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  • Rotenone induces gastrointestinal pathology and microbiota alterations in a rat model of Parkinson’s disease
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-20
    Michaela E. Johnson, Andrea Stringer, Larisa Bobrovskaya

    While people are often aware of the motor symptoms in Parkinson’s disease (PD), few know of the many non-motor symptoms, which patients report have a greater impact on their quality of life. Gastrointestinal (GI) dysfunction is one of the most common non-motor symptoms, which can occur at any stage of PD, even years prior to diagnosis, and can affect all sections along the GI tract causing a range of symptoms including drooling, gastroparesis and constipation. We have investigated whether a neurotoxin model of PD- rotenone, a mitochondrial complex I inhibitor, is capable of reproducing the GI dysfunction seen clinically. Sprague-Dawley rats were administered 2.75 mg/kg rotenone, 5 days/week for 4 weeks, via intraperitoneal injection. Rats underwent behavioural testing, including the one-hour stool and gastric emptying tests before GI contents and tissues were collected for microbiota and histological analysis. Rats exposed to rotenone had more days with evidence of diarrhoea and significantly delayed gastric emptying, reproducing the clinical symptom of gastroparesis. Microbiota analysis revealed alterations in the small intestine and colon of rotenone-treated rats, relatively consistent with changes described in PD patients. Histological analysis demonstrated mucosal thickening and goblet cell hyperplasia in the colon of rotenone rats, which may be an adaptive response to the toxin or changes in GI microbiota. Our results indicate rotenone may be a good model for investigating the mechanisms involved with Parkinson’s GI symptoms and for screening potential therapeutic options as it is capable of recapitulating some key GI changes that occur during PD progression.

  • Hsp90 Co-chaperone p23 Contributes to Dopaminergic Mitochondrial Stress via Stabilization of PHD2: Implications for Parkinson’s disease
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-20
    Anand Rane, Subramanian Rajagopalan, Manuj Ahuja, Bobby Thomas, Shankar J. Chinta, Julie K. Andersen

    The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson’s disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD. We discovered an increased interaction between PHD2 and the p23:Hsp90 chaperone complex in response to mitochondrial stress elicited by the mitochondrial neurotoxin 1-methyl-4-phenylpyridine (MPP+) within cultured DAergic cells. Genetic p23 knockdown was found to result in decreases in steady-state PHD2 protein and activity and reduced susceptibility to MPP+ neurotoxicity. Administration of the p23 inhibitor gedunin was also neuroprotective in these cells as well as in human induced pluripotent stem cell (iPSC)-derived neurons. Our data suggests that mitochondrial stress-mediated elevations in PHD2 interaction with the p23-hsp90 complex have detrimental effects on the survival of DAergic neurons, while p23 inhibition is neuroprotective. We propose that neurotoxic effects are tied to enhanced PHD2 stabilization by the hsp90-p23 chaperone complex that is abrogated by p23 inhibition. This demonstrates a novel connection between two independent pathways previously linked to PD, hsp90 and PHD2-HIF1α, which could have important implications for here-to-fore unexplored mechanisms underlying PD neuropathology.

  • Development of neuropathology following soman poisoning and medical countermeasures
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-15
    Trond Myhrer, Espen Mariussen, Pål Aas

    Nerve agent-induced seizures can cause varying degrees of neuropathology depending on level of poisoning and duration of seizing. The intention of this review was to validate a novel approach for establishing effective treatment regimens against soman poisoning. Identification of seizure controlling sites in the forebrain of rats poisoned by soman was made by means of lesions, and the anticonvulsive properties of a number of relevant drugs were tested by microinfusions into the identified areas. By using these procedures, procyclidine emerged as the most potent drug. Its potency was confirmed in systemic studies and is further enhanced when combined with levetiracetam. Acute treatment with a combination of HI-6, levetiracetam and procyclidine (procyclidine regimen) can effectively manage supralethal poisoning by any of the classical nerve agents. Extended treatment with the procyclidine regimen is able to terminate residual “silent”, local epileptiform activity in the severely poisoned rats. Evident advantages are seen when the same regimen exerts both powerful anticonvulsant and neuroprotectant efficacies. According to the results presented, the new strategy for establishing therapies against soman-induced seizures appears to be valid.

  • Exposure to low level of lead during preweaning period increases metallothionein-3 expression and dysregulates divalent cation levels in the brain of young rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-13
    Abdur Rahman, Khalid M. Khan, Muddanna S. Rao

    Lead (Pb) is a neurotoxic heavy metal, but the mechanism of its neurotoxicity is not clearly understood. Expression of metallothioneins (MTs) is induced in response to heavy metal exposure as a protective mechanism against heavy metal toxicity. There are several isoforms of MTs (MT-1 to 4), of which MT-3 is the neuron specific isoform, which also has neurite growth inhibitory effects. Whereas, the induction of MT-1 and 2 in response to Pb has been reported, the effect of Pb on the expression of MT-3 in the brain has not been documented. This study aimed at investigating the effect of Pb exposure on the expression of MT-3 in the cerebrum and hippocampus. Wistar rat pups were exposed to Pb via their dams’ drinking water (0.2% lead acetate in deionized water) from postnatal day (PND) 0 to 21 and directly via drinking water until PND30. Expression of MT-3 was measured by Western blot and quantitative RT-PCR. MT-3 localization was done by immunohistochemistry. Divalent metal ions were analysed by atomic absorption spectrophotometry. Levels of Pb in blood and cerebrum were significantly increased, while that of copper (Cu), zinc (Zn) and manganese (Mn) were significantly decreased in the Pb-exposed rats at both PND21 and PND30. MT-3 protein was significantly increased in the cerebrum (by 2.5-fold) and in hippocampus (1.4 to 3.2-fold) in both PND21 and PND30 Pb-exposed rats over controls. MT-3 gene expression also increased in the cerebrum (by 42%), and in the hippocampus (by 65% and 43% in the PND21 and PND30 rats, respectively), in the Pb-exposed rats over controls, but the increase was statistically significant (p < 0.05) only in the PND30 rats. Pb exposure significantly increased (p < 0.05) percentage of MT-3 immunoreactive cells in Cornu Ammonis and dentate gyrus regions in the PND21 rats, and in the Cornu Ammonis 1, dentate gyrus and cortex regions in the PND30 rats. Our data thus provide convincing evidence that exposure to low levels of Pb during preweaning period increases the expression of MT-3 in the brain of rats.

  • Color vision impairments with low-level methylmercury exposure of an Amazonian population – Brazil
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-09
    Cláudia Feitosa-Santana, Givago da Silva Souza, Esaú Sirius Ventura Pupo, Anderson Raiol Rodrigues, Maria Izabel Tentes Cortes, Dora Fix Ventura

    Land exploitation that follows deforestation and mining can result in soil erosion and the release of mercury to the waters of rivers in the Amazon Basin. Inorganic mercury is methylated by bacteria that are present in the environment and it serves as a source of human contamination through fish consumption in the form of methylmercury. Long-term exposure to low-level methylmercury in the riverside populations can lead to nervous system alterations, some of which are visual impairments such as loss of luminance contrast sensitivity, restricted visual fields and color vision defects. The present study sought to examine color vision in a group of adults living in the central Brazilian Amazon who were exposed to low-levels of methylmercury. Total Hg concentrations were measured from hair collected at the time of the testing. The D15d and FM100 color vision arrangement tests were applied in a population of 36 (22 males) and 42 (25 males). Controls were healthy volunteers from the cities of São Paulo for the D15d and Belem for the FM100. There was a statistically significant difference in performance between those who were exposed and controls for both tests (p < 0.01 and p < 0.0001, respectively, Mann-Whitney U-test), meaning that adults living in this region of the Amazon made more mistakes on both tests when compared to controls. A linear regression was performed using Hg concentrations and test scores. Hg concentrations accounted for 7% and 2% of color D15d and FM100 arrangement test errors, respectively. Although other studies have previously found color vision impairment in the Amazon, they tested individuals on the east side of the Amazon, while this study was conducted in the central Amazon region. These results suggest that long-term exposure to low-level methylmercury in riverside populations is wider spread in the Amazon Basin than previously verified. This information is needed to implement public health policies that will ensure a safer environment for the Amazonian population.

  • Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-09
    Chrissie Ferreira de Carvalho, Youssef Oulhote, Marina Martorelli, Carla Oliveira de Carvalho, José Antônio Menezes-Filho, Nayara Argollo, Neander Abreu

    Manganese (Mn) is an essential element, however high levels of Mn have been associated with lower neuropsychological performance and behavioral problems in children. We investigated the associations between hair Mn concentrations and neuropsychological and behavioral performances among children with long-term exposure to airborne Mn aged between 7 and 12 years. Neuropsychological performance included tests of: verbal memory, inhibitory control, cognitive flexibility, verbal fluency, and motor function. We used the Conners Abbreviated Rating Scale for teachers to assess students’ behaviors of hyperactivity. Hair manganese (MnH) concentrations in children and exposure to airborne manganese from a ferro-manganese alloy plant were analyzed and correlated with tests scores. Multivariable linear models adjusting for potential confounders showed that elevated levels of MnH were associated with lower performance in verbal memory, as measured by the free recall after interference (β = – 1.8; 95% CI: – 3.4, – 0.2), which indicates susceptibility to interference, and Delayed Effect (β = –2.0; 95% CI: –3.7, – 0.2), representing a loss of information over time. Additionally, we found patterns of effect modification by sex in three subtests measuring verbal memory: the free recall after interference score, Interference Effect, and Delayed Effect (all at p < 0.10). Overall, the results suggest that long-term airborne Mn exposure may be associated with lower performance in verbal memory, and hyperactivity behaviors.

  • Neurobehavioral effects of 1,2-propanediol in zebrafish (Danio rerio)
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-09
    Andrey Massarsky, Ayham Abdel, Lilah Glazer, Edward D. Levin, Richard T. Di Giulio

    The use of electronic cigarettes (e-cigarettes) is increasing despite insufficient information concerning their long-term effects, including the effects of maternal e-cigarette use on pre- and postnatal development. Our previous study demonstrated that developmental exposure to 1,2-propanediol (a principal component of e-cigarette liquid) affected early development of zebrafish, causing reduced growth, deformities, and hyperactive swimming behavior in larvae. The current study extends assessment of the developmental toxicity of 1,2-propanediol by examining additional long-term behavioral effects. We demonstrate that embryonic/larval exposure of zebrafish to 1,2-propanediol (0.625% or 1.25%) not only affected behavioral parameters in the larvae, but also caused persisting behavioral effects in adults after early developmental exposure. Additional parameters, including neural and vascular development in larvae, stress response in adults, and concentration of neurotransmitters dopamine and serotonin in adult brain were examined, in order to explain the behavioral differences. These additional studies did not find 1,2-propanediol exposure to significantly affect Tg(Neurog1:GFP) or the transcript abundance of neural genes (Neurog1, Ascl1a, Elavl3, and Lef1). Vascular development was not found to be affected by 1,2-propanediol exposure, as inferred from experiments with Tg(Flk1:eGFP) zebrafish; however, transcript abundance of vascular genes (Flk1, Vegf, Tie-2, and Angpt1) was decreased. No statistically significant changes were noted for plasma cortisol or brain neurotransmitters in adult fish. Lastly, analysis of gene transcripts involved with 1,2-propanediol metabolism (Adh5, Aldh2.1, and Ldha) showed an increase in Adh5 transcript. This is the first study to demonstrate that developmental exposure to 1,2-propanediol has long-term neurobehavioral consequences in adult zebrafish, showing that e-cigarettes contain substances potentially harmful to neurodevelopment.

  • Physiological assesment of vestibular function and toxicity in humans and animals
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-08
    Jordi Llorens, Angela Callejo, Erin A. Greguske, Alberto F. Maroto, Blanca Cutillas, Vanessa Martins-Lopes

    Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity.

  • Cross-sectional study to assess the association of color vision with mercury hair concentration in children from Brazilian Amazonian riverine communities
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-08
    Joyce dos Santos Freitas, Eliza Maria da Costa Brito Lacerda, Isabelle Christine Vieira da Silva Martins, Dario Rodrigues Jr., Daniela Maria Oliveira Bonci, Maria Izabel Tentes Cortes, Tereza Cristina Oliveira Corvelo, Dora Fix Ventura, Luiz Carlos de Lima Silveira, Maria da Conceição Nascimento Pinheiro, Givago da Silva Souza

    Background Mercury exposure in the Brazilian Amazon region has been an important concern since the 1980s, when gold mining activities contaminated many Amazonian river basins and the fish therein. Mercury exposure in humans can lead to changes in neural function. The visual system has been used as a functional indicator of methylmercury (organic) and mercury vapour (inorganic) toxicity. Children are particularly vulnerable to this metal exposure. Objective To compare the color vision of children from riverine communities of mercury-exposed (Tapajós basin) and non-exposed Amazonian rivers (Tocantins basin). Methods The study sample was 176 children, aged 7 to 14 years old. Children from two locations in the mercury-exposed Tapajós river basin, Barreiras (n=71) and São Luiz do Tapajos (n=41), were compared to children from Limoeiro do Ajuru (n=64), a non-exposed area in the Tocantins river basin. No caregiver reported that any children had contact with mercury vapour during their lifetime, and probably most of the mercury in their bodies was obtained by fish consumption. Because of this, we decided to evaluate the mercury exposure by total mercury levels in hair samples, a good marker for organic mercury, and not in the urine, a marker for inorganic mercury. Color vision was assessed by the Lanthony Desaturated D-15 test. We used the Vingrys and King-Smith method (1988) to quantify the hue ordering test. The primary visual outcomes from this analysis were C-index (magnitude of the hue ordering error) and angle of the hue ordering. Results The Tapajós children had a higher mean hair mercury level (mean: 4.5 μg/g; range: 0.26-22.38 μg/g) than that of Tocantins children (mean: 0.49 μg/g; range: 0.03-1.91 μg/g) (p < 0.05). Mean difference was approximately 4.01 μg/g with a 95% confidence interval of 2.79 to 5.23. The results of the Lanthony D-15d test showed no significant difference between the C-index mean values of the Tapajós and Tocantins groups (p > 0.05). There was a weak linear correlation in the average C-index obtained from both eyes and the total mercury concentration. Multiple logistic regression analysis indicated that the location of the community and the age had a greater influence on the visual outcomes than the sex of the children and within-locale variation in mercury concentration. Conclusion Our results suggest a difference in one aspect of vision, that is, color vision, between children living in two different river basins in the Brazilian Amazon. The association may be related to Hg exposure but also appeared related to the location of the community and age.

  • Microglial activation and vascular responses that are associated with early thalamic neurodegeneration resulting from thiamine deficiency
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-07
    John F. Bowyer, Karen M. Tranter, Sumit Sarkar, Joseph P. Hanig

    Thiamine/ vitamin B1 deficiency can lead to behavioral changes and neurotoxicity in humans. This may due in part to vascular damage, neuroinflammation and neuronal degeneration in the diencephalon, which is seen in animal models of pyrithiamine-enhanced thiamine deficiency. However, the time course of the progression of these changes in the animal models has been poorly characterized. Therefore, in this study, the progression of: 1) activated microglial association with vasculature; 2) neurodegeneration; and 3) any vascular leakage in the forebrain during the progress of thiamine deficiency were determined. A thiamine deficient diet along with 0.25 mg/ kg/ d of pyrithiamine was used as the mouse model. Vasculature was identified with Cd-31 and microglia with Cd-11b and Iba1 immunoreactivity. Neurodegeneration was determined by FJc labeling. The first sign of activated microglia within the thalamic nuclei were detected after 8 d of thiamine deficiency, and by 9 d activated microglia associated primarily with vasculature were clearly present but only in thalamus. At the 8 d time point neurodegeneration was not present in thalamus. However at 9 d, the first signs of neurodegeneration (FJc+ neurons) were seen in most animals. Over 80% of the microglia were activated at 10 d but almost exclusively in the thalamus and the number of degenerating neurons was less than 10% of the activated microglia. At 10 d, there were sporadic minor changes in IgG presence in thalamus indicating minor vascular leakage. Dizocilpine (0.2 to 0.4 mg/ kg) or phenobarbital (10 to 20 mg/ kg) was administered to groups of mice from day 8 through day 10 to block neurodegeneration but neither did. In summary, activated microglia start to surround vasculature 1 to 2 d prior to the start of neurodegeneration. This response may be a means of controlling or repairing vascular damage and leakage. Glutamate excitotoxicity and vascular leakage likely only play a minor role in the early neurodegeneration resulting from thiamine deficiency. However, failure of dysfunctional vasculature endothelium to supply sufficient nutrients to neurons could be contributing to the neurodegeneration.

  • Comparison of quantitative T2 and ADC mapping in the assessment of 3-nitropropionic acid-induced neurotoxicity in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-07
    Serguei Liachenko, Jaivijay Ramu, Merle G. Paule, Joseph Hanig

    To assess the relative performance of MRI T2 relaxation and ADC mapping as potential biomarkers of neurotoxicity, a model of 3-nitropropionic acid (NP)-induced neurodegeneration in rats was employed. Male Sprague-Dawley rats received NP (N = 20, 16-20 mg/kg, ip or sc) or saline (N = 6, 2 ml/kg, ip) daily for 3 days. MRI was performed using a 7 tesla system employing quantitative T2 and ADC mapping based on spin echo pulse sequence. All maps were skull stripped and co-registered and the changes were quantified using baseline subtraction and anatomical segmentation. Following the in vivo portion of the study, rat brains were histologically examined. Four NP-treated rats were considered responders based on their MRI and histology data. T2 values always increased in the presence of toxicity, while ADC changes were bidirectional, decreasing in some lesion areas and increasing in others. In contrast to T2 in some cases, ADC did not change. The effect sizes of T2 and ADC signals suggestive of neurotoxicity were 2.64 and 1.66, respectively, and the variability of averaged T2 values among anatomical regions was consistently lower than that for ADC. The histopathology data confirmed the presence of neurotoxicity, however, a more detailed assessment of the correlation of MRI with histology is needed. T2 mapping provides more sensitive and specific information than ADC about changes in the rat brain thought to be associated with neurotoxicity due to a higher signal-to-noise ratio, better resolution, and unidirectional changes, and presents a better opportunity for biomarker development.

  • Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-06
    Cleide dos Santos Souza, Maria Socorro grangeiro, Erica Patricia Lima Pereira, Cleonice Creusa dos Santos, Alessandra Bispo da Silva, Geraldo Pedral Sampaio, Daiana Dias Ribeiro Figueiredo, Jorge Mauricio David, Juceni Pereira David, Victor Diogenes Amaral da Silva, Arthur Morgan Butt, Silvia Lima Costa

    Flavonoids are bioactive compounds that are known to be neuroprotective against glutamate-mediated excitotoxicity, one of the major causes of neurodegeneration. The mechanisms underlying these effects are unresolved, but recent evidence indicates flavonoids may modulate estrogen signaling, which can delay the onset and ameliorate the severity of neurodegenerative disorders. Furthermore, the roles played by glial cells in the neuroprotective effects of flavonoids are poorly understood. The aim of this study was to investigate the effects of the flavonoid agathisflavone (FAB) in primary neuron-glial co-cultures from postnatal rat cerebral cortex. Compared to controls, treatment with FAB significantly increased the number of neuronal progenitors and mature neurons, without increasing astrocytes or microglia. These pro-neuronal effects of FAB were suppressed by antagonists of estrogen receptors (ERα and ERβ). In addition, treatment with FAB significantly reduced cell death induced by glutamate and this was associated with reduced expression levels of pro-inflammatory (M1) microglial cytokines, including TNFα, IL1β and IL6, which are associated with neurotoxicity, and increased expression of IL10 and Arginase 1, which are associated with anti-inflammatory (M2) neuroprotective microglia. We also observed that FAB increased neuroprotective trophic factors, such as BDNF, NGF, NT4 and GDNF. The neuroprotective effects of FAB were also associated with increased expression of glutamate regulatory proteins in astrocytes, namely glutamine synthetase (GS) and Excitatory Amino Acid Transporter 1 (EAAT1). These findings indicate that FAB acting via estrogen signaling stimulates production of neurons in vitro and enhances the neuroprotective properties of microglia and astrocytes to significantly ameliorate glutamate-mediated neurotoxicity.

  • Minocycline diminishes the rotenone induced neurotoxicity and glial activation via suppression of apoptosis, nitrite levels and oxidative stress
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Dinesh Kumar Verma, Dhirendra Kumar Singh, Sonam Gupta, Parul Gupta, Abhishek Singh, Joyshree Biswas, Sarika Singh
  • Caloric restriction ameliorates acrolein-induced neurotoxicity in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Ying-Juan Huang, Li Zhang, Lan-Ying Shi, Yuan-Yuan Wang, Yu-Bin Yang, Bin Ke, Ting-Ying Zhang, Jian Qin

    Objective Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and oxidative damage induced by acrolein is hypothesized to involve in the etiology of Alzheimer’s disease (AD). Calorie restriction (CR) is the only non-genetic intervention that has consistently been verified to retard aging by ameliorating oxidative stress. Therefore, we investigated the effects of CR on acrolein-induced neurotoxicity in Sprague-Dawley (SD) rats. Methods A total of 45 weaned and specific-pathogen-free SD rats (male, weighing 180–220 g) were gavage-fed with acrolein (2.5 mg/kg/day) and fed ab libitum of 10 g/day or 7 g/day (representing 30% CR regimen), or gavage-fed with same volume of tap water and fed al libitum as vehicle control for 12 weeks. After behavioral test conducted by Morris Water Maze, SD rats were sacrificed and brain tissues were prepared for histochemical evaluation and Western blotting to detect alterations in oxidative stress, BDNF/TrkB pathway and key enzymes involved in amyloid precursor protein (APP) metabolism. Results Treatment with 30% CR in SD rats significantly attenuated acrolein-induced cognitive impairment. Oxidative damage including deletion of glutathione and superoxide dismutase and sharp rise in malondialdehyde were notably improved by 30% CR. Further study suggested that 30% CR showed protective effects against acrolein by modulating BDNF/TrkB signaling pathways. Moreover, 30% CR restored acrolein-induced changes of APP, β-secretase, α-secretase and receptor for advanced glycation end products. Conclusion These findings suggest that CR may provide a promising approach for the treatment of AD, targeting acrolein.

  • Assessment of brain oxygenation imbalance following soman exposure in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Kevin Lee, Sara Bohnert, Ying Wu, Cory Vair, John Mikler, G. Campbell Teskey, Jeff F. Dunn

    Nerve agents (NAs) are potent organophosphorus (OP) compounds with applications in chemical warfare. OP compounds act by inhibiting acetylcholinesterase (AChE). Soman (O-pinacolyl methylphosphonofluoridate) is one of the most potent NAs. It is well known that small doses of NAs can be lethal, and that even non-lethal exposure leads to long-term mental debilitation/neurological damage. However, the neuropathology following exposure to sub-lethal nerve agents is not well understood. In this study we examined changes in tissue oxygenation (pO2) in the cortex and hippocampus after a sub-lethal dose of soman [80–90 μg/kg; subcutaneous]. pO2 changes can provide information regarding oxygen delivery and utilization and may be indicative of disruption in cerebral blood flow and/or metabolism. Changes in oxygenation were measured with chronically implanted oxygen sensors in awake and freely moving rats. Measurements were taken before, during, and after soman-induced convulsive seizures. Soman exposure resulted in an immediate increase in pO2 in the cortex, followed by an even greater increase that precedes the onset of soman-induced convulsive seizures. The rise in hippocampus pO2 was delayed relative to the cortex, although the general pattern of brain oxygenation between these two regions was similar. After convulsive seizures began, pO2 levels declined but usually remained hyperoxygenated. Following the decline in pO2, low frequency cycles of large amplitude changes were observed in both the cortex and hippocampus. This pattern is consistent with recurring seizures. Measuring real-time changes in brain pO2 provides new information on the physiological status of the brain following soman exposure. These results highlight that the measurement of brain oxygenation could provide a sensitive marker of nerve agent exposure and serve as a biomarker for treatment studies.

  • Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    L. Melo-Thomas, A.L. Gil-Martínez, L. Cuenca, C. Estrada, A. Gonzalez-Cuello, R.K. Schwarting, M.T. Herrero

    The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. Additionally, the IC has been implicated in processing sensorimotor responses. Glutamatergic and GABAergic manipulations in the IC can improve motor deficits as demonstrated by the animal model of haloperidol-induced catalepsy. However, how the IC influences motor function remains unclear. We investigated the effects of either intracollicular deep brain stimulation (DBS) or microinjection of the glutamatergic antagonist MK-801 or the agonist NMDA in C57BL/6J mice chronically treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After DBS or microinjections, the mice were submitted to rotarod and open field tests, respectively. DBS in the IC was effective to increase the time spent on the rotarod in MPTP-treated mice. After unilateral microinjection of MK-801, but not NMDA, MPTP-treated mice increased the distance travelled in the open field (p < 0.05). In conclusion, intracollicular DBS or MK-801 microinjection can improve motor performance in parkinsonian mice suggesting the IC as a new and non-conventional therapeutic target in motor impairment.

  • The Association between Early-life Relative Telomere Length and Childhood Neurodevelopment
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Marina Oktapodas Feiler, Deven Patel, Huiqi Li, Philip J. Meacham, Gene E. Watson, Conrad Shamlaye, Alison Yeates, Karin Broberg, Edwin van Wijngaarden

    Purpose To examine the association between telomere length and neurodevelopment in children. Methods We examined the relationship between relative telomere length (rTL) and neurodevelopmental outcomes at 9 and 30 months, and 5 years of age in children enrolled in the Seychelles Child Development Study Nutrition Cohort 1 (NC1). Relative telomere length was measured in cord blood and in child blood at age five. Multivariable linear regression examined associations between neurodevelopmental outcomes and rTL adjusting for relevant covariates. Results Mean rTL was 1.18 at birth and 0.71 at age five. Increased cord blood rTL was associated with better scores on two neurodevelopmental tests, the psychomotor developmental index (β = 4.01; 95% confidence interval (CI) = 0.17, 7.85) at age 30 months, and the Woodcock Johnson test of achievement letter-word score (β=2.88; CI = 1.21-4.56) at age five. The Woodcock Johnson test of achievement letter-word score remained statistically significant after two outliers were excluded (β=2.83; CI = 0.69, 4.97); the psychomotor developmental index did not (β = 3.62; CI = −1.28, 8.52). None of the neurodevelopmental outcomes at age five were associated with five-year rTL. Conclusion Although increased cord blood rTL was associated with better test scores for a few neurodevelopmental outcomes, this study found little consistent evidence of an association between rTL and neurodevelopment. Future studies with a larger sample size, longer follow-up, and other relevant biological markers (e.g. oxidative stress) are needed to clarify the role of rTL in neurodevelopment and its relevance as a potential surrogate measure for oxidative stress in the field of developmental neurotoxicity.

  • Prenatal exposure to valproic acid alters the development of excitability in the postnatal rat hippocampus
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-05
    Yukiko Fueta, Yuko Sekino, Sachiko Yoshida, Yasunari Kanda, Susumu Ueno

    Prenatal valproic acid (VPA) exposure is a well-known animal model of autism spectrum disorder (ASD) that produces alterations in embryonic and adult neurogenesis as well as adolescent/adulthood neurobehavioral phenotypes. However, the effects of prenatal VPA exposure on neural network excitability, especially during the synaptogenic period around eye opening, are not fully understood. In this study, we orally administered VPA (300 mg/kg) to pregnant Wistar rats on gestation day 15 and subsequently performed field potential recording in the CA1 area of hippocampal slices obtained from control (saline-exposed) and VPA-exposed rat pups between postnatal day (PND) 13 and PND18. In control slices, we observed an abrupt enhancement of stimulation-dependent responses including population spike (PS) amplitudes and field excitatory postsynaptic potential (fEPSP) slopes at PND16, which coincided with the average day of eye opening. In contrast, VPA-exposed pups exhibited delayed eye opening (PND17) and gradual rather than abrupt increases in PS amplitudes and fEPSP slopes over the duration of the synaptogenic period. We next investigated the involvement of ambient GABA in PS generation using bicuculline methiodide (BMI), a γ-aminobutyric acid type A (GABAA) receptor antagonist. In control slices, BMI enhanced PS amplitudes during PND14–15 (before eye opening) and had little effect thereafter during PND16–17; a subsequent regression model analysis of BMI ratios (the ratio of PS amplitudes in the presence and absence of BMI) indicated a possible developmental change between these periods. In contrast, almost identical regression models were obtained for BMI ratios during PND14–15 and PND16–17 in the VPA-exposed group, indicating the absence of a developmental change. Our results suggest that prenatal VPA exposure accelerates the development of hippocampal excitability before eye opening. Moreover, our experimental model can be used as a novel approach for the evaluation of developmental neurotoxicity.

  • Occupational exposure to extremely low frequency magnetic field and risk of Alzheimer disease: A systematic review and meta-analysis
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-24
    Hamed Jalilian, Saeed Hosseini Teshnizi, Martin Röösli, Masoud Neghab

    Introduction Occupational exposure to extremely low frequency magnetic fields (ELF-MF) occurs in many occupations such as welders, electric utility workers, train drivers and sewing machine operators. There is some evidence suggesting ELF-MF exposure to be a risk factor for Alzheimer’s disease (AD). The current study aims at systematically reviewing the literature and conducting a meta-analysis to evaluate the risk of AD amongst workers exposed to ELF-MF. Methods Bibliographic databases were searched including PubMed, EMBASE, Cochrane Library, and Web of Science in November 2017. Risk of bias was assessed in the all included studies. Pooled estimates were obtained using random-effects meta-analysis. In addition, sources of heterogeneity between studies and publication bias were explored. Results In total, 20 articles met the inclusion criteria. The pooled results suggest an increased risk of AD (RR: 1.63; 95% CI: 1.35, 1.96). Higher risk estimates were obtained from case-control studies (OR: 1.80; 95% CI: 1.40, 2.32) than from cohort studies (RR: 1.42; 95% CI: 1.08, 1.87). A moderate to high heterogeneity (I2 = 61.0%) and indication for publication bias (Egger test: p < .001) were found. Conclusion The results suggested that occupational exposure to ELF-MF might increase the risk of AD. However, this suggestion should be interpreted with caution given the moderate to high heterogeneity and indication for publication bias.

  • The brains of bats foraging at wastewater treatment works accumulate arsenic, and have low non-enzymatic antioxidant capacities
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-14
    Kate Hill, M. Corrie Schoeman, Dalene Vosloo

    Increasing rates of urbanisation cause ubiquitous infrastructures that remove anthropogenic contaminants – particularly Wastewater Treatment Works (WWTW) – to become stressed, and hence pollute surrounding water systems. Neoromicia nana bats are suitable models to study the effects of pollution in these environments because they exploit abundant pollutant-tolerant chironomid midges that breed at WWTW, and consequently accumulate metals such as iron, copper and zinc in their livers and kidneys. If these metals persist in their circulatory systems, and cross the blood brain barrier (BBB) they can have adverse effects on critical functions such as flight and echolocation. The aim of this study was to investigate the potential neurological effects on N. nana foraging at WWTW versus bats at reference sites in Durban, South Africa. Our objectives were to 1) compare trace metal levels in brain and hair samples (as a proxy for circulating metals) between N. nana foraging at WWTW and reference sites to determine if excess metals pass through the BBB via the circulatory system; and 2) compare biomarkers of neuron function (acetylcholinesterase activity), protection (antioxidant capacity), DNA integrity (DNA fragmentation), lipid integrity (lipid peroxidation) and cell viability (caspase-3 activity) between N. nana foraging at WWTW and reference sites. We found a significantly higher concentration of arsenic in hair (p < 0.05) and brain tissue (p < 0.1) of WWTW bats compared to bats at reference sites. By contrast, acetylcholinesterase activity did not differ in bats among sites and there was no evidence of significant differences in lipid peroxidation, compromised DNA integrity or apoptosis in the brains between WWTW bats and reference site bats. However, total antioxidant capacity was significantly lower in brains of WWTW bats than bats at reference sites suggesting that antioxidant protection may be compromised. Long-term exposure to environmental pollutants at WWTW may therefore affect cellular processes and protection mechanisms in brains of N. nana bats. It may also affect other mechanisms and functions in the brain such as mitochondrial efficiency and other neurotransmitters but that remains to be tested.

  • Developmental Exposure to Low Level Ambient Ultrafine Particle Air Pollution and Cognitive Dysfunction
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-13
    D.A. Cory-Slechta, J.L. Allen, K. Conrad, E. Marvin, M. Sobolewski

    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 behaivors 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/m3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4 hr/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.

  • HEK-293 secretome attenuates kainic acid neurotoxicity through insulin like growth factor-phosphatidylinositol-3-kinases pathway and by temporal regulation of antioxidant defense machineries
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-06
    Chaitra Venugopal, Y.S.Harish Chandra Prasad, K. Shobha, Venkata Bharatkumar Pinnelli, Anandh Dhanushkodi

    A major impediment in the success of cell therapy for neurodegenerative diseases is the poor survival of grafted cells in the in vivo milieu, predominantly due to accumulated reactive oxygen species, thus prompting the search for suitable alternatives. Accumulating evidence suggests that the therapeutic potential of transplanted cells is partially attributed to the secretome released by them into the extracellular milieu. Studies that investigated the neuroprotective potential of the secretome attributes to the mere presence of growth factors without addressing other underlying cellular/molecular changes that occur upon post-secretome intervention like re-establishing the host cell’s free radical scavenging machineries. In the present study, we investigated the neuroprotective effects of human embryonic kidney (HEK-293) cell line derived secretome (HEK-S) in an in vitro model of kainic acid (KA) induced neurodegeneration and explored the possible neuroprotective mechanism(s) of HEK-S. Murine hippocampal cells were exposed to toxic doses of KA (200 μM) for 6 hours (H) or 24H to induce excitotoxicity. Kainic acid exposed hippocampal cells were then treated with HEK-S either simultaneously or 6 h post-KA exposure. Our results revealed that HEK-S confers significant neuroprotection in early/later stages of neurodegeneration through insulin like growth factor (IGF) – phosphatidylinositol-3-kinases (PI3 K) pathway, efficiently restoring the host’s free radical scavenging mechanisms at molecular-cellular-biochemical levels and also by modulating kainate receptor subunit expressions in host neurons.

  • LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-05
    Yuan Chen, Ya-jun Lian, Yun-qing Ma, Chuan-jie Wu, Ya-ke Zheng, Nan-chang Xie

    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.

  • Can we predict intermediate syndrome? A review
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-05
    Chanika Alahakoon, Tharaka Lagath Dassanayake, Indika Bandara Gawarammana, Vajira Senaka Weerasinghe

    Introduction Ingestion of organophosphorus insecticides (OPI) is a common method of deliberate self harm in the developing world. Deaths mainly follow as a result of the respiratory failure associated with both cholinergic crisis and the intermediate syndrome. Even though death can be prevented by early mechanical ventilation of these patients, limited studies are available regarding the prediction of intermediate syndrome and subsequent respiratory failure. Objective To systematically review articles that are published with regard to possible prediction of intermediate syndrome using clinical, biochemical and electrophysiological parameters. Methods A systematic review on literature published in English language was done in the PubMed database without a date limitation. Two sets of search terms were used. The first set consisted of MeSH Terms “organophosphates”, “organophosphate poisoning”, “op poisoning” “organophosphate insecticide poisoning” and “organophosphorus”. The second set included the MeSH Terms “Intermediate syndrome”, “proximal muscle weakness”, “cranial nerve palsies”, “respiratory depression” and “neck muscle weakness”. Articles containing at least one word from each set were reviewed. Results At least one MeSH term from each set was incorporated in 179 articles. Of these, 69 were rejected as they were not related to organophosphate poisoning or intermediate syndrome. Prediction of IMS Clinical prediction is mostly based on ICU scoring systems. Biochemical markers such as reduced levels of serum and erythrocyte acetylcholine esterase have been studied many times. Both clinical and biochemical markers show a modest relationship in predicting IMS. Single fibre electromyography show promising results as it directly assesses neuromuscular junction. Conclusion The intermediate syndrome which follows organophosphate poisoning still remains a significant problem with its high morbidity. Clinical and biochemical markers show modest results in predicting IMS. Neurophysiological markers such as single fibre EMG should be studied further as they measure activity of affected nicotinic receptors directly.

  • Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children’s Health
    Neurotoxicology (IF 3.1) Pub Date : 2017-12-02
    Keiko Yamazaki, Atsuko Araki, Sonomi Nakajima, Chihiro Miyashita, Tamiko Ikeno, Sachiko Itoh, Machiko Minatoya, Sumitaka Kobayashi, Futoshi Mizutani, Yoichi Chisaki, Reiko Kishi

    Organochlorine pesticides (OCPs) are environmental contaminants that persist in the environment and bioaccumulate through the food chain in humans and animals. Although previous studies have shown an association between prenatal OCP exposure and subsequent neurodevelopment, the levels of OCPs included in these studies were inconsistent. A hospital-based prospective birth cohort study was conducted to examine the associations between prenatal exposure to relatively low levels of OCPs and neurodevelopment in infants at 6 (n = 164) and 18 (n = 115) months of age. Blood samples were analyzed using gas chromatography/mass spectrometry techniques to quantify 29 OCPs. The Bayley Scales of Infant Development 2nd edition (BSID-II) was used to assess the Mental and Psychomotor Developmental Index. After controlling for confounders, we found an inverse association between prenatal exposure to cis-heptachlor epoxide and the Mental Developmental Index at 18 months of age. Furthermore, infants born to mothers with prenatal concentrations of cis-heptachlor epoxide in the highest quartile had Mental Developmental Index scores −9.8 (95% confidence interval: −16.4, −3.1) lower than that recorded for infants born to mothers with concentrations of cis-heptachlor epoxide in the first quartile (p for trend <0.01). These results support the hypothesis that prenatal exposure to OCPs, especially cis-heptachlor epoxide, may have an adverse effect on the neurodevelopment of infants at specific ages, even at low levels.

  • 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-26
    Edward Pajarillo, James Johnson Jr., Judong Kim, Pratap Karki, Deok-Soo Son, Michael Aschner, Eunsook Lee

    Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson’s disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.

  • A magnetic resonance imaging study of early brain injury in a rat model of acute DFP intoxication
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-26
    Brad A. Hobson, Douglas J. Rowland, Suangsuda Supasai, Danielle J. Harvey, Pamela J. Lein, Joel R. Garbow

    Current treatments for seizures induced by organophosphates do not protect sufficiently against progressive neurodegeneration or delayed cognitive impairment. Developing more effective therapeutic approaches has been challenging because the pathogenesis of these delayed consequences is poorly defined. Using magnetic resonance imaging (MRI), we previously reported brain lesions that persist for months in a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP). However, the early spatiotemporal progression of these lesions remains unknown. To address this data gap, we used in vivo MRI to longitudinally monitor brain lesions during the first 3 d following acute DFP intoxication. Adult male Sprague Dawley rats acutely intoxicated with DFP (4 mg/kg, sc) were MR imaged at 6, 12, 18, 24, 48, 72 h post-DFP, and their brains then taken for correlative histology to assess neurodegeneration using FluoroJade C (FJC) staining. Acute DFP intoxication elicited moderate-to-severe seizure activity. T2-weighted (T2w) anatomic imaging revealed prominent lesions within the thalamus, piriform cortex, cerebral cortex, hippocampus, corpus striatum, and substantia nigra that corresponded to neurodegeneration, evident as bands of FJC positive cells. Semi-quantitative assessment of lesion severity demonstrated significant regional variation in the onset and progression of injury, and suggested that lesion severity may be modulated by isoflurane anesthesia. These results imply that the timing of therapeutic intervention for attenuating brain injury following OP intoxication may be regionally dependent, and that longitudinal assessment of OP-induced damage by MRI may be a powerful tool for assessing therapeutic response.

  • Mechanism of Rhinella icterica (Spix, 1824) toad poisoning using in vitro neurobiological preparations
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-23
    Raquel Soares Oliveira, Allan Pinto Leal, Barbara Ogata, Carlos Gabriel Moreira de Almeida, Douglas Silva dos Santos, Leandro Homrich Lorentz, Cleci Menezes Moreira, Karla de Castro Figueiredo Bordon, Eliane Candiani Arantes, Tiago Gomes dos Santos, Cháriston André Dal Belo, Lúcia Vinadé

    The biological activity of Rhinella icterica toxic secretion (RITS) was evaluated on chick neuromuscular junctions, rat heart́s tissue and mice hippocampal slices. At chick biventer cervicis preparation, RITS (5, 10 and 20 μg/mL) produced a concentration-independent irreversible neuromuscular blockade, which was preceded by a transitory increase of muscle twitch tension with the lowest concentration, in 120 min recordings. In this set of experiments, RITS incubation partially prevented the curare neuromuscular blockade. The assessment of chick biventer cervicis muscle acetylcholinesterase (AChE) in the presence of RITS showed a significant inhibition of the enzyme, similarly to neostigmine. The incubation of muscles with digoxin or ouabain mimicked the poison activity by increasing the amplitude of the twitches followed by a progressive depression of the muscle strength. In addition, RITS demonstrated a digitalic-like activity, by inhibiting significantly the cardiac Na+, K+-ATPase. When the central nervous system was accessed, RITS induced an increase in the cell viability, in the lowest concentration. In addition, the poison protected slices subject to oxygen/glucose deprivation. Altogether, these data indicate that the poisonous extract of R. icterica is able to interfere with peripheral and central neurotransmission, probably due to a direct interaction with AChE, calcium channels and Na+, K+-ATPase. A further investigation upon the poison toxic components will unveil the components involved in such a pharmacological activity and the potential biotechnological application of this poison.

  • Neurotoxicity of carbon monoxide targets caudate-mediated dopaminergic system
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-22
    Tzu-Kuan Sun, Yen-Yu Chen, Shu-Hua Huang, Shih-Wei Hsu, Chen-Chang Lee, Wen-Neng Chang, Chi-Wei Huang, Chun-Chung Lui, Chia-Yi Lien, Ju-Ling Cheng, Chiung-Chih Chang

    The clinical features of parkinsonism in carbon monoxide (CO) intoxication have been associated with striatal-related neuronal networks. As parkinsonian and neuropsychiatric features are both related to presynaptic dopaminergic integrity, the aim of this study was to explore the clinical significance of 99mTcTRODAT-1 in grading neurobehavioral scores and parkinsonian severity in CO intoxication. We enrolled 64 patients with CO intoxication, including 29 with parkinsonism (parkinsonism[+] group) and 35 without (parkinsonism[−] group). All of the patients received 99mTcTRODAT-1 neuroimaging evaluations, comprehensive neurobehavioral tests and assessments of the severity of parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS)-part III motor score. Univariate and multivariate regression analyses were used to test the predictive factors and scores for a diagnosis of parkinsonism and its severity. The parkinsonism(+) group had significantly lower cognitive scores and higher neuropsychiatric total scores compared with the parkinsonism(−) group, both of which were independently related to the severity of parkinsonism. 99mTcTRODAT-1 regional caudate signals were correlated with tremors at rest, action or postural tremors of the hands, bradykinesia and hypokinesia, and visuospatial, verbal fluency, abstract thinking and digit backwards scores. Scores of the neurobehavioral tests and UPDRS items were highly correlated (p < 0.01). Our results validated the initial hypothesis in that neurobehavioral deficits and parkinsonian symptoms were highly related. This association was independent of demographic factors and initial carboxyhemoglobin level. Within the presynaptic dopaminergic circuit, the clinical role of the caudate in mediating the clinical symptoms in CO intoxication may outweigh the putamen.

  • Manganese chloride induces histone acetylation changes in neuronal cells: Its role in manganese-induced damage
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-16
    Zhenkun Guo, Zhipeng Zhang, Qingqing Wang, Jie Zhang, Lijin Wang, Qunwei Zhang, Huangyuan Li, Siying Wu

    Manganese neurotoxicity presents with Parkinson-like symptoms, with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a better understanding of the mechanism of Parkinson’s disease. Here, we examined the effects of manganese on histone acetylation, a major epigenetic change in chromatin that can regulate gene expression, chromatin remodelling, cell cycle progression, DNA repair and apoptosis. In this study, we found that manganese chloride (MnCl2) may significantly suppress the acetylation of histone H3 and H4 in PC12 cells and SHSY5Y cells in a time-dependent manner. Then we tested the role of manganese chloride on histone acetyltransferase (HAT) and histone deacetylase (HDAC). The results showed that MnCl2 increased the activity of HDAC but decreased that of HAT in PC12 cells. Further experiments showed that MnCl2 selectively increased the expression levels of HDAC3 and HDAC4 rather than HDAC1 and HDAC2, but decreased that of HAT in PC12 cells and SHSY5Y cells. Pretreatment with the HAT inhibitor anacardic acid (AA) enhanced manganese-induced decrease in cell viability and apoptosis, but HDAC inhibition by TSA drug had an opposite effect in PC12 cells. Collectively, MnCl2 inhibited the acetylation of core histones in cell culture models of PD, and that inhibition of HDAC activity by TSA protects against manganese-induced cell death, indicating that histone acetylation may represent key epigenetic changes in manganese-induced dopaminergic neurotoxicity.

  • Early changes in M2 muscarinic acetylcholine receptors (mAChRs) induced by sarin intoxication may be linked to long lasting neurological effects
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-08
    Zipora Pittel, Shlomi Lazar, Rellie Gez, Shira Chapman

    The effect of sarin on the binding parameters (KD & Bmax) of M2 muscarinic acetylcholine receptor (mAChR) was studied 24 h and 1 week post exposure. Male & female Sprague-Daweley rats were poisoned with 1XLD50 sarin (80 μg/kg, im) followed by treatment of trimedoxime bromide and atropine (7.5:5 mg/kg, im) 1 min later. Brains were removed and analyzed for M2 mAChR binding, using [3H]AFDX384, an M2 selective antagonist. A significant increase in KD of M2 mAChR was found in the cortex 24 h post poisoning, displaying elevation from 4.65 ± 1.16 to 8.45 ± 1.06 nM and 5.24 ± 0.93 to 9.29 ± 1.56 nM in male and female rats, respectively. A rise in KD was also noted 1 week following exposure from 5.04 ± 1.20 to 11.75 ± 2.78 and from 5.37 ± 1.02 to 11.66 ± 1.73 nM, presenting an added increase of 51 and 40% (compared to 24 h) in males and females, respectively. Analysis of M2 receptor density (Bmax) revealed a significant reduction of 68% in males and insignificant reduction of 22% in females, 24 h after sarin exposure which was followed by 37% recovery in males and 100% recovery in females, 1 week later. These results indicate that sarin induces a long-term decreased affinity in M2 mAChR (elevated KDs) and a transient effect on the number of this receptor subtype (Bmax). We hypothesize that the reduced affinity of the M2 receptors (negative auto-regulatory receptors) may cause long-term brain deficits by impairing the normal regulation release of ACh into the synaptic cleft.

  • Reducing occupational lead exposures: Strengthened standards for a healthy workforce
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-08
    Rachel M. Shaffer, Steven G. Gilbert

    Outdated federal and state occupational lead standards leave workers and their families vulnerable to the adverse effects of lead. Standards should be updated to reflect the best available scientific and medical evidence, which documents harm to multiple organ systems even at low levels of exposure. This commentary will review the inadequacies of existing policies, highlight susceptible populations, and briefly summarize state revision efforts to date. Federal policies must be strengthened to protect all workers and their families from this well-documented hazard.

  • Cellular responses of human astrocytoma cells to dust from the Acheson process: An in vitro study
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-04
    Yke Jildouw Arnoldussen, Torunn Kringlen Ervik, Balazs Berlinger, Ida Kero, Sergey Shaposhnikov, Shanbeh Zienolddiny

    Silicon carbide (SiC) is largely used in various products such as diesel particulate filters and solar panels. It is produced through the Acheson process where aerosolized fractions of SiC and other by-products are generated in the work environment and may potentially affect the workers’ health. In this study, dust was collected directly on a filter in a furnace hall over a time period of 24 h. The collected dust was characterized by scanning electron microscopy and found to contain a high content of graphite particles, and carbon and silicon containing particles. Only 6% was classified as SiC, whereof only 10% had a fibrous structure. To study effects of exposure beyond the respiratory system, neurotoxic effects on human astrocytic cells, were investigated. Both low, occupationally relevant, and high doses from 9E-6 μg/cm2 up to 4.5 μg/cm2 were used, respectively. Cytotoxicity assay indicated no effects of low doses but an effect of the higher doses after 24 h. Furthermore, investigation of intracellular reactive oxygen species (ROS) indicated no effects with low doses, whereas a higher dose of 0.9 μg/cm2 induced a significant increase in ROS and DNA damage. In summary, low doses of dust from the Acheson process may exert no or little toxic effects, at least experimentally in the laboratory on human astrocytes. However, higher doses have implications and are likely a result of the complex composition of the dust.

  • Perinatal exposure to concentrated ambient particulates results in autism-like behavioral deficits in adult mice
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-02
    Jamie S. Church, Pamella B. Tijerina, Felicity J. Emerson, Morgan A. Coburn, Jason L. Blum, Judith T. Zelikoff, Jared J. Schwartzer

    Exposure to fine ambient particulates (PM2.5) during gestation or neonatally has potent neurotoxic effects. While biological and behavioral data indicate a vulnerability to environmental pollutants across distinct neurodevelopmental windows, the behavioral consequences following exposure across the entire developmental period remain unknown. Moreover, several epidemiological studies support a link between developmental exposure to air pollution and an increased risk of later receiving a diagnosis of autism spectrum disorders (ASD), a neurodevelopmental disorder that persists throughout life. In the current study we sought to determine whether perinatal exposure to PM2.5 would reduce sociability and increase repetitive deficits in mice, two hallmark characteristics of ASD. Pregnant female B6C3F1 mice were exposed daily to concentrated ambient PM2.5 (CAPs) (135.8 μg/m3) or filtered air (3.1 μg/m3) throughout gestation followed by additional exposures to both dams and their litters from days 2–10 postpartum. Adult offspring were subsequently assessed for social and repetitive behaviors at 20 weeks of age. Daily perinatal exposure to CAPs significantly decreased sociability in male and female mice as measured by the social approach task; however, reductions in reciprocal social interaction and increased grooming behavior were only present in male offspring exposed to CAPs. These findings demonstrate that exposure to particulate air pollutants throughout early neurodevelopment induces long lasting behavioral deficits in a sex-dependent manner and may be an underlying cause of neurodevelopmental disorders such as ASD.

  • The importance of controlling in vitro oxygen tension to accurately model in vivo neurophysiology
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-01
    Evan A. Bordt

    The majority of in vitro studies modeling in vivo conditions are performed on the lab bench in atmospheric air. However, the oxygen tension (pO2) present in atmospheric air (160 mm Hg, ∼21% O2) is in great excess to the pO2 that permeates tissues within the brain (5–45 mm Hg, ∼1–6% O2). This review will discuss the differentiation between pO2 in the in vivo environment and the pO2 commonly used during in vitro experiments, and how this could affect assay outcomes. Also highlighted are studies linking changes in pO2 to changes in cellular function, particularly the role of pO2 in mitochondrial function, reactive oxygen species production, and cellular growth and differentiation. The role of hypoxia inducible factor 1 and oxygen sensing is also presented. Finally, emerging literature exploring sex differences in tissue oxygenation is discussed.

  • Hypoxia regulates the level of glutamic acid decarboxylase enzymes and interrupts inhibitory synapse stability in primary cultured neurons
    Neurotoxicology (IF 3.1) Pub Date : 2017-10-28
    Seojin Hwang, Sangwoo Ham, Seong-Eun Lee, Yunjong Lee, Gum Hwa Lee

    Gamma-aminobutyric acid (GABA) is the main neurotransmitter of inhibitory synaptic transmission, which is critical for oscillatory activity and synchronization of neurons in neural networks. GABA is synthesized by glutamic acid decarboxylase (GAD) enzymes in the inhibitory neuron and, thus, the deregulation of GAD enzymes and subsequent change of GABAergic activity are involved in various neurological and neuropsychiatric diseases. Under hypoxic conditions, neurons undergo neuropathological alterations which can be subtle or severe. Many studies have focused on the alteration of excitatory neurons by hypoxic injury, while inhibitory neuronal changes have not been well determined. Here, we demonstrated that hypoxic conditions decrease the expression of inhibitory neuron-related proteins, including GAD enzymes, through transcript downregulation and proteasomal degradation. Hif-1α induction and glutamate release under hypoxic conditions were implicated in the mechanism of GAD enzyme level reduction. Surprisingly, these conditions altered the density and size of inhibitory synapses, which was irreversible by reoxygenation, but was mediated by glutamate activity. Our findings suggest that potential implication of the compositional and structural alterations of inhibitory neuron in the pathogenesis of various hypoxic injuries.

  • Prenatal bisphenol A (BPA) exposure alters the transcriptome of the neonate rat amygdala in a sex-specific manner: a CLARITY-BPA consortium study
    Neurotoxicology (IF 3.1) Pub Date : 2017-10-28
    Sheryl E. Arambula, Dereje Jima, Heather B. Patisaul

    Bisphenol A (BPA) is a widely recognized endocrine disruptor prevalent in many household items. Because experimental and epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, even at levels below the current US FDA No Observed Adverse Effect Level (NOAEL) of 5 mg/kg body weight (bw)/day, there is concern that early life exposure may alter neurodevelopment. The current study was conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and examined the full amygdalar transcriptome on postnatal day (PND) 1, with the hypothesis that prenatal BPA exposure would alter the expression of genes and pathways fundamental to sex-specific affective behaviors. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (2.5, 25, 250, 2500, or 25000 μg/kg bw/day), a reference estrogen (0.05 or 0.5 μg ethinyl estradiol (EE2)/kg bw/day), or vehicle. PND 1 amygdalae were microdissected and gene expression was assessed with qRT-PCR (all exposure groups) and RNAseq (vehicle, 25 and 250 μg BPA, and 0.5 μg EE2 groups only). Our results demonstrate that that prenatal BPA exposure can disrupt the transcriptome of the neonate amygdala, at doses below the FDA NOAEL, in a sex-specific manner and indicate that the female amygdala may be more sensitive to BPA exposure during fetal development. We also provide additional evidence that developmental BPA exposure can interfere with estrogen, oxytocin, and vasopressin signaling pathways in the developing brain and alter signaling pathways critical for synaptic organization and transmission.

  • Exposure to fine and ultrafine particulate matter during gestation alters postnatal oligodendrocyte maturation, proliferation capacity, and myelination
    Neurotoxicology (IF 3.1) Pub Date : 2017-10-24
    Carolyn Klocke, Joshua L. Allen, Marissa Sobolewski, Jason L. Blum, Judith T. Zelikoff, Deborah A. Cory-Slechta

    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.

  • Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study
    Neurotoxicology (IF 3.1) Pub Date : 2017-10-08
    Melanie L. Foster, Thomas B. Bartnikas, Hailey C. Maresca-Fichter, Courtney Mercadante, Miriam Dash, Chelsea Miller, David C. Dorman

    It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson’s disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25 mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. Motor activity was measured on PND 19–22 and 29–32. Tissue Mn concentrations were measured in liver, femur, olfactory bulb, frontal cortex, and striatum on PND 29. Hepatic and frontal cortex gene expression of Slc11a2, Slc40a1, Slc30a10, Hamp (liver only), and Park2 were also measured on PND 29. Some strain differences were seen. As expected, decreased hepatic and frontal cortex Park2 expression was seen in the parkin mice when compared with C57BL/6J mice. Untreated parkin mice also had higher liver and femur Mn concentrations when compared with the C57BL/6J mice. Exposure to ≥ 11 mg Mn/kg-day was associated with increased brain Mn concentrations in all mice, no strain difference was observed. Manganese exposure in C57Bl6, but not parkin mice, was associated with a negative correlation between striatal Mn concentration and motor activity. Manganese exposure was not associated with changes in frontal cortex gene expression. Decreased hepatic Slc30a10, Slc40a1, and Hamp expression were seen in PND 29 C57BL/6J mice given 25 mg Mn/kg-day. In contrast, Mn exposure was only associated with decreased Hamp expression in the parkin mice. Our results suggest that the Parkin gene defect did not increase the susceptibility of neonatal mice to adverse health effects associated with high-dose Mn exposure.

  • Environmental exposure to manganese in air: Tremor, motor and cognitive symptom profiles
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-28
    E.S. Kornblith, S.L. Casey, D.T. Lobdell, M.A. Colledge, R.M Bowler

    Background Excessive exposure to manganese (Mn) may cause parkinsonian-like motor and tremor symptoms and adverse cognitive effects, including problems with executive functioning (EF), resembling those found in later-stage Parkinson’s disease (PD). Studies seeking to differentiate PD patients into subgroups with associated cognitive and functional outcomes using motor and tremor symptoms identified tremor-dominant (TD) and non-tremor dominant (NTD) subtypes. It is unclear whether differing patterns of pathophysiology and symptoms exist in Mn neurotoxicity, as they do in PD. Methods Residents of East Liverpool (n = 83) and Marietta, OH (n = 99) exposed to chronic (>10 years) environmental Mn through industrial pollution were administered neuropsychological measures and a physician-rated scale of movement-disorder symptoms. Two-step cluster analysis was used to group residents based on tremor symptoms, bradykinesia/rigidity symptoms, gait disturbance, and executive function. Cluster membership was validated using modeled air-Mn exposure and a computerized tremor measure. Results Elevated tremor and motor symptoms and executive dysfunction were observed, and TD and NTD symptom clusters were identified. Two additional clusters were also identified: Executive Dysfunction and Normal Functioning. The NTD residents, with elevated levels of gait disturbance and other movement disorder symptoms, did not evidence EF impairment, as predicted. Instead, residents with EF impairment formed their own cluster, and were relatively free of movement disorder symptoms. Conclusions Results resemble reports in the PD literature with TD and NTD clusters identified, but executive dysfunction did not cluster with NTD symptoms. PD and Mn exposure likely have differing pathophysiology and developmental courses, and therefore different symptom patterns, even when similar symptoms are present.

  • Developmental exposure to low concentrations of two brominated flame retardants, BDE-47 and BDE-99, causes life-long behavioral alterations in zebrafish
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-19
    Lilah Glazer, Corinne N. Wells, Meghan Drastal, Kathryn-Ann Odamah, Richard E. Galat, Mamta Behl, Edward D. Levin

    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.

  • Changes in water manganese levels and longitudinal assessment of intellectual function in children exposed through drinking water
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-18
    Laurie-Anne Dion, Dave Saint-Amour, Sébastien Sauvé, Benoit Barbeau, Donna Mergler, Maryse F. Bouchard

    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.

  • Olfactory toxicity in rats following manganese chloride nasal instillation: A pilot study
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-14
    Melanie L. Foster, Deepa B. Rao, Taylor Francher, Samantha Traver, David C. Dorman

    Following inhalation, manganese travels along the olfactory nerve from the olfactory epithelium (OE) to the olfactory bulb (OB). Occupational exposure to inhaled manganese is associated with changes in olfactory function. This pilot study evaluated two related hypotheses: (a) intranasal manganese administration increases OE and OB manganese concentrations; and (b) intranasal manganese exposure impairs performance of previously trained rats on a go-no-go olfactory discrimination (OD) task. Male Fischer 344 rats were trained to either lever press (“go”) in response to a positive conditioned stimulus (CS+: vanillin) or to do nothing (“no go”) when a negative conditioned stimulus (CS−: amyl acetate) was present. Following odor training, rats were randomly assigned to either a manganese (200 mM MnCl2) or 0.9% saline treatment group (n = 4–5 rats/group). Administration of either saline or manganese was performed on isoflurane-anesthetized rats as 40 μL bilateral intranasal instillations. Rats were retested 48 h later using the vanillin/amyl acetate OD task, then euthanized, followed by collection of the OE and OB. Manganese concentrations in tissue samples were analyzed by ICP-MS. An additional cohort of rats (n = 3–4/group) was instilled similarly with saline or manganese and nasal and OB pathology assessed 48 h later. Manganese-exposed rats had increased manganese levels in both the OE and OB and decreased performance in the OD task when compared with control animals. Histopathological evaluation of the caudal nasal cavity showed moderate, acute to subacute suppurative inflammation of the olfactory epithelium and submucosa of the ethmoid turbinates and mild suppurative exudate in the nasal sinuses in animals given manganese. No histologic changes were evident in the OB. The nasal instillation and OD procedures developed in this study are useful methods to assess manganese – induced olfactory deficits.

  • Polymorphisms in manganese transporters show developmental stage and sex specific associations with manganese concentrations in primary teeth
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-13
    Karin Wahlberg, Manish Arora, Austen Curtin, Paul Curtin, Robert O. Wright, Donald R. Smith, Roberto G. Lucchini, Karin Broberg, Christine Austin

    Background Manganese (Mn) is an essential metal that can become neurotoxic at elevated levels with negative consequences on neurodevelopment. We have evaluated the influence of single nucleotide polymorphisms (SNPs) in Mn transporter genes SLC30A10 and SLC39A8 on Mn concentrations in dentine, a validated biomarker that reflects Mn tissue concentrations early in life. Methods The study included 195 children with variable environmental Mn exposure. Mn concentrations in dentine representing fetal, early postnatal and early childhood developmental periods were measured using laser ablation-inductively coupled plasma mass spectrometry. SLC30A10 rs12064812 (T/C) and SLC39A8 rs13107325 (C/T) were genotyped by TaqMan real time PCR and SLC30A10 rs1776029 (G/A) by pyrosequencing; and SNPs were analyzed in association with Mn in dentine. Results SLC39A8 rs13107325 rare allele (T) carriers had significantly higher Mn concentrations in postnatal dentine (110%, p = 0.008). For all SNPs we also observed non-significant associations with Mn concentrations in dentine in opposite directions for fetal and early postnatal periods. Furthermore, there were significant differences in the influence of SLC30A10 rs1776929 genotypes on Mn concentrations in dentine between sexes. Discussion The findings from this study indicate that common SNPs in Mn transporters influence Mn homeostasis in early development and may therefore be important to consider in future studies of early life Mn exposure and health effects. Our results also suggest that the influence of these transporters on Mn regulation may differ by developmental stage, as well as between girls and boys.

  • Evaluation of the effect of an environmental management program on exposure to manganese in a mining zone in Mexico
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-10
    Marlene Cortez-Lugo, Horacio Riojas-Rodríguez, Hortensia Moreno-Macías, Sergio Montes, Yaneth Rodríguez-Agudelo, David Hernández-Bonilla, Minerva Catalán-Vázquez, Raúl Díaz-Godoy, Sandra Rodríguez-Dozal

    Background In the state of Hidalgo, Mexico, is found the largest second deposit of Manganese (Mn) in Latin America. Various studies on the sources of emission, exposure, and the effects on the health of children and adults have been conducted utilizing an ecosystem approach. Given the findings of Mn levels in air and the neurocognitive effects, an Environmental Management Program (EMP) was designed and implemented with the purpose of reducing exposure to Mn of the population, including various actions for reducing Mn emissions into the atmosphere. Objective To evaluate the impact of the EMP on the concentrations of Mn in air, as well as the modification of exposure to Mn in the blood and hair of adult residents of the communities intervened. Methods A quasi-experimental study was conducted in five rural communities, in which Mn concentrations were evaluated in air and in blood in the years 2002 and 2007, pre-intervention, and in 2013, postintervention. In 2003, the concentration of hair Mn among the communities was evaluated. Measurements were carried out of Particulate Matter (PM) of >10 and 2.5 μm (PM10 and PM2.5), and Mn in PM10 and PM2.5 were measured using proton-induced X-ray emissions (PIXE). The method of Difference in Differences (DID) was applied to estimate the impact of EMP on Mn concentrations in particulate matter via linear regression through multilevel models. To evaluate the effect of Mn concentrations in air over Mn concentrations in blood in both study periods in the mining communities per year (2002 and 2013), a linear regression model for each year was employed. Results We estimated that the EMP contributed to reducing the average daily concentrations of Mn in PM10 and PM2.5 by 92 and 85%, respectively. The adjusted model did not show an effect of Mn concentrations in air over Mn concentrations in blood in both study periods. Conclusions The results suggest that the measures implemented to reduce Mn emissions in air exerted a significant impact on the reduction of inhaled exposure in adult population.

  • Impact of air manganese on child neurodevelopment in East Liverpool, Ohio
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-06
    Erin N. Haynes, Heidi Sucharew, Timothy J. Hilbert, Pierce Kuhnell, Alonzo Spencer, Nicholas C. Newman, Roxanne Burns, Robert Wright, Patrick J. Parsons, Kim N. Dietrich

    Background East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community. Methods Children 7–9 years of age from East Liverpool and its surrounding communities, were enrolled (N = 106) in the Communities Actively Researching Exposure Study from between March 2013–June 2014. Blood and hair were analyzed for Mn and lead, and serum was analyzed for cotinine. We used linear regression to assess associations between biological measures and IQ subscale scores. Results Geometric mean blood lead (n = 67), blood Mn (n = 66), hair Mn (n = 98), and serum cotinine (n = 69) concentrations were 1.13 ± 1.96 μg/dL, 10.06 ± 1.30 μg/L, and 360.22 ± 2.17 ng/g, 0.76 ± 6.12 μg/L respectively. After adjusting for potential confounders, hair Mn was negatively associated with Full Scale IQ. Conclusions Hair Mn was negatively associated with child IQ scores. Community partners were instrumental in the conception and implementation of this study.

  • Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-02
    Ruoyun E. Ma, Eric J. Ward, Chien-Lin Yeh, Sandy Snyder, Zaiyang Long, Fulya Gokalp Yavuz, S. Elizabeth Zauber, Ulrike Dydak

    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 ± 0.1 mg/m3; High: N = 13; mean air Mn = 0.23 ± 0.18 mg/m3), as well as unexposed control workers (N = 22, mean air Mn = 0.002 ± 0.001 mg/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.

  • Assessment of saliva, hair and toenails as biomarkers of low level exposure to manganese from drinking water in children
    Neurotoxicology (IF 3.1) Pub Date : 2017-09-01
    Ruth Ntihabose, Céline Surette, Delphine Foucher, Olivier Clarisse, Maryse F. Bouchard

    We evaluated hair, toenails, and saliva (whole and supernatant) as biomarkers of exposure to manganese (Mn) in 274 school age children (6–13 years) consuming well water in southeastern New Brunswick, Canada. Mn concentrations in tap water ranged from <0.03 to 1046 μg L−1 (geometric mean 5.96 μg L−1). The geometric mean of Mn intake resulting from the consumption of water was 0.25 (0–34.95) μg kg−1 day−1. Both Mn concentration in water and Mn intake were significantly correlated with Mn in hair (r = 0.60 and r = 0.53, respectively), Mn in toenail (r = 0.29 and r = 0.37 respectively) and to a lesser extent with Mn in saliva supernatant (r = 0.14 and r = 0.18, respectively). Mn in whole saliva did not correlate with Mn in water or Mn intake. Both Mn in hair and Mn in toenail allowed to discriminate the most exposed group from the least exposed group, based on Mn in water and Mn intake from water. In this group of children with low level Mn exposure, Mn concentrations in hair, and toenails reflected reasonably well Mn exposure from drinking water, whereas Mn content in saliva correlated less strongly.

  • Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study
    Neurotoxicology (IF 3.1) Pub Date : 2017-08-25
    Beate Pesch, Ulrike Dydak, Anne Lotz, Swaantje Casjens, Clara Quetscher, Martin Lehnert, Jessica Abramowski, Christoph Stewig, Chien-Lin Yeh, Tobias Weiss, Christoph van Thriel, Lennard Herrmann, Siegfried Muhlack, Dirk Woitalla, Benjamin Glaubitz, Tobias Schmidt-Wilcke, Thomas Brüning

    Objective Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. Material and methods We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. Results MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn > 100 μg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. Conclusions MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB.

  • Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites — Neuroimaging results from the WELDOX II study
    Neurotoxicology (IF 3.1) Pub Date : 2017-08-11
    Swaantje Casjens, Urike Dydak, Shalmali Dharmadhikari, Anne Lotz, Martin Lehnert, Clara Quetscher, Christoph Stewig, Benjamin Glaubitz, Tobias Schmidt-Wilcke, David Edmondson, Chien-Lin Yeh, Tobias Weiss, Christoph van Thriel, Lennard Herrmann, Siegfried Muhlack, Dirk Woitalla, Michael Aschner, Thomas Brüning, Beate Pesch

    Objective Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. Material and methods GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson’s disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). Results The median shift exposure to respirable Mn and Fe in active welders was 23 μg/m3 and 110 μg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β) = 0.87, p < 0.01) and choline (exp(β) = 0.84, p = 0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. Conclusions Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.

  • Manganese and neurobehavioral impairment. A preliminary risk assessment
    Neurotoxicology (IF 3.1) Pub Date : 2017-08-10
    Robert M. Park, Shannon L. Berg

    Similar patterns of cognitive and motor deficits have been widely reported from manganese exposures in welding, metallurgical and chemical industry workers. A risk assessment was performed based on studies reported in the literature, extending some earlier work, and deriving new estimates of exposure response and excess risk. Many investigations of manganese neurological effects in humans have insufficient information to derive an exposure response; however, findings from a chemical manufacturer, two smelter and two welder populations permitted application of the benchmark dose procedure for continuous end-points. Small particles and aggregates of condensation fume (condensing vaporized metal, <0.1 μm in diameter) appear to have a higher potency per unit mass than larger particles from dusts (>1.0 μm). Consideration was given to long-term effects of continuous low exposures that instead of producing increasing toxicity attain a steady-state condition. Impairment was defined as excursions beyond the 5th percentile in a normal population and the concentrations of manganese predicted to result in 1% excess prevalence of impairment over different time periods were calculated. Over five years, exposures resulting in 1% excess prevalence of impairment (for purposes of discussion) were in the vicinity of 10 μg/m3 for manganese fume and 25 μg/m3 for larger particle dusts. These levels are below current recommendations for occupational limits on manganese exposure in the United States.

  • Familial manganese-induced neurotoxicity due to mutations in SLC30A10 or SLC39A14
    Neurotoxicology (IF 3.1) Pub Date : 2017-08-05
    Somshuvra Mukhopadhyay

    Over the last few years, two rare, familial diseases that lead to the onset of manganese (Mn)-induced neurotoxicity have been discovered. Loss-of-function mutations in SLC30A10, a Mn efflux transporter, or SLC39A14, a Mn influx transporter, increase Mn levels in blood and brain, and induce severe neurotoxicity. The discoveries of these genetic diseases have transformed our understanding of Mn homeostasis, detoxification, and neurotoxicity. Current knowledge about the mechanisms by which mutations in these transporters alter Mn homeostasis to induce human disease is reviewed here.

  • Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line
    Neurotoxicology (IF 3.1) Pub Date : 2017-08-02
    Miles R. Bryan, Michael A. Uhouse, Kristen D. Nordham, Piyush Joshi, Daniel I.R. Rose, Michael T. O’Brien, Michael Aschner, Aaron B. Bowman

    In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdhQ7/Q7, a concentration of KU55933 far exceeding its IC50 for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC50s for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC50s for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5 μM) or LY294002(7 μM), supporting PI3K’s upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line.

  • Prenatal co-exposure to manganese and depression and 24-months neurodevelopment
    Neurotoxicology (IF 3.1) Pub Date : 2017-07-17
    Teresa Verenice Muñoz-Rocha, Marcela Tamayo y Ortiz, Martín Romero, Ivan Pantic, Lourdes Schnaas, David Bellinger, Birgit Claus-Henn, Rosalind Wright, Robert O. Wright, Martha María Téllez-Rojo

    Background Normal prenatal neurodevelopment follows stages that are potentially influenced by both chemical and psychosocial environments. Exposure to elevated manganese during this critically vulnerable period has been found to be neurotoxic. Independently, maternal prenatal depression has been associated with subsequent neurodevelopmental decrements in children. The association between child neurodevelopment and prenatal co-exposure to manganese and maternal depression has not been sufficiently studied. Methods During pregnancy and at birth, we measured maternal blood and cord blood manganese levels respectively. Maternal depression was assessed in the 3rd trimester of pregnancy using the Edinburgh Depression Scale. Neurodevelopment was evaluated at 24 months of age with the Bayley Scales of Infant Development. A multivariate multiple regression model was used to analyze cognitive, language and motor scores simultaneously for 473 children from the PROGRESS birth cohort in Mexico City. Results Over 25% of our study participants reported having depressive symptoms. 3rd trimester blood manganese as well as depressive symptoms were independently negatively associated with all neurodevelopment scores in adjusted models. In stratified analyses, the negative association between manganese (maternal as well as cord blood) and 24-month language scores was stronger among women with depressive symptoms. Receptive language was mostly affected. Inverted U-shaped curves were seen for the association between with cord blood manganese and neurodevelopment scores. Conclusions Our findings are in line with previous studies of manganese and depression neurotoxicity. The prenatal period may be particularly sensitive to manganese and depression co-exposures and should be of interest for public health interventions to promote healthy emotional and nutritional pregnancies.

  • Low level exposure to manganese from drinking water and cognition in school-age children
    Neurotoxicology (IF 3.1) Pub Date : 2017-07-15
    Maryse F. Bouchard, Céline Surette, Pierre Cormier, Delphine Foucher

    Background Manganese (Mn) is an element found in the environment and certain geographic areas have elevated concentrations in soil and water du to natural conditions or anthropic activities. A growing body of data suggests that exposure to manganese in drinking water could be neurotoxic. Objective Firstly, we aimed to examine the association between exposure to manganese from drinking water and cognition in children consuming well water. Secondly, we also aimed to examine the relation between cognition and manganese concentrations in children’s hair, nail, and saliva. Methods A total 259 children from 189 households consuming well water were included in the present study (ages 5.9 to 13.7 years). We assessed children’s cognition with the WISC-IV, and we used five indicators of manganese exposure: concentration in tap water, intake from the consumption of water divided by child’s weight, manganese concentration in children’s hair, toe nail, and saliva. We used General Estimating Equation analysis to assess the relation between manganese exposure indicators and IQ scores, adjusting for potential confounders, and taking into account family clusters. Results Drinking water manganese concentrations were generally low, with 48% of children consuming water <5 μg/L, 25% >50 μg/L, and 4% >400 μg/L. Results differed by sex. In girls, higher manganese concentration in water, hair, and toe nail were associated with poorer Performance IQ scores but this was significant only for toe nail (for a 10-fold increase in manganese, β: −5.65, 95% CIs: −10.97, −0.32). Opposite associations were observed in boys, i.e., better Performance IQ scores with higher manganese concentration hair, toe nail, and water, the latter being significant (β: 2.66, 95% CIs: 0.44, 4.89). Verbal IQ scores did not seem to be associated with manganese exposure indicators. Conclusions Drinking water manganese levels were considerably lower than in previous studies reporting neurotoxic effects. There was no clear indication of an association between exposure to manganese and cognitive development in this sample of school-age children although the data suggest there might be sex-specific associations. Given the low levels of exposure and sex-specific associations, a larger sample size would have been required to increase the statistical power and better characterize the relations.

  • [18F]FDOPA positron emission tomography in manganese-exposed workers
    Neurotoxicology (IF 3.1) Pub Date : 2017-07-08
    Susan R. Criswell, Susan Searles Nielsen, Mark Warden, Joel S. Perlmutter, Stephen M. Moerlein, Hubert P. Flores, John Huang, Lianne Sheppard, Noah Seixas, Harvey Checkoway, Brad A. Racette

    Occupational manganese (Mn) exposure is associated with the development of parkinsonism; however, the mechanism of neurotoxicity is unknown. Brain positron emission tomography (PET) imaging provides a non-invasive method of assessing dopamineric neuronal function. 6-[18F]fluoro-L-DOPA (FDOPA) PET reflects in-vivo nigrostriatal function, but results in Mn exposure are conflicting. The objective of this study was to investigate the association between Mn exposure secondary to occupational welding, FDOPA striatal uptake, and clinical parkinsonism as measured by Unified Parkinson Disease Rating Scale motor subscore 3 (UPDRS3) scores. FDOPA PET scans were acquired on 72 subjects (27 Mn-exposed welders, 14 other Mn-exposed workers, and 31 non-exposed subjects). We estimated cumulative welding exposure from detailed work histories, and a movement disorders specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance imaging (MRI) for each subject. Specific striatal FDOPA uptake was calculated with a graphical analysis method. We used linear regression while adjusting for age to assess the association between welding exposure and FDOPA uptake in the caudate, anterior putamen, and posterior putamen. Compared to the non-exposed subjects, mean caudate FDOPA uptake was 0.0014 min−1 (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012 min−1 (95% CI 0.0005, 0.0019) lower in other Mn-exposed workers (both p ≤ 0.001). There was no clear dose-response association between caudate FDOPA uptake and Mn exposure or UPDRS3 scores. Mn-exposed welders and workers demonstrated lower caudate FDOPA uptake, indicating pre-synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism.

  • Manganese testing under a clean air act test rule and the application of resultant data in risk assessments
    Neurotoxicology (IF 3.1) Pub Date : 2017-07-01
    Darcie Smith, George M. Woodall, Annie M. Jarabek, William K. Boyes

    In the 1990′s, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use. Among the uncertainties identified were: the chemical forms of Mn emitted in automotive exhaust; the relative toxicity of different Mn species; the potential for exposure among sensitive subpopulations including females, the young and elderly; differences in sensitivity between test species and humans; differences between inhalation and oral exposures; and the influence of dose rate and exposure duration on tissue accumulation of Mn. It was anticipated that development of specific sets of pharmacokinetic (PK) information and models regarding Mn could help resolve many of the identified uncertainties and serve as the best foundation for available data integration. The results of the test program included development of several unique Mn datasets, and a series of increasingly sophisticated Mn physiologically-based pharmacokinetic (PBPK) models. These data and models have helped address each of the uncertainties originally identified in the Test Rule. The output from these PBPK models were used by the Agency for Toxic Substances and Disease Registry (ATSDR) in 2012 to inform the selection of uncertainty factors for deriving the manganese Minimum Risk Level (MRL) for chronic exposure durations. The EPA used the MRL in the Agency’s 2015 evaluation of potential residual risks of airborne manganese released from ferroalloys production plants. This resultant set of scientific data and models likely would not exist without the CAA section 211(b) test rule regulatory procedure.

  • Welding-related brain and functional changes in welders with chronic and low-level exposure
    Neurotoxicology (IF 3.1) Pub Date : 2017-06-23
    Eun-Young Lee, Michael R. Flynn, Mechelle M. Lewis, Richard B. Mailman, Xuemei Huang

    Although an essential nutrient, manganese (Mn) can be toxic at high doses. There is, however, uncertainty regarding the effects of chronic low-level Mn-exposure. This review provides an overview of Mn-related brain and functional changes based on studies of a cohort of asymptomatic welders who had lower Mn-exposure than in most previous work. In welders with low-level Mn-exposure, we found: 1) Mn may accumulate in the brain in a non-linear fashion: MRI R1 (1/T1) signals significantly increased only after a critical level of exposure was reached (e.g., ≥300 welding hours in the past 90 days prior to MRI). Moreover, R1 may be a more sensitive marker to capture short-term dynamic changes in Mn accumulation than the pallidal index [T1-weighted intensity ratio of the globus pallidus vs. frontal white matter], a traditional marker for Mn accumulation; 2) Chronic Mn-exposure may lead to microstructural changes as indicated by lower diffusion tensor fractional anisotropy values in the basal ganglia (BG), especially when welding years exceeded more than 30 years; 3) Mn-related subtle motor dysfunctions can be captured sensitively by synergy metrics (indices for movement stability), whereas traditional fine motor tasks failed to detect any significant differences; and 4) Iron (Fe) also may play a role in welding-related neurotoxicity, especially at low-level Mn-exposure, evidenced by higher R2* values (an estimate for brain Fe accumulation) in the BG. Moreover, higher R2* values were associated with lower phonemic fluency performance. These findings may guide future studies and the development of occupation- and public health-related polices involving Mn-exposure.

  • Sodium P-aminosalicylic acid inhibits sub-chronic manganese-induced neuroinflammation in rats by modulating MAPK and COX-2
    Neurotoxicology (IF 3.1) Pub Date : 2017-06-23
    Shao-Jun Li, Wen-Xia Qin, Dong-Jie Peng, Zong-Xiang Yuan, Sheng-Nan He, Yi-Ni Luo, Michael Aschner, Yue-Ming Jiang, Dian-Yin Liang, Bing-Yan Xie, Fang Xu

    Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti-inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl2·4H2O (15 mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1β, IL-6, TNF-αand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti-inflammatory agent.

  • Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson’s disease: Relevance to gene and environment interactions in metal neurotoxicity
    Neurotoxicology (IF 3.1) Pub Date : 2017-06-20
    Monica R. Langley, Shivani Ghaisas, Muhammet Ay, Jie Luo, Bharathi N. Palanisamy, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy

    Parkinson’s disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10 mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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