| 1. |
- Engelsen, Bernt, et al.
(author)
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Effect of Insulin‐Induced Hypoglycemia on the Concentrations of Glutamate and Related Amino Acids and Energy Metabolites in the Intact and Decorticated Rat Neostriatum
- 1986
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 47:5, s. 1634-1641
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Journal article (peer-reviewed)abstract
- Abstract The glutamate (Glu) terminals in rat neostriatum were removed by a unilateral frontal decortication. One to two weeks later the effects of insulin‐induced hypoglycemia on the steady‐state levels of amino acids [Glu, glutamine (Gin), aspartate (Asp), γ‐aminobutyric acid (GABA), tau‐rine] and energy metabolites (glucose, glycogen, α‐ketoglu‐tarate, pyruvate, lactate, ATP, ADP, AMP, phosphocre‐atine) were examined in the intact and decorticated neostriatum from brains frozen in situ. The changes in the metabolite levels were examined during normoglycemia, hypoglycemia with burst‐suppression (BS) EEG, after 5 and 30 min of hypoglycemic coma with isoelectric EEG, and 1 h of recovery following 30 min of isoelectric EEG. In normoglycemia Glu decreased and Gin and glycogen increased significantly on the decorticated side. During the BS period no significant differences in the measured compounds were noted between the two sides. After 5 min of isoelectric EEG Glu, Gin, GABA, and ATP levels were significantly lower and Asp higher on the intact than on the decorticated side. No differences between the two sides were found after 30 min of isoelectric EEG. After 1 h of recovery from 30 min of isoelectric EEG Glu, Gin, and glycogen had not reached their control levels. Glu was significantly lower, and Gin and glycogen higher on the decorticated side. The Asp and GABA levels were not significantly different from control levels. The results indicate that the turnover of Glu is higher in the intact than in decorticated neostriatum during profound hypoglycemia.
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| 2. |
- Mariussen, Espen, et al.
(author)
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Effect of Polychlorinated Biphenyls on the Uptake of Dopamine into Rat Brain Synaptic Vesicles: A Structure–Activity Study
- 2001
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In: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X. ; 175:2, s. 176-83
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Journal article (peer-reviewed)abstract
- PCBs are neurotoxic compounds that have a known effect on the dopaminergic system in the brain. In a previous work it was established that PCBs are potent inhibitors of the uptake of dopamine into rat brain synaptic vesicles. In this work we further investigated the vesicular dopamine uptake in response to different PCBs to explore the structure–activity relationship involved in this effect. Twenty PCB congeners were selected, based on multivariate chemical characterization, to cover the chemical variation within tetra- to hepta-chlorinated PCBs. PCBs of large structural variation were tested and the general finding was that only the ortho-substituted PCBs inhibited the dopamine uptake. The most active congeners were the penta- and hexa-chlorinated PCBs. Furthermore, the uptake was correlated with parameters describing the absolute hardness, the octanol–water partition coefficient, and the Henry's law constant. These parameters are correlated to the number of chlorine atoms in ortho positions and to the size of the molecule. Notably the most active PCBs are highly prevalent in the environment and are disposed to bioaccumulate in wildlife. Thus, these neurotoxic effects should be included in the risk assessment of PCBs.
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| 3. |
- Mariussen, Espen, et al.
(author)
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The effect of various substituents in ortho position of biphenyls on respiratory burst, intracellular calcium elevation in human granulocytes, and uptake of dopamine into rat brain synaptic vesicles and synaptosomes
- 2003
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In: Environmental Toxicology and Pharmacology. ; 14:1-2, s. 43-50
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Journal article (peer-reviewed)abstract
- Polychlorinated biphenyls (PCBs) are a group of compounds, which have effects on the immune and nervous system. We have investigated the effects of seven diortho-substituted biphenyls with different substituents on activation of respiratory burst and calcium elevation in human granulocytes, and inhibition of the uptake of dopamine into synaptic vesicles and synaptosomes isolated from rat brain. We have attempted to find the chemical and physical properties, which can contribute to the variation in biological effects. These properties include the absolute hardness, the molecular size, the hydrophobicity of the molecules, the retention time on a DB5-MS GC-column and the electronegativity of the substituents. In general the dichloro- and dibromobiphenyls were the most potent in all biological tests. The difluorosubstituted was less potent than the other two halide-biphenyls presumably because of the smaller size of the substituent. Dimethylbiphenyl was active in all tests. Dihydroxy- and dimethanolbiphenyl were inactive in all tests, whereas dinitrobiphenyl was only active as a vesicular dopamine uptake inhibitor. Important physico-chemical parameters correlated to the effects were absolute hardness, molecular size and lipophilicity. Among the tested diortho-substituted biphenyls the most active were the chlorinated, brominated, and methylated. This indicates the significance of the molecular size in combination with the hydrophobicity for the studied toxic effects.
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| 4. |
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| 5. |
- Stenberg, Mia, 1979-, et al.
(author)
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Multivariate toxicity profiles and QSAR modeling of non-dioxin-like PCBs : an investigation of in vitro screening data from ultra-pure congeners
- 2011
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In: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 85:9, s. 1423-1429
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Journal article (peer-reviewed)abstract
- The non-dioxin-like PCBs (NDL-PCBs) found in food and human samples have a complex spectrum of adverse effects, but lack a detailed risk assessment. The toxicity profiles of 21 carefully selected PCBs (19 NDL-PCBs) were identified by in vitro screening in 17 different assays on specific endpoints related to neurotoxicity, endocrine disruption and tumor promotion. To ensure that the test results were not affected by polychlorinated dioxins, dibenzofurans or DL-PCB contaminants, the NDL-PCB congeners were thoroughly purified before testing. Principal component analysis (PCA) was used to derive general toxicity profiles from the in vitro screening data. The toxicity profiles indicated different structure-activity relationships (SAR) and distinct mechanisms of action. The analysis also indicated that the NDL-PCBs could be divided into two groups. The first group included generally smaller, ortho-substituted congeners, comprising PCB 28, 47, 51, 52, 53, 95, 100, 101, 104 and 136, with PCB 95, 101 and 136 as generally being most active. The second group comprising PCB 19, 74, 118, 122, 128, 138, 153, 170, 180 and 190 had lower biological activity in many of the assays, except for three endocrine-related assays. The most abundant congeners, PCB 138, 153, 170, 180 and 190, cluster in the second group, and thereby show similar SAR. Two quantitative structure-activity relationship (QSAR) models could be developed that added information to the SAR and could aid in risk assessments of NDL-PCBs. The QSAR models predicted a number of congeners as active and among these e.g., PCB 18, 25, 45 and 49 have been found in food or human samples.
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| 6. |
- Viluksela, Matti, et al.
(author)
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Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.
- 2014
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104639-
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Journal article (peer-reviewed)abstract
- PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.
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| 7. |
- Wigestrand, Mattis B., et al.
(author)
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Non-dioxin-like PCBs inhibit [3H]WIN-35,428 binding to the dopamine transporter : a structure–activity relationship study
- 2013
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In: Neurotoxicology. - : Elsevier. - 0161-813X .- 1872-9711. ; 39, s. 18-24
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Journal article (peer-reviewed)abstract
- Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are neurotoxic compounds with known effects at the dopaminergic system in the brain. In a previous study we demonstrated that NDL-PCBs inhibit uptake of dopamine into rat brain synaptosomes, an effect most likely mediated by inhibition of the dopamine transporter (DAT). Here, using the cocaine analogue [3H]WIN-35,428 binding assay and synaptosomes, we directly investigate whether NDL-PCBs act via DAT and explore the structure–activity relationship of this effect. In total, thirty PCBs were investigated, including a previously selected training set of twenty PCBs covering the structural variation within tri- to hepta-chlorinated NDL-PCBs, and an additional set of ten NDL-PCB congeners selected to validate the structure–activity pattern of neurotoxic PCBs. Since previous work has demonstrated that NDL-PCBs can also inhibit the vesicular monoamine transporter 2 (VMAT2), we additionally examined whether some PCB congeners favour an effect on VMAT2 and others on DAT. Our results show that NDL-PCBs are potent inhibitors of [3H]WIN-35,428 binding to DAT. In fact, we identify a PCB congener (PCB 110) with similar potency for [3H]WIN-35,428 binding inhibition as cocaine. All active congeners were ortho-chlorinated PCBs, and in particular, tetra- and penta-chlorinated with 2–3 chlorine atoms in the ortho position were potent inhibitors of [3H]WIN-35,428 binding. Notably, the most active PCBs are highly prevalent in commercial mixtures of PCBs (Aroclor 1242, 1254 and 1260), which indicates that DAT inhibition could be one of the factors contributing to behavioural effects after Aroclor exposure. Derived data correlated well with the recently derived neurotoxic equivalency factors (NEQs), indicating the generality and applicability of the NEQ scheme in risk assessments of PCBs.
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