Showing papers in "Neurotoxicology in 2017"

Neurotoxicity of traffic-related air pollution

Abstract: The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m3 for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence.

Abstract: A systematic review was conducted to identify risk factors associated with the onset and progression of Alzheimer's disease (AD). Moderate and high quality systematic reviews were eligible for inclusion. Primary studies reporting on non-genetic risk factors associated with neuropathologically or clinically confirmed AD were considered. Eighty one systematic reviews reporting on AD onset and 12 reporting on progression satisfied the eligibility criteria. Four hundred and thirty-two relevant primary studies reporting on onset were identified; however, only those published between 2010 and 2012 (n=65) were included in the qualitative synthesis. Several factors including statins, light-to-moderate alcohol consumption, compliance with a Mediterranean diet, higher educational attainment, physically and cognitively stimulating activities, and APOE e2 appeared to be associated with a decreased risk of AD onset. The evidence was suggestive of an increased risk of AD associated with head injury in males, age, diabetes mellitus, conjugated equine estrogen use with medroxyprogesterone acetate, current smoking, and lower social engagement. With respect to genetic factors, APOE e4 remained the strongest predictor of AD. Physical and cognitive activities were associated with a beneficial effect on cognitive function and other indicators of dementia progression while higher educational attainment was associated with faster cognitive decline. Although suggestive of an association, the current evidence for a majority of the identified putative factors for AD onset and progression was weak, at best due to conflicting findings across studies or inadequate evidence. Further research is required to confirm the etiological or protective role of a number of risk factors.

Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders.

Abstract: Accumulating evidence from both human and animal studies show that brain is a target of air pollution. Multiple epidemiological studies have now linked components of air pollution to diagnosis of autism spectrum disorder (ASD), a linkage with plausibility based on the shared mechanisms of inflammation. Additional plausibility appears to be provided by findings from our studies in mice of exposures from postnatal day (PND) 4-7 and 10-13 (human 3rd trimester equivalent), to concentrated ambient ultrafine (UFP) particles, considered the most reactive component of air pollution, at levels consistent with high traffic areas of major U.S. cities and thus highly relevant to human exposures. These exposures, occurring during a period of marked neuro- and gliogenesis, unexpectedly produced a pattern of developmental neurotoxicity notably similar to multiple hypothesized mechanistic underpinnings of ASD, including its greater impact in males. UFP exposures induced inflammation/microglial activation, reductions in size of the corpus callosum (CC) and associated hypomyelination, aberrant white matter development and/or structural integrity with ventriculomegaly (VM), elevated glutamate and excitatory/inhibitory imbalance, increased amygdala astrocytic activation, and repetitive and impulsive behaviors. Collectively, these findings suggest the human 3rd trimester equivalent as a period of potential vulnerability to neurodevelopmental toxicity to UFP, particularly in males, and point to the possibility that UFP air pollution exposure during periods of rapid neuro- and gliogenesis may be a risk factor not only for ASD, but also for other neurodevelopmental disorders that share features with ASD, such as schizophrenia, attention deficit disorder, and periventricular leukomalacia.

Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis.

Abstract: Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta-analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta-N-methylamino-l-alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based.

Environmental toxicology: Sensitive periods of development and neurodevelopmental disorders.

Abstract: Development of the mammalian central nervous system is a complex process whose disruption may have severe and long-lasting consequences upon brain structure and function, potentially resulting in a neurodevelopmental disorder (NDD). Many NDDs are known to be genetic in origin, with symptom onset and their underlying mechanisms now known to be regulated during time-dependent windows or 'critical periods' during normal brain development. However, it is increasingly evident that similar disturbances to the developing nervous system may be caused by exposure to non-genetic, environmental factors. Strikingly, at least 200 industrially applied or produced chemicals have been associated with neurotoxicity in humans and exposure to these modifying compounds, through consumer products or environmental pollution, therefore poses serious threats to public health. Through a combination of human epidemiological and animal experimental studies, we identified developmental periods for increased vulnerability to environmentally-modifying compounds and determined whether and how exposure during specific sensitive time-windows could increase the risk for the NDDs of autism, ADHD or schizophrenia in the developing organism. We report that many environmental toxicants have distinct sensitive time-windows during which exposure may disrupt critical developmental events, thereby increasing the risk of developing NDDs. The majority of these time-windows occur prenatally rather than postnatally. We propose four underlying mechanisms that mediate pathogenesis, namely oxidative stress, immune system dysregulation, altered neurotransmission and thyroid hormone disruption. Given the complexity of underlying mechanisms and their prenatal inception, treatment options are currently limited. Thus, we conclude that preventing early exposure to environmental toxicants, by increasing public awareness and improving government and industry guidelines, may ultimately lead to a significant reduction in the incidence of NDDs.

Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review.

Abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960 to 2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.

LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells

Abstract: Numerous long non-coding RNAs (lncRNAs) have been identified as aberrantly expressed in Parkinson's disease (PD). However, limited knowledge is available concerning the roles of dysregulated lncRNAs and the underlying molecular regulatory mechanism in the pathological process of PD. In this study, we found that lncRNA small nucleolar RNA host gene 1 (SNHG1) and seven in absentia homolog 1 (SIAH1) were upregulated, but microRNA-15b-5p (miR-15b-5p) was downregulated in SH-SY5Y cells pretreated with MPP+, as well as in MPTP-induced mouse model of PD. Overexpression of SIAH1 enhanced cellular toxicity of α-synuclein in SH-SY5Y cells, as indicated by the reduction of cell viability and elevation of LDH release. The percentage of α-synuclein aggregate-positive cells and the number of α-synuclein aggregates per cell were increased in SH-SY5Y cells transfected with pcDNA-SIAH1, while decreased after transfection with short interfering RNA specific for SIAH1 (si-SIAH1). Bioinformatics and luciferase reporter assay revealed that SIAH1 was a direct target of miR-15b-5p. We also found that SNHG1 could directly bind to miR-15-5p and repress miR-15-5p expression. Upregulation of miR-15b-5p alleviated α-synuclein aggregation and apoptosis by targeting SIAH1 in SH-SY5Y cells overexpressing α-synuclein. Overexpression of SNHG1 enhanced, whereas SNHG1 knockdown inhibited α-synuclein aggregation and α-synuclein-induced apoptosis. Moreover, the neuroprotective effect of si-SNHG1 was abrogated by downregulation of miR-15b-5p. In summary, our data suggest that SNHG1, as a pathogenic factor, promotes α-synuclein aggregation and toxicity by targeting the miR-15b-5p/SIAH1 axis, contributing to a better understanding of the mechanisms of Lewy body formation and loss of dopaminergic neurons in PD.

Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-κB pathways.

Abstract: Chronic exposure to cadmium has been linked to brain cancers, learning disabilities and memory deficits. Previous studies of cadmium toxicity in the central nervous system report cadmium induces oxidative stress in neurons and astrocytes. In the peripheral system, cadmium promotes interleukin-6 (IL-6) and IL-8 production and release. Elevation of IL-6 expression is linked to the pathogenesis of neurodegenerative diseases and astrogliosis. IL-8 plays a role in angiogenesis of gliomas and neurodegenerative diseases. Herein, the effects of non-toxic concentrations of cadmium on the production of IL-6 and IL-8 and the underlying mechanisms were investigated. U-87 MG human astrocytoma cells and primary human astrocytes were exposed to cadmium chloride. At 24h post-exposure to 1 and 10μM, levels of intracellular cadmium in U-87 MG cells were 11.89±3.59 and 53.08±7.59μg/g wet weight, respectively. These concentrations had minimal effects on cell morphology and viability. IL-6 and IL-8 mRNA levels and secretion increased in dose- and time-dependent manners post cadmium exposure. Acute exposure to cadmium increased phosphorylation of ERK1/2, p38 MAPK, and p65 NF-κB. Pretreatment with U0126-an inhibitor of MEK1 and MEK2 kinases-SB203580-a p38 MAPK inhibitor-and SC-514-an IKKβ inhibitor-suppressed cadmium-induced IL-8 expression and release. Upregulation of cadmium-induced IL-6 was inhibited by U0126 and SC-514, but not SB203580. On the other hand, SP600125-a JNK inhibitor-and celecoxib-a selective COX-2 inhibitor-had no effect on production of both cytokines. In conclusion, non-toxic concentrations of cadmium can stimulate IL-6 and IL-8 release through MAPK phosphorylation and NF-κB activation. Suppressing IL-6 and IL-8 production could be novel approaches to prevent cadmium-induced angiogenesis in gliomas and inflammation in the brain.

Prenatal environmental chemical exposures and longitudinal patterns of child neurobehavior.

Abstract: Background Prenatal chemical exposures may adversely affect neurodevelopment, but few studies have examined the persistence of these associations. We examined whether associations between prenatal bisphenol A (BPA) or polybrominated diphenyl ether (PBDE) exposures persist or resolve as children age.

Parkinson's disease-like motor and non-motor symptoms in rotenone-treated zebrafish.

Abstract: The pesticide rotenone is widely used to produce Parkinson’s disease (PD)-like symptoms in rodents, but few studies have examined whether rotenone-treated zebrafish can serve as an animal model of PD. Here, we report that 4 weeks of rotenone treatment induced motor and non-motor PD-like symptoms in adult zebrafish. Compared with control fish, rotenone-treated fish spent less time swimming at a fast speed, indicating a deficit in motor function. In the light-dark box test, rotenone-treated fish exhibited longer latencies to enter the dark compartment and spent more time in the light compartment, reflecting anxiety- and depression-like behavior. Furthermore, rotenone-treated fish showed less of an olfactory preference for amino acid, indicating olfactory dysfunction. These behavioral symptoms were associated with decreased levels of dopamine in the brains of rotenone-treated fish. Taken together, these results suggest that rotenone-treated zebrafish are a suitable model of PD.

Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson's disease: Relevance to α-synuclein misfolding in metal neurotoxicity.

Abstract: Many chronic neurodegenerative disorders share a common pathogenic mechanism involving the aggregation and deposition of misfolded proteins. Recently, it was shown that these aggregated proteins could be transferred from one cell to another via extracellular nanovesicles called exosomes. Initially thought to be a means of cellular waste removal, exosomes have since been discovered to actively participate in cell-to-cell communication. Importantly, various inflammatory and signaling molecules, as well as small RNAs are selectively packaged in these vesicles. Considering the important role of environmental manganese (Mn) in Parkinson's disease (PD)-like neurological disorders, we characterized the effect of Mn on exosome content and release using an MN9D dopaminergic cell model of PD, which was generated to stably express wild-type human α-synuclein (αSyn). Mn exposure (300μM MnCl2) for 24h induced the release of exosomes into the extracellular media prior to cytotoxicity, as determined by NanoSight particle analysis and electron microscopy. Strikingly, Western blot analysis revealed that Mn treatment in αSyn-expressing cells increases the protein Rab27a, which regulates the release of exosomes from cells. Moreover, next-generation sequencing showed more small RNAs in exosomes isolated from Mn-exposed cells than from control exosomes. Our miRNA profiling analysis led to the discovery of increased expression of certain miRNAs previously shown to regulate key biological pathways, including protein aggregation, autophagy, inflammation and hypoxia. Collectively, our results provide a glimpse of Mn's role in modulating extracellular miRNA content through exosomal release from dopaminergic neuronal cells and thus potentially contributing to progressive neurodegeneration. Further characterization of extracellular miRNAs and their targets will have major impacts on biomarker discovery and translational strategies for environmentally linked neurodegenerative diseases including PD.

A multi-laboratory evaluation of microelectrode array-based measurements of neural network activity for acute neurotoxicity testing ☆

Abstract: There is a need for methods to screen and prioritize chemicals for potential hazard, including neurotoxicity. Microelectrode array (MEA) systems enable simultaneous extracellular recordings from multiple sites in neural networks in real time and thereby provide a robust measure of network activity. In this study, spontaneous activity measurements from primary neuronal cultures treated with three neurotoxic or three non-neurotoxic compounds was evaluated across four different laboratories. All four individual laboratories correctly identifed the neurotoxic compounds chlorpyrifos oxon (an organophosphate insecticide), deltamethrin (a pyrethroid insecticide) and domoic acid (an excitotoxicant). By contrast, the other three compounds (glyphosate, dimethyl phthalate and acetaminophen) considered to be non-neurotoxic ("negative controls"), produced only sporadic changes of the measured parameters. The results were consistent across the different laboratories, as all three neurotoxic compounds caused concentration-dependent inhibition of mean firing rate (MFR). Further, MFR appeared to be the most sensitive parameter for effects of neurotoxic compounds, as changes in electrical activity measured by mean frequency intra burst (MFIB), and mean burst duration (MBD) did not result in concentration-response relationships for some of the positive compounds, or required higher concentrations for an effect to be observed. However, greater numbers of compounds need to be tested to confirm this. The results obtained indicate that measurement of spontaneous electrical activity using MEAs provides a robust assessment of compound effects on neural network function.

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

Abstract: The Adverse Outcome Pathway (AOP) concept has recently been proposed to support a paradigm shift in regulatory toxicology testing and risk assessment. This concept is similar to the Mode of Action (MOA), in that it describes a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis for predicting effects of structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed. A variety of cellular and molecular processes are known to be critical for normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of the principles of MOA and AOPs, examples of potential or putative adverse outcome pathways specific for developmental or adult neurotoxicity are summarized and aspects of their assessment considered. Their possible application in developing mechanistically informed Integrated Approaches to Testing and Assessment (IATA) is also discussed.

Rapid selection for resistance to diamide insecticides in Plutella xylostella via specific amino acid polymorphisms in the ryanodine receptor.

Abstract: Diamide insecticides, such as flubendiamide and chlorantraniliprole, are a new class of insecticide with a novel mode of action, selectively activating the insect ryanodine receptor (RyR). They are particularly active against lepidopteran pests of cruciferous vegetable crops, including the diamondback moth, Plutella xylostella. However, within a relatively short period following their commercialisation, a comparatively large number of control failures have been reported in the field. In this review we summarise the current body of knowledge regarding the molecular mechanisms of diamide resistance in P. xylostella. Resistant phenotypes collected from different countries can often be linked to specific target-site mutation(s) in the ryanodine receptors' transmembrane domain. Metabolic mechanisms of resistance have also been proposed. Rapid resistance development is probably a consequence of over-reliance on this one class of chemistry for diamondback moth control.

Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning.

Abstract: Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β -4.50, 95% CI -8.05, -0.95), Depression (β -3.21, 95% CI -6.38, -0.05), Somatization (β -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (β -3.59, 95% CI -6.97, -0.21), Emotional Control (β -3.35, 95% CI -6.58, -0.12), Shifting (β -3.42, 95% CI -6.73, -0.11), and Monitoring (β -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β -4.74, 95% CI -9.37, -0.10), Conduct Problems (β -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (β -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (β -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits.

Caffeine for apnea of prematurity: Effects on the developing brain

Abstract: Caffeine is a methylxanthine that is widely used to treat apnea of prematurity (AOP). In preterm infants, caffeine reduces the duration of respiratory support, improves survival rates and lowers the incidence of cerebral palsy and cognitive delay. There is, however, little evidence relating to the immediate and long-term effects of caffeine on brain development, especially at the cellular and molecular levels. Experimental data are conflicting, with studies showing that caffeine can have either adverse or benefical effects in the developing brain. The aim of this article is to review current understanding of how caffeine ameliorates AOP, the cellular and molecular mechanisms by which caffeine exerts its effects and the effects of caffeine on brain development. A better knowledge of the effects of caffeine on the developing brain at the cellular and/or molecular level is essential in order to understand the basis for the impact of caffeine on postnatal outcome. The studies reviewed here suggest that while caffeine has respiratory benefits for preterm infants, it may have adverse molecular and cellular effects on the developing brain; indeed a majority of experimental studies suggest that regardless of dose or duration of administration, caffeine leads to detrimental changes within the developing brain. Thus there is an urgent need to assess the impact of caffeine, at a range of doses, on the structure and function of the developing brain in preclinical studies, particularly using clinically relevant animal models. Future studies should focus on determining the maximal dose of caffeine that is safe for the preterm brain.

Effect of caffeine, caffeic acid and their various combinations on enzymes of cholinergic, monoaminergic and purinergic systems critical to neurodegeneration in rat brain-In vitro.

Abstract: Caffeine and caffeic acid are two bioactive compounds that are present in plant foods and are major constituent of coffee, cocoa, tea, cola drinks and chocolate. Although not structurally related, caffeine and caffeic acid has been reported to elicit neuroprotective properties. However, their different proportional distribution in food sources and possible effect of such interactions are not often taken into consideration. Therefore, in this study, we investigated the effect of caffeine, caffeic acid and their various combinations on activities of some enzymes [acetylcholinesterase (AChE), monoamine oxidase (MAO) ecto-nucleoside triphosphate diphosphohydrolase (E-NTPase), ecto-51-nucleotidase (E-NTDase) and Na+/K+ ATPase relevant to neurodegeneration in vitro in rat brain. The stock concentration of caffeine and caffiec acid and their various proportional combinations were prepared and their interactions with the activities of these enzymes were assessed (in vitro) in different brain structures. The Fe2+ and Cu2+ chelating abilities of the samples were also investigated. The results revealed that caffeine, caffeic acid and their various combinations exhibited inhibitory effect on activities of AChE, MAO, E-NTPase and E-NTDase, but stimulatory effect on Na+/K+ ATPase activity. The combinations also exhibited Fe2+ and Cu2+ chelating abilities. Considering the various combinations, a higher caffeine to caffeic acid ratio produced significantly highest enzyme modulatory effects; these were significantly lower to the effect of caffeine alone but significantly higher than the effect of caffeic acid alone. These findings may provide new insight into the effect of proportional combination of these bioactive compounds as obtained in many foods especially with respect to their neuroprotective effects.

Manganese exposure facilitates microglial JAK2-STAT3 signaling and consequent secretion of TNF-a and IL-1β to promote neuronal death.

Abstract: Chronic manganese (Mn) exposure can lead to neuroinflammation and neurological deficit, which resemble idiopathic Parkinson's disease (IPD). However, the precise mechanisms underlying Mn exposure-induced neurotoxicity remain incompletely understood. Microglia can become hyperactivated and plays a vital role in neuroinflammation and consequent neurodegeneration in response to pro-inflammatory stimuli. In the present study, we found that HAPI microglial cells exhibited increased secretion of pro-inflammatory TNF-α and IL-1β following Mn exposure in dose- and time-dependent manners. In addition, we showed that Mn exposure could trigger the activation of JAK2/STAT3 signaling pathway in microglia. Notably, Mn-induced secretion of TNF-α and IL-1β was significantly attenuated by the treatment of JAK2 inhibitor. Finally, through incubating PC12 neuronal cells with Mn-treated microglial conditioned medium, we demonstrated that Mn-induced secretion of microglial TNF-α and IL-1β facilitated neuronal apoptosis. Thus, we speculate that Mn exposure might trigger JAK2-STAT3 signal pathway in microglia, leading to resultant neuroinflammation and neuronal loss.

Developmental exposure to low concentrations of two brominated flame retardants, BDE-47 and BDE-99, causes life-long behavioral alterations in zebrafish

Abstract: Background Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2′,4,4′,5,-Pentabromodiphenyl ether (BDE-99) and 2,2′,4,4′,-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short- and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. Methods Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3 μM CPF; 0.01, 0.03, 0.1, 0.3 μM BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20 μM BDE-99 from 5 until 120 h post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. Results In the short-term, larval locomotor activity was reduced in larvae treated with 0.3 μM CPF and 0.1 μM BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3 μM causing hyperactivity and 1 μM or higher causing hypoactivity. In the long-term, adult anxiety-related behavior was reduced in all treatments as measured in both the novel tank dive test and tap test. Discussion We show that exposure of zebrafish embryos to low concentrations of the brominated flame retardants BDE-47 and BDE-99, and the organophosphate pesticide CPF, caused both short- and long-term behavioral impairments. Interestingly, we also found that at very low exposure concentrations, where there were no visible effects on larval activity, adult behavior was still strongly affected.

Prenatal phthalate, triclosan, and bisphenol A exposures and child visual-spatial abilities.

Abstract: Introduction During fetal development, sex steroids influence sexually dimorphic behaviors, such as visual-spatial abilities. Thus, endocrine disrupting chemicals that impact sex steroids during gestation may affect these behaviors. Objective We investigated the relationship between prenatal urinary phthalate metabolite, triclosan, and BPA concentrations and visual-spatial abilities in a prospective cohort of 198 mother-child dyads. Methods Data are from a prospective cohort in Cincinnati, OH (HOME Study). We measured nine phthalate metabolites, triclosan, and BPA in maternal urine samples collected at 16 and 26 weeks of gestation. We assessed children’s visual-spatial abilities at 8 years of age using the Virtual Morris Water Maze (VMWM), a computerized version of the rodent Morris Water Maze. We quantified the covariate-adjusted change in the time or distance to complete the VMWM and time spent in the correct quadrant during a probe trial with an interquartile range increase in chemical concentrations using linear mixed models and linear regression, respectively. Results Boys completed the VMWM faster (4.1 s; 95% CI:−7.1, −1.2) and in less distance (1.4 units; 95% CI:−2.8, 0) than girls. Overall, children with higher mono-n-butyl (MnBP), mono-benzyl (MBzP), and mono-carboxypropyl phthalate concentrations completed the VMWM in less time and distance than children with lower concentrations. For example, children with higher MnBP concentrations completed the VMWM in 0.9 less distance units (95% CI:−1.8, −0.0). Child sex modified the association between MnBP and VMWM performance. In girls, higher MnBP concentrations were associated with longer time (1.7 s; 95% CI: −0.7, 4.1) and shorter distance (−1.7 units; 95% CI: −2.8, −0.5), whereas in boys, it was associated with shorter time (-3.0 s; 95% CI:−5.6, −0.4), but not distance (−0.1 units; 95% CI:1.4, 1.0). Other phthalate metabolites, triclosan, and BPA were not associated with VMWM performance, and sex did not consistently modify these associations. Conclusions In this cohort, greater prenatal urinary concentrations of some phthalate metabolites were associated with improved VMWM performance, particularly among boys. Future studies should confirm these findings and determine if phthalates affect other hormonally sensitive aspects of child neurobehavior.

A systematic review of the risks factors associated with the onset and natural progression of spina bifida

Abstract: Epilepsy is a neurological condition that affects more than 50 million individuals worldwide. It presents as unpredictable, temporary and recurrent seizures often having negative physical, psychological and social consequences. To inform disease prevention and management strategies, a comprehensive systematic review of the literature on risk factors for the onset and natural progression of epilepsy was conducted. Computerized bibliographic databases for systematic reviews, meta-analyses, observational studies and genetic association studies published between 1990 and 2013 describing etiological risk factors for epilepsy was searched. The quality of systematic reviews was validated using the AMSTAR tool and articles were reviewed by two referees. A total of 16,958 articles went through stage one review of abstracts and titles. A total of 76 articles on genetic and non-genetic risk factors for the onset and progression of epilepsy met the eligibility criteria for data extraction. Dozens of risk factors were significantly associated with onset of epilepsy. Inconsistent levels of evidence for risk of onset included family history of epilepsy, history of febrile seizures, alcohol consumption, CNS and other infections, brain trauma, head injury, perinatal stroke, preterm birth and three genetic markers. Limited evidence showed that symptomatic epilepsy, focal seizures/syndromes, slow waves on EEG, higher seizure frequency, high stress or anxiety, and lack of sleep decreased the odds of seizure remission. High quality studies were rare and while a large body of work exists, relatively few systematic reviews were found.

Changes in water manganese levels and longitudinal assessment of intellectual function in children exposed through drinking water.

Abstract: Background Manganese is commonly found in water but potential neurotoxic effects from exposure through drinking water are poorly understood. We previously reported a cross-sectional study showing that drinking water Mn concentration was associated with lower IQ in children aged 6 to 13 years. Objective For this follow-up study, we aimed to re-assess the relation between exposure to Mn from drinking water and IQ at adolescence. In addition, we aimed to examine whether changes in drinking water Mn concentration was associated with changes in IQ scores. Methods From the 380 children enrolled in the baseline study, 287 participated to this follow-up study conducted in average 4.4 years after. Mn concentration was measured in home tap water and children's hair. The relationships between these Mn exposure indicators and IQ scores (Weschsler Abbreviated Scale of Intelligence) at follow-up were assessed with linear regression analysis, adjusting for potential confounders. Intra-individual differences in IQ scores between the two examinations were compared for children whose Mn concentration in water remained stable between examinations, increased or decreased. Results The mean age at follow-up was 13.7 years (range, 10.5 to 18.0 years). Geometric mean of Mn concentration in water at follow-up was 14.5 μg/L. Higher Mn concentration in water measured at follow-up was associated with lower Performance IQ in girls (β for a 10-fold increase = −2.8, 95% confidence intervals [CI] −4.8 to −0.8) and higher Performance IQ in boys (β = 3.9, 95% CI 1.4 to 6.4). IQ scores were not significantly associated with Mn concentration in hair, although similar trends as for concentration in water were observed. For children whose Mn concentration in water increased between baseline and follow-up, Performance IQ scores decreased significantly (intra-individual difference, −2.4 points). Conclusion Higher levels of Mn in drinking water were associated with lower Performance IQ in girls, whereas the opposite was observed in boys. These findings suggest long-term exposure to Mn through drinking water is associated differently with cognition in boys and girls.

In utero exposure to fluoride and cognitive development delay in infants

Abstract: The objective of this study was to evaluate the association between in utero exposure to fluoride (F) and Mental and Psychomotor Development (MDI and PDI) evaluated through the Bayley Scale of Infant Development II (BSDI-II) in infants. The sample included 65 mother-infant pairs. Environmental exposure to F was quantified in tap and bottled water samples and F in maternal urine was the biological exposure indicator; samples were collected during the 1st, 2nd and 3rd trimester of pregnancy. The mean values of F in tap water for the 1st, 2nd and 3rd trimester were 2.6±1.1mg/l, 3.1±1.1mg/l and 3.7±1.0mg/l respectively; above to 80% of the samples exceeded the reference value of 1.5mg/l (NOM-127-SSA1-1994). Regarding F in maternal urine, mean values were 1.9±1.0mg/l, 2.0±1.1mg/l and 2.7±1.1mg/l for the 1st, 2nd and 3rd trimester respectively. The infants with MDI and PDI scores less than 85 points were 38.5% and 20.9% respectively. After adjusting for potential confounding factors (gestational age, age of child, marginalization index and type of water for consumption), the MDI showed an inverse association with F levels in maternal urine for the first (β=-19.05, p=0.04) and second trimester (β=-19.34, p=0.01). Our data suggests that cognitive alterations in children born from exposed mothers to F could start in early prenatal stages of life.

Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.

Abstract: Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.

Rifampicin inhibits rotenone-induced microglial inflammation via enhancement of autophagy.

Abstract: Mitochondrial and autophagic dysfunction, as well as neuroinflammation, are associated with the pathophysiology of Parkinson's disease (PD). Rotenone, an inhibitor of mitochondrial complex I, has been associated as an environmental neurotoxin related to PD. Our previous studies reported that rifampicin inhibited microglia activation and production of proinflammatory mediators induced by rotenone, but the precise mechanism has not been completely elucidated. BV2 cells were pretreated for 2h with rifampicin followed by 0.1μM rotenone, alone or in combination with chloroquine. Here, we demonstrate that rifampicin pretreatment alleviated rotenone induced release of IL-1β and IL-6, and its effects were suppressed when autophagy was inhibited by chloroquine. Moreover, preconditioning with 50μM rifampicin significantly increased viability of SH-SY5Y cells cocultured with rotenone-treated BV2 cells in the transwell coculture system. Chloroquine partially abolished the neuroprotective effects of rifampicin pretreatment. Rifampicin pretreatment significantly reversed rotenone-induced mitochondrial membrane potential reduction and reactive oxygen species accumulation. We suggest that the mechanism for rifampicin-mediated anti-inflammatory and antioxidant effects is the enhancement of autophagy. Indeed, the ratio of LC3-II/LC3-I in rifampicin-pretreated BV2 cells was significantly higher than that in cells without pretreatment. Fluorescence and electron microscopy analyses indicate an increase of lysosomes colocalized with mitochondria in cells pretreated with rifampicin, which confirms that the damaged mitochondria were cleared through autophagy (mitophagy). Taken together, the data provide further evidence that rifampicin exerts neuroprotection against rotenone-induced microglia inflammation, partially through the autophagy pathway. Modulation of autophagy by rifampicin is a novel therapeutic strategy for PD.

Effects of low-level prenatal lead exposure on child IQ at 4 and 8 years in a UK birth cohort study.

Abstract: Background The association between childhood exposure to lead (Pb) and deficits in cognitive function is well established. The association with prenatal exposure, however, is not well understood, even though the potential adverse effects are equally important. Objectives To evaluate the association between low prenatal exposure to lead and IQ in children, to determine whether there were sex differences in the associations, and to evaluate the moderation effect of prenatal Pb exposure on child IQ. Methods Whole blood samples from pregnant women enrolled in ALSPAC (n = 4285) and from offspring at age 30 months (n = 235) were analysed for Pb. Associations between prenatal blood lead concentrations (B-Pb) and child IQ at age 4 and 8 years (WPPSI and WISC-III, respectively) were examined in adjusted regression models. Results There was no association of prenatal lead exposure with child IQ at 4 or 8 years old in adjusted regression models, and no moderation of the association between child B-Pb and IQ. However, there was a positive association for IQ at age 8 years in girls with a predicted increase in IQ (points) per 1 μg/dl of: verbal 0.71, performance 0.57, total 0.73. In boys, the coefficients tended to be negative (−0.15, −0.42 and −0.29 points, respectively). Conclusion Prenatal lead exposure was not associated with adverse effects on child IQ at age 4 or 8 years in this study. There was, however, some evidence to suggest that boys are more susceptible than girls to prenatal exposure to lead. Further investigation in other cohorts is required.

Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction.

Abstract: Developmental exposures to ambient ultrafine particles (UFPs) can produce multiple neuropathological and neurochemical changes that might contribute to persistent alterations in cognitive-type functions. The objective of the current study was to test the hypothesis that developmental UFP exposure produced impairments in learning, memory and impulsive-like behaviors and to determine whether these were selective and thus independent of deficits in other behavioral domains such as motor activity or motivation. Performance on measures of learning (repeated learning), memory (novel object recognition, NOR), impulsive-like behavior (differential reinforcement of low rate (DRL), schedule of reward and delay of reward (DOR)), motor activity (locomotor behavior) and motivation (progressive ratio schedule) were examined in adult mice that had been exposed to concentrated (10–20x) ambient ultrafine particles (CAPS) averaging approximately 45 ug/m 3 particle mass concentrations from postnatal day (PND) 4–7 and 10–13 for 4 h/day. Given the number of behavioral tests, animals were tested in different groups. Results showed male-specific alterations in learning and memory functions (repeated learning, NOR and DRL) specifically during transitions in reinforcement contingencies (changes in rules governing behavior) that did not appear to be related to alterations in locomotor function or motivation. Females did not exhibit cognitive-like deficits at these exposure concentrations, but displayed behaviors consistent with altered motivation, including increases in response rates during repeated learning, significantly increased latencies to respond on the delay of reward paradigm, and reductions in the progressive ratio break point. Consistent with our prior findings, male-specific learning and memory-related deficits were seen and occurred even at relatively low level developmental UFP exposures, while females show alterations in motivational behaviors but not final performance. These findings add to the evidence suggesting the need to regulate UFP levels.

Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI.

Abstract: Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13±0.1mg/m3; High: N=13; mean air Mn=0.23±0.18mg/m3), as well as unexposed control workers (N=22, mean air Mn=0.002±0.001mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.

The early history of manganese and the recognition of its neurotoxicity, 1837-1936

Abstract: The history of the biomedical recognition manganese-caused neurotoxicity mirrors changing technologies as much as it does the ontology of parkinsonism. The initial 1837 report of manganese-induced neurologic injury was made by John Couper, a university-based physician in Scotland. He made clear that the outbreak occurred among workers at the Charles Tennant bleach manufactory in the environs of Glasgow. The relatively new technology of chlorine generation using manganese accounted for the novel exposure involved. At the time, this factory was the largest hypochlorite bleaching powder producer in the world. As the 19th century progressed, technological change in steel fabrication requiring higher manganese content greatly increased demand for the metal. Nonetheless, more than six decades elapsed before the next reports of manganese neurotoxicity emerged. Two unrelated outbreaks (both on Continental Europe) were reported within weeks of each other in 1901, one by von Jaksch and the other by Embden. All the cases were heavily exposed to manganese-containing dust. By the eve of the First World War, a total of 9 patients with manganese-caused neurologic illness had been reported in five separate Continental European publications. Meanwhile, new technology led to another exposure source. Magnetic separation techniques allowed the extraction of zinc from mixed ore also containing iron and manganese, leading to exploitation of a unique source of high manganese-content ore found in New Jersey. Not long after that technology's introduction, in 1912 Casamajor reported the first U.S. cases of manganism, detailing classic findings. Additional cases from the same cohort were reported a few years later, with continued exposure driven by First World War-driven demand for manganese to be used in armaments. The nosology of chronic manganese neurotoxicity remained in flux, with considerable emphasis on shared attributes with Wilson's disease, a syndrome only then recently described. A landmark 1924 primate study by Mella showed manganese-induced basal ganglion damage; human autopsy study data in the years following further supported the view that manganese toxicity represented a parkinsonian syndrome. As the 1937 centenary of Couper's first report approached, newer technologies (electric arc welding and battery making) were being linked to manganese-caused disease, even as mineral extraction was expanding as a global source of exposure.

Exposure to fine and ultrafine particulate matter during gestation alters postnatal oligodendrocyte maturation, proliferation capacity, and myelination

Abstract: Accumulating studies indicate that the brain is a direct target of air pollution exposure during the fetal period. We have previously demonstrated that exposure to concentrated ambient particles (CAPs) during gestation produces ventriculomegaly, periventricular hypermyelination, and enlargement of the corpus callosum (CC) during postnatal development in mice. This study aimed to further characterize the cellular basis of the observed hypermyelination and determine if this outcome, among other effects, persisted as the brain matured. Analysis of CC-1+ mature oligodendrocytes in the CC at postnatal days (PNDs) 11-15 suggest a premature maturational shift in number and proportion of total cells in prenatally CAPs-exposed males and females, with no overall change in total CC cellularity. The overall number of Olig2+ lineage cells in the CC was not affected in either sex at the same postnatal timepoint. Assessment of myelin status at early brain maturity (PNDs 57-61) revealed persistent hypermyelination in CAPs-exposed animals of both sexes. In addition, ventriculomegaly was persistent in CAPs-treated females, with possible amelioration of ventriculomegaly in CAPs-exposed males. When oligodendrocyte precursor cell (OPC) pool status was analyzed at PNDs 57-61, there were significant CAPs-induced alterations in cycling Ki67+/Olig2+ cell number and proportion of total cells in the female CC. Total CC cellularity was slightly elevated in CAPs-exposed males at PNDs 57-61. Overall, these data support a growing body of evidence that demonstrate the vulnerability of the developing brain to environmental insults such as ambient particulate matter. The sensitivity of oligodendrocytes and myelin, in particular, to such an insult warrants further investigation into the mechanistic underpinnings of OPC and myelin disruption by constituent air pollutants.