Mn Intoxication Research Articles

Effects of Acute Manganese Neurotoxicity in Young Chicks

Manganese (Mn) is an industrial neurotoxicant in humans and animal models limited to rodent species. The present study analyses the potential neurotoxicity of acute Mn administration in young chicks. The acute (24 h) LD50 values of Mn following intraperitoneal, intramuscular, subcutaneous and oral administrations of MnCl2 in seven-day-old chicks were 21.3 mg kg-1, 28.1 mg kg-1, 28.1 mg kg-1 and 469.5 mg kg-1 body weight of Mn, respectively. Signs of Mn poisoning appeared in the chicks within 2 min and 13 min after parenteral administration and within 20 min and 32 min after oral administration. The signs demonstrated the depressant action of Mn in the chicks. The behavioural effects of Mn given at 5 mg kg-1, 10 mg kg-1 and 20 mg kg-1 intramuscularly were examined in 7 to 12 day old chicks using the three-minute open-field and tonic immobility tests. Manganese decreased the overall locomotor activity of the chicks in the open-field arena as manifested by a significant increase in the latency to move from the central square and decreases in line crossing, frequency of defecation and vocalization score when compared to control values. It also increased the duration of the chicks' tonic immobility response. Pharmacological challenges of Mn-treated chicks with general anaesthetics xylazine-ketamine and thiopental caused the loss of right reflex at a faster rate in comparison with control values. Thiopental increased the duration of loss of righting reflex in Mn-treated chicks when compared with that of the control group. Chlorpromazine challenge of Mn-treated chicks significantly increased the depressant action of Mn in the open-field arena and increased the duration of tonic immobility response produced by the metal. The injections of Mn at 10 mg kg-1, 20 mg kg-1, 50 mg kg-1 and 100 mg kg-1 intramuscularly significantly increased the Mn levels in the plasma, liver, kidneys and entire brain of the chicks. The data suggests acute neurotoxicity of Mn chloride in the young chicks as a form of depressant action that could be determined by open-field and tonic immobility tests with further support from pharmacological challenges.

X-ray fluorescence imaging of the hippocampal formation after manganese exposure

Manganese (Mn) intoxication results in neurological conditions similar, but not identical, to idiopathic Parkinson's disease. While the mechanism(s) by which Mn exposure leads to neurotoxic effects remains unclear, studies by magnetic resonance imaging demonstrate a high Mn accumulation in the hippocampal formation (HPCf) of the brain. Metal quantification using this method is not possible. Using X-ray fluorescence imaging, we measured the distribution of Mn in the HPCf for a rodent model of chronic Mn exposure and quantitatively compared it with distributions of other biologically relevant metals. We found considerable increases in average Mn concentrations in all analyzed areas and we identified the dentate gyrus (DG) and the cornus ammonis 3 (CA3) layer as areas accumulating the highest Mn content (∼1.2 μg Mn per g tissue). The DG is significantly enriched with iron (Fe), while the CA3 layer has high zinc (Zn) content. Additionally, significant spatial correlations were found for Mn-Zn concentrations across the HPCf substructures and for Mn-Fe concentrations in the DG. Combined results support that at least two mechanisms may be responsible for Mn transport and/or storage in the brain, associated with either Fe or Zn. Subcellular resolution images of metal distribution in cells of the CA3 show diffuse Mn distributions consistent with Mn localization in both the cytoplasm and nucleus. Mn was not increased in localized intracellular Fe or copper accumulations. A consistent Mn-Zn correlation both at the tissue (40 μm × 40 μm) and cellular (0.3 μm × 0.3 μm) levels suggests that a Zn transport/storage mechanism in the HPCf is likely associated with Mn accumulation.

The effect of manganese exposure on children's learning and memory

Manganese(Mn) is an essential element,but overexposure can lead to toxicity.Most reports focus on Mn toxicity.More and more studies have showed the main effect of Mn poisoning is the functional impairment of learning and memory.However,the infant is more sensitive to Mn exposure due to their immature organs.This review discusses children's normal blood Mn levels and requirements,and summarizes the toxic susceptibility to child and different effects of Mn during the different period exposure on children's learning and memory. Key words: Manganese exposure; Children; Learning and memory

X-Ray Fluorescence Imaging: A New Tool for Studying Manganese Neurotoxicity

The neurotoxic effect of manganese (Mn) establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state, confirming the relevance of the chelation therapy currently used to treat Mn intoxication. In cells with accumulated Mn, it can cause neurotoxic action by affecting the mitochondrial respiratory chain. This can result in increased susceptibility of the neurons of the globus pallidus, thalamus, and substantia nigra pars compacta to various environmental or genetic insults. The obtained data is the first demonstration of Mn accumulation in the substantia nigra pars compacta, and thus, can represent a link between Mn exposure and its potential effects for development of Parkinson's disease.

High levels of Mn2+ inhibit secretory pathway Ca2+/Mn2+‐ATPase (SPCA) activity and cause Golgi fragmentation in neurons and glia

Excess Mn(2+) in humans causes a neurological disorder known as manganism, which shares symptoms with Parkinson's disease. However, the cellular mechanisms underlying Mn(2+) -neurotoxicity and the involvement of Mn(2+) -transporters in cellular homeostasis and repair are poorly understood and require further investigation. In this work, we have analyzed the effect of Mn(2+) on neurons and glia from mice in primary cultures. Mn(2+) overload compromised survival of both cell types, specifically affecting cellular integrity and Golgi organization, where the secretory pathway Ca(2+) /Mn(2+) -ATPase is localized. This ATP-driven Mn(2+) transporter might take part in Mn(2+) accumulation/detoxification at low loads of Mn(2+) , but its ATPase activity is inhibited at high concentration of Mn(2+) . Glial cells appear to be significantly more resistant to this toxicity than neurons and their presence in cocultures provided some protection to neurons against degeneration induced by Mn(2+) . Interestingly, the Mn(2+) toxicity was partially reversed upon Mn(2+) removal by wash out or by the addition of EDTA as a chelating agent, in particular in glial cells. These studies provide data on Mn(2+) neurotoxicity and may contribute to explore new therapeutic approaches for reducing Mn(2+) poisoning.

Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats

Oxidative stress has been proposed as a possible mechanism involved in manganese (Mn) toxicity. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. The present study investigated the beneficial role of silymarin, a natural flavonoid, in Mn-induced hepatotoxicity focusing on histopathology and biochemical approaches. Male Wistar rats were exposed orally to manganese chloride (20 mg/mL) for 30 days followed by intraperitoneal cotreatment with silymarin (100 mg/kg). Exposure to Mn resulted in a significant elevation of the plasma marker enzyme activities and bilirubin level related to liver dysfunction of reactive oxygen species (ROS) production and hepatic oxidative stress indices. This metal reduced the activities of superoxide dismutase, catalase and glutathione peroxidase and nonenzymatic antioxidant levels such as reduced glutathione, total sulfhydryl groups and vitamin C. In addition, it caused hepatic hemorrhage, cellular degeneration and necrosis of hepatocytes as indicated by liver histopathology and DNA fragmentation studies. Coadministration of silymarin alleviated Mn oxidative damage effects by inhibiting ROS generation. Histological studies also supported the beneficial role of silymarin against Mn-induced hepatic damages. Combining all, results suggested that silymarin could protect hepatic tissues against Mn-induced oxidative stress probably through its antioxidant activity. Therefore, its supplementation could provide a new approach for the reduction in hepatic complication due to Mn poisoning.

Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo

Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood–brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain's olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2–200μg MnCl2 solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2μg MnCl2 and a 90% reduction compared to vehicle controls with a 200μg exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn's action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn's action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects.

Electrophysiological and biochemical response in rats on intratracheal instillation of manganese

Abstract Chronic exposure to excess manganese via inhalation of metal fumes causes central nervous system damage. For modelling Mn aerosol inhalation, male Wistar rats were intratracheally instilled with MnCl2 solution (0.5 mg/kg b.w. MnCl2; n=12) 5 days a week for 5 weeks. At the end of the treatment, somatosensory cortical evoked potentials, elicited by double-pulse stimulation, were recorded from the animals in urethane anaesthesia. Body weight gain, organ weights, and Mn level in brain, lung and blood samples were also measured. In brain samples, gene expression level of MnSOD (Mn superoxide dismutase) was determined. The effect of Mn was mainly seen on the evoked potential amplitudes, and on the second:first ratio of these. Tissue Mn concentration was elevated in brain and lungs, but changed hardly in the blood. Relative weight of heart, thymus, lungs and brain was significantly altered. The level of MnSOD transcript in brain tissue decreased. The observed effects showed that Mn had access to the brain and that somatosensory cortical responses evoked by double-pulse stimulation might be suitable biomarkers of Mn intoxication.

Effect of in Utero Exposure to Manganese on the Neurodevelopment of the Infant

O-29C7-3 Background/Aims: Manganese (Mn) is an essential trace element and common component of food, water and air. Prenatal Mn exposure during gestation may affect fetal and infantile neurodevelopment. However, reports on in utero Mn exposure and infant's neurodevelopment are rare. This study was conducted to establish a possible relationship between prenatal exposure to Mn and mental/psychomotor development of infant at 6 months of age. Methods: We analyzed data from a birth cohort, Mothers and Children's Environmental Health (MOCEH). Study population included 259 pregnant women and infant (at 6 months of age) pairs, excluding infants <37 weeks of gestation. We assessed mental and psychomotor development in infancy using the Mental/Psychomotor Development Index (MDI/PDI) of Korean version of Bayley Scales of Infant Development II (BSID-II). The relationship between prenatal Mn exposure and MDI/PDI scores was evaluated with linear regression and ANOVA. Blood Mn was measured at third trimester of pregnancy. Results: An adverse effect of prenatal Mn exposure on MDI scores at 6 months of age was not significant. PDI scores were significantly related to the prenatal maternal blood Mn level. A nonlinear relationship was associated between prenatal manganese levels and PDI scores after adjustment for potential confounders: gestational age, infant's gender, birth order, maternal body mass index, maternal age, maternal education, breastfeeding, exposure to environmental tobacco smoke during pregnancy, and presence of atopic dermatitis after birth. Conclusion: The results of study show that prenatal manganese levels impairs psychomotor development in infancy. While no cut off point is established to define Mn poisoning, it is suggested that blood Mn level of ≥30μg/L may be associated with an adverse neurobehavioral function in infants.

Genetic polymorphism of CYP2D6∗2 C → T 2850, GSTM1, NQO1 genes and their correlation with biomarkers in manganese miners of Central India

Manganese (Mn) intoxication is most often regarded as an occupational manifestation and occurs in places such as manganese mines, dry cell battery plants and ceramic industries. In the present study, the influence of genetic polymorphism in cytochrome P450 2D6 (CYP2D6∗2), glutathione S-transferase M1 (GSTM1) and NAD(P)H quinone oxidoreductase 1 (NQO1) genes on blood manganese and plasma prolactin concentrations in manganese miners was investigated. Genotyping of CYP2D6∗2 C → T 2850 and NQO1 C → T 609 was carried out using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) whereas the genotyping of GSTM1 was carried out by multiplex PCR using beta globin as an internal control. Manganese miners with CYP2D6∗2 C → T 2850 variant genotype had relatively low Mn concentration [GM: 21.4 ± 8.9 μg L −1] than the subjects with wild (GM: 36.3 ± 8.5 μg L −1) and heterozygous (GM: 34.4 ± 6.9 μg L −1) genotypes. Miners with CYP2D6∗2 variant genotypes showed low prolactin levels (GM: 13.13 ± 1.6 ng mL −1) compared to the wild (GM: 16.4.4 ± 1.5 μg L −1) and heterozygous (GM: 18.7 ± 1.6 ng mL −1) genotypes. Gene–gene interaction studies also revealed that the subjects with CYP2D6∗2 C → T 2850 variant genotypes had low levels of Mn and prolactin. Our new findings suggest that CYP2D6∗2 C → T 2850 variant genotypes can regulate plasma prolactin levels in manganese miners of Central India and could be involved in the fast metabolism of blood manganese, compared to wild and heterozygous genotypes.

P02-233 - Acute paranoid psychosis due to past chronic mangenese exposure

A male patient aged 49 was referred for evaluation of an acute paranoid psychotic state followed by an apathy syndrome. Since his history, apart from hypertension, did not mention any somatic complaints or psychiatric symptoms, and he had been involved in an adequate professional career as metalworker and welder, MRI- scanning of the brain was performed. There appeared to be bilateral hyperdensity of the globus pallidus, suggestive for chronic manganese (Mn) intoxication. Subsequently, a Mn plasma level of 31 nmol/l (range: 7-20nmol/l) that confirmed the diagnosis.Mn is a trace element that regulates many enzymes and is essential for normal development and body function. Chronic Mn 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 leading to increased heart rate and/or blood pressure, elevated total cholesterol levels, and lowered fertility in males. With respect to neurotoxicity, Mn primarily affects the globus pallidus and the striatum of the basal ganglia, and induces damage to the dopaminergic system. This may ultimately lead to dystonic movements and a parkinsonian syndrome that is dominated by generalized bradykinesia and rigidity.As 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.In conclusion, subacute psychotic symptoms in the absence of a psychiatric history, may point towards rare occupational diseases.

Relationship between Blood Levels of Heavy Metals and Parkinson’s Disease in China

Background: Idiopathic Parkinson’s disease (PD) and the Parkinsonian syndrome caused by manganese (Mn) poisoning are known to be indistinguishable in terms of symptoms. We thus suspect that many patients who have accumulated Mn in the body in daily life are diagnosed as having idiopathic PD. We examined the relationship between PD and blood levels of heavy metals, and the influence of intake from food in a general population. Methods: The subjects comprised PD patients and sex- and age-matched controls recruited from the outpatient clinic of Xiangfan No. 1 People’s Hospital in Hubei, China, between 2006 and 2008. Information was obtained on previous eating habits before diagnosis of PD and other factors. Morning blood samples were collected before breakfast and were used to measure concentrations of metals. Results: The whole-blood Mn and serum iron (Fe) levels were significantly higher in PD patients than in controls. However, no differences in intake of each metal from food or experience of Mn poisoning were seen between the groups. Conclusions: In China, accumulation of Mn and Fe via unknown routes might be involved in the etiology of PD in the general population.

Gestational manganese intoxication and anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist 8-OH-DPAT in male Wistar rats

In the present study, the effects of prenatal manganese (Mn) intoxication on the anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist R-(+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) were examined. Wistar dams were exposed to MnCl2•4H2O at 5, 000 ppm in the drinking water for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive in the drinking water. Control rats were derived from dams that consumed tap water and had no exposure to Mn. Male offspring were tested at the age of 12 weeks. The anxiolytic-like effect was assessed in an elevated plus maze device and with the Vogel conflict test. The benzodiazepine anxiolytic diazepam (5mg/kg, ip) increased the percentage of time spent in open arms in control rats (in comparison to saline treatment) (p<0.05); no such effect was seen in Mn-exposed rats. Conversely, the serotoninergic 5-HT1A agonist 8-OH-DPAT (0.3mg/kg, ip) increased the percentage of time spent in open arms in both experimental groups. In the Vogel drinking test, an anxiolytic-like effect was also observed in both test groups (in controls this was of borderline significance). In contrast, 8-OH-DPAT did not evoke an anxiolytic-like action in control or in Mn-exposed rats in the anticonflict test. In conclusion, findings indicate that gestational Mn exposure attenuated benzodiazepine-mediated anxiolytic-like effects but not those of the 5-HT1A receptor agonist 8-OH-DPAT.

Effect of prenatal manganese intoxication on [3H]glucose uptake in the brain of rats lesioned as neonates with 6-hydroxydopamine

In the present study we examined the effects of prenatal manganese (Mn) intoxication on [3H]glucose uptake in the brain of rats lesioned as neonates with 6-hydroxydopamine (6-OHDA). MnCl2 • 4H2O (10,000ppm) was added to the drinking water of pregnant Wistar rats for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive to the drinking water. The control group consisted of rats that consumed water without Mn. Three days after birth, rats in both groups (control and Mn) were pretreated with desipramine hydrochloride (20mg/kg) and pargyline hydrochloride (50mg/kg) and injected bilaterally icv with one of three doses of 6-OHDAhydrobromide (15μg, 30μg or 67μg base form in saline on each side) or with saline (control). 6-[3H]-Dglucose (500μCi/kg, ip) was administered to male offspring in adulthood; after 15min, brain specimens were taken (frontal cortex, hippocampus, striatum, thalamus with hypothalamus, pons and cerebellum) for determination of radioactivity in a liquid scintillation counter. Low dose 6-OHDA (15μg icv) increased [3H]glucose uptake in all brain regions (p<0.05) in both control and Mnintoxicated animals. In rats lesioned with a moderate dose of 6-OHDA(30μg icv), [3H]glucose uptake was unaltered in both control and Mn-exposed rats. High dose 6-OHDA(67μg icv) reduced [3H]glucose uptake in all brain regions of Mn-exposed rats (except for cerebellum) compared with the saline group (all, p<0.05). There was no change in regional brain uptake of [3H]glucose in control rats. In conclusion, this study shows that mild neuronal insult (15μg icv 6-OHDA) increased glucose uptake in the brain while severe damage (concomitant 60μg icv 6-OHDA and Mn treatment) significantly diminished this process.

Morphological changes and manganese content in the brains of rat pups subjected to subchronic poisoning with manganese chloride

Morphological changes in neurons and the distributions of nerve and glial cells were studied, the glial index was calculated, and manganese (Mn) contents were determined in the caudate nucleus, the nucleus accumbens, the dorsal and ventral septal nuclei, and the frontoparietal areas of the cerebral cortex in the 40-day-old offspring of rats given different doses (10 and 20 mg/kg) of manganese chloride (MnCl2.4H2O) 15-20 days before pregnancy, during pregnancy, and for one month after parturition with the first portion of food. Mn poisoning increased Mn contents in the brains of rat pups, damaged a small proportion of neurons, and produced marked gliosis. These changes are believed to underlie previously described impairments to learning processes and emotional state in rat pups.

Manganese intoxication decreases the expression of manganoproteins in the rat basal ganglia: An immunohistochemical study

Manganese (Mn) is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase (Mn-SOD), a mitochondrial enzyme predominantly localized in neurons, and glutamine synthetase (GS), which is selectively expressed in astroglial cells. The detoxifying effects of GS and Mn-SOD in the brain, involve catabolizing glutamate and scavenging superoxide anions, respectively. Mn intoxication is characterized by impaired function of the basal ganglia. However, it is unclear whether regional central nervous system expression of manganoproteins is also affected. Here, we use immunocytochemistry in the adult rat brain, to examine whether Mn overload selectively affects the expression of GS, Mn-SOD, Cu/Zn-SOD, another component of the SOD family, and glial fibrillary acid protein (GFAP), a specific marker of astrocytes. After chronic Mn overload in drinking water for 13 weeks, we found that the number and immunostaining intensity of GS- and Mn-SOD-positive cells was significantly decreased in the striatum and globus pallidus, but not in the cerebral frontal cortex. In addition, we found that GS enzymatic activity was decreased in the strio-pallidal regions but not in the cerebral cortex of Mn-treated animals. In contrast, Cu/Zn-SOD- and GFAP-immunoreactivity was unchanged in both the cerebral cortex and basal ganglia of Mn-treated rats. Thus, we conclude that in response to chronic Mn overload, a down-regulation of some manganoproteins occurs in neurons and astrocytes of the striatum and globus pallidus, probably reflecting the vulnerability of these regions to Mn toxicity.

Manganese accumulation in the brain: MR imaging

Manganese (Mn) accumulation in the brain is detected as symmetrical high signal intensity in the globus pallidi on T1-weighted MR images without an abnormal signal on T2-weighted images. In this review, we present several cases of Mn accumulation in the brain due to acquired or congenital diseases of the abdomen including hepatic cirrhosis with a portosystemic shunt, congenital biliary atresia, primary biliary cirrhosis, congenital intrahepatic portosystemic shunt without liver dysfunction, Rendu-Osler-Weber syndrome with a diffuse intrahepatic portosystemic shunt, and patent ductus venosus. Other causes of Mn accumulation in the brain are Mn overload from total parenteral nutrition and welding-related Mn intoxication.

Effective Treatment of Manganese-Induced Occupational Parkinsonism With p-Aminosalicylic Acid: A Case of 17-Year Follow-Up Study

Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963-1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.

Manganese-Induced Neurotoxicity: The Role of Astroglial-Derived Nitric Oxide in Striatal Interneuron Degeneration

Chronic exposure to excessive manganese (Mn) is the cause of a neurodegenerative movement disorder, termed manganism, resulting from degeneration of neurons within the basal ganglia. Pathogenic mechanisms underlying this disorder are not fully understood but involve inflammatory activation of glial cells within the basal ganglia. It was postulated in the present studies that reactive astrocytes are involved in neuronal injury from exposure to Mn through increased release of nitric oxide. C57Bl/6 mice subchronically exposed to Mn by intragastric gavage had increased levels of Mn in the striatum and displayed diminutions in both locomotor activity and striatal DA content. Mn exposure resulted in neuronal injury in the striatum and globus pallidus, particularly in regions proximal to the microvasculature, indicated by histochemical staining with fluorojade and cresyl fast violet. Neuropathological assessment revealed marked perivascular edema, with hypertrophic endothelial cells and diffusion of serum albumin into the perivascular space. Immunofluorescence studies employing terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (DUTP)-biotin nick-end labeling revealed the presence of apoptotic neurons expressing neuronal nitric oxide synthase (NOS), choline acetyltransferase, and enkephalin in both the striatum and globus pallidus. In contrast, soma and terminals of dopaminergic neurons were morphologically unaltered in either the substantia nigra or striatum, as indicated by immunohistochemical staining for tyrosine hydroxylase. Regions with evident neuronal injury also displayed increased numbers of reactive astrocytes that coexpressed inducible NOS2 and localized with areas of increased neuronal staining for 3-nitrotyrosine protein adducts, a marker of NO formation. These data suggest a role for astrocyte-derived NO in injury to striatal-pallidal interneurons from Mn intoxication.

Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination

This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn). The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1) direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2) transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3) mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the bloodbrain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.