnerable peri-/postnatal periods in mice which are essential for understanding the etiology behind radiation induced neurotoxicity and functional defects, including evaluation of neurotoxicity between sexes or commonly used laboratory mouse strains following low/moderate doses of ionizing radiation (IR). Male Naval Medical Research Institute (NMRI) mice, whole body irradiated to a single 500 mGy IR dose, on postnatal day (PND) 3 or PND 10 showed an altered adult spontaneous behaviour and impaired habituation capacity, whereas irradiation on PND 19 did not have any impact on the studied variables. Both NMRI and C57bl/6 male and female mice showed an altered adult spontaneous behaviour and impaired habituation following a single whole body irradiation of 500 or 1000 mGy, but not after 20 or 100 mGy, on PND 10. The present study shows that exposure to low/moderate doses of IR during critical life stages might be involved in the induction of neurological/neurodegenerative disorder/disease. A specifically vulnerable period for radiation induced neurotoxicity seems to be around PND 3-10 in mice. Further studies are needed to investigate mechanisms involved in induction of developmental neurotoxicity following low dose irradiation.

    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-282365 (URN)10.1016/j.bbr.2016.02.008 (DOI)000372939400002 ()26876140 (PubMedID)
    Funder
    Swedish Radiation Safety AuthorityEU, FP7, Seventh Framework Programme, 29552
    Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-11-30Bibliographically approved
    2. Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice
    Open this publication in new window or tab >>Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice
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    2014 (English)In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 45, p. 48-55Article in journal (Refereed) Published
    Abstract [en]

    Medical use of ionizing radiation (IR) has great benefits for treatment and diagnostic imaging, butprocedures as computerized tomography (CT) may deliver a significant radiation dose to the patient.Recently, awareness has been raised about possible non-cancer consequences from low dose exposure toIR during critical phases of perinatal and/or neonatal brain development.In the present study neonatal NMRI mice were whole body irradiated with a single dose of gammaradiation (0; 350 and 500 mGy) on postnatal day 10 (PND 10). At 2 and 4 months of age, mice of bothsexes were observed for spontaneous behaviour in a novel home environment. The neuroproteinsCaMKII, GAP-43, synaptophysin and total tau in male mouse cerebral cortex and hippocampus wereanalysed 24 h post-irradiation and in adults at 6 months of age exposed to 0 or 500 mGy on PND 10.A significantly dose-response related deranged spontaneous behaviour in 2- and 4-month-old micewas observed, where both males and females displayed a modified habituation, indicating reducedcognitive function. The dose of 350 mGy seems to be a tentative threshold. Six-month-old male miceshowed a significantly increased level of total tau in cerebral cortex after irradiation to 500 mGy compared to controls. This demonstrates that a single moderate dose of IR, given during a defined criticalperiod of brain development, is sufficient to cause persistently reduced cognitive function. Moreover, anelevation of tau protein was observed in male mice displaying reduced cognitive function.

    National Category
    Other Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-240576 (URN)10.1016/j.neuro.2014.09.002 (DOI)000346955100006 ()25265567 (PubMedID)
    Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2017-06-30Bibliographically approved
    3. Developmental effects of fractionated low-dose exposure to gamma radiation on behaviour and susceptibility of the cholinergic system in mice
    Open this publication in new window or tab >>Developmental effects of fractionated low-dose exposure to gamma radiation on behaviour and susceptibility of the cholinergic system in mice
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    2016 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 92, no 7, p. 371-379Article in journal (Refereed) Published
    Abstract [en]

    Purpose: To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. Materials and methods: Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 μg/kg b.w.) twice daily on postnatal day (PND) 10, 10–11, 10–12 or 10–13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. Results: Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. Conclusions: The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.

    Keywords
    Low-dose radiation, nicotine, cholinergic system, cognition, brain development, behavior
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-282366 (URN)10.3109/09553002.2016.1164911 (DOI)000379933800003 ()27043364 (PubMedID)