Chronic Manganese Exposure Research Articles

Manganese Exposure Induces Neuroinflammation by Impairing Mitochondrial Dynamics in Astrocytes

Chronic manganese (Mn) exposure induces neurotoxicity, which is characterized by Parkinsonian symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia. Mitochondrial dysfunction and oxidative stress are considered key pathophysiological features of Mn neurotoxicity. Recent evidence suggests astrocytes as a major target of Mn neurotoxicity since Mn accumulates predominantly in astrocytes. However, the primary mechanisms underlying Mn‐induced astroglial dysfunction and its role in metal neurotoxicity are not completely understood. In this study, we examined the interrelationship between mitochondrial dysfunction and astrocytic inflammation in Mn neurotoxicity. We first evaluated whether Mn exposure alters mitochondrial bioenergetics in cultured astrocytes. Metabolic activity assessed by MTS assay revealed an IC50 of ~ 100 μM Mn at 24 h in both primary mouse astrocytes (PMAs) and the human astrocytic cell line U373s. Furthermore, Mn treatment reduced mitochondrial mass, indicative of impaired mitochondrial function and biogenesis, which is substantiated by the significant reduction in mRNA of mitofusin‐2, a protein that serves as a ubiquitination target for mitophagy. Seahorse analysis of bioenergetics status in Mn‐treated astrocytes revealed that Mn significantly impaired the basal mitochondrial oxygen consumption rate as well as the ATP‐linked respiration rate. The effect of Mn on mitochondrial energy deficits was further supported by a reduction in ATP production. Mn‐exposed PMAs also exhibited a severe quiescent energy phenotype, which was substantiated by the inability of oligomycin to increase the extracellular acidification rate. Since astrocytes regulate immune functions in CNS, we also evaluated whether Mn modulates astrocytic inflammation. Mn exposure in astrocytes not only stimulated the release of proinflammatory cytokines, but also exacerbated the inflammatory response induced by aggregated α‐synuclein. Lastly, the novel mitochondria‐targeted antioxidant, mito‐apocynin, significantly attenuated Mn‐induced inflammatory gene expression in U373s, further supporting the role of mitochondria dysfunction and oxidative stress in mediating astrogliosis. Collectively, we demonstrate for the first time that Mn drives proinflammatory events in astrocytes by impairing mitochondrial bioenergetics.Support or Funding InformationNIH grants ES026892 and NS088206

Neurocognitive disorders and chronic manganese exposure

Neurocognitive disorders and chronic manganese exposure

Mapping the basal ganglia alterations in children chronically exposed to manganese

Chronic manganese (Mn) exposure is associated with neuromotor and neurocognitive deficits, but the exact mechanism of Mn neurotoxicity is still unclear. With the advent of magnetic resonance imaging (MRI), in-vivo analysis of brain structures has become possible. Among different sub-cortical structures, the basal ganglia (BG) has been investigated as a putative anatomical biomarker in MR-based studies of Mn toxicity. However, previous investigations have yielded inconsistent results in terms of regional MR signal intensity changes. These discrepancies may be due to the subtlety of brain alterations caused by Mn toxicity, coupled to analysis techniques that lack the requisite detection power. Here, based on brain MRI, we apply a 3D surface-based morphometry method on 3 bilateral basal ganglia structures in school-age children chronically exposed to Mn through drinking water to investigate the effect of Mn exposure on brain anatomy. Our method successfully pinpointed significant enlargement of many areas of the basal ganglia structures, preferentially affecting the putamen. Moreover, these areas showed significant correlations with fine motor performance, indicating a possible link between altered basal ganglia neurodevelopment and declined motor performance in high Mn exposed children.

Early Detection of Manganese Intoxication Based on Occupational History and T1-weighted MRI

Manganese regulates many enzymes and is essential for normal cell function. Chronic manganese intoxication has an insidious and progressive course terminating to atypical parkinsonism with little therapeutic efficacy. For subjects with chronic manganese exposure such as welders, manganese intoxication can be detected early based on the presence of hyperintensity in the globus pallidus on T(1)-weighted MRI and abnormally high urinary excretion of manganese with a chelating agent even in cases of normal serum/urine level of manganese.

Effects of chronic manganese exposure on the learning and memory of rats by observing the changes in the hippocampal cAMP signaling pathway

Chronic manganese exposure can produce cognitive deficits; however, the underlying mechanism remains unclear; reliable peripheral biomarker of Mn neurotoxicity have not yet been fully developed. Hence, this study aimed to investigate the mechanism of Mn-induced cognitive deficits and the potential biomarker of Mn neurotoxicity in rats. Thirty-two male Sprague Dawley rats were divided into four groups; these groups received intraperitoneal injections of 0, 5, 10 and 20 mg Mn/kg once daily, five days/week for 18 weeks. Learning and memory were assessed via Morris water maze test. Hippocampal and plasma Mn concentrations were measured through graphite furnace atomic absorption spectrometry. The levels of plasma BDNF, hippocampal BDNF, cAMP, protein kinase A, and pCREB were assessed through ELISA or Western blot. Results showed that the Mn concentrations in the hippocampus and plasma of the Mn-treated rats were higher than those of the control rats. Mn exposure impaired the learning and memory of rats. Plasma BDNF levels and hippocampal BDNF, cAMP, protein kinase A, and pCREB levels were significantly lower in the Mn-treated rats than in the control rats. Plasma BDNF levels were negatively correlated with the escape latency and the hippocampal and plasma Mn concentrations. By contrast, plasma BDNF levels were positively correlated with the number of platform crossings and the hippocampal cAMP and BDNF levels. Therefore, Mn impaired learning and memory probably by inhibiting the hippocampal cAMP signaling pathway in rats. Plasma BDNF levels may also be a potential effect biomarker of Mn neurotoxicity.

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.

Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats.

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure.

Quantitative neuropathology associated with chronic manganese exposure in South African mine workers

Manganese (Mn) is a common neurotoxicant associated with a clinical syndrome that includes signs and symptoms referable to the basal ganglia. Despite many advances in understanding the pathophysiology of Mn neurotoxicity in humans, with molecular and structural imaging techniques, only a few case reports describe the associated pathological findings, and all are in symptomatic subjects exposed to relatively high-level Mn. We performed an exploratory, neurohistopathological study to investigate the changes in the corpus striatum (caudate nucleus, putamen, and globus pallidus) associated with chronic low-level Mn exposure in South African Mn mine workers. Immunohistochemical techniques were used to quantify cell density of neuronal and glial components of the corpus striatum in eight South African Mn mine workers without clinical evidence of a movement disorder and eight age–race–gender matched, non-Mn mine workers. There was higher mean microglia density in Mn mine workers than non-Mn mine workers in the globus pallidus external and internal segments [GPe: 1.33 and 0.87 cells per HPF, respectively (p=0.064); GPi: 1.37 and 0.99 cells per HPF, respectively (p=0.250)]. The number of years worked in the Mn mines was significantly correlated with microglial density in the GPi (Spearman's rho 0.886; p=0.019). The ratio of astrocytes to microglia in each brain region was lower in the Mn mine workers than the non-Mn mine workers in the caudate (7.80 and 14.68; p=0.025), putamen (7.35 and 11.11; p=0.117), GPe (10.60 and 16.10; p=0.091) and GPi (9.56 and 12.42; p=0.376). Future studies incorporating more detailed occupational exposures in a larger sample of Mn mine workers will be needed to demonstrate an etiologic relationship between Mn exposure and these pathological findings.

232 Striatal pathology associated with chronic manganese exposure

ObjectiveThe purpose of this study was to investigate the neuropathology of chronic Mn exposure in South African Mn miners.MethodsWe performed a neuropathologic study of eight deceased Mn miners and ten...

Chronic manganese exposure impairs visuospatial associative learning in non-human primates

Manganese (Mn) is an essential trace metal nutrient, however, excess Mn can be neurotoxic. The degree to which chronic environmental or occupational exposures to Mn in adults cause neuropsychological dysfunction is of considerable interest. Descriptions of neuropsychological dysfunction following chronic Mn exposure have been somewhat inconsistent though, likely owing to different measures of exposure in different populations, complicated by factors of mixed exposures and differences in neuropsychological tests administered. We previously described up-regulation of the mRNA expression for amyloid-beta (A-beta) precursor-like protein 1 (APLP1) and the presence of A-beta diffuse plaques in frontal cortex of Mn-exposed monkeys. The present study examined Mn-induced changes in performance on a paired associate learning (PAL) task that has been suggested as a marker for preclinical Alzheimer's disease. Aspects of performance of this task were affected early following initiation of Mn exposure. Thus, PAL performance may be a sensitive and valuable tool for the early, preclinical detection of incipient dementia and it may also be a sensitive tool for detecting cognitive dysfunction from Mn exposure. The current cognitive data, combined with our previous findings, suggest that frontal cortex may be a particularly sensitive target for the effects of Mn on cognition and that chronic Mn exposure may initiate or accelerate a process that could lead to or predispose to Alzheimer's like pathology and cognitive dysfunction.

Manganese regulates caspase-3 gene promoter activity by inducing Sp1 phosphorylation in PC12 cells

Chronic manganese exposure causes selective toxicity to the dopaminergic system, resulting in a parkisonian-like neurological condition known as manganism. Manganese causes a typical apoptosis, which includes activation of the caspase cascade and DNA fragmentation in PC12 cells. Caspase-3 is a major contributor to the execution of neuronal apoptosis. In a previous study, we demonstrated that caspase-3 cleavage and expression of pro-caspase-3 mRNA and protein increased in PC12 cells treated with manganese, but this response was not observed with other apoptosis inducers. To understand the molecular mechanisms that regulate expression of caspase-3 in manganese-treated PC12 cells, we characterized the 5′-flanking region of the rat caspase-3 gene and identified both a core promoter and a manganese-responsive region that contains three putative Sp1 binding sites. Furthermore, manganese treatment induced robust Sp1 phosphorylation and increased its DNA binding activity. Overexpression of mutant Sp1 lacking phosphorylation sites attenuated Sp1's ability to stimulate manganese-induced caspase-3 promoter activity. In conclusion, our results indicate that Sp1 phosphorylation is required for manganese-induced transactivation of caspase-3.

Application of a Multi-Route Physiologically Based Pharmacokinetic Model for Manganese to Evaluate Dose-Dependent Neurological Effects in Monkeys

Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594-605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal.

Manganese and iron species in Sprague–Dawley rats exposed with MnCl2∙ 4H2O (i.v.)

Chronic manganese exposure leads to accumulation in brain mainly in the basal ganglia. Continuous incorporation finally causes neural damage (Manganism, Mn-PD) with disease pattern comparable to idiopathic Parkinson's disease (I-PD). Obviously, Mn is transported by an active mechanism across the blood–brain barrier (BBB) into the brain, but the exact transport mechanism is still not completely understood. The transferrin receptor shuttle is involved but it seems that this is not the only mechanism. Excretion of Mn follows slow simple diffusion. The exact transport mechanism is still unknown. Mn-metabolism involves a multiplicity of Mn species specifically affecting Mn-homeostasis. Low molecular mass (LMM) Mn species potentially facilitate Mn accumulation in brain.Therefore, this paper investigated the formation and distribution of Mn- and Fe-Species in vivo (Sprague–Dawley rats) after a single intravenous (i.v.) injection of a non-toxic dose of MnCl2∙4H2O. Speciation analysis used a specifically developed sample preparation under cryogenic conditions and was performed with size exclusion chromatography online coupled to inductively coupled plasma-mass spectrometry (SEC-ICP-MS). The sample preparation method was previously shown to maintain species stability at enhanced extraction efficiency. One hour after i.v. injection overload of native Mn-carriers (Mn–transferrin) and formation of LMM Mn species, eluting at the retention time (RT) of Mn–citrate, were found in serum. After four days, serum and feces seemed to be Mn-cleared, but brain and kidney showed significantly elevated Mn levels. Even in lung and muscle tissue Mn was increased, but to a smaller extent. Accumulation of Mn especially in brain and kidney originated from increased concentrations of inorganic Mn and Mn bound to LMM Mn species. Iron status and iron species pattern appeared to be completely unaffected from i.v. injected Mn. The results underlined that specifically LMM-Mn-compounds permeated the BBB and accumulated in brain and kidney. It is discussed that kidney may play a regulatory role in the homeostasis of LMM Mn species.

Regional cerebral metabolism in mouse under chronic manganese exposure: Implications for Manganism

Chronic manganese (Mn) exposure in rodents, non-human primates and humans has been linked to Parkinson’s disease like condition known as Manganism. Mn being a cofactor for many enzymes in brain has been known to be accumulated in various regions differentially and thus exert toxic effect upon chronic overexposure. In present study, neuropathology of Manganism was investigated by evaluating regional neuronal and astroglial metabolism in mice under chronic Mn exposure. Male C57BL6 mice were treated with MnCl2 (25mg/kg, i.p.) for 21days. Cerebral metabolism was studied by co-infusing [U-13C6]glucose and [2-13C]acetate, and monitoring 13C labeling of amino acids in brain tissue extract using 1H–[13C] and 13C–[1H]-NMR spectroscopy. Glutamate, choline, N-acetyl aspartate and myo-inositol were found to be reduced in thalamus and hypothalamus indicating a loss in neuronal and astroglial cells due to Mn neurotoxicity. Reduced labeling of GluC4 from [U-13C6]glucose and [2-13C]acetate indicates an impairment of glucose oxidation by glutamatergic neurons and glutamate–glutamine neurotransmitter cycle in cortex, striatum, thalamus–hypothalamus and olfactory bulb with chronic Mn exposure. Additionally, reduced labeling of GlnC4 from [2-13C]acetate indicates a decrease in acetate oxidation by astroglia in the same regions. However, GABAergic function was alleviated only in thalamus–hypothalamus. Our findings indicate that chronic Mn impairs excitatory (glutamatergic) function in the majority of regions of brain while inhibitory (GABAergic) activity is perturbed only in basal ganglia.

Manganese and acute paranoid psychosis: a case report

IntroductionManganese regulates many enzymes and is essential for normal development and body function. Chronic manganese intoxication has an insidious and progressive course and usually starts with complaints of headache, fatigue, sleep disturbances, irritability and emotional instability. Later, several organ systems may be affected and, due to neurotoxicity, an atypical parkinsonian syndrome may emerge. With regard to neuropsychiatry, an array of symptoms may develop up to 30 years after intoxication, of which gait and speech abnormalities, cognitive and motor slowing, mood changes and hallucinations are the most common. Psychotic phenomena are rarely reported.Case presentationWe describe the case of a 49-year-old Caucasian man working as a welder who was referred to our facility for evaluation of acute paranoid psychotic behavior. Our patient's medical history made no mention of any somatic complaints or psychiatric symptoms, and he had been involved in a professional career as a metalworker. On magnetic resonance imaging scanning of his brain, a bilateral hyperdensity of the globus pallidus, suggestive for manganese intoxication, was found. His manganese serum level was 52 to 97 nmol/L (range: 7 to 20 nmol/L). A diagnosis of organic psychotic disorder due to manganese overexposure was made. His psychotic symptoms disappeared within two weeks of treatment with low-dose risperidone. At three months later, serum manganese was decreased to slightly elevated levels and the magnetic resonance imaging T1 signal intensity was reduced. No signs of Parkinsonism were found and a definite diagnosis of manganese-induced apathy syndrome was made.ConclusionAlthough neuropsychiatric and neurological symptoms caused by (chronic) manganese exposure have been reported frequently in the past, in the present day the disorder is rarely diagnosed. In this report we stress that manganese intoxication can still occur, in our case in a confined-space welder, and may present clinically with a paranoid psychotic state that necessitates a rapid diagnostic procedure in order to avoid the permanent structural brain damage that may occur with chronic exposure.

Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice

Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl 2-enriched (1%) or control food, starting at the age of 4 months. Locomotor activity was increased by Mn without significant effect of the transgenes. Mice were sacrificed at the age of 7 or 20 months. Striatal Mn was significantly increased about three-fold in those exposed to MnCl 2. The number of tyrosine hydroxylase positive substantia nigra compacta neurons was significantly reduced in 20 months old mice (−10%), but Mn or transgenes were ineffective (three-way ANOVA with the factors gene, Mn and age). In 7 months old mice, striatal homovanillic acid (HVA)/dopamine (DA) ratios and aspartate levels were significantly increased in control mice with human α-syn as compared to non-transgenic controls (+17 and +11%, respectively); after Mn exposure both parameters were significantly reduced (−16 and −13%, respectively) in human α-syn mice, but unchanged in non-transgenic animals and mice with mutated α-syn (two-way ANOVA with factors gene and Mn). None of the parameters were changed in the 20 months old mice. Single HVA/DA ratios and single aspartate levels significantly correlated across all treatment groups suggesting a causal relationship between the rate of striatal DA metabolism and aspartate release. In conclusion, under our experimental conditions, Mn and human α-syn, wild-type and doubly mutated, did not interact to induce PD-like neurodegenerative changes. However, Mn significantly and selectively interacted with human wild-type α-syn on indices of striatal DA neurotransmission, the neurotransmitter most relevant to PD.

The effects of the administration of two different doses of manganese on short-term spatial memory and anxiety-like behavior in rats

Manganese is a very well known neurotoxic agent. It has been mainly linked to impaired motor skills and disturbed psychomotor development. However, very few aspects are known about the cognitive deficits and behavioral consequences of chronic manganese exposure. In this context, we report herein our findings regarding short-term spatial memory, motor and anxiety-like behavior assessments in male Wistar rats exposed for 45 days to two different doses (3 mg/kg b.w., i.p. and 10 mg/kg b.w., i.p.) of manganese. Behavior testing (Y-maze task and elevated plus maze) was performed after 45 days of manganese administration. Chronic manganese exposure in Wistar rats led to behavioral alterations consisting of cognitive deficiencies in the Y-maze task and anxiety/compulsive-like behaviors in the elevated plus maze, but no motor disturbances as tested by the number of arm entries in the Y-maze. Additional work is necessary to understand the longterm effects of different doses and dosing regimens of manganese on cognitive/affective and motor functioning.

Impact of open manganese mines on the health of children dwelling in the surrounding area

Introduction:Chronic manganese (Mn) exposure is a health hazard associated with the mining and processing of Mn ores. Children living in an area with increased environmental exposure to Mn may have symptoms of chronic toxicity that are different from adults who experience occupational exposure. The aim of the study was to compare health outcomes in a pediatric population living near open Mn mines with a group of children from a reference area and then to develop and implement preventive/rehabilitation measures to protect the children in the mining region.Methods:After environmental assessment, a group of 683 children living in a Mn-rich region of Ukraine were screened by clinical evaluation, detection of sIgA (37 children), micronucleus analysis (56 children), and hair Mn content (166 children).Results:Impaired growth and rickets-like skeletal deformities were observed in 33% of the children. This was a significantly higher percentage than in children in the reference region (15%). The children from the Mn-mining region also had increased salivary levels of immunoglobulin A (104.4±14.2 mcg/ml vs. 49.7±6.1 mcg/ml among the controls (p<0.05), increased serum alpha 1 proteinase inhibitor levels (4.93±0.21 g/l compared with 2.91±0.22 g/l for controls; p<0.001) and greater numbers of micronuclei in the mucous cells of the oral cavity (0.070±0.008 vs. 0.012±0.009, p<0.001).Conclusions:These findings indicate the deleterious health consequences of living in a Mn-mining area. Medical rehabilitation programs were conducted and produced positive results, but further validation of their effectiveness is required. The study provided background information to formulate evidence-based decisions about public health in a region of high Mn exposure.

Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates

Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3–5.0, 5.0–6.7, 8.3–10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function.

Altered working memory process in the manganese-exposed brain

Chronic manganese (Mn) exposure often leads to impairments in fine motor and cognitive functions, particularly memory. However, the neural correlates of Mn-induced alterations in memory remain unclear. In the present study, we performed functional MRI (fMRI) with 2-back memory tests to assess the neural correlates of Mn-induced memory impairment in response to subclinical dysfunction in the working memory networks in welders exposed to Mn for extended periods of time. Within-group and between-group analyses revealed that brain activity in working memory networks was increased in welders with chronic Mn exposure during the 2-back verbal working memory task compared to healthy control individuals. Therefore, our fMRI findings indicate that welders might require more neural resources in working memory networks to compensate for subtle deficits in working memory and altered working memory processes, even if they performed the tasks at the same level as healthy control individuals.