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1.  Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior 
Neurotoxicology  2015;52:134-143.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The most toxic PCBs are the non-ortho-substituted (“dioxin-like”) congeners that act through the aryl hydrocarbon receptor (AHR) pathway. In humans, perinatal exposure to dioxin-like PCBs is associated with neurodevelopmental toxicity in children. Yet, the full potential for later-life neurobehavioral effects that result from early-life low level exposure to dioxin-like PCBs is not well understood. The objective of this study was to determine the effects of developmental exposure to low levels of dioxin-like PCBs on early-and later-life behavioral phenotypes using zebrafish as a model system. We exposed zebrafish embryos to either vehicle (DMSO) or low concentrations of PCB126 (0.3, 0.6, 1.2 nM) for 20 hours (4–24 hours post fertilization), and then reared them to adulthood in clean water. Locomotor activity was tested at two larval stages (7 and 14 days post fertilization). Adult fish were tested for anxiety-related behavior using the novel tank and shoaling assays. Adult behavioral assays were repeated several times on the same group of fish and effects on intra-and inter-trial habituation were determined. While there was no effect of PCB126 on larval locomotor activity in response to changes in light conditions, developmental exposure to PCB126 resulted in impaired short-and long-term habituation to a novel environment in adult zebrafish. Cyp1a induction was measured as an indicator for AHR activation. Despite high induction at early stages, cyp1a expression was not induced in the brains of developmentally exposed adult fish that showed altered behavior, suggesting that AHR was not activated at this stage. Our results demonstrate the effectiveness of the zebrafish model in detecting subtle and delayed behavioral effects resulting from developmental exposure to an environmental contaminant.
PMCID: PMC4753093  PMID: 26616910
Zebrafish; PCB126; dioxin; developmental neurotoxicity; anxiety; habituation
2.  Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish 
Neurotoxicology  2015;52:23-33.
Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities.
During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0-5 dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2 nM) or valproic acid (0, 0.5, 5.0 or 50 uM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance).
There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation.
Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed.
PMCID: PMC4753107  PMID: 26439099
Zebrafish; retinoic acid; vitamin A valproic acid; behavior; cognition; social behavior; development
3.  Prenatal exposure to the organophosphate pesticide chlorpyrifos and childhood tremor 
Neurotoxicology  2015;51:80-86.
The organophosphate insecticide chlorpyrifos (CPF), widely used for agricultural purposes, has been linked to neurodevelopmental deficits. Possible motor effects at low to moderate levels of exposure have not been evaluated.
Prenatal exposure to CPF was measured in umbilical cord blood in a sample of 263 inner-city minority children, who were followed prospectively. At approximately 11 years of age (mean age 10.9 ± 0.85 years, range = 9.0–13.9), during a neuropsychological assessment, children were asked to draw Archimedes spirals. These were rated by a senior neurologist specializing in movement disorders who was blind to CPF exposure level.
Compared to all other children, those with prenatal CPF exposure in the upper quartile range (n = 43) were more likely to exhibit mild or mild to moderate tremor (≥1) in either arm (p = 0.03), both arms (p = 0.02), the dominant arm (p = 0.01), and the non-dominant arm (p = 0.055). Logistic regression analyses showed significant CPF effects on tremor in both arms, either arm, the dominant arm (p-values < 0.05), and the non-dominant arm (p = 0.06), after adjustment for sex, age at testing, ethnicity, and medication.
Prenatal CPF exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.
PMCID: PMC4809635  PMID: 26385760
Chlorpyrifos; Neurodevelopment; Tremor; Brain; Children
4.  Prenatal mercury exposure and offspring behaviour in childhood and adolescence 
Neurotoxicology  2016;57:87-94.
•There is controversy as to whether prenatal mercury levels are associated with adverse child behaviour, especially if the mother does not eat fish.•This study compares the relationship between maternal total blood mercury in the first half of pregnancy and child behaviour at seven time points.•No evidence was found to suggest that the mercury level was associated with adverse behaviour, whether or not the mother ate fish.
There is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations.
Data were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16–17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10.
Prenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16–17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10–11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference.
There were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters.
PMCID: PMC5138154  PMID: 27633321
ALSPAC; Prenatal mercury exposure; Dietary fish; Child behaviour; Adolescent behaviour
5.  MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains 
Neurotoxicology  2016;55:40-47.
Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5 mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.
PMCID: PMC5051270  PMID: 27182044
Recombinant inbred mice; Sex differences; QTL
6.  Characterization of binge-dosed methamphetamine-induced neurotoxicity and neuroinflammation 
Neurotoxicology  2015;50:131-141.
Methamphetamine (MA) is a potent, highly addictive psychostimulant abused by millions of people worldwide. MA induces neurotoxicity, damaging striatal dopaminergic terminals, and neuroinflammation, with striatal glial activation leading to pro-inflammatory cytokine and reactive oxygen species production. It is unclear whether MA-induced neuroinflammation contributes to MA-induced neurotoxicity. In the current study, we examined the linkage between the time course and dose response of MA-induced neurotoxicity and neuroinflammation. Adult male mice underwent a binge dosing regimen of four injections given every two hours with doses of 2, 4, 6, or 8 mg/kg MA per injection, and were sacrificed after 1, 3, 7, or 14 days. Binge MA treatment dose-dependently caused hyperthermia and induced hypoactivity after one day, though activity returned to control levels within one week. Striatal dopamine (DA) was diminished one day after treatment with at least 4 mg/kg MA, while DA turnover rates peaked after seven days. Although striatal tyrosine hydroxylase and DA transporter levels were also decreased one day after treatment with at least 4 mg/kg MA, they trended toward recovery by day 14. All doses of MA activated striatal glia within one day. While astrocyte activation persisted, microglial activation was attenuated over the two weeks of the study. These findings help clarify the relationship between MA-induced neuroinflammation and neurotoxicity, particularly regarding their temporal and dose-specific dynamics.
PMCID: PMC4644445  PMID: 26283213
methamphetamine; striatum; neurotoxicity; neuroinflammation; astrocytes; microglia
7.  Comparative Effects of Parathion and Chlorpyrifos on Endocannabinoid and Endocannabinoid-Like Lipid Metabolites in Rat Striatum 
Neurotoxicology  2015;50:20-27.
Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications.
PMCID: PMC4767275  PMID: 26215119
acetylcholinesterase; organophosphorus; cholinergic; cannabinoid; endocannabinoid-like; anandamide; 2-arachidonoyl glycerol; N-palmitoylethanolamine; N-oleoylethanolamine
8.  Chlorpyrifos and Malathion have opposite effects on behaviors and brain size that are not correlated to changes in AChE activity 
Neurotoxicology  2015;49:50-58.
Organophosphates, a type of neurotoxicant pesticide, are used globally for the treatment of pests on croplands and are therefore found in a large number of conventional foods. These pesticides are harmful and potentially deadly if ingested or inhaled in large quantities by causing a significant reduction in acetylcholinesterase (AChE) activity in the central and peripheral nervous system. However, much less is known about the effects of exposure to small quantities of the pesticides on neural systems and behavior during development. In the current study we used zebrafish larvae in order to determine the effects of two of the most widely used organophosphates, chlorpyrifos and malathion, on zebrafish behavior and AChE activity. Embryos and larvae were exposed to the organophosphates during different time points in development and then tested at 5 days post-fertilization for behavioral, neurodevelopmental and AChE abnormalities. The results of the study indicate that chlorpyrifos and malathion cause opposing behaviors in the larvae such as swim speed (hypoactivity vs. hyperactivity) and rest. Additionally, the pesticides affect only certain behaviors, such as thigmotaxis, during specific time points in development that are unrelated to changes in AChE activity. Larvae treated with malathion but not chlorpyrifos also had significantly smaller forebrain and hindbrain regions compared to controls by 5 days post-fertilization. We conclude that exposure to very low concentrations of organophosphate pesticides during development cause abnormalities in behavior and brain size.
PMCID: PMC4523399  PMID: 25983063
Acetylcholinesterase; Organophosphates; Zebrafish larvae; High-throughput screening; Thigmotaxis; Hyperactivity
9.  Ex-Vivo Magnetic Resonance Imaging in South African Manganese Mine Workers 
Neurotoxicology  2015;49:8-14.
Manganese (Mn) exposure is associated with increased T1-weighted Magnetic Resonance Imaging (MRI) signal in the basal ganglia. T1 signal intensity has been correlated with occupational Mn exposure but not with clinical symptomatology or neuropathology.
This study investigated predictors of ex-vivo T1 MRI basal ganglia signal intensity in neuropathologic tissue obtained from deceased South African mine workers.
A 3.0T MRI was performed on ex-vivo brain tissue obtained from 19 Mn mine workers and 10 race- and sex-matched mine workers of other commodities. Basal ganglia regions of interest were identified for each subject with T1-weighted intensity indices generated for each region. In a pathology subset, regional T1 indices were compared to neuronal and glial cell density and tissue metal concentrations.
Intensity indices were higher in Mn mine workers than non-Mn mine workers for the globus pallidus, caudate, anterior putamen, and posterior putamen with the highest values in subjects with the longest cumulative Mn exposure. Intensity indices were inversely correlated with the neuronal cell density in the caudate (p = 0.040) and putamen (p = 0.050). Tissue Mn concentrations were similar in Mn and non-Mn mine workers. Tissue iron (Fe) concentration trended lower across all regions in Mn mine workers.
Mn mine workers demonstrated elevated basal ganglia T1 indices when compared to non-Mn mine workers. Predictors of ex-vivo T1 MRI signal intensity in Mn mine workers include duration of Mn exposure and neuronal density.
PMCID: PMC4523412  PMID: 25912463
Manganese; Ex-vivo; MRI; Miners
10.  Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: the Normative Aging Study 
Neurotoxicology  2015;49:158-164.
Olfactory dysfunction has been identified as an early warning sign for Alzheimer’s disease, Parkinson’s disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone.
Olfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-Ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE).
The average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD = 5.7) years. Mean tibia lead was 16.3 (SD = 12.0) μg/g bone, mean patella lead was 22.4 (SD = 14.4) μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD = 7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15 μg/g tibia lead: β = −1.57; 95% CI: −2.93, −0.22; p = 0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE β = 2.26; 95% CI: 0.09, 4.43; p = 0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15 μg/g tibia lead: β = −1.25; 95% CI: −2.64, 0.14; p = 0.08) while the HFE term dropped 15% (β = 1.91; 95% CI: −0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene-lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n = 149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15 μg/g tibia lead β = −1.39; 95% CI: −3.00, 0.22; p = 0.09)
Cumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene status may also affect olfactory function.
PMCID: PMC4523435  PMID: 26121922
Olfaction; aging; bone lead; HFE; ApoE; GSTP1
11.  Environmental exposure to manganese in air: Associations with cognitive functions 
Neurotoxicology  2015;49:139-148.
Manganese (Mn), an essential element, can be neurotoxic in high doses. This cross-sectional study explored the cognitive function of adults residing in two towns (Marietta and East Liverpool, Ohio, USA) identified as having high levels of environmental airborne Mn from industrial sources.
Air-Mn site surface emissions method modeling for total suspended particulate (TSP) ranged from 0.03 to 1.61 μg/m3 in Marietta and 0.01–6.32 μg/m3 in East Liverpool. A comprehensive screening test battery of cognitive function, including the domains of abstract thinking, attention/concentration, executive function and memory was administered. The mean age of the participants was 56 years (±10.8 years). Participants were mostly female (59.1) and primarily white (94.6%). Significant relationships (p < 0.05) were found between Mn exposure and performance on working and visuospatial memory (e.g., Rey-O Immediate β = −0.19, Rey-O Delayed β = −0.16) and verbal skills (e.g., Similarities β = −0.19).
Using extensive cognitive testing and computer modeling of 10-plus years of measured air monitoring data, this study suggests that long-term environmental exposure to high levels of air-Mn, the exposure metric of this paper, may result in mild deficits of cognitive function in adult populations.
PMCID: PMC4803288  PMID: 26096496
Manganese; Neuropsychology; Cognitive function; Environmental; Air
12.  Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake 
Neurotoxicology  2013;38:1-8.
Various forms of mercury possess different rates of absorption, metabolism and excretion, and consequently, toxicity. Methylmercury (MeHg) is a highly neurotoxic organic mercurial. Human exposure is mostly due to ingestion of contaminated fish. Ethylmercury (EtHg), another organic mercury compound, has received significant toxicological attention due to its presence in thimerosal-containing vaccines. This study was designed to compare the toxicities induced by MeHg and EtHg, as well as by their complexes with cysteine (MeHg-S-Cys and EtHg-S-Cys) in the C6 rat glioma cell line. MeHg and EtHg caused significant (p < 0.0001) decreases in cellular viability when cells were treated during 30 min with each mercurial following by a washing period of 24 h (EC50 values of 4.83 and 5.05 μM, respectively). Significant cytotoxicity (p < 0.0001) was also observed when cells were treated under the same conditions with MeHg-S-Cys and EtHg-S-Cys, but the respective EC50 values were significantly increased (11.2 and 9.37 μM). L-Methionine, a substrate for the L-type neutral amino acid carrier transport (LAT) system, significantly protected against the toxicities induced by both complexes (MeHg-S-Cys and EtHg-S-Cys). However, no protective effects of L-methionine were observed against MeHg and EtHg toxicities. Corroborating these findings, L-methionine significantly decreased mercurial uptake when cells were exposed to MeHg-S-Cys (p = 0.028) and EtHg-S-Cys (p = 0.023), but not to MeHg and EtHg. These results indicate that the uptake of MeHg-S-Cys and EtHg-S-Cys into C6 cells is mediated, at least in part, through the LAT system, but MeHg and EtHg enter C6 cells by mechanisms other than LAT system.
PMCID: PMC4922646  PMID: 23727015
Methylmercury; Ethylmercury; Toxicity; L-Type neutral amino acid carrier transport
13.  Considerations on methylmercury (MeHg) treatments in in vitro studies 
Neurotoxicology  2012;33(3):512-513.
PMCID: PMC4919664  PMID: 22608940
14.  Differential response to acrylonitrile toxicity in rat primary astrocytes and microglia 
Neurotoxicology  2013;37:93-99.
Acrylonitrile (ACN) is a widely used chemical in the production of plastics, resins, nitriles, acrylic fibers, synthetic rubber and acrylamide. While acute high level exposures to ACN are known to be lethal, chronic low dose exposures causes glial cell tumors in rats. Recently, these glial tumors have been characterized as microglial in origin. While effects of ACN on astrocytes, the more numerous glial cell, have been investigated, the effects on microglia are unknown. This study was conducted to compare the responses of astrocytes and microglia to ACN treatment in vitro to address differential sensitivities and adaptive responses to this toxic chemical. Cell viability, ACN uptake, lipid peroxidation byproducts (F2-isoprostanes), glutathione (GSH) levels and expression of NF-E2-related factor 2 (Nrf2) were evaluated in primary rat microglia and astrocytes following ACN treatment. Results indicate that microglia are more sensitive to ACN than astrocytes, accumulating less ACN while demonstrating higher F2-isoprostane levels. GSH levels were up-regulated in both cell types, as a protective mechanism against ACN-induced oxidative stress, while Nrf2 levels were only induced in microglia. Our data suggest that microglia and astrocytes exhibit different sensitivities and responses to ACN, which are linked to the intracellular thiol status inherent to each of these cell types.
PMCID: PMC4917379  PMID: 23628792
Acrylonitrile; Astrocytes; Microglia; Glutathione; Oxidative stress
Neurotoxicology  2010;31(4):373-384.
Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are seafood contaminants known for their adverse effects on neurodevelopment. This study examines the relation of developmental exposure to these contaminants to information processing assessed with event-related potentials (ERPs) in school-aged Inuit children from Nunavik (Arctic Québec). In a prospective longitudinal study on child development, exposure to contaminants was measured at birth and 11 years of age. An auditory oddball protocol was administered at 11 years to measure ERP components N1 and P3b. Multiple regression analyses were performed to examine the associations of levels of the contaminants to auditory oddball performance (mean reaction time, omission errors and false alarms) and ERP parameters (latency and amplitude) after control for potential confounding variables. A total of 118 children provided useable ERP data. Prenatal MeHg exposure was associated with slower reaction times and fewer false alarms during the oddball task. Analyses of the ERP parameters revealed that prenatal MeHg exposure was related to greater amplitude and delayed latency of the N1 wave in the target condition but not to the P3b component. MeHg effects on the N1 were stronger after control for seafood nutrients. Prenatal PCB exposure was not related to any endpoint for sample as a whole but was associated with a decrease in P3b amplitude in the subgroup of children who had been breast-fed for less than 3 months. Body burdens of MeHg and PCBs at 11 years were not related to any of the behavioural or ERP measures. These data suggest that prenatal MeHg exposure alters attentional mechanisms modulating early processing of sensory information. By contrast, prenatal PCB exposure appears to affect information processing at later stages, when the information is being consciously evaluated. These effects seem to be mitigated in children who are breast-fed for a more extended period.
PMCID: PMC4852376  PMID: 20403381
Children; Event-related potentials; Methylmercury; Neurotoxicity; P3b; Polychlorinated biphenyls
16.  Effects of Chronic Manganese Exposure on Attention and Working Memory in Non-Human Primates 
Neurotoxicology  2015;48:217-222.
Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self-ordered spatial search (SOSS) task and a five choice serial reaction time (5-CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure.
PMCID: PMC4442708  PMID: 25917687
Manganese; cognition; nonhuman primates
17.  Neurobehavioral effects of exposure to organophosphates and pyrethroid pesticides among Thai children 
Neurotoxicology  2015;48:90-99.
The use of pesticides for crop production has grown rapidly in Thailand during the last decade, resulting in significantly greater potential for exposure among children living on farms. Although some previous studies assessed exposures to pesticides in this population, no studies have been conducted to evaluate corresponding health effects. Twenty-four children from a rice farming community (exposed) and 29 from an aquaculture (shrimp) community (control) completed the study. Participants completed a neurobehavioral test battery three times at 6 month intervals: Session I: preliminary orientation; Session II: high pesticide use season; Session III: low pesticide-use season. Only sessions II and III were used in the analyses. High and low pesticide use seasons were determined by pesticide use on rice farms. Urinary metabolites of organophosphates (OPs) and pyrethroids (PYR) were analyzed from first morning void samples collected the day of neurobehavioral testing. Rice farm participants had significantly higher concentrations of dialkylphosphates (DAPs) (common metabolites of OPs) and TCPy (a specific metabolite of chlorpyrifos) than aquaculture farm children regardless of season. But, TCPy was significantly higher during the low rather than the high pesticide use season for both participant groups. Rice farm children had significantly higher DCCA, a metabolite of PYR, than aquaculture participants only during the high exposure season. Otherwise, no significant differences in PYR metabolites were noted between the participant groups or seasons. No significant adverse neurobehavioral effects were observed between participant groups during either the high or low pesticide use season. After controlling for differences in age and the Home Observation for Measurement of the Environment (HOME) scores, DAPs, TCPy, and PYR were not significant predictors of adverse neurobehavioral performance during either season. Increasing DAP and PYR metabolites predicted some relatively small improvement in latency of response. However, due to the small sample size and inability to characterize chronic exposure, any significant differences observed should be regarded with caution.
PMCID: PMC4442703  PMID: 25721160
neurobehavior; Behavioral Assessment and Research System; organophosphates; pyrethroids; pesticides; Thailand; children
18.  The brominated flame retardant BDE-47 causes oxidative stress and apoptotic cell death in vitro and in vivo in mice 
Neurotoxicology  2015;48:68-76.
Polybrominated diphenyl ethers (PBDEs), used for decades as flame retardants, have become widespread environmental contaminants. Exposure is believed to occur primarily through diet and dust, and infants and toddlers have the highest body burden, raising concern for potential developmental neurotoxicity. The exact mechanisms of PBDE neurotoxicity have not been elucidated, but two relevant modes of action relate to impairment of thyroid hormone homeostasis and to direct effects on brain cells causing alterations in signal transduction, oxidative stress and apoptotic cell death. The present study shows that BDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) induces oxidative stress and ensuing apoptotic cell death in mouse cerebellar granule neurons in vitro. Similarly, in vivo administration of BDE-47, according to an exposure protocol shown to induce behavioral and biochemical alterations (10 mg/kg, per os on post-natal day 10), induces oxidative stress and apoptosis, without altering serum levels of thyroid hormones. The effects of BDE-47 both in vitro and in vivo were more pronounced in a mouse model lacking the modifier subunit of glutamate cysteine ligase (GCLM) which results in reduced anti-oxidant capability due to low levels of GSH. Concentrations of BDE-47 in brain were in the mid-nanomolar range. These findings indicate that effects observed with BDE-47 in vitro are also present after in vivo administration, suggesting that in addition to potential endocrine effects, which were not seen here, direct interactions with brain cells should be considered as a potential mechanism of BDE-47 neurotoxicity.
PMCID: PMC4442709  PMID: 25797475
BDE-47; Oxidative stress; Glutathione; Apoptosis; Thyroid hormone; In vivo-in vitro
19.  Prenatal Exposure of Guinea Pigs to the Organophosphorus Pesticide Chlorpyrifos Disrupts the Structural and Functional Integrity of the Brain 
Neurotoxicology  2015;48:9-20.
This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (20 mg/kg, s.c.) or vehicle (peanut oil) once per day for ten consecutive days, starting approximately on the 50th day of gestation. Cognitive behavior of female offspring was examined starting at 40–45 post-natal days (PND) using the Morris Water Maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T2-weighted anatomical scans and Diffusion Kurtosis Imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of pre-natal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment.
PMCID: PMC4442734  PMID: 25704171
Chlorpyrifos; MRI; diffusion tensor imaging; prenatal exposure; neurodevelopment
20.  Combined Diazepam and MK-801 Therapy Provides Synergistic Protection from Tetramethylenedisulfotetramine-induced Tonic-Clonic Seizures and Lethality in Mice 
Neurotoxicology  2015;48:100-108.
The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or simultaneous administration of, these two agents in treating TMDT poisoning.
PMCID: PMC4442737  PMID: 25783504
tetramethylenedisulfotetramine; GABA; NMDA; seizures; neurotoxicity; isobologram
21.  Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges 
Neurotoxicology  2015;52:84-88.
We have evidence that methamphetamine (METH)-induced neuronal death is morphologically necrotic, not apoptotic, as is currently believed, and that electrographic seizures may be responsible. We administered 40 mg/kg i.p. to 12 male C57BL/6 mice and monitored EEGs continuously and rectal temperatures every 15 min, keeping rectal temperatures <41.0 °C. Seven of the 12 mice had repetitive electrographic seizure discharges (RESDs) and 5 did not. The RESDs were often not accompanied by behavioral signs of seizures–i.e., they were often not accompanied by clonic forelimb movements. The 7 mice with RESDs had acidophilic neurons (the H&E light-microscopic equivalent of necrotic neurons by ultrastructural examination) in all of 7 brain regions (hippocampal CA1, CA2, CA3 and hilus, amygdala, piriform cortex and entorhinal cortex), the same brain regions damaged following generalized seizures, 24 h after METH administration. The 5 mice without RESDs had a few acidophilic neurons in 4 of the 7 brain regions, but those with RESDs had significantly more in 6 of the 7 brain regions. Maximum rectal temperatures were comparable in mice with and without RESDs, so that cannot explain the difference between the two groups with respect to METH-induced neuronal death. Our data show that METH-induced neuronal death is morphologically necrotic, that EEGs must be recorded to detect electrographic seizure activity in rodents without behavioral evidence of seizures, and that RESDs may be responsible for METH-induced neuronal death.
PMCID: PMC4844464  PMID: 26562800
Electrographic seizures; Excitotoxicity; Methamphetamine; Mouse; Necrosis; Apoptosis
22.  Phenobarbital use and neurological problems in FMR1 premutation carriers 
Neurotoxicology  2016;53:141-147.
Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55–200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital. Here we present a study of three sisters with the premutation who were exposed differentially to phenobarbital therapy throughout their lives, allowing us to compare the neurological effects of this drug in these patients.
PMCID: PMC4808401  PMID: 26802682
Premutation; Fragile X; FMR1; Neurotoxicity; Phenobarbital; Pesticides
23.  Downregulation of Pink1 influences mitochondrial fusion–fission machinery and sensitizes to neurotoxins in dopaminergic cells 
Neurotoxicology  2014;44:140-148.
It is now well established that mitochondria are organelles that, far from being static, are subject to a constant process of change. This process, which has been called mitochondrial dynamics, includes processes of both fusion and fission. Loss of Pink1 (PTEN-induced putative kinase 1) function is associated with early onset recessive Parkinson’s disease and it has been proposed that mitochondrial dynamics might be affected by loss of the mitochondrial kinase. Here, we report the effects of silencing Pink1 on mitochondrial fusion and fission events in dopaminergic neuron cell lines. Cells lacking Pink1 were more sensitive to cell death induced by C2-Ceramide, which inhibits proliferation and induces apoptosis. In the same cell lines, mitochondrial morphology was fragmented and this was enhanced by application of forskolin, which stimulates the cAMP pathway that phosphorylates Drp1 and thereby inactivates it. Cells lacking Pink1 had lower Drp1 and Mfn2 expression. Based on these data, we propose that Pink1 may exert a neuroprotective role in part by limiting mitochondrial fission.
PMCID: PMC4778252  PMID: 24792327
Pink1; Ceramide; Parkinson; Rotenone; Mitochondrial dynamics
24.  Drug-Dependent Behaviors and Nicotinic Acetylcholine Receptor Expressions in Caenorhabditis elegans Following Chronic Nicotine Exposure 
Neurotoxicology  2014;47:27-36.
Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans’ (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine-induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine-induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software. Our results indicate that the combined system is an advantageous alternative to define drug-dependent locomotion behavior in C. elegans. Chronic (24-hour dosing) nicotine exposure at 6.17 and 61.7 μM induced nicotine-dependent behaviors, including drug stimulation, tolerance/adaption, and withdrawal responses. Specifically, the movement speed of naïve worms on nicotine-containing environments was significantly higher than on nicotine-free environments, suggesting locomotion stimulation by nicotine. In contrast, the 24-hour 6.17 μM nicotine-treated worms exhibited significantly higher speeds on nicotine-free plates than on nicotine-containing plates. Furthermore significantly increased locomotion behavior during nicotine cessation was observed in worms treated with a higher nicotine concentration of 61.7 μM. The relatively low locomotion speed of nicotine-treated worms on nicotine-containing environments also indicates adaption/tolerance of worms to nicotine following chronic nicotine exposure. In addition, this study provides useful information regarding the comprehensive in vivo expression profile of the 28 “core” nAChRs following different dosages of chronic nicotine treatments. Eleven genes (lev-1, acr-6, acr-7, acr-11, lev-8, acr-14, acr-16, acr-20, acr-21, ric-3, and unc-29) were significantly up-regulated following 61.7 μM nicotine treatment, in which worms showed significantly increased locomotion behavior. This study provides insights into the linkage between nicotine-induced locomotion behavior and the regulation of nicotinic acetylcholine receptors.
PMCID: PMC4385460  PMID: 25530353
nicotine; drug-dependent behaviors; nAChRs; gene expression; C. elegans
25.  Prenatal p,p′-DDE exposure and establishment of lateralization and spatial orientation in Mexican preschooler 
Neurotoxicology  2015;47:1-7.
Prenatal exposure to p,p′-DDE is associated with impairments in motor development during the first year of life, with no related repercussions on mental or motor development at 12 to 30 months and with impairments in cognitive areas, but not in perceptual and motor areas at preschool age. However, its association with particular psychomotor factors, such as establishment of lateralization and spatial orientation, essential elements to the overall learning and specifically reading, writing and spelling in preschoolers, has not been independently evaluated, since cognitive and motor areas have only been explored globally.
To determine the association between prenatal exposure to p,p′DDE and the establishment of lateralization and spatial orientation in children 5 years of age.
Material and Methods
Establishment of lateralization and spatial orientation was evaluated using the McCarthy Scale of Children's Abilities, with 167 children 5 years of age who participated in a birth cohort in the state of Morelos, Mexico. The information available for each child included: serum concentrations of p,p′-DDE of the mother during at least one trimester of pregnancy, mothers' intelligence quotients, stimulation at home and anthropometry. A logistic regression model was used to calculate the association between prenatal exposure to p,p′-DDE and lateralization and a multiple linear regression model was used for the association with spatial orientation.
A two-fold increase in p,p′DDE in lipid base during the second trimester of pregnancy was associated with a significant reduction, -0.18 points (95%CI -0.41;0.04, in the spatial orientation index, with no impairment in the establishment of hemispheric dominance. Attending preschool and the maternal intelligence quotient were the main determinants of spatial orientation and the establishment of hemispheric dominance.
Prenatal exposure to p,p′-DDE may affect the 5 year old's ability to identify spatial orientation of oneself and surrounding objects. Given the observed role of attending preschool in the functions studied, early attendance in formal education might serve as a stimulation strategy for preschoolers. These preliminary results should be verified and expanded in further prospective studies with DDE.
PMCID: PMC4385466  PMID: 25572880
DDE; lateralization; McCarthy Scales; spatial orientation

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