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  • 1.
    Ankarberg, Emma
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Neurotoxic Effects of Nicotine During Neonatal Brain Development: Critical Period and Adult Susceptibility2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis examined neurotoxic effects of nicotine exposure during a defined critical period of neonatal brain development in mice.

    In our environment there are numerous hazardous contaminants that an individual can be exposed to during its entire lifetime. In many mammalian species the neonatal period is characterised by a rapid development of the brain. The present studies have identified a defined critical period during the neonatal brain development in mice, where exposure to low doses of nicotine causes permanent disturbances in the cholinergic nicotinic receptors and altered behaviour response to nicotine at adult age. This adult reaction to nicotine, a hypoactive response, was the opposite of that observed in control animals and animals exposed to nicotine before or after this period. Animals showing a hypoactive response to nicotine lacked nicotinic low affinity binding sites in the cerebral cortex. Furthermore, neonatal exposure to nicotine affected learning and memory in adult animals, an effect that was time-dependent. This thesis also showed that neonatal exposure to nicotine increased adult susceptibility to a repeated exposure of nicotine, manifested as an even more pronounced effect in spontaneous behaviour after challenging doses of nicotine. In these animals the nicotinic receptors in the cerebral cortex, assayed by a-bungarotoxin, was decreased.

    Neonatal exposure to nicotine was also shown to increase adult susceptibility to the organophosphate paraoxon, a known cholinergic agent, and to the brominated flame retardant 2,2´,4,4´,5-pentabromodiphenyl ether, a novel environmental agent, at adult age. This was seen at doses that did not affect behaviour in control animals, and was manifested as deranged spontaneous behaviour and reduced habituation, aberrations that also worsened with age.

    The results indicate that differences in adult susceptibility to environmental pollutants are not necessarily an inherited condition. Rather they may well be acquired by low dose exposure to toxic agents during early life.

    List of papers
    1. Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice
    Open this publication in new window or tab >>Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice
    2000 In: Brain Research, Vol. 853, p. 41-48Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91050 (URN)
    Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
    2. Neurobehavioural defects in adult mice neonatally exposed to nicotine: changes in nicotine-induced behaviour and maze learning performance
    Open this publication in new window or tab >>Neurobehavioural defects in adult mice neonatally exposed to nicotine: changes in nicotine-induced behaviour and maze learning performance
    2001 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 123, no 2, p. 185-192Article in journal (Refereed) Published
    Abstract [en]

    Neonatal exposure to low doses of nicotine has been shown to disturb the development of low-affinity nicotinic binding sites in the cerebral cortex and to elicit a deviant behavioural response to nicotine in adult mice. In this study, 10-day-old male NMRI mice were exposed to one of three different doses of nicotine (3.3, 33, or 66 μg nicotine-base/kg body wt.) s.c. twice daily on 5 consecutive days to study dose–response effects of nicotine on adult spontaneous and nicotine-induced motor behaviour. The nicotine-induced behaviour test revealed a hypoactive response to nicotine in 4-month-old mice neonatally exposed to 33 or 66 μg nicotine-base, whereas the response to nicotine in control animals and mice exposed to 3.3 μg nicotine-base was an increased activity. Learning and memory functions were also investigated in adult animals neonatally exposed to 66 μg nicotine-base/kg body wt. in the same manner, in the Morris water maze and in the Radial arm maze. In the swim maze and the Radial arm maze tests, no significant differences were observed between nicotine-treated and control animals at the age of 4 months. At 7 months, however, a significant difference in performance was evident, indicating a time-response/time-dependent effect. Furthermore, it was shown that in mice exposed neonatally to a nicotine dose known to inhibit the development of the nicotinic low affinity-binding site (LA), the response to nicotine could not cause any increase in spontaneous motor activity as seen in controls.

    Keywords
    nicotine, neonatal, development, spontaneous behaviour, adult, maze
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-91051 (URN)10.1016/S0166-4328(01)00207-8 (DOI)
    Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2017-12-14Bibliographically approved
    3. Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine
    Open this publication in new window or tab >>Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine
    2004 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 555-561Article in journal (Refereed) Published
    Abstract [en]

    Low-dose exposure of neonatal mice to nicotine has earlier been shown to induce an altered behavioral response to nicotine in adulthood. Organophosphorus insecticides are known to affect the cholinergic system by inhibition of acetylcholinesterase. This study was undertaken to investigate whether neonatal exposure to nicotine makes mice more susceptible to a known cholinergic agent. Neonatal, 10-day-old, male mice were exposed to nicotine-base (33 microg/kg body weight) or saline s.c. twice daily on five consecutive days. At 5 months of age the animals were exposed to paraoxon (0.17 or 0.25 mg/kg body weight [29% and 37% inhibition of cholinesterase, respectively]) or saline sc every second day for 7 days. Before the first paraoxon injection, the animals were observed for spontaneous motor behavior. The spontaneous motor behavior test did not reveal any differences in behavior between the treatment groups. Immediately after the spontaneous behavior test, the animals received the first injection of paraoxon and were observed for acute effects of paraoxon on spontaneous motor behavior. The acute response to paraoxon in the spontaneous motor behavior test was a decreased level of activity in mice neonatally exposed to nicotine. Control animals showed no change in activity. Two months after the paraoxon treatment, the animals were again tested for spontaneous motor behavior. Animals neonatally exposed to nicotine and exposed to paraoxon as adults showed a deranged spontaneous motor behavior, including hyperactivity and lack of habituation.

    Keywords
    Animals, Animals; Newborn/*physiology, Behavior; Animal/drug effects, Cholinesterase Inhibitors/*toxicity, Cholinesterases/metabolism, Habituation (Psychophysiology)/drug effects, Insecticides/*toxicity, Male, Mice, Motor Activity/drug effects, Nicotine/*pharmacology, Nicotinic Agonists/*pharmacology, Paraoxon/*toxicity, Receptors; Muscarinic/drug effects, Receptors; Nicotinic/drug effects, Research Support; Non-U.S. Gov't
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-91052 (URN)10.1093/toxsci/kfh274 (DOI)15356346 (PubMedID)
    Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2017-12-14Bibliographically approved
    4. Increased adult susceptibility to paraoxon in mice neonatally exposed to nicotine
    Open this publication in new window or tab >>Increased adult susceptibility to paraoxon in mice neonatally exposed to nicotine
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91053 (URN)
    Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2010-01-13Bibliographically approved
    5. Increased adult susceptibility to a brominated flame retardant, 2,2´4,4´,5-pentabromodiphenyl ether (PBDE 99) in mice neonatally exposed to nicotine
    Open this publication in new window or tab >>Increased adult susceptibility to a brominated flame retardant, 2,2´4,4´,5-pentabromodiphenyl ether (PBDE 99) in mice neonatally exposed to nicotine
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91054 (URN)
    Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2010-01-13Bibliographically approved
  • 2.
    Ankarberg, Emma
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Fredriksson, Anders
    Eriksson, Per
    Increased adult susceptibility to paraoxon in mice neonatally exposed to nicotineManuscript (Other academic)
  • 3.
    Ankarberg, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine2004In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 555-561Article in journal (Refereed)
    Abstract [en]

    Low-dose exposure of neonatal mice to nicotine has earlier been shown to induce an altered behavioral response to nicotine in adulthood. Organophosphorus insecticides are known to affect the cholinergic system by inhibition of acetylcholinesterase. This study was undertaken to investigate whether neonatal exposure to nicotine makes mice more susceptible to a known cholinergic agent. Neonatal, 10-day-old, male mice were exposed to nicotine-base (33 microg/kg body weight) or saline s.c. twice daily on five consecutive days. At 5 months of age the animals were exposed to paraoxon (0.17 or 0.25 mg/kg body weight [29% and 37% inhibition of cholinesterase, respectively]) or saline sc every second day for 7 days. Before the first paraoxon injection, the animals were observed for spontaneous motor behavior. The spontaneous motor behavior test did not reveal any differences in behavior between the treatment groups. Immediately after the spontaneous behavior test, the animals received the first injection of paraoxon and were observed for acute effects of paraoxon on spontaneous motor behavior. The acute response to paraoxon in the spontaneous motor behavior test was a decreased level of activity in mice neonatally exposed to nicotine. Control animals showed no change in activity. Two months after the paraoxon treatment, the animals were again tested for spontaneous motor behavior. Animals neonatally exposed to nicotine and exposed to paraoxon as adults showed a deranged spontaneous motor behavior, including hyperactivity and lack of habituation.

  • 4.
    Ankarberg, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Neurobehavioural defects in adult mice neonatally exposed to nicotine: changes in nicotine-induced behaviour and maze learning performance2001In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 123, no 2, p. 185-192Article in journal (Refereed)
    Abstract [en]

    Neonatal exposure to low doses of nicotine has been shown to disturb the development of low-affinity nicotinic binding sites in the cerebral cortex and to elicit a deviant behavioural response to nicotine in adult mice. In this study, 10-day-old male NMRI mice were exposed to one of three different doses of nicotine (3.3, 33, or 66 μg nicotine-base/kg body wt.) s.c. twice daily on 5 consecutive days to study dose–response effects of nicotine on adult spontaneous and nicotine-induced motor behaviour. The nicotine-induced behaviour test revealed a hypoactive response to nicotine in 4-month-old mice neonatally exposed to 33 or 66 μg nicotine-base, whereas the response to nicotine in control animals and mice exposed to 3.3 μg nicotine-base was an increased activity. Learning and memory functions were also investigated in adult animals neonatally exposed to 66 μg nicotine-base/kg body wt. in the same manner, in the Morris water maze and in the Radial arm maze. In the swim maze and the Radial arm maze tests, no significant differences were observed between nicotine-treated and control animals at the age of 4 months. At 7 months, however, a significant difference in performance was evident, indicating a time-response/time-dependent effect. Furthermore, it was shown that in mice exposed neonatally to a nicotine dose known to inhibit the development of the nicotinic low affinity-binding site (LA), the response to nicotine could not cause any increase in spontaneous motor activity as seen in controls.

  • 5.
    Ankarberg, Emma
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Fredriksson, Anders
    Jacobsson, Eva
    Eriksson, Per
    Increased adult susceptibility to a brominated flame retardant, 2,2´4,4´,5-pentabromodiphenyl ether (PBDE 99) in mice neonatally exposed to nicotineManuscript (Other academic)
  • 6.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Induction of ethoxyresorufin O-deethylase (EROD) and endothelial activation of the heterocyclic amine Trp-P-1 in bird embryo hearts1998In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 72, no 7, p. 402-410Article in journal (Refereed)
    Abstract [en]

    The xenobiotic-metabolizing activity of avian heart was investigated in chicken and Eider duck embryos exposed to aryl hydrocarbon (Ah) receptor agonists in ovo. Both beta-naphthoflavone (BNF) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) induced 7-ethoxyresorufin O-deethylase (EROD) activities in chicken embryo hearts whereas Eider duck embryos only responded to BNF. The differential responses of chicken and Eider duck embryos were used to examine the involvement of Ah receptor-mediated enzyme induction in the activation of the environmental and food mutagen 3-amino- 1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1). As determined by light microscopic autoradiography, there was a highly selective binding of non-extractable 3H-Trp-P-1-derived radioactivity in endothelial cells of large vessels and capillaries in hearts of BNF- and PCB 126-treated chicken embryos. No binding occurred at these sites in vehicle-treated controls. There was also a strong endothelial binding of 3H-Trp-P-1 in hearts of BNF-treated Eider duck embryos whereas no binding occurred in hearts of PCB 126-treated Eider duck embryos. A positive correlation between induction of EROD activity and covalent binding of 3H-Trp-P-1 to protein in heart homogenates from BNF- and PCB 126-treated chicken and Eider duck embryos was also observed. The results suggest a cytochrome P450 1A (CYP1A)-mediated activation of Trp-P-1 in avian heart endothelial cells although involvement of other Ah receptor-regulated enzymes is also possible. We propose that heart endothelial cells may be targets for bioactivation and toxicity of environmental contaminants in birds exposed to Ah receptor agonists.

  • 7.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granberg, Lena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Strandberg, William
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Basal and induced EROD activity in the chorioallantoic membrane during chicken embryo development1999In: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 8, no 1, p. 49-52Article in journal (Other academic)
    Abstract [en]

    The chorioallantoic membrane (CAM) is a highly vascularized tissue that takes part in the respiratory exchange of gases through the eggshell. Although the CAM may be exposed to environmental contaminants, its response to pollutants has not been studied. We examined the cytochrome P4501A (CYP1A)-catalyzed deethylation of 7-ethoxyresorufin (EROD) in the CAM during chicken embryo development. EROD was constitutively present and was inducible by the aryl hydrocarbon (Ah) receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Our results suggest the CAM as a first line of defence of the avian embryo against toxic compounds, but also as a target for CYP1A-activated chemicals.

  • 8.
    Carlsson, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO2). In mice, both substances bind firmly in the olfactory mucosa and the olfactory bulb, which are important components of the sensory system. The 2,6-isomer induces olfactory mucosal necrosis with permanent loss of olfactory neuroepithelium and olfactory nerves. A major objective was to clarify the cause of this isomer-specific toxicity, and to identify which physicochemical characteristics determine the olfactory toxicity. The neurobehavioural toxicity of these substances was also examined.

    The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO2 in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound.

    Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO2 induced Bowman’s glands necrosis and sloughing of the olfactory epithelium similar to that previously reported in mice. At 3 weeks, however, there were dramatic differences in histological lesions. In mice, large parts of olfactory epithelium were replaced by respiratory-like epithelium. Large, bilateral, fibrous, cartilage and bone containing polyps occluding the lumen were confirmed. In rats, only minor patches of olfactory epithelium were replaced by a metaplastic atypical respiratory-like epithelium. 2,5-diClPh-MeSO2 was non-toxic in rats as well as in mice.

    In mice, 2,6-diClPh-MeSO2 induced a dose-dependent and long-lasting ( ≥12 weeks) hyperactivity as well as long-lasting maze learning deficits. At 2 weeks hyperactivity and maze learning deficits were observed also in rats. Unexpectedly, 2,5-diClPh-MeSO2 induced hyperactivity that lasted for two weeks. No effect on maze learning was observed with this isomer. No major differences between male and female rats or mice were found.

    In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO2-metabolite in the Bowman’s glands precede the high olfactory mucosal toxicity in rodents. As determined by QSAR-modelling, a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron withdrawing substituent in the primary position has the potential of being an olfactory mucosal toxicant. The observed 2,6-diClPh-MeSO2-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO2 causes a direct effect in the brain leading to neurobehaviuoral deficits.

    List of papers
    1. Isomer-specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa
    Open this publication in new window or tab >>Isomer-specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa
    2003 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 31, no 4, p. 364-372Article in journal (Refereed) Published
    Abstract [en]

    This study aimed to explain the isomer- and site-specific toxic effects of dichlorophenyl methylsulphone in the olfactory mucosa of rats. A single ip dose of the 2,6-chlorinated isomer (16 or 65 mg/kg) induced necrosis preferentially in the Bowman's glands and neuroepithelium in the dorsomedial part of the olfactory region. Only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer (65 mg/kg). A strong concentration- and time-dependent covalent binding of the C-14-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the C-14-labeled 2,5-isomer was observed. The cytochrome P450 (CYP) inhibitors metyrapone, tranylcypromine and acetonitrile inhibited covalent binding of the 2,6-isomer to olfactory microsomes. Glutathione (GSH) appeared to play a protective role as a scavenger of a reactive intermediate whereas methyl-GSH did not alter covalent binding to olfactory microsomes. As determined by microautoradiography, binding of the 2,6-chlorinated isomer in the olfactory mucosa was confined to the Bowman's glands. Both isomers showed a low binding to liver microsomes and caused no liver injury. We suggest that a CYP2A-catalyzed activation of the 2,6-chlorinated dichlorophenyl methylsulphone to a reactive intermediate and adduct formation in the Bowman's glands will initiate a site-specific toxicity of this isomer in the olfactory mucosa.

    Keywords
    Bowman's gland, olfactory epithelium, 2, 6-dichlorophenyl methylsulphone, covalent binding, CYP2A, olfactory mucosa, rat, nasal toxicity
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-93786 (URN)10.1080/01926230390201075 (DOI)12851101 (PubMedID)
    Available from: 2005-11-25 Created: 2005-11-25 Last updated: 2018-01-13Bibliographically approved
    2. Behavioural changes related to olfactory mucosal metaplasia and bulbar Glial Fibrillary Acidic Protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice
    Open this publication in new window or tab >>Behavioural changes related to olfactory mucosal metaplasia and bulbar Glial Fibrillary Acidic Protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice
    2002 In: Archives of Toxicology, ISSN 0340-5761, Vol. 76, no 8, p. 474-483Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90538 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    3. 2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia
    Open this publication in new window or tab >>2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia
    2003 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, no 4, p. 156-168Article in journal (Refereed) Published
    Abstract [en]

    2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90539 (URN)10.1034/j.1600-0773.2003.930402.x (DOI)14629739 (PubMedID)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2017-12-14Bibliographically approved
    4. Olfactory mucosal toxicity screening and multivariate QSAR modelling for chlorinated benzene derivatives
    Open this publication in new window or tab >>Olfactory mucosal toxicity screening and multivariate QSAR modelling for chlorinated benzene derivatives
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90540 (URN)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2010-01-13Bibliographically approved
  • 9.
    Carlsson, Carina
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Bahrami, Fariba
    Fredriksson, Anders
    Brandt, Ingvar
    Behavioural changes related to olfactory mucosal metaplasia and bulbar Glial Fibrillary Acidic Protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice2002In: Archives of Toxicology, ISSN 0340-5761, Vol. 76, no 8, p. 474-483Article in journal (Refereed)
  • 10.
    Carlsson, Carina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, no 4, p. 156-168Article in journal (Refereed)
    Abstract [en]

    2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.

  • 11.
    Carlsson, Carina
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Harju, Mikael
    Bahrami, Fariba
    Cantillana, Tatiana
    Tysklind, Mats
    Brandt, Ingvar
    Olfactory mucosal toxicity screening and multivariate QSAR modelling for chlorinated benzene derivativesManuscript (Other academic)
  • 12. Eriksson, Per
    et al.
    Ankarberg, Emma
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Fredriksson, Anders
    Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice2000In: Brain Research, Vol. 853, p. 41-48Article in journal (Refereed)
  • 13. Eriksson, Per
    et al.
    Viberg, Henrik
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Jakobsson, Eva
    Örn, Ulrika
    Fredriksson, Anders
    A brominated flame-retardant, 2,2',4,4',5-pentabromodiphenyl ether: Uptake, retention and induction of neurobehavioural derangement in mice, during a critical phase of neonatal brain development.2002In: Toxicological Sciences, Vol. 67, p. 98-103Article in journal (Refereed)
  • 14.
    Franzén, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Isomer-specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa2003In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 31, no 4, p. 364-372Article in journal (Refereed)
    Abstract [en]

    This study aimed to explain the isomer- and site-specific toxic effects of dichlorophenyl methylsulphone in the olfactory mucosa of rats. A single ip dose of the 2,6-chlorinated isomer (16 or 65 mg/kg) induced necrosis preferentially in the Bowman's glands and neuroepithelium in the dorsomedial part of the olfactory region. Only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer (65 mg/kg). A strong concentration- and time-dependent covalent binding of the C-14-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the C-14-labeled 2,5-isomer was observed. The cytochrome P450 (CYP) inhibitors metyrapone, tranylcypromine and acetonitrile inhibited covalent binding of the 2,6-isomer to olfactory microsomes. Glutathione (GSH) appeared to play a protective role as a scavenger of a reactive intermediate whereas methyl-GSH did not alter covalent binding to olfactory microsomes. As determined by microautoradiography, binding of the 2,6-chlorinated isomer in the olfactory mucosa was confined to the Bowman's glands. Both isomers showed a low binding to liver microsomes and caused no liver injury. We suggest that a CYP2A-catalyzed activation of the 2,6-chlorinated dichlorophenyl methylsulphone to a reactive intermediate and adduct formation in the Bowman's glands will initiate a site-specific toxicity of this isomer in the olfactory mucosa.

  • 15.
    Granberg, Lizette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Östergren, Anna
    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 Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    CYP1A1 and CYP1B1 in blood-brain interfaces:: CYP1A1-dependent bioactivation of 7,12-dimethylbenz[a]anthracene in endothelial cells2003In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 31, no 3, p. 259-265Article in journal (Refereed)
    Abstract [en]

    Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.

  • 16.
    Halldin, Krister
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Endocrine modulators and sexual differentiation in Japanese quail: With emphasis on the neuroendocrine system2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chemical disruption of the endocrine system in various animal species is currently attracting considerable interest, but avian models are not yet widely used in studying endocrine disturbances. This thesis shows the occurrence of alterations in sexual behavior and reproductive organs in adult Japanese quail (Coturnix japonica) following embryonic exposure to estrogen-like chemicals.

    Exposure to synthetic estrogens and the environmental pollutant o,p´-DDT caused depressed male sexual behavior. Testis weight asymmetry, cloacal gland area and plasma testosterone levels were also changed, albeit not by all compounds. In females, o,p´-DDT caused disturbed egg laying and malformations of the oviducts. The pollutants bisphenol A and tetrabromobisphenol A did not cause estrogen-like effects at the doses tested. Sexual differentiation of the brain in birds is directed by estrogen, and in adult males, sexual behavior is activated by testosterone after local aromatization into estrogen in the brain. Consequently, the expression of estrogen receptors (ERs) is important both during differentiation and for activation of sexual behavior. The localization of ERα and ERβ mRNA in the brain was studied by in situ hybridization in embryos and adults of both sexes. Both receptors were localized in brain areas regulating sexual behavior. No distinct sex differences in localization or density of the mRNAs were found, but ERβ seemed to be present in higher density in the male nucleus taeniae. In embryos, ERβ was detected earlier than ERα, but by the end of incubation, both receptors were shown to be present.

    In conclusion, it was found that several reproductive variables in adult quail are disturbed by exposure to estrogen-like chemicals during the critical period of sexual differentiation. Sexual behavior was the most sensitive endpoint in males and it is suggested in the thesis that this variable be included in avian in vivo testing for endocrine modulating chemicals. In females, functional and morphological changes of the oviducts are useful endpoints for estrogen-like effects. The roles of ERα and ERβ in normal sexual differentiation in birds and in chemically induced disruptions of this process need to be elucidated further.

  • 17.
    Jaensson, Alia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Effects of glyphosate on olfactory mediated endorcine responses to female odours and reproductive behaviour in male brown trout (slamo trutta)In: Ecotoxicology, ISSN 0963-9292, E-ISSN 1573-3017Article in journal (Refereed)
  • 18.
    Jaensson, Alia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Olsén, K. Håkan
    Södertörns University.
    Prolonged cypermthrin exposure increases sex steroid plasma hormone levels in mature male brown trout (Salmo trutta) parr in spawning groupsIn: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514Article in journal (Refereed)
  • 19.
    Johansson, M.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Johansson, N.
    Lund, B-O
    Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cellsManuscript (Other academic)
  • 20.
    Johansson, M.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Larsson, C.
    Peters, N.
    Ellerichmann, T.
    Lund, B-O
    Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathwayManuscript (Other academic)
  • 21.
    Johansson, M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Sanderson, J. T.
    Lund, B-O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line2002In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 16, no 2, p. 113-121Article in journal (Refereed)
    Abstract [en]

    The formation of steroids in the H295R human adrenocortical carcinoma cell line was analysed by HPLC or RIA, and based on these data the apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in this cell line were calculated. The environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP) inhibitors ketoconazole, metyrapone and aminoglutethimide were studied for their effects on the steroid formation. Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM). Aminoglutethimide was examined only for effects on CYP11A activity and was shown to inhibit pregnenolone formation (20 microM: 61 +/- 4% of control). The possibility of studying all CYP enzymes in the corticosteroidogenesis makes this cell line a valuable test system to examine effects of chemicals, such as suspected endocrine disruptors, on the human glucocorticoid hormone synthesis. The inhibition of cortisol formation by 3-MeSO2-DDE supports an interaction with the active site of CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In mice, this interaction led to metabolic activation and a high adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity of 3-MeSO2-DDE in humans are needed.

  • 22.
    Johansson, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Persistent environmental pollutants were examined for their interaction with the glucocorticoid hormone system. The focus was placed on interference with the glucocorticoid synthesis and the glucocorticoid-signalling pathway in various in vitro test systems.

    Several aryl methyl sulphones competitively inhibited CYP11B1 activity in mouse adrenocortical Y1 cells. The DDT metabolite, 3-methylsulphonyl-2,2’-bis(4-chlorophenyl)-1,1’-dichloroethene (3-MeSO2-DDE) had a higher affinity to the enzyme than the endogenous substrate, 11-deoxycorticosterone. In fact, 3-MeSO2-DDE (Ki 1.6 μM) was almost as potent as the drug metyrapone (Ki 0.8 μM), a well-known inhibitor of the enzyme. 3-MeSO2-DDE inhibited CYP11B1 activity in human adrenocortical H295R carcinoma cells, and at higher concentrations the CYP21 activity. The human H295R cell line seems to be a useful test system for studies of enzyme activities and could be used to screen endocrine disrupting chemicals interfering with the glucocorticoid hormone synthesis.

    Several chiral PCB methyl sulphones and the fungicide tolylfluanid proved to be antagonists to the glucocorticoid receptor (GR) in rat hepatoma cells and/or Chinese hamster ovary cells stable transformed with a human GR and a responsive reporter vector. The 4-methylsulphonyl-2,3,6,2’,4’,5’-hexachlorobiphenyl (4-MeSO2-CB149) enantiomers had similar antagonistic effect on the GR. Co-exposure of substances led to additive inhibitory effects on glucocorticoid-regulated protein synthesis in rat hepatoma cells. In general, 4-substituted but not 3-substituted methylsulphonyl-PCBs interacted with the glucocorticoid hormone system.

    In the environment, humans and wildlife are constantly exposed to a wide range of chemicals. Considering the effects of these substances via mechanisms of actions described in this thesis, interference of xenobiotics with the glucocorticoid hormone system deserves further attention. In conclusion, environmental pollutants can interact with the glucocorticoid hormone system in vitro, yet the effects of the tested substances on this hormone system remain to be established in vivo.

    List of papers
    1. Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
    Open this publication in new window or tab >>Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
    1998 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 83, no 5, p. 225-230Article in journal (Refereed) Published
    Abstract [en]

    The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-89828 (URN)10.1111/j.1600-0773.1998.tb01473.x (DOI)9834972 (PubMedID)
    Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
    2. Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line
    Open this publication in new window or tab >>Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line
    2002 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 16, no 2, p. 113-121Article in journal (Refereed) Published
    Abstract [en]

    The formation of steroids in the H295R human adrenocortical carcinoma cell line was analysed by HPLC or RIA, and based on these data the apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in this cell line were calculated. The environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP) inhibitors ketoconazole, metyrapone and aminoglutethimide were studied for their effects on the steroid formation. Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM). Aminoglutethimide was examined only for effects on CYP11A activity and was shown to inhibit pregnenolone formation (20 microM: 61 +/- 4% of control). The possibility of studying all CYP enzymes in the corticosteroidogenesis makes this cell line a valuable test system to examine effects of chemicals, such as suspected endocrine disruptors, on the human glucocorticoid hormone synthesis. The inhibition of cortisol formation by 3-MeSO2-DDE supports an interaction with the active site of CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In mice, this interaction led to metabolic activation and a high adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity of 3-MeSO2-DDE in humans are needed.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-89829 (URN)10.1016/S0887-2333(01)00111-4 (DOI)11869873 (PubMedID)
    Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
    3. Interactions between methylsulfonyl PCBs and the glucocorticoid receptor
    Open this publication in new window or tab >>Interactions between methylsulfonyl PCBs and the glucocorticoid receptor
    1998 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 106, no 12, p. 769-772Article in journal (Refereed) Published
    Abstract [en]

    Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-89830 (URN)9831536 (PubMedID)
    Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
    4. Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells
    Open this publication in new window or tab >>Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-89831 (URN)
    Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2010-01-13Bibliographically approved
    5. Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathway
    Open this publication in new window or tab >>Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathway
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-89832 (URN)
    Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2010-01-13Bibliographically approved
  • 23.
    Johansson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Larsson, C.
    Bergman, Å.
    Lund, B-O
    Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones1998In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 83, no 5, p. 225-230Article in journal (Refereed)
    Abstract [en]

    The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

  • 24.
    Johansson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Nilsson, S.
    Lund, B-O
    Interactions between methylsulfonyl PCBs and the glucocorticoid receptor1998In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 106, no 12, p. 769-772Article in journal (Refereed)
    Abstract [en]

    Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.

  • 25.
    Jönsson, E. Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Abrahamson, Alexandra
    Brunström, Björn
    Brandt, Ingvar
    EROD activities in gills and liver and CYP1A localisation in gills of fish exposed to waterborne benzo[a]pyrene, PCB#126 and indigo.Manuscript (Other academic)
  • 26.
    Jönsson, E. Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Abrahamson, Alexandra
    Brunström, Björn
    Brandt, Ingvar
    Ingebrigtsen, Kristian
    Jørgensen, Even H.
    EROD activity in gills of anadromous and marine fish as a biomarker of dioxin-like pollutants.2003In: Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, Vol. 136, no 3, p. 235-243Article in journal (Refereed)
  • 27.
    Jönsson, E. Maria
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    Brandt, Ingvar
    Brunström, Björn
    A gill filament-based EROD assay for monitoring waterborne dioxin-like pollutants in fish.2002In: Environmental Science and Technology, ISSN 0013-936X, Vol. 36, no 15, p. 3340-3344Article in journal (Refereed)
  • 28.
    Jönsson, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
    A Gill Filament EROD Assay: Development and Application in Environmental Monitoring2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A gill filament-based assay for the cytochrome P450 1A (CYP1A)-catalysed activity ethoxyresorufin O-deethylase (EROD) was developed in rainbow trout (Oncorhynchus mykiss) and applied to Atlantic salmon (Salmo salar), Arctic charr (Salvelinus alpinus), Atlantic cod (Gadus morhua), saithe (Pollachius virens), and spotted wolffish (Anarhichas minor). Exposure to waterborne β-naphthoflavone (βNF; 10-6 M) induced branchial EROD activity in all species but the spotted wolffish. In rainbow trout exposed to low concentrations of benzo[a]pyrene (BaP; 10-9 M) and the textile dye indigo (10-8 M) the gills responded more rapidly than the liver to BaP, and indigo induced branchial but not hepatic EROD activity.

    A CYP1A-dependent BaP adduct formation was shown in gills of fish exposed to waterborne 3H-BaP, i.e. the adduct formation was enhanced by βNF and blocked by ellipticine (CYP1A inhibitor). The predominant location for BaP adducts was the secondary lamellae (most exposed part of the gill filament), whereas the CYP1A enzyme was also present in the primary lamellae of the gill filament. Hence, in addition to the cell-specific expression of CYP1A an important determinant for the localisation of adducts seemed to be the bioavailability of BaP. This idea is supported by the fact that the CYP1A enzyme was induced only in secondary lamellae by BaP (10-7 M) and indigo (10-6 M), whereas it was induced in both primary and secondary lamellae by 3,3´,4,4´,5-pentachlorobiphenyl (10-8 M). Apparently, readily metabolised inducers (BaP and indigo) are biotransformed in the secondary lamellae.

    My results show that gill filament EROD activity is a sensitive biomarker of exposure to waterborne dioxin-like pollutants, and that the assay has potential for use in monitoring. Furthermore, the results suggest that readily metabolised dioxin-like compounds absorbed via the gills may undergo first-pass metabolism in the gill cells and therefore remain undetected by monitoring of EROD activity in the liver.

    List of papers
    1. A gill filament-based EROD assay for monitoring waterborne dioxin-like pollutants in fish.
    Open this publication in new window or tab >>A gill filament-based EROD assay for monitoring waterborne dioxin-like pollutants in fish.
    2002 In: Environmental Science and Technology, ISSN 0013-936X, Vol. 36, no 15, p. 3340-3344Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91223 (URN)
    Available from: 2003-12-22 Created: 2003-12-22Bibliographically approved
    2. EROD activity in gills of anadromous and marine fish as a biomarker of dioxin-like pollutants.
    Open this publication in new window or tab >>EROD activity in gills of anadromous and marine fish as a biomarker of dioxin-like pollutants.
    Show others...
    2003 In: Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, Vol. 136, no 3, p. 235-243Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91224 (URN)
    Available from: 2003-12-22 Created: 2003-12-22Bibliographically approved
    3. Cell-specific CYP1A expression and benzo(a)pyrene adduct formation in gills of rainbow trout (Oncorhynchus mykiss ) following CYP1A induction in the laboratory and in the field
    Open this publication in new window or tab >>Cell-specific CYP1A expression and benzo(a)pyrene adduct formation in gills of rainbow trout (Oncorhynchus mykiss ) following CYP1A induction in the laboratory and in the field
    2004 (English)In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 23, no 4, p. 874-882Article in journal (Refereed) Published
    Abstract [en]

    The effect of cytochrome P4501A (CYP1A)induction on cell-specific benzo[a]pyrene (BaP) adduct formation was studied in rainbow trout (Oncorhynchus mykiss) gills. Fish preexposed to β-naphthoflavone (βNF) or caged in a polluted river were exposed to waterborne 3H-benzo[a]pyrene (3H-BaP). The 3H-benzo[a]pyrene adducts in the gill filaments were localized by autoradiography and CYP1A protein by immunohistochemistry. Ethoxyresorufin O-deethylase (EROD) activity was measured using a gill filament-based ex vivo assay. Branchial 3H-BaP binding and EROD activity were enhanced by exposure to βNF or to the river water, and completely blocked by the CYP1A inhibitor ellipticine. The predominant sites of adduct formation were in epithelium of the secondary lamellae and in epithelium of the efferent edge of the gill filament. In βNF-exposed fish, the strongest CYP1A immunoreactivity was observed in differentiating cells and in pillar cells. In fish caged in the polluted river, strong CYP1A immunoreactivity was found in most cells in the secondary lamellae, whereas the primary lamellae were almost devoid of immunoreactivity. Our results reveal a discrepancy between the localization of CYP1A protein and BaP adducts in the gill. Consequently, other factors, such as bioavailability of waterborne polycyclic aromatic hydrocarbons (PAHs) to the target cells, are important for the localization of PAH adducts in the gill.

    Keywords
    Gill, Cytochrome P4501A, Benzo[a]pyrene, Adduct
    Identifiers
    urn:nbn:se:uu:diva-91225 (URN)10.1897/03-211 (DOI)
    Available from: 2003-12-22 Created: 2003-12-22 Last updated: 2017-12-14Bibliographically approved
    4. EROD activities in gills and liver and CYP1A localisation in gills of fish exposed to waterborne benzo[a]pyrene, PCB#126 and indigo.
    Open this publication in new window or tab >>EROD activities in gills and liver and CYP1A localisation in gills of fish exposed to waterborne benzo[a]pyrene, PCB#126 and indigo.
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91226 (URN)
    Available from: 2003-12-22 Created: 2003-12-22 Last updated: 2010-01-13Bibliographically approved
  • 29.
    Lindhe, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Lund, Bert-Ove
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Bergman, Åke
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture2001In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 109, no 2, p. 105-110Article in journal (Refereed)
    Abstract [en]

    The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (MeSO(2)-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, MeSO(2)-DDE induces mitochondrial degeneration and cellular necrosis in the adrenal zona fasciculata. In this study, we used precision-cut tissue slice culture to examine local CYP11B1-catalyzed irreversible binding of MeSO(2)-DDE in the murine adrenal cortex. We also examined effects on steroid hormone secretion, histology, and ultrastructure. As determined by microautoradiography, selective binding occurred in zona fasciculata of slices exposed to MeSO(2)-[(14)C]-DDE. Quantification of binding by phosphorautoradiography revealed a 3-fold reduction of binding in slices co-exposed to the CYP11B1 inhibitor metyrapone. As measured by HPLC, corticosterone and 11-deoxycorticosterone secretion to the medium increased linearly for at least 24 hr. Addition of the ACTH analog tetracosactide caused an 8-fold increase in corticosterone secretion. Addition of metyrapone reduced corticosterone secretion 4-fold. Exposure of slices to MeSO(2)-DDE (50 microM) reduced the rate of corticosterone secretion by 90% after 24 hr of incubation. As determined by electron microscopy, vacuolated mitochondria were present in zona fasciculata of slices exposed to MeSO(2)-DDE (50 microM) for 24 hr. Our findings show that all effects of MeSO(2)-DDE previously reported in vivo could be reproduced in adrenal slice culture ex vivo. This test system allows analysis of zone-specific irreversible binding and effects on steroid hormone secretion and target cell ultrastructure. We propose adrenal slice culture as a simple ex vivo test system with which to examine the adrenocorticolytic activity of xenobiotics in human and wild animal tissue.

  • 30.
    Piras, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Franzén, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fernández, Estíbaliz
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Raffalli-Mathieu, Francoise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lang, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, p. 1545-1555Article in journal (Refereed)
    Abstract [en]

    We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.