Developmental lead (Pb) exposure is associated with cognitive impairments in humans and rodents alike. In particular, impaired spatial learning and memory, as assessed using the Morris water maze (MWM), has been noted in developmentally Pb –exposed rats. Although sex and rearing environment can influence MWM performance in normal animals, the interactions of sex and rearing environment on the impact of developmental Pb exposure on hippocampal-dependent processes has not been well characterized. The present study examined the effects of perinatal exposure (i.e., gestation through weaning) to different levels of Pb (250, 750 and 1,500 ppm Pb acetate in food) in males and females raised in a non-enriched environment (standard cage with 3 animals and no toys) or an enriched environment (large cage containing a variety of toys that were changed twice weekly). Testing in the MWM began at postnatal day 55. Behavioral outcomes were influenced by sex and rearing environment, with complex interactions with Pb exposure. In non-Pb exposed control animals, beneficial effects of environmental enrichment on spatial learning and memory were observed in males and females, with greater effects in females. Pb exposure in females mitigated at least some of the benefits of enrichment on learning, particularly at the lowest and highest exposure levels. In males, enrichment conferred a modest learning advantage and for the most part, Pb exposure did not affect this. However, in males with the highest Pb exposure, enrichment did help to overcome detrimental effects of Pb on learning. In females, any potential benefit to reference memory contributed by enrichment was muted by exposure to Pb and for the most part, this was not reproduced in males. Thus, there are complex interactions between sex, environment, and Pb exposure on spatial learning and memory. Environmental manipulation is a potential risk modifier of developmental Pb exposure and interacts with other factors including sex and amount of Pb exposure to affect the functional influences of Pb on the brain.
Lead; Sex; Environment; Learning; Memory
Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood-brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain’s olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2–200 μg MnCl2 solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2 μg MnCl2 and a 90% reduction compared to vehicle controls with a 200 μg exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn’s action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn’s action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects.
Manganese; Olfactory; Olfaction; Imaging; Pathophysiology; Exocytosis
Lead (Pb) was one of the first poisons identified, and the developing nervous system is particularly vulnerable to its toxic effects. Relatively low, subclinical doses, of Pb that produce no overt signs of encephalopathy can affect cognitive, emotional, and motor functions. In the present study, the effects of developmental Pb-exposure on behavioral performance and gene expression in BALB/cAnNTac mice were evaluated. Pups were exposed to Pb from gestational-day (gd) 8 to postnatal-day (pnd) 21 and later evaluated in exploratory behavior, rotarod, Morris water maze, and resident-intruder assays as adults. Pb-exposure caused significant alterations in exploratory behavior and water maze performance during the probe trial, but rotarod performance was not affected. Pb-exposed males displayed violent behavior towards their cage mates, but not to a stranger in the resident-intruder assay. Gene expression analysis at pnd21 by microarray and qRT-PCR was performed to provide a molecular link to the behavior changes that were observed. Pb strongly up-regulated gene expression within the signaling pathways of mitogen activated protein kinases (MAPKs), extra-cellular matrix (ECM) receptor, focal adhesion, and vascular endothelial growth-factor (VEGF), but Pb down-regulated gene expression within the pathways for glycan structures-biosynthesis 1, purine metabolism, and N-glycan biosynthesis. Pb increased transcription of genes for major histocompatibility (MHC) proteins, the chemokine Ccl28, chemokine receptors, IL-7, IL7R, and proteases. The qRT-PCR analysis indicated an increase of gene expression in the whole brain for caspase 1 and NOS2. Analysis of IL-1β, caspase 1, NOS2, Trail, IL-18 and IL-33 gene expression of brain regions indicated that Pb perturbed the inter-regional expression pattern of pro-inflammatory genes. Brain region protein concentrations for IL-10, an anti-inflammatory cytokine, showed a significant decrease only within the cortex region. Results indicate that Pb differentially affects the behavior of male and female mice in that females did less exploration and the males were selectively more aggressive. Gene expression data pointed to evidence of neuroinflammation in the brain of both female and male mice. Pb had more of an effect in the males on expression of vomeronasal receptor genes associated with odor detection and social behavior.
Behavior; Brain; Cytokines; Gene Expression; Inflammation; Lead; Microarray
An exaggerated response to emotional stimuli is one of several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1–3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity.
Gulf War Illness; hyperarousal; ERPs; P1; P3a; P3b; cholinergic; dopaminergic
Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1ppm) but also levels previously considered to be low (<100 ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50 ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50 ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic.
Arsenic (As); Hypothalamic-Pituitary-Adrenal (HPA) axis; Glucocorticoid Receptor (GR); Neuroendocrine; corticotrophin-releasing factor (CRF); adrenocorticotrophin hormone (ACTH); corticosterone
Polychlorinated biphenyls (PCBs) are synthetic chemicals primarily used as coolants and insulators in electrical equipment. Although banned for several decades, PCBs continue to exist in the environment because of their long half-life, continued presence in items produced before the ban, and poor disposal practices. Epidemiological and experimental studies have identified exposure to PCBs as a potential risk factor for Parkinson’s disease, perhaps more so in females. The objective of this work was to examine the association between PCB levels in post-mortem human brain tissue and the diagnosis of Parkinson’s disease, as well as the degree of nigral depigmentation. We also sought to determine if this association was more significant when patients were stratified by sex. Post-mortem brain samples from control patients and those diagnosed with Parkinson’s disease were obtained from the Emory University Brain Bank and from the Nun Study. Concentrations of eight prevalent PCB congeners were extracted from post-mortem brain tissue and analyzed using gas chromatography-mass spectrometry. PCB congeners 153 and 180 were significantly elevated in the brains of Parkinson’s disease patients. When stratified by sex, the female Parkinson’s disease group demonstrated significantly elevated concentrations of total PCBs and specifically congeners 138, 153, and 180 compared to controls, whereas PCB concentrations in males were not significantly different between control and Parkinson’s disease groups. In a separate population of women (Nun Study) who had no clinical signs or symptoms of PD, elevated concentrations total PCB and congeners 138, 153 and 180 were also observed in post-mortem brain tissue exhibiting moderate nigral depigmentation compared to subjects with mild or no depigmentation. These quantitative data demonstrate an association between brain PCB levels and Parkinson’s disease-related pathology. Furthermore, these data support epidemiological and laboratory studies reporting a link between PCB exposure and an increased risk for Parkinson’s disease, including greater susceptibility of females.
Parkinson’s disease; polychlorinated biphenyl; PCB; sex; exposure; neurodegenerative disease; mass spectrometry
Both lead (Pb) exposure and prenatal stress (PS) can produce cognitive deficits, and in a prior study we demonstrated enhanced cognitive deficits in repeated learning of female rats exposed to both of these developmental insults (Cory-Slechta et al., 2010). However, PS can also lead to improved cognitive outcomes that are both gender-and context-dependent. Thus, the current study examined whether Pb ± PS likewise produced repeated learning deficits in males, either after maternal or lifetime Pb exposure. Repeated learning was evaluated using a multiple schedule of repeated learning and performance that required learning 3-response sequences in male offspring that had been subjected to either maternal Pb (0 or 150 ppm) or lifetime Pb exposure (0 or 50 ppm) beginning two mos prior to dam breeding, to prenatal immobilization restraint stress (gestational days 16–17), or to both Pb and PS. Blood Pb, corticosterone, hippocampal glucocorticoid receptor density and brain monoamines were also measured. In contrast to outcomes in females, sequence-specific enhancements of repeated learning accuracy were produced by PS, particularly when combined with Pb, results that appeared to be more robust in combination with lifetime than maternal Pb exposure. A common behavioral mechanism of these improvements appears to be an increase reinforcement density associated with increased response rates and shorter session times seen with PS ± Pb that could both shorten time to reinforcement. Trends towards lower levels of nucleus accumbens dopamine activity seen after both maternal Pb and lifetime Pb combined with PS suggest a possible role for this region/neurotransmitter in enhanced accuracy, whereas PS ± Pb-induced corticosterone changes did not exhibit an obvious systematic relationship to accuracy enhancements. While PS ± Pb-based increases in accuracy appear to be an improved outcome, the benefits of increased response rate are by no means universal, but highly context-dependent and can lead to adverse behavioral effects in other conditions.
lead; prenatal stress; reversal learning; sex; corticosterone; nucleus accumbens dopamine
Mitochondrial dysfunction and subsequent energy failure is a contributing factor to degeneration of the substantia nigra pars compacta associated with Parkinson’s disease (PD). In this study, we investigate molecular events trigger by 1-methyl-4-phenylpyridine (MPP+) using whole genome-expression microarray, western blot and HPLC quantification of metabolites. The data show that MPP+ (500μM) evokes obstruction of mitochondrial respiration/oxidative phosphorylation (OXPHOS) in mouse neuroblastoma Neuro-2a cells, juxtapose to accelerated glucose consumption and production of lactic acid. While additional glucose concentrations restored viability at MPP+ (500μM), loss of OXPHOS was sustained suggesting that compensatory anaerobic metabolic systems were fulfilling required energy needs. Under these conditions, MPP+ initiated significant changes to the transcription of 799 genes (596 up-regulated and 203 down-regulated) of which 612 David IDS were applied and 136 functional annotation clusters were identified. Prominent changes were as follows; MPP+ initiated loss of mRNA for mitochondrial encoded NADH dehydrogenase 4, 5 genes, cytochrome b and NADH dehydrogenase (ubiquinone) flavoprotein 3, concomitant to rise in a mitochondrial fission gene; ganglioside-induced differentiation-associated-protein 1 (GDAP1). These negative changes to OXPHOS components were accompanied by a number of protective forces to the mitochondria including elevated ratio of mitochondrial anti/pro-apoptotic processes including a loss of apoptotic Bcl-2/adenovirus E1B 19-kDa-interacting protein (BNIP3) and family with sequence similarity 162, member A (FAM162a) and rise of heat shock protein 1 and Lon peptidase 1. There were no changes indicative of free radical damage (e.g. SOD, GSH-Px), rather MPP+ initiated a large number of significant G protein signaling components (which trigger catabolic processes) and anaerobic metabolic systems involving carboxylic acid/ transamination reactions (e.g. glutamate oxaloacetate transaminase 1 (GOT1), glutamic pyruvate-alanine transaminase 2 (GPT2), cystathionase and redox proteins such as cytochrome b5 reductase 1 and ferredoxin reductase. Counter-intuitively, the data show reduction of mRNA in glycolytic processes [DAVID enrichment score 9.96 p value 1.90E-19], some corroborated by western blot, bringing in to question the sources of lactate observed in the presence of MPP+. Examining this aspect, the data show that diverse carboxylic acids (succinate, oxaloacetate and a-ketoglutarate) are capable of contributing to the lactate pool in addition to phosph(enolpyruvate) or pyruvate in the absence of glucose by this cell line. In conclusion, these findings show that MPP+ negatively affects the transcriptome involved with complex I, but evoked elevation in G protein signaling and anaerobic metabolic systems involved with nitrogen/carboxylic acid metabolism and redox reactions. Anaerobic survival systems appear to be far more complex than previously believed, and future research will be required to elucidate the survival pathways that drive anaerobic substrate level phosphorylation, and define functional ramification to the loss of mitochondrial FAM162a and BNIP3 proteins.
MPP+; Neuro 2a; Parkinson’s disease; whole genome; glycolysis; Complex I
Resin-based dental restorations may intra-orally release their components and bisphenol A. Gestational bisphenol A exposure has been associated with poorer executive functioning in children.
To examine whether exposure to resin-based composite restorations is associated with neuropsychological development in children.
Secondary analysis of treatment level data from the New England Children’s Amalgam Trial, a 2-group randomized safety trial conducted from 1997–2006. Children (N=534) aged 6–10 y with >2 posterior tooth caries were randomized to treatment with amalgam or resin-based composites (bisphenol-A-diglycidyl-dimethacrylate-composite for permanent teeth; urethane dimethacrylate-based polyacid-modified compomer for primary teeth). Neuropsychological function at 4- and 5-year follow-up (N=444) was measured by a battery of tests of executive function, intelligence, memory, visual-spatial skills, verbal fluency, and problem-solving. Multivariable generalized linear regression models were used to examine the association between composite exposure levels and changes in neuropsychological test scores from baseline to follow-up. For comparison, data on children randomized to amalgam treatment were similarly analyzed.
With greater exposure to either dental composite material, results were generally consistent in the direction of slightly poorer changes in tests of intelligence, achievement or memory, but there were no statistically significant associations. For the four primary measures of executive function, scores were slightly worse with greater total composite exposure, but statistically significant only for the test of Letter Fluency (10-surface-years β= −0.8, SE=0.4, P=0.035), and the subtest of color naming (β= −1.5, SE=0.5, P=0.004) in the Stroop Color-Word Interference Test. Multivariate analysis of variance confirmed that the negative associations between composite level and executive function were not statistically significant (MANOVA P=0.18). Results for greater amalgam exposure were mostly nonsignificant in the opposite direction of slightly improved scores over follow-up.
Dental composite restorations had statistically insignificant associations of small magnitude with impairments in neuropsychological test change scores over 4- or 5-years of follow-up in this trial.
Composite dental resin; Composite resins; Bisphenol A-Glycidyl Methacrylate; Compomers; Child Development; Neuropsychological tests; Executive Function; Epidemiology; Prospective Studies
Comparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The Radial Arm Maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies.
To describe the characteristics and correlates of the Virtual Radial Arm Maze (VRAM) in 255 children age 10–15 years from Italy.
We administered the VRAM using a laptop computer and measured children’s performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills.
Children’s VRAM performance tended to improve between trials 1–6 and then plateaued between trials 6–8. Males finished the task 14 seconds faster (95% Confidence Interval [CI]:-20, -9) than females. Children who played 2+ hours of video games per day finished 16 seconds faster (CI:-26, -6) and with 34% (CI:5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher Cognitive/Inattention CPRS scores were associated with more working (11%; CI:1, 22) and reference memory errors (7%; CI:1, 12).
Consistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants.
Child behavior; computerized tests; environmental chemicals; epidemiology; toxicology
Synthetic stimulants commonly sold as “bath salts” are an emerging abuse problem in the U.S. Users have shown paranoia, delusions, and self-injury. Previously published in vivo research has been limited to only two components of bath salts (mephedrone and methylone). The purpose of the present study was to evaluate in vivo effects of several synthetic cathinones found in bath salts and to compare them to those of cocaine (COC) and methamphetamine (METH). Acute effects of methylenedioxyphyrovalerone (MDPV), mephedrone, methylone, methedrone, 3-fluoromethcathinone (3-FMC), 4-fluoromethcathinone (4-FMC), COC, and METH were examined in male ICR mice on locomotor activity, rotorod, and a functional observational battery (FOB). All drugs increased locomotor activity, with different compounds showing different potencies and time courses in locomotor activity. 3-FMC and methylone decreased performance on the rotorod. The FOB showed that in addition to typical stimulant induced effects, some synthetic cathinones produced ataxia, convulsions, and increased exploration. These results suggest that individual synthetic cathinones differ in their profile of effects, and differ from known stimulants of abuse. Effects of 3-FMC, 4-FMC, and methedrone indicate these synthetic cathinones share major pharmacological properties with the ones that have been banned (mephedrone, MDPV, methylone), suggesting that they may be just as harmful.
locomotor activity; MDPV; mephedrone; methylone; mouse; synthetic cathinones
Humans and wildlife are exposed to environmental pollutants that have been shown to interfere with the thyroid hormone system and thus may affect brain development. Our goal was to expose pregnant rats to propylthiouracil (PTU) to measure the effects of a goitrogen on white matter development in offspring using magnetic resonance imaging (MRI) and volumetric analysis. We exposed pregnant Sprague Dawley (SD) rats to 3 or 10 ppm PTU from gestation day 7 (GD7) until postnatal day 25 (P25) to determine the effects on white matter (WM), gray matter (GM), and hippocampus volumes in offspring. We sacrificed offspring at P25 but continued the life of some offspring to P90 to measure persistent effects in adult animals. P25 offspring exposed to 10 ppm PTU displayed lowered levels of triiodothyronine (T3) and thyroxine (T4); cerebral WM, GM, and total brain volumes were significantly lower than the volumes in control animals. P90 adults exposed to 10 ppm PTU displayed normal T3 levels but lowered T4 levels; WM, GM, total brain, and hippocampal volumes were significantly lower than the volumes in control adults. Both P25 and P90 rats exposed to 10 ppm PTU displayed significant reductions in percent WM as well as heterotopias in the corpus callosum. Exposure to 3 ppm PTU did not produce any significant effects. These results suggest that MRI coupled with volumetric analysis is a powerful tool in assessing the effects of thyroid hormone disruption on white matter development and brain structure. This approach holds great promise in assessing neurotoxicity of xenobiotics in humans and wildlife.
Myelination; White matter; Magnetic Resonance Imaging; Brain; Thyroid Hormone
Sodium channel inhibitor (SCI) insecticides are hypothesized to inhibit voltage-gated sodium channels by binding selectively to the slow-inactivated state. Replacement of valine at position 787 in the S6 segment of homology domain II of the rat Nav1.4 sodium channel by lysine (V787K) enchances slow inactivation of this channel whereas replacement by alanine or cysteine (V787A, V787C) inhibits slow inactivation. To test the hypothesis that SCI insecticides bind selectively to the slow-inactivated state, we constructed mutated Nav1.4/V787A, Nav1.4/V787C, and Nav1.4/V787K cDNAs, expressed wildtype and mutated channels with the auxiliary β1 subunit in Xenopus oocytes, and used the two-electrode voltage clamp technique to examine the effects of these mutations on channel inhibition by four SCI insecticides (indoxacarb, its bioactivated metabolite DCJW, metaflumizone, and RH3421). Mutations at Val787 affected SCI insecticide sensitivity in a manner that was independent of mutation-induced changes in slow inactivation gating. Sensitivity to inhibition by 10 μM indoxacarb was significantly increased in all three mutated channels, whereas sensitivity to inhibition by 10 μM metaflumizone was significantly reduced in Nav1.4/V787A channels and completely abolished in Nav1.4/V787K channels. The effects of Val787 mutations on metaflumizone were correlated with the hydrophobicity of the substituted amino acid rather than the extent of slow inactivation. None of the mutations at Val787 significantly affected the sensitivity to inhibition by DCJW or RH3421. These results demonstrate that the impact of mutations at Val787 on sodium channel inhibition by SCI insecticides depends on the specific insecticide examined and is independent of mutation-induced changes in slow inactivation gating. We propose that Val787 may be a unique determinant of metaflumizone binding.
Sodium channel; inhibition; insecticide; slow inactivation; indoxacarb; metaflumizone
The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.
To draw inferences about windows of susceptibility using the pattern of associations between serial childhood blood lead (BPb) concentrations and children’s cognitive abilities at 4 years of age among 1035 mother–child pairs enrolled in 4 prospective birth cohorts from Mexico City.
Multiple longitudinally collected BPb measurements were obtained from children (1, 2, 3, and 4 years) between 1994 and 2007. Child cognitive abilities were assessed at 4 years using the general cognitive index (GCI) of the McCarthy Scales of Children’s Abilities. We used multivariable linear regression to estimate the change in cognitive abilities at 4 years of age with a 10 μg/dL increase in childhood BPb concentrations adjusting for maternal IQ, education, marital status, child sex, breastfeeding duration, and cohort.
In separate models for each BPb measurement, 2 year BPb concentrations were most strongly associated with reduced GCI scores at 4 years after adjusting for confounders (β: −3.8; 95% confidence interval CI: −6.3, −1.4). Mutual adjustment for other BPb concentrations in a single model resulted in larger, but less precise estimate between 2 year BPb concentrations and GCI scores at 4 years of age (β: −7.1; 95% CI: −12, −2.0). The association between 2 year BPb and GCI was not heterogeneous (p = 0.89), but some BPb and GCI associations varied in magnitude and direction across the cohorts. Additional adjustment for child hemoglobin, birth weight, gestational age, gestational BPb concentrations, or test examiner did not change the pattern of associations.
Higher BPb concentrations at 2 years of age were most predictive of decreased cognitive abilities among these Mexico City children; however, the observed pattern may be due to exposure, outcome, or cohort related factors. These results may help developing countries more efficiently implement childhood Pb prevention strategies.
Lead; Children; Epidemiology; Cognitive abilities; Windows of development
Manganese (Mn), an established neurotoxicant, is a common component of welding fume. The neurological phenotype associated with welding exposures has not been well described. Prior epidemiologic evidence linking occupational welding to parkinsonism is mixed, and remains controversial.
This was a cross-sectional and nested case–control study to investigate the prevalence and phenotype of parkinsonism among 811 shipyard and fabrication welders recruited from trade unions. Two reference groups included 59 non-welder trade workers and 118 newly diagnosed, untreated idiopathic PD patients. Study subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism cases were defined as welders with UPDRS3 score ≥15. Normal was defined as UPDRS3 < 6. Exposure was classified as intensity adjusted, cumulative years of welding. Adjusted prevalence ratios for parkinsonism were calculated in relation to quartiles of welding years.
The overall prevalence estimate of parkinsonism was 15.6% in welding exposed workers compared to 0% in the reference group. Among welders, we observed a U-shaped dose–response relation between weighted welding exposure-years and parkinsonism. UPDRS3 scores for most domains were similar between welders and newly diagnosed idiopathic Parkinson disease (PD) patients, except for greater frequency of rest tremor and asymmetry in PD patients.
This work-site based study among welders demonstrates a high prevalence of parkinsonism compared to nonwelding-exposed workers and a clinical phenotype that overlaps substantially with PD.
Parkinsonism; Parkinson disease; Welding; Manganese; Occupational exposures
Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.
Air pollution; brain; particulate matter; ozone; central nervous system; susceptibility; epidemiology; neuroinflammation; neurotoxicity; behavior
Potential contributions of environmental chemicals and conditions to the etiology of Autism Spectrum Disorders are the subject of considerable current research and speculation. The present paper describes the results of a study undertaken as part of a larger project devoted to the connection between properties of the indoor environment and asthma and allergy in young Swedish children. The larger project, The Dampness in Buildings and Health (DBH) Study, began in the year 2000 with a questionnaire distributed to parents of all children 1-6 years of age in one Swedish county (DBH-I). A second, follow-up questionnaire (DBH-III) was distributed in 2005. The original survey collected information about the child, the family situation, practices such as smoking, allergic symptoms, type of residence, moisture-related problems, and type of flooring material, which included polyvinyl chloride (PVC). The 2005 survey, based on the same children, now 6-8 years of age, also asked if, during the intervening period, the child had been diagnosed with Autism, Asperger's syndrome, or Tourette's syndrome. From a total of 4,779 eligible children, 72 (60 boys, 12 girls) were identified with parentally-reported autism spectrum disorder. A random sample of 10 such families confirmed that the diagnoses had been made by medical professionals, in accordance with the Swedish system for monitoring children's health. An analysis of the associations between indoor environmental variables in 2000 as well as other background factors and the ASD diagnosis indicated five statistically significant variables: (1) maternal smoking; (2) male sex; (3) economical problems in the family; (4) condensation on windows, a proxy for low ventilation rate in the home; (5) PVC flooring, especially in the parents' bedroom. In addition, airway symptoms of wheezing and physician-diagnosed asthma in the baseline investigation (2000) were associated with ASD five years later. Results from the second phase of the DBH-study (DBH-II) indicate PVC flooring to be one important source of airborne phthalates indoor, and that asthma and allergy prevalence are associated with phthalate concentrations in settled dust in the children's bedroom. Because these associations are among the few linking ASD with environmental variables, they warrant further and more extensive exploration.
Allergy; Asthma; Autism spectrum disorders; Phthalates; Polyvinyl chloride (PVC)
We developed Drosophila melanogaster as a model to study correlated behavioral, neuronal and genetic effects of the neurotoxin lead, known to affect cognitive and behavioral development in children. We showed that, as in vertebrates, lead affects both synaptic development and complex behaviors (courtship, fecundity, locomotor activity) in Drosophila. By assessing differential behavioral responses to developmental lead exposure among recombinant inbred Drosophila lines (RI), derived from parental lines Oregon R and Russian 2b, we have now identified a genotype by environment interaction (GEI) for a behavioral trait affected by lead. Drosophila Activity Monitors (TriKinetics, Waltham, MA), which measure activity by counting the number of times a single fly in a small glass tube walks through an infrared beam aimed at the middle of the tube, were used to measure activity of flies, reared from eggs to 4 days of adult age on either control or lead-contaminated medium, from each of 75 RI lines. We observed a significant statistical association between the effect of lead on average daytime activity across lines and one marker locus, 30AB, on chromosome 2; we define this as a Quantitative Trait Locus (QTL) associated with behavioral effects of developmental lead exposure. When 30AB was from Russian 2b, lead significantly increased locomotor activity, whereas, when 30AB was from Oregon R, lead decreased it. 30AB contains about 125 genes among which are likely “candidate genes” for the observed lead-dependent behavioral changes. Drosophila are thus a useful, underutilized model for studying behavioral, synaptic and genetic changes following chronic exposure to lead or other neurotoxins during development.
developmental lead exposure; developmental plasticity; behavior; quantitative trait locus; locomotor activity; Drosophila; developmental neurotoxicology; neurotoxin; endocrine disruptor
This summary provides a synopsis of talks included in a symposium entitled “Current Needs and Future Directions of Occupational Safety and Heath in a Globalized World”. The purpose of the symposium was to (1) highlight national and international agencies with occupational health related activities; (2) address electronic (e-)waste issues in developing countries where exposures are secondary to the handling and scavenging of scrap; and (3) discuss the effects of hazardous materials, such as polycyclic aromatic hydrocarbon (PAH) and tobacco smoke on child intelligence quotient (IQ) in developing countries.
The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can results in neurobehavioural alterations, and these have been be used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-D-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically-induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment.
neurite growth; neurodifferentiation; neurotransmitter; electrophysiology neurogenetics; stem cells
Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal rat primary astrocytes. Astrocytes were pretreated for 66 hours with 5µg/ml IIIM1 (4.95 µM) followed by 6 hour exposure to MeHg (5 µM). MeHg significantly increased F2-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E2 (PGE2), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.
Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt’s Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt’s Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure.
biomarkers; chlorpyrifos; occupational exposure; organophosphorus pesticides; neurotoxicity
The fact that a conference on neurotoxicity was held in China triggered the idea to provide an insight into occupational diseases, their development and the approaches to investigate them in Asian countries. A historical review, a meta-analysis, and studies on humans and animals provide impressions on past and current problems.
The Korean example showed that each newly introduced industry is accompanied by its own problems as regards occupational diseases. Mercury and carbon disulfide were of importance in the beginning, whereas solvents and manganese became important later. Outbreaks of diseases were important reasons to guide both the public and the governmental attention to prevention and allowed within a relatively short time considerable progress. As the example on the replacement of 2-bromopropane by 1-bromopropane showed, also the introduction of chemicals that are more beneficial for the environment may result in additional occupational risks. A lower mutagenicity of 1-bromopopane was shown to be associated with a greater neurotoxicity in Japanese studies. Although occupational health and diseases are commonly related to adults, child workers exposed to solvents were examined in a Lebanese study. The study started outlining the health hazards in young workers because they might be at a much greater risk due to the not yet completed maturation of their nervous system. That some occupational diseases are not yet a focus of prevention was shown by the study on pesticides. If at all, the serious health consequences resulting from excessive exposure were investigated. Research enabling precautionary actions was not available from the international literature.
Despite globalization the knowledge on occupational diseases is not yet “globalized” and each country obviously undergoes its own development triggered by local experiences. Economic development that requires a healthy workforce, but also public interest that challenges governmental regulations further efforts on the prevention of occupational diseases.
The paper reflects a summary of the talks presented at the symposium “Occupational Neurotoxicities in Asian Countries” as part of the 11th International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health.
Neurobehavioral Toxicology; Neuropsychological Tests; Occupational Disease; 1-Bromopropane; Working Children; Pesticides; Manganese
Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide.(Couper, 1837) Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms.(Rodier J, 1955) Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures.(Rodier J, 1955; Hobson et al., 2011) The clinical syndrome associated with Mn neurotoxicity has been called manganism.
Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers.(Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011) Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers,(Huang et al., 2003) many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system.(Jankovic, 2005)
The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from C. elegans to humans. Dr. Aschner’s presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte’s experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette’s presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system.
Manganese; parkinsonism; PET; MRI
Background and Objective
Increased prevalence of Parkinsonism was observed in Valcamonica, Italy, a region impacted by ferroalloy plants emissions containing manganese and other metals for a century until 2001. The aim of this study was to assess neurobehavioral functions in adolescents from the impacted region and the reference area of Garda Lake.
Adolescents age 11–14 yrs were recruited through the school system for neuro-behavioral testing. Metals including manganese, lead, iron, zinc, copper were measured in airborne particulate matter collected with 24-hour personal samplers, and in soil, tap water, blood, urine and hair. Independent variables included parental education and socio-economic status, children’s body mass index, number of siblings, parity order, smoking and drinking habits.
A total of 311 subjects (49.2% females), residing in either the exposed (n=154) or the reference (n=157) area participated. Average airborne and soil manganese were respectively 49.5 ng/m3 (median 31.4, range 1.24–517) and 958 ppm (median 897, range 465–1729) in the impacted area, and 27.4 ng/m3 (median 24.7, range 5.3–85.9) ng/m3 and 427 ppm (median 409 range 160–734) in the reference area. Regression models showed significant impairment of motor coordination (Luria-Nebraska test, p=0.0005), hand dexterity (Aiming Pursuit test, p= 0.0115) and odor identification (Sniffin’ task, p=0.003 ) associated with soil manganese. Tremor intensity was positively associated with blood (p=0.005) and hair (p=0.01) manganese.
Historical environmental exposure to manganese from ferroalloy emission reflected by the concentration in soil and the biomarkers was associated with subclinical deficits in olfactory and motor function among adolescents.
neuromotor changes; children; airborne particles; soil; metals; manganese