| 1. |
- Carter, N, et al.
(författare)
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EUROQUEST - A questionnaire for solvent related symptoms: Factor structure, item analysis and predictive validity
- 2002
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Ingår i: NeuroToxicology. - 1872-9711 .- 0161-813X. ; 23:6, s. 711-717
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Tidskriftsartikel (refereegranskat)abstract
- The study evaluates the factor structure and predictive validity of the symptom questionnaire EUROQUEST (EQ) that had been developed with the goal of simplifying the evaluation of health effects associated with long-term solvent exposure. The EQ was added to the normal evaluation procedures for 118 male patients with suspected solvent-induced toxic encephalopathy (TE) referred to seven Swedish clinics of occupational medicine during an 18-month period. EQ was also completed by 239 males from a random sample of 400 Swedish males aged 25-64 years selected from the general population and a sample of 559 occupationally active male spray painters aged 25-64 years. Factor and item analyses of EQ responses were performed. Ordinary least square regression analysis was used to evaluate sensitivity and correlation to evaluate the specificity of EQ and the separate components. Questions concerning memory and concentration symptoms alone showed better sensitivity than the other five EQ dimensions singly or combined for the entire EQ and for a subset of questions approximating Q16, a widely used organic solvent symptom screening questionnaire. However, the diagnosis of TE required information in addition to exposure and responses to EQ and Q16-like questions. The results indicate that the subset of EQ questions concerning memory and concentration might replace the more cumbersome EQ and less sensitive Q16 in screening for TE, although none of the screening instruments alone replaces current clinical diagnostic procedures. (C) 2002 Elsevier Science Inc. All rights reserved.
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| 2. |
- Alm, Henrik, et al.
(författare)
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Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex
- 2008
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 29:4, s. 628-637
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Tidskriftsartikel (refereegranskat)abstract
- Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.
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| 3. |
- Aschner, Michael, et al.
(författare)
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Gene-environment interactions : Neurodegeneration in non-mammals and mammals
- 2010
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 31:5, s. 582-8
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Tidskriftsartikel (refereegranskat)abstract
- The understanding of how environmental exposures interact with genetics in central nervous system dysfunction has gained great momentum in the last decade. Seminal findings have been uncovered in both mammalian and non-mammalian model in large result of the extraordinary conservation of both genetic elements and differentiation processes between mammals and non-mammalians. Emerging model organisms, such as the nematode and zebrafish have made it possible to assess the effects of small molecules rapidly, inexpensively, and on a miniaturized scale. By combining the scale and throughput of in vitro screens with the physiological complexity and traditional animal studies, these models are providing relevant information on molecular events in the etiology of neurodegenerative disorders. The utility of these models is largely driven by the functional conservation seen between them and higher organisms, including humans so that knowledge obtained using non-mammalian model systems can often provide a better understanding of equivalent processes, pathways, and mechanisms in man. Understanding the molecular events that trigger neurodegeneration has also greatly relied upon the use of tissue culture models. The purpose of this summary is to provide-state-of-the-art review of recent developments of non-mammalian experimental models and their utility in addressing issues pertinent to neurotoxicity (Caenorhabditis elegans and Danio rerio). The synopses by Aschner and Levin summarize how genetic mutants of these species can be used to complement the understanding of molecular and cellular mechanisms associated with neurobehavioral toxicity and neurodegeneration. Next, studies by Suñol and Olopade detail the predictive value of cultures in assessing neurotoxicity. Suñol and colleagues summarize present novel information strategies based on in vitro toxicity assays that are predictive of cellular effects that can be extrapolated to effects on individuals. Olopade and colleagues describe cellular changes caused by sodium metavanadate (SMV) and demonstrate how rat primary astrocyte cultures can be used as predicitive tools to assess the neuroprotective effects of antidotes on vanadium-induced astrogliosis and demyelination.
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| 4. |
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| 5. |
- Bergström, Ulrika, et al.
(författare)
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Differential gene expression in the olfactory bulb following exposure to the olfactory toxicant 2,6-dichlorophenyl methylsulphone and its 2,5-dichlorinated isomer in mice
- 2007
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 28:6, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- 2,6-Dichlorophenyl methylsulphone and a number of structurally related chemicals are CYP-activated toxicants in the olfactory mucosa in mice and rats. This toxicity involves both the olfactory neuroepithelium and its subepithelial nerves. In addition, 2,6-dichlorophenyl methylsulphone, induces glial acidic fibrillary protein expression (Gfap, a biomarker for gliosis) in the olfactory bulb, as well as long-lasting learning deficits and changes in spontaneous behavior in mice and rats. So far the 2,5-dichlorinated isomer has not been reported to cause toxicity in the olfactory system, although it gives rise to transient changes in spontaneous behavior. In the present study we used 15k cDNA gene arrays and real-time RTPCR to determine 2,6-dichlorophenyl methylsulphone-induced effects on gene expression in the olfactory bulb in mice. Seven days following a single ip dose of 2,6-dichlorophenyl methylsulphone, 56 genes were found to be differentially expressed in the olfactory bulb. Forty-one of these genes clustered into specific processes regulating, for instance, cell differentiation, cell migration and apoptosis. The genes selected for real-time RT-PCR were chosen to cover the range of B-values in the cDNA array analysis. Altered expression of Gfap, mt-Rnr2, Ncor1 and Olfml3 was confirmed. The expression of these genes was measured also in mice dosed with 2,5-dichlorophenyl methylsulphone, and mt-Rnr2 and Olfml3 were found to be altered also by this isomer. Combined with previous data, the results support the possibility that the persistent neurotoxicity induced by 2,6-dichlorophenyl methylsulphone in mice represents both an indirect and a direct effect on the brain. The 2,5-dichlorinated isomer, negative with regard to CYP-catalyzed toxicity in the olfactory mucosa, may prove useful to resolve this issue.
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| 6. |
- Buratovic, Sonja, et al.
(författare)
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Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice
- 2014
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 45, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Cao, Yang, Associate Professor, 1972-, et al.
(författare)
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Does background postnatal methyl mercury exposure in toddlers affect cognition and behavior?
- 2010
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Ingår i: Neurotoxicology. - : Elsevier. - 0161-813X .- 1872-9711. ; 31:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb)-exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 microg/L and 0.52 microg/L and post-treatment concentrations were 0.51 microg/L and 0.48 microg/L for placebo and succimer groups, respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable.
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| 8. |
- Capela, Joao Paulo, et al.
(författare)
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The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons
- 2013
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Ingår i: NeuroToxicology. - : Elsevier BV. - 1872-9711 .- 0161-813X. ; 34, s. 254-263
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Tidskriftsartikel (refereegranskat)abstract
- 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24 h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24 h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT2A-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT2A-receptors. (C) 2012 Elsevier Inc. All rights reserved.
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| 9. |
- Carpenter, J. M., et al.
(författare)
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Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models : Modulation by the immunotherapeutic LNFPIII
- 2020
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Ingår i: Neurotoxicology. - : ELSEVIER. - 0161-813X .- 1872-9711. ; 77, s. 40-50
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Tidskriftsartikel (refereegranskat)abstract
- Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethylmethylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-FIT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.
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| 10. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Epigenetics of methylmercury
- 2023
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 97, s. 34-46
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of review: Methylmercury (MeHg) is neurotoxic at high levels and particularly affects the developing brain. One proposed mechanism of MeHg neurotoxicity is alteration of the epigenetic programming. In this review, we summarise the experimental and epidemiological literature on MeHg-associated epigenetic changes.Recent findings: Experimental and epidemiological studies have identified changes in DNA methylation following in utero exposure to MeHg, and some of the changes appear to be persistent. A few studies have evaluated associations between MeHg-related changes in DNA methylation and neurodevelopmental outcomes. Experimental studies reveal changes in histone modifications after MeHg exposure, but we lack epidemiological studies supporting such changes in humans. Experimental and epidemiological studies have identified microRNA-related changes associated with MeHg; however, more research is needed to conclude if these changes lead to persistent and toxic effects.Summary: MeHg appears to interfere with epigenetic processes, potentially leading to persistent changes. However, observed associations of mercury with epigenetic changes are as of yet of unknown relevance to neurodevelopmental outcomes.
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