Behavioral and neurochemical studies of inherited manganese-induced dystonia-parkinsonism in Slc39a14-knockout mice.

Inherited autosomal recessive mutations of the manganese (Mn) transporter gene SLC39A14 in humans, results in elevated blood and brain Mn concentrations and childhood-onset dystonia-parkinsonism. The pathophysiology of this disease is unknown, but the nigrostriatal dopaminergic system of the basal ganglia has been implicated. Here, we describe pathophysiological studies in Slc39a14-knockout (KO) mice as a preclinical model of dystonia-parkinsonism in SLC39A14 mutation carriers. Blood and brain metal concentrations in Slc39a14-KO mice exhibited a pattern similar to the human disease with highly elevated Mn concentrations. We observed an early-onset backward-walking behavior at postnatal day (PN) 21 which was also noted in PN60 Slc39a14-KO mice as well as dystonia-like movements. Locomotor activity and motor coordination were also impaired in Slc39a14-KO relative to wildtype (WT) mice. From a neurochemical perspective, striatal dopamine (DA) and metabolite concentrations and their ratio in Slc39a14-KO mice did not differ from WT. Striatal tyrosine hydroxylase (TH) immunohistochemistry did not change in Slc39a14-KO mice relative to WT. Unbiased stereological cell quantification of TH-positive and Nissl-stained estimated neuron number, neuron density, and soma volume in the substantia nigra pars compacta (SNc) was the same in Slc39a14-KO mice as in WT. However, we measured a marked inhibition (85-90%) of potassium-stimulated DA release in the striatum of Slc39a14-KO mice relative to WT. Our findings indicate that the dystonia-parkinsonism observed in this genetic animal model of the human disease is associated with a dysfunctional but structurally intact nigrostriatal dopaminergic system. The presynaptic deficit in DA release is unlikely to explain the totality of the behavioral phenotype and points to the involvement of other neuronal systems and brain regions in the pathophysiology of the disease.

Toxic boost: Acute, reversible neurotoxicity after ingestion of methylcyclopentadienyl manganese tricarbonyl (MMT) mistaken for an energy drink.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organometallic compound used as a gasoline additive for its antiknock properties. Human ingestion of MMT has not previously been reported. We present the case of a 54-year-old man who developed seizures and altered mental status after drinking 12 oz. of MMT-containing NOS Octane Booster Racing Formula. Due to label similarities, he mistook this for the NOS High Performance energy drink. The patient was intubated due to persistent seizures despite benzodiazepine treatment and admitted to the intensive care unit. He had two further seizures while intubated, but he was successfully extubated on the 4th day post-ingestion. He was confused and ataxic following extubation, but one day later his symptoms resolved and he was discharged without further incident. This case highlights the importance of responsible labeling of consumables. It is important for clinicians and poison centers to report any such instances to the United States Food and Drug Administration.

Manganese induced nervous injury by α-synuclein accumulation via ATP-sensitive K(+) channels and GABA receptors.

Manganese (Mn) is an environmental pollutant having a toxic effect on Parkinson's disease, with significant damage seen in the neurons of basal ganglia. Hence, Mn pollution is a public health concern. A Sprague-Dawley rat model was used to determine the damage to basal nuclei, and the effect of Mn intake was detected using the Morris water maze test and transmission electron microscopy. The SH-SY5Y cell line was exposed to Mn, and downstream signaling was assessed to determine the mechanism of toxicity. Mn exposure injured neurons, repressing GABAAR receptors and inducing GABABR receptors. The synergistic effect of the GABABR receptor and Kir6.1-SUR1 or Kir6.2-SUR1 was found to be one of the potential factors for the secretion of α-synuclein. The accumulation of α-synuclein regulated downstream factors calmodulin (CAM) cAMP response element-binding protein (CREB), thereby impairing learning and memory. Other genes downstream of CREB, rather than the feedback regulation of CREB, and brain-derived neurotrophic factor might also be involved.

The role of zinc, copper, manganese and iron in neurodegenerative diseases.

Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses ß-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to ß-amyloid may enhance formation of fibrillar ß-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.

Caregiving and infants' neurodevelopment in rural Costa Rica: Results from the Infants' Environmental Health Study (ISA).

Early caregiving is one of the strongest influences on children's development, and among the most significant modifiable environmental factor. The aim of this study was to explore the association between quality of caregiver-infant interactions and neurodevelopment of infants living in banana-growing communities in rural Costa Rica characterized as having environmental toxic exposures. Home visits were conducted with 94 caregiver-infant dyads from the Infants' Environmental Health Study (ISA), living within Matina county, Limón province. One-year infant neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III). Quality of caregiver-infant interaction was assessed with a standardized observational task: Nursing Child Assessment Satellite Training Teaching scale (NCATS) at around two years of age. Multiple regression analyses examined associations between components of caregiver-infant interactions and neurodevelopmental outcomes, adjusting for mancozeb and manganese exposure and other potential confounders. Compared to NCATS normative data for U.S. Hispanic mothers, 35% of the sample had overall caregiving interaction scores ≤10th percentile cut-off, indicating less than optimal interactions. Higher quality of caregiver-infant interaction was associated with higher expressive communication ability in infants [ß = 0.03 (95% CI: 0.01, 0.06)], controlling for pesticide exposure and confounders. Aspects of caregiving such as stimulation and growth-fostering of infants were most strongly associated with language outcomes. Results suggest an association between positive caregiving on language development for infants living in a rural agricultural area in Costa Rica, and highlight aspects of caregiving that could be targeted to improve resilience of these children who live in vulnerable conditions.

Latent subgroups of cognitive performance in lead- and manganese-exposed Uruguayan children: Examining behavioral signatures.

OBJECTIVES: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals. METHOD: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested. RESULTS: Mean ± SD of blood Pb was 4.1 ± 2.1 µg/dL and 35% of children had blood Pb ≥ 5 µg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn. CONCLUSIONS: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children.

Ethanol increases manganese-Induced spatial learning and memory deficits via oxidative/nitrosative stress induced p53 dependent/independent hippocampal apoptosis.

Manganese (Mn) is an essential nutrient element. However, Mn is causing great environmental and occupational exposure health risk concern globally, even high rate of alcohol consumption. There is dearth of scientific information on the interaction of manganese (Mn) and ethanol (EtOH) on hippocampal functions. This study was designed to investigate the effect of EtOH on Mn - induced hippocampal toxicity with special reference to spatial learning and memory and its underlying mechanism in adults male Wistar Rats. Rats were exposed to Mn alone at 30 mg/kg or co-expose with EtOH at 1.25 and 5 g/kg body weight by oral gavage for 35 consecutive days. Morris Water Maze task was used to assessed spatial learning and memory. Subsequently, oxidative/nitrosative stress, neuro-inflammation (myeloperoxidase and cyclooxygenase-2) and protein expression of apoptotic proteins (p53 and Bax), active executioner caspase (caspase-3) and B - cell lymphoma - 2 (Bcl - 2) markers in the hippocampus were investigated. The results indicate that Mn and EtOH exposure induces spatial learning and memory deficits, increase oxidative/nitrosative stress, neuro-inflammation resulting in enhanced hippocampal apoptosis. Moreover, the results indicated that Mn co-exposure with EtOH at 1.25 and 5 g/kg body weight further exacerbates neurotoxicity in rat hippocampus when compared with single dose of Mn and EtOH alone. Collectively, EtOH increases Mn - induced oxidative/nitrosative stress, neuro-inflammation and hippocampal apoptosis via mechanism involving oxidative damages of cellular constituents, neuronal inflammation and subsequent upregulation of Bax and caspase-3 and downregulation of Bcl-2 protein expression via p53 dependent/independent pathways to induced hippocampal apoptosis associated with impaired spatial learning and memory.

The effects of manganese exposure from drinking water on school-age children: A systematic review.

The aim of this study was to analyse the published literature on the potential effects of manganese exposure from drinking water on school-age children, with emphasis on cognitive, and neurodevelopment and behavioural effects. A systematic review of up-to-date scientific evidence published from 2006 to 2017 was conducted using Science Direct. A further search was carried out using PubMed and Web of Science. A total of 21 studies were reviewed and categorised into 12 cognitive and 9 neurodevelopment and behavioural effects. The most utilised cognitive test was the Wechsler Intelligence Scale for Children (WISC) or some subtests from it. 10 of the 12 studies on cognitive effects reported an adverse effect of manganese exposure from drinking water on children. 3 out of the 9 studies on neurodevelopment and behavioural effects reported that manganese exposure from drinking water was associated with poorer neurobehavioural performances in school children. 4 others implied the presence of some sex-specific associations with manganese exposure. 1 study suggested that children suffering from attention deficit hyperactivity disorder (ADHD) may be more susceptible to manganese exposure. Another study suggested that manganese was a beneficial nutrient as well as a neurotoxicant. Regardless of the limitations of the studies analysed, the adverse effects of manganese exposure from drinking water on school-aged children is sufficiently demonstrated. Further investigation into the subject to address inconsistencies in existing studies is recommended.

Exploration of the establishment of manganese poisoning rat model and analysis of discriminant methods.

OBJECTIVE: We explored methods to establish an animal model of manganese poisoning and evaluate the feasibility of the determination method. METHODS: Twenty-four specific pathogen-free male rats were randomly divided into four groups: control, low-dose (15.0 mg/kg), middle-dose (25.0 mg/kg), and high-dose (50.0 mg/kg). Intraperitoneal injection of MnCl2·H2O was administered every 48 h for three months. Rats were tested for behavior, muscle tension, and with a balance beam experiment at the end of each month. Three months later, the rats were sacrificed and brain tyrosine hydroxylase (TH) expression levels were measured. RESULTS: Rats in each group exhibited changes in behavior, muscle tone, and balance after exposure to manganese, and the scores of each test for the high-dose and middle-dose groups were statistically different from the low-dose and control groups. Finally, a rat model of manganese poisoning was identified with the TH expression less than 30% of the normal value. We find that the modeling success rate of the middle-dose and high-dose groups were 66.67% and 100%, respectively. In addition, there were negative correlations between the three assessment methods such as behavioral tests and TH expression levels. CONCLUSIONS: Intraperitoneal injection of MnCl2·H2O (25 mg/kg) can successfully establish a manganese poisoning rat model with low mortality rate. Muscle tension, balance beam, and behavioral tests can be used as preliminary determination methods for modeling.

Association of MRI T1 relaxation time with neuropsychological test performance in manganese- exposed welders.

This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11±0.05mg/m3. Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times.

Impact of air manganese on child neurodevelopment in East Liverpool, Ohio.

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±1.96µg/dL, 10.06±1.30µg/L, and 360.22±2.17ng/g, 0.76±6.12µg/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.

Inherited Disorders of Manganese Metabolism.

While the neurotoxic effects of manganese were recognized in 1837, the first genetic disorder of manganese metabolism was described only in 2012 when homozygous mutations in SLC30A10 were reported to cause manganese-induced neurotoxicity. Two other genetic disorders of manganese metabolism have now been described - mutations in SLC39A14 cause manganese toxicity, while mutations in SLC39A8 cause manganese and zinc deficiency. Study of rare genetic disorders often provides unique insights into disease pathobiology, and the discoveries of these three inherited disorders of manganese metabolism are already transforming our understanding of manganese homeostasis, detoxification, and neurotoxicity. Here, we review the mechanisms by which mutations in SLC30A10, SLC39A14, and SLC39A8 impact manganese homeostasis to cause human disease.

Manganese and Developmental Neurotoxicity.

Manganese (Mn) is an essential metal that plays a fundamental role for brain development and functioning. Environmental exposure to Mn may lead to accumulation in the basal ganglia and development of Parkinson-like disorders. The most recent research is focusing on early-life overexposure to Mn and the potential vulnerability of younger individuals to Mn toxicity also in regard to cognitive and executive functions through the involvement of the frontal cortex.Neurodevelopmental disturbances are increasing in the society, and understanding the potential role of environmental determinants is a key for prevention. Therefore, assessing the environmental sources of Mn exposure and the mechanisms of developmental neurotoxicity and defining appropriate biomarkers of exposure and early functional alterations represent key issues to improve and address preventive strategies. These themes will be reviewed in this chapter.

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats.

Manganese (Mn) is used in industrial metal alloys and can be released into the atmosphere during methylcyclopentadienyl manganese tricarbonyl combustion. Increased Mn deposition in the brain after long-term exposure to the metal by inhalation is associated with altered dopamine metabolism and neurobehavioral problems, including impaired motor skills. However, neurotoxic effects of short-term exposure to inhaled Mn are not completely characterized. The purpose of this study is to define the neurobehavioral and neurochemical effects of short-term inhalation exposure to Mn at a high concentration using rats. Male Sprague-Dawley rats were exposed to MnCl2 aerosol in a nose-only inhalation chamber for 3 weeks (1.2 µm, 39 mg/m(3)). Motor coordination was tested on the day after the last exposure using a rotarod device at a fixed speed of 10 rpm for 2 min. Also, dopamine transporter and dopamine receptor protein expression levels in the striatum region of the brain were determined by Western blot analysis. At a rotarod speed of 10 rpm, there were no significant differences in the time on the bar before the first fall or the number of falls during the two-minute test observed in the exposed rats, as compared with controls. The Mn-exposed group had significantly higher Mn levels in the lung, blood, olfactory bulb, prefrontal cortex, striatum, and cerebellum compared with the control group. A Mn concentration gradient was observed from the olfactory bulb to the striatum, supporting the idea that Mn is transported via the olfactory pathway. Our results demonstrated that inhalation exposure to 39 mg/m(3) Mn for 3 weeks induced mild lung injury and modulation of dopamine transporter expression in the brain, without altering motor activity.

Effects of chronic manganese exposure on attention and working memory in non-human primates.

Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self-ordered spatial search (SOSS) task and a five choice serial reaction time (5-CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure.

Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

BACKGROUND: Manganese (Mn) is an essential element that can become neurotoxic through various exposure windows over the lifespan. While there is clear evidence of Mn neurotoxicity in pediatric and adult occupational populations, little is known about effects in the elderly who may exhibit enhanced susceptibilities due to compromised physiology compared to younger adults. In the province of Brescia, Italy, the Valcamonica area has been the site of three ferroalloy plants operating from 1902 to 2001. Metal emissions of Mn and to a lesser extent lead (Pb) have impacted the surrounding environment, where a high prevalence of Parkinsonism was previously observed. This study aimed to assess neurocognitive and motor functions in healthy elderly subjects residing for most of their lifetime in Valcamonica or in a reference area unimpacted by ferroalloy plant activity. METHODS: Subjects were enrolled for extensive neurobehavioral assessment of motor, cognitive and sensory functions. Exposure was assessed with 24h personal air sampling for PM10 airborne particles, surface soil and tap water measurement at individual households, Mn levels in blood and urine and Pb in blood. Dose-response relationships between exposure indicators and biomarkers and health outcomes were analyzed with generalized (linear and logistic) additive models (GAM). RESULTS: A total of 255 subjects (55% women) were examined; most (52.9%) were within the 65-70 years age class. Average airborne Mn was 26.41 ng/m(3) (median 18.42) in Valcamonica and 20.96 ng/m(3) (median 17.62) in the reference area. Average Mn in surface soil was 1026 ppm (median 923) in Valcamonica and 421 ppm (median 410) in the reference area. Manganese in drinking water was below the LDL of 1 µg/L. The GAM analysis showed significant association between airborne Mn (p=0.0237) and the motor coordination tests of the Luria Nebraska Neuropsychological Battery. The calculation of the Benchmark Dose using this dose-response relationship yielded a lower level confidence interval of 22.7 ng/m(3) (median 26.4). For the odor identification score of the Sniffin Stick test, an association was observed with soil Mn (p=0.0006) and with a significant interaction with blood Pb (p=0.0856). Significant dose-responses resulted also for the Raven's Colored Progressive Matrices with the distance from exposure point source (p=0.0025) and Mn in soil (p=0.09), and for the Trail Making test, with urinary Mn (p=0.0074). Serum prolactin (PRL) levels were associated with air (p=0.061) and urinary (p=0.003) Mn, and with blood Pb (p=0.0303). In most of these associations age played a significant role as an effect modifier. CONCLUSION: Lifelong exposure to Mn was significantly associated with changes in odor discrimination, motor coordination, cognitive abilities and serum PRL levels. These effects are consistent with the hypothesis of a specific mechanism of toxicity of Mn on the dopaminergic system. Lead co-exposure, even at very low levels, can further enhance Mn toxicity.

Respiratory manganese particle size, time-course and neurobehavioral outcomes in workers at a manganese alloy production plant.

The progression of manganism with chronic exposure to airborne manganese (Mn) is not well understood. Here, we further investigate the findings on exposure and neurobehavioral outcomes of workers from a silico- and ferromanganese production plant and non-exposed workers from the same community in 1990 and 2004, using a variety of exposure metrics that distinguish particle size and origin within the range of respirable airborne exposures. Mn exposure matrices for large respirable particulate (Mn-LRP, dust) and small respirable particulate (Mn-SRP, fume), based on process origins, were used together with detailed work histories since 1973 (plant opening), to construct exposure metrics including burdens and cumulative burdens with various clearance half-lives. For three out of eight 1990 neurobehavioral tests analyzed with linear regression models, duration of Mn exposure was the best predictor: Luria-Nebraska Neuropsychological Battery - Motor Scale, Trail-Making B and Finger Tapping. The Luria-Nebraska Motor Scale had the strongest association (t ∼ 5.0, p < 10(-6)). For outcomes on three other tests, the duration and Mn-SRP metrics were comparable: Trail Making Test A, Cancellation H and Stroop Color-Word Test (color/word subtest). Delayed Word Recall was best predicted by Mn-SRP (based on square root or truncated air-concentrations). The Word score on the Stroop Color-Word Test was the only outcome for which Mn-LRP was the leading predictor (t = -2.92, p = 0.003), while performance on the WAIS-R Digit Span Test was not significantly predicted by any metric. For outcomes evaluated in both 1990 and 2004, a mixed-effect linear regression model was used to examine estimates of within-individual trends. Duration and Mn-SRP were associated with performance on the Luria-Nebraska Motor Scale, as well as with other outcomes that appeared to have both reversible and progressive features, including Trail Making A and B, Cancellation H and Delayed Word Recall. With the mixed-effect model, Digit Span exhibited a significant irreversible association with exposure duration (t = -2.34, p = 0.021) and Mn-SRP (square root; t = -2.38, p = 0.019) metrics. The strong prediction using duration of exposure is consistent with effective homeostatic regulation of tissue-level Mn in the observed exposure range of respirable Mn (< 0.2mg/m(3)).

Elevated manganese exposure and school-aged children's behavior: a gender-stratified analysis.

High levels of waterborne manganese have been associated with problematic behavior in school-aged children, however to date this has not been reported for children exposed to airborne manganese. The objective of the present study was to examine behavioral traits among children with exposure to airborne manganese from a ferro-manganese alloy plant, located in the metropolitan region of Salvador, Brazil. The study included 34 boys and 36 girls, aged 7-12 years, living in two communities within a 3-km radius from the plant. For each child, hair manganese levels (MnH) and blood lead (PbB) levels were analyzed by graphite furnace atomic absorption spectrometry. The Children's Behavior Check List (CBCL) (Portuguese version validated in Brazil) was administered to parents or caregivers, providing scale scores of internalizing (withdrawn, somatic complaints, and anxious/depressed scales), externalizing (disruptive and aggressive) behaviors and a separate scale for attention problems. Median and range for MnH and PbB were 11.48 µg/g (range: 0.52-55.74); 1.1 µg/dL (range: 0.5-6.1), respectively. Spearman correlation analyses showed that several behavioral indices were significantly correlated with MnH levels for girls, but not for boys: total externalizing behavior (rho=0.484 vs rho=0.041) and attention problem scores (rho=0.542 vs rho=0.003) coefficients were significantly at p<0.001 level, respectively for girls and boys. No significant correlation was observed with any of the internalizing sub-scales. A linear regression model was fitted with the total externalizing behavior, inattention and total CBCL scores as dependent variables, with log transformed MnH stratified by sex, adjusting for age and maternal IQ. Total externalizing behaviors and attention problem scores were significantly associated with girls' MnH levels but not with boys'. Adjusting for maternal IQ, the ß-coefficients for LogMnH associations with total externalizing and attention problems are 8.85 (95%CI 2.44-15.24) and 4.03 (95%CI 1.50-6.56) for girls. For boys, after adjusting for age, the ß-coefficients are 0.08 (95%CI 11.51-11.66) and -0.05 (95%CI 4.34-4.25), respectively. The findings of this study suggest a positive association between elevated Mn exposure and externalizing behavioral problems and inattention, with girls presenting more pronounced effects. Future studies on Mn exposure in children should attempt to further elucidate sex and/or gender differences in Mn exposed populations.

Elevated airborne manganese and low executive function in school-aged children in Brazil.

Exposure to airborne manganese (Mn) has been associated with neurotoxic effects, including motor and cognitive deficits. The main deficits related to excessive exposure to Mn are predominantly the dysfunction of fronto-striatal and dopaminergic circuits observed in animal experimental studies, which are involved in attention, working memory and motor function. The present study aims to assess the association between elevated Mn exposure and performance on executive function and attention neuropsychological tests in children living in two communities near a ferro-manganese alloy plant. Seventy children aged between 7 and 12 years with no history of neurologic disease and an estimated IQ >68 (Vocabulary and Block Design subtests) that had lived near the iron-Mn production alloy plant for at least 1.5 years were included. Participants were assessed for cognitive functioning with neuropsychological measures for sustained attention (Test of Visual Attention - TAVIS-3R), cognitive flexibility (WCST), and verbal and visual working memory (WISC-III Digit Span subtest and Corsi Block). Manganese hair (MnH) levels were used as a biomarker of exposure. Mean scores among study participants were lower than general population norms/averages for block design, digit span, reaction time and commission errors. The median MnH level was 11.48 (range 0.52-55.74) µg/g, and no difference between sexes was observed. Spearman's correlation analysis showed a significant inverse correlation between MnH levels and estimated IQ (rho=-0.448, p=0.0001), Vocabulary (rho=-0.272, p=0.02), Block Design (rho=-0.485, p=0.00002) and Digit Span (rho=-0.410, p=0.0004). Multiple regression analyses detected inverse associations between log MnH and scores on estimated IQ (ß=-9.67; 95%CI=-16.97 to -2.37), Block Design (ß=-2.50; 95%CI=-3.91 to -1.10) and Digit Span Total (ß=-2.59; 95%CI=-4.13 to -1.05) standardized scores and the number of correct answers in forward and backward Digit Span methods, after adjusting for covariates (ß=-1.32=95%CI=-2.23 to -0.40; ß=-1.09 95%CI=-2.02 to -0.16, respectively). The results suggest that airborne Mn exposure may be associated with lower IQ and neuropsychological performance in tests of executive function of inhibition responses, strategic visual formation and verbal working memory. Executive function is dependent on the fronto-striatal circuit, which may be disrupted by Mn accumulation in the brain.