Manganese Abstracts 3

© 2012

Nutritional aspects of manganese homeostasis

            (Aschner and Aschner 2005) Download

Manganese (Mn) is an essential mineral. It is present in virtually all diets at low concentrations. The principal route of intake for Mn is via food consumption, but in occupational cohorts, inhalation exposure may also occur (this subject will not be dealt with in this review). Humans maintain stable tissue levels of Mn. This is achieved via tight homeostatic control of both absorption and excretion. Nevertheless, it is well established that exposure to high oral, parenteral or ambient air concentrations of Mn can result in elevations in tissue Mn levels. Excessive Mn accumulation in the central nervous system (CNS) is an established clinical entity, referred to as manganism. It resembles idiopathic Parkinson's disease (IPD) in its clinical features, resulting in adverse neurological effects both in laboratory animals and humans. This review focuses on an area that to date has received little consideration, namely the potential exposure of parenterally fed neonates to exceedingly high Mn concentrations in parenteral nutrition solutions, potentially increasing their risk for Mn-induced adverse health sequelae. The review will consider (1) the essentiality of Mn; (2) the concentration ranges, means and variation of Mn in various foods and infant formulas; (3) the absorption, distribution, and elimination of Mn after oral exposure and (4) the factors that raise a theoretical concern that neonates receiving total parenteral nutrition (TPN) are exposed to excessive dietary Mn.

Manganese and its role in Parkinson's disease: from transport to neuropathology

            (Aschner, Erikson et al. 2009) Download

The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

Hip dislocation and manganese deficiency

         (Barlow and Sylvester 1983) Download

Manganese toxicity and parenteral nutrition

            (Beath, Gopalan et al. 1996) Download

Brain manganese deposition and blood levels in patients undergoing home parenteral nutrition

            (Bertinet, Tinivella et al. 2000) Download

BACKGROUND: Extrapyramidal syndrome and alterations in brain magnetic resonance images are described in patients undergoing long-term home parenteral nutrition (HPN) and in cholestatic patients. These abnormalities have been correlated to basal ganglia manganese (Mn) accumulation. METHODS: A longitudinal 1-year study was conducted on 15 patients undergoing HPN (median duration, 3.8 years; range, 1.7-10; median Mn parenteral supplementation, 0.1 mg/d). Whole-blood, plasma, intra-erythrocytes, and urinary Mn concentrations were measured and brain magnetic resonance was performed at the beginning (time 0) and after 1 year of Mn intravenous supplementation withdrawal (time 1). No patients showed psychosis, extrapyramidal syndrome, or cholestasis. RESULTS: At time zero, 10 of 15 patients (67%) showed paramagnetic accumulation on cerebral magnetic resonance images; at time 1 there was a reduction of cerebral Mn accumulation. In all patients, blood-Mn levels were significantly reduced after 1 year of Mn intravenous supplementation withdrawal. CONCLUSIONS: Patients receiving long-term HPN showed an elevated incidence of alterations in brain magnetic resonance images with a median Mn intravenous supplementation of 0.1 mg/d. Mn supplementation withdrawal significantly decreased metal levels in blood and brain storage. We noticed that the intra-erythrocyte Mn level was a good index of Mn status.


Manganese intoxication and parenteral nutrition

            (Dickerson 2001) Download

Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter

            (Erikson and Aschner 2006) Download

Neurotoxicity due to excessive brain manganese (Mn) accumulation can occur via occupational exposure to aerosols or dusts that contain extremely high levels (>1-5 mg Mn/m(3)) of Mn, or metabolic aberrations (decreased biliary excretion). Given the putative role of astrocytes in regulating the movement of metals across the blood-brain barrier, we sought to examine the relationship between iron (Fe) status and Mn transport in astrocytes. Furthermore, our study examined the effect of Fe status on astrocytic transferrin receptor (TfR) and divalent metal transporter (DMT-1) levels and their relationship to Mn uptake, as both have been implicated as putative Mn transporters. All experiments were carried out in primary astrocyte cultures derived from neonatal rats when the cells reached full confluency (about three weeks in culture). Astrocytes were incubated for 24h in astrocyte growth medium (AGM) containing 200 microM desferroxamine (ID), 500 microM ferrous sulfate (+Fe), or no compound (CN). After 24h, 5 min (54)Mn uptake was measured and protein was harvested from parallel culture plates for DMT-1 and TfR immunoblot analysis. Both iron deprivation (ID) and iron overload (+Fe) caused significant increases (p<0.05) in (54)Mn uptake in astrocytes. TfR levels were significantly increased (p<0.05) due to ID and decreased in astrocytes exposed to +Fe treatments. As expected, DMT-1 was increased due to Fe deprivation, but surprisingly, DMT-1 levels were also increased due to +Fe treatment, albeit not to the extent noted in ID. The decreased TfR associated with +Fe treatment and the increased DMT-1 levels suggest that DMT-1 is a likely putative transporter of Mn in astrocytes.

Manganese toxicity in children receiving long-term parenteral nutrition

            (Fell, Reynolds et al. 1996) Download

BACKGROUND: In patients receiving long-term parenteral nutrition (PN), cholestatic disease and nervous system disorders have been associated with high blood concentrations of manganese. In such patients, the normal homoeostatic mechanisms of the liver and gut are bypassed and the requirement for this trace element is not known; nor has it been certain whether hypermanganesaemia causes the cholestasis or vice versa. We explored the direction of effect by serial tests of liver function after withdrawal of manganese supplements from children receiving long-term PN. We also examined the relation between blood manganese concentrations and brain lesions, as indicated by clinical examination and magnetic resonance imaging (MRI). METHODS: From a combined group of 57 children receiving PN we identified 11 with the combination of hypermanganesaemia and cholestasis; one also had a movement disorder. Manganese supplements were reduced in the first three and withdrawn in the remainder. MRI was done in two of these children. We also looked at manganese concentrations and MRI scans in six children who had received PN for more than 2 years without developing liver disease. FINDINGS: In the hypermanganesaemia/cholestasis group, four of the 11 patients died. In the seven survivors baseline whole-blood manganese was 615-1840 nmol/L, and after 4 months it had declined by a median of 643 nmol/L (p < 0.01). Over the same interval total bilirubin declined by a median of 70 mumol/L (p < 0.05). Two of these children had movement disorders, one of whom survived to have an MRI scan; this showed, with T1 weighted images, bilateral symmetrically increased signal intensity in the globus pallidus and subthalamic nuclei. Such changes were also seen in five other children--one from the hypermanganesaemia/cholestasis group and four of six in the long-term PN group without liver disease (in all of whom blood manganese was above normal). INTERPRETATION: The cholestasis complicating PN is multifactorial, but these results add to the evidence that manganese contributes. In view of the additional hazard of basal ganglia damage from high manganese levels in children receiving long-term PN, we recommend a low dose regimen of not more than 0.018 mumol/kg per 24 h together with regular examination of the nervous system.

Manganese deficiency and toxicity: are high or low dietary amounts of manganese cause for concern?

            (Finley and Davis 1999) Download

Manganese is an essential trace element that is required for the activity of several enzymes. Manganese is also quite toxic when ingested in large amounts, such as the inhalation of Mn-laden dust by miners. This review examines Mn intake by way of the food supply and poses the question: Is there reason to be concerned with Mn toxicity or deficiency in free-living populations in North America? Although much remains to be learned of the functions of Mn, at present there are only a few vaguely described cases of Mn deficiency in the medical literature. Given the heterogeneity of the North American food supply, it is difficult to see the possibility of more than greatly isolated and unique instances of Mn deficiency. However, low Mn-dependent superoxide dismutase activity may be associated with cancer susceptibility, and deserves further study. There may be reasons, however, to be concerned about Mn toxicity under some very specialized conditions. Increasing numbers of young people are adopting a vegetarian lifestyle which may greatly increase Mn intake. Iron deficiency may increase Mn absorption and further increase the body-burden of Mn, especially in vegetarians. Mn is eliminated primarily through the bile, and hepatic dysfunction could depress Mn excretion and further contribute to the body burden. Would such a combination of events predispose substantial numbers of people to chronic Mn toxicity? At present, there is no definite proof of this occurring, but given the state of knowledge at the present time, more studies with longer time-frames and more sensitive methods of analysis are needed.

Manganese absorption and retention in rats is affected by the type of dietary fat

         (Finley and Davis 2001) Download

There is evidence that manganese (Mn) metabolism may be altered by the form and amount of dietary fat. Also, iron (Fe) absorption is greater with saturated fats, as compared to polyunsaturated fatty acids (PUFAs). The absorption of Fe and Mn are interrelated in many aspects; therefore, the form of dietary fat may indirectly alter Mn absorption. The reported studies were conducted to determine whether saturated fat, as compared to unsaturated fat, affected Mn absorption, retention, and metabolism. In experiment I, adult rats were fed diets containing either 0.7 or 100.4 microg/g Mn with the fat source as high-linoleic safflower oil or stearic acid. After 2 wk of equilibration, the animals were fed a test meal of 54Mn followed by whole-body counting for 10 d. Manganese absorption was significantly (p < 0.05) lower in the stearic acid group (0.9-4.8%) than in the safflower oil group (20-33.8%); however, the biological half-life was shorter in the safflower oil group. Retention of 54Mn and total Mn was always significantly (p < 0.05) greater in the safflower oil group when dietary Mn was low, but it was the same when dietary Mn was high. In experiment II, weanling rats were fed 1.3, 39.3, or 174.6 microg Mn/g and either stearate, high-oleic safflower oil or high-linoleic safflower oil for 8 wk. Long-term feeding of the stearate and low Mn-containing diet resulted in a significant (p < 0.0001) reduction in heart superoxide dismutase activity and kidney and liver Mn concentrations compared to the other diets. These data show that stearic acid inhibitits Mn absorption, but it may not inhibit Mn retention when dietary Mn is high.

Is manganese an essential supplement for parenteral nutrition?

            (Hardy, Gillanders et al. 2008) Download

PURPOSE OF REVIEW: To summarize the role of the essential trace element, manganese, its potential toxicity, monitoring methods and dosage recommendations for nutrition support. RECENT FINDINGS: Parenteral nutrition usually contains manganese as part of a fixed concentration multiple trace element supplement. Recent literature identifies potential problems in this approach and reports toxic symptoms resulting from hypermanganesaemia in paediatric and long-term home patients. Elimination by the hepatobiliary system is frequently impaired, and parenteral administration bypasses the regulatory mechanisms of homeostasis. Together with occasional oral intake and product contamination, this can lead to brain accumulation and neurotoxicity, with individual responses to supplementation difficult to predict. Regular monitoring is recommended, but plasma and serum analyses are poor indicators of body stores. Whole blood concentrations are more accurate and correlate with signal intensity of MRI. We have identified a need for individual trace element additives to be more widely available and for multitrace element products to be reformulated. There is now a persuasive argument for not routinely adding manganese to parenteral nutrition admixtures. SUMMARY: High intravenous doses of manganese can lead to neurotoxicity. Current dosage guidelines and trace element formulations need revision. Frequent monitoring to identify tissue accumulation is recommended for paediatric and long-term home parenteral nutrition patients.

Manganese in parenteral nutrition: who, when, and why should we supplement?

            (Hardy 2009) Download

Micronutrient requirements are not fully understood. Parenteral nutrition (PN) usually contains the trace element (TE) manganese (Mn) from fixed-concentration TE supplements. Multiple TE formulations may not be optimal in pediatric and home PN. Moreover, most PN products contain Mn as a ubiquitous contaminant. Excessive Mn can lead to Parkinson-like symptoms resulting from hypermanganesemia. A survey of 40 Australasian hospitals that contributed data on 108 patients to the annual home PN register and a systematic review of the literature were conducted to establish the scope of the potential problem of Mn toxicity in PN patients. Exposure to Mn doses 5-6 times current daily requirements, together with the TE contamination that is reported in PN products, can lead to neurotoxicity. Whole-blood levels are more accurate for monitoring and correlate well with signal intensity of magnetic resonance imaging. Current TE formulations restrict prescribing options. The regulatory mechanisms of Mn homeostasis are bypassed via the parenteral route so elimination via the hepatobiliary system is impaired, resulting in tissue or brain accumulation. Published dosage recommendations may be excessive and official guidelines require revision. Variability in clinical practices necessitates that individual TE additives are more widely available and multiple TE products reformulated. More frequent monitoring for any brain accumulation is recommended. The scarcity of PN-associated Mn deficiency, plus the growing evidence for Mn toxicity, leads to the conclusion that it is unnecessary for Mn to be prescribed routinely for pediatric or long-term PN patients.


Manganese superoxide dismutase vs. p53: regulation of mitochondrial ROS

            (Holley, Dhar et al. 2010) Download

Coordination of mitochondrial and nuclear activities is vital for cellular homeostasis, and many signaling molecules and transcription factors are regulated by mitochondria-derived reactive oxygen species (ROS) to carry out this interorganellar communication. The tumor suppressor p53 regulates myriad cellular functions through transcription-dependent and -independent mechanisms at both the nucleus and mitochondria. p53 affect mitochondrial ROS production, in part, by regulating the expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD). Recent evidence suggests mitochondrial regulation of p53 activity through mechanisms that affect ROS production, and a breakdown of communication amongst mitochondria, p53, and the nucleus can have broad implications in disease development.

Blood manganese concentration is elevated in iron deficiency anemia patients, whereas globus pallidus signal intensity is minimally affected

            (Kim, Park et al. 2005) Download

OBJECTIVES: To determine whether blood manganese (Mn) concentration is elevated in patients with iron deficiency anemia (IDA), and whether this affects signal intensities in the globus pallidus. METHODS: Twenty-seven patients with IDA and 10 control subjects were tested for blood Mn, and brain magnetic resonance images (MRI) were also examined. Seventeen of the 27 patients were followed-up after iron therapy. RESULTS: IDA patients had a mean blood Mn concentration of 2.05 +/- 0.44 microg/dl, which was higher than controls. The mean pallidal index (PI) of anemic patients was not different from that of controls. There was a correlation between log blood Mn and PI (rho = 0.384, P = 0.048; n = 27) in IDA patients. None of the patients showed increased signals in the globus pallidus in T1-weighted MRI. Blood Mn levels decreased and hemoglobin levels increased after iron therapy (P < 0.05). CONCLUSION: Although blood Mn is elevated in IDA patients, there is no increase in globus pallidus MRI signal intensity. These findings stand in contrast to those of our other studies showing patients with chronic liver disease or occupational Mn exposure have elevated signal intensities remarkably.


Essential tremor: occupational exposures to manganese and organic solvents

            (Louis, Applegate et al. 2004) Download

Occupational exposures to manganese and organic solvents cause parkinsonism as well as prominent action tremor, resembling essential tremor (ET), yet their association with ET has not been studied. These chemicals cause cerebellar pathology. Cerebellar changes have been linked with ET. Using lifetime occupational histories, the authors demonstrated that occupational exposures were similar in cases and controls, which does not support an etiologic link between occupational exposures to these chemicals and ET.

Risk assessment of an essential element: manganese

            (Santamaria and Sulsky 2010) Download

Manganese (Mn) is an essential element for humans, animals, and plants and is required for growth, development, and maintenance of health. Mn is present in most tissues of all living organisms and is present naturally in rocks, soil, water, and food. High-dose oral, parenteral, or inhalation exposures are associated with increased tissue Mn levels that may lead to development of adverse neurological, reproductive, or respiratory effects. Manganese-induced clinical neurotoxicity is associated with a motor dysfunction syndrome commonly referred to as manganism. Because Mn is an essential element and absorption and excretion are homeostatically regulated, a reasonable hypothesis is that there should be no adverse effects at low exposures. Therefore, there should be a threshold for exposure, below which adverse effects may occur only rarely, if at all, and the frequency of occurrence of adverse effects may increase with higher exposures above that threshold. Lowest-observed-adverse-effect levels (LOAELs), no-observed-adverse-effect levels (NOAELs), and benchmark dose levels (BMDs) have been derived from studies that were conducted to evaluate subclinical neurotoxicity in human occupational cohorts exposed to Mn. Although there is some uncertainty about the predictive value of the subclinical neuromotor or neurobehavioral effects that were observed in these occupational cohort studies, results of the neurological tests were used in risk assessments to establish guidelines and regulations for ambient air levels of Mn in the environment. A discussion of the uncertainties associated with these tests is provided in this review. The application of safety and uncertainty factors result in guidelines for ambient air levels that are lower than the LOAELs, NOAELs, or BMDs from occupational exposure studies by an order of magnitude, or more. Specific early biomarkers of effect, such as subclinical neurobehavioral or neurological changes or magnetic resonance imaging (MRI) changes, have not been established or validated for Mn, although some studies attempted to correlate certain biomarkers with neurological effects. Pharmacokinetic studies with rodents and monkeys provide valuable information about the absorption, bioavailability, and tissue distribution of various Mn compounds with different solubilities and oxidation states in different age groups. These pharmacokinetic studies showed that rodents and primates maintain stable tissue Mn levels as a result of homeostatic mechanisms that tightly regulate absorption and excretion of ingested Mn and limit tissue uptake at low to moderate levels of inhalation exposure. In addition, physiologically based pharmacokinetic (PBPK) models are being developed to provide for the ability to conduct route-to-route extrapolations, evaluate nasal uptake to the central nervous system (CNS), and determine life-stage differences in Mn pharmacokinetics. Such models will facilitate more rigorous quantitative analysis of the available human pharmacokinetic data for Mn and will be used to identify situations that may lead to increased brain accumulation related to altered Mn kinetics in different human populations, and to develop quantitatively accurate predictions of elevated Mn levels that may serve as a basis of dosimetry-based risk assessments. Such dosimetry-based risk assessments will permit for the development of more scientifically refined and robust recommendations, guidelines, and regulations for Mn levels in the ambient environment and occupational settings.

Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity

            (Tong, Dong et al. 2009) Download

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) frequently overlap with Alzheimer's disease, which is linked to brain impairments in insulin, insulin-like growth factor (IGF), and neurotrophin signaling. We explored whether similar abnormalities occur in PD or DLB, and examined the role of manganese toxicity in PD/DLB pathogenesis. Quantitative RT-PCR demonstrated reduced expression of insulin, IGF-II, and insulin, IGF-I, and IGF-II receptors (R) in PD and/or DLB frontal white matter and amygdala, and reduced IGF-IR and IGF-IIR mRNA in DLB frontal cortex. IGF-I and IGF-II resistance was present in DLB but not PD frontal cortex, and associated with reduced expression of Hu, nerve growth factor, and Trk neurotrophin receptors, and increased levels of glial fibrillary acidic protein, alpha-synuclein, dopamine-beta-hydroxylase, 4-hydroxy-2-nonenal (HNE), and ubiquitin immunoreactivity. MnCl2 treatment reduced survival, ATP, and insulin, IGF-I and IGF-II receptor expression, and increased alpha-synuclein, HNE, and ubiquitin immunoreactivity in cultured neurons. The results suggest that: 1) IGF-I, IGF-II, and neurotrophin signaling are more impaired in DLB than PD, corresponding with DLB's more pronounced neurodegeneration, oxidative stress, and alpha-synuclein accumulation; 2) MnCl2 exposure causes PD/DLB associated abnormalities in central nervous system neurons, and therefore may contribute to their molecular pathogenesis; and 3) molecular abnormalities in PD/DLB overlap with but are distinguishable from Alzheimer's disease.


Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration

            (Yokel 2006) Download

The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc; and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.


Manganese flux across the blood-brain barrier

         (Yokel 2009) Download

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn(2+) ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was reduced by mitochondrial energy inhibitors. Mn and Fe do not appear to compete for brain uptake. Brain Mn uptake appears to be mediated by a Ca uptake mechanism, thought to not be a p-type ATPase, but a store-operated calcium channel. Efflux of Mn from the brain was found to be slower than markers used as membrane impermeable reference compounds, suggesting diffusion mediates brain Mn efflux. Owing to carrier-mediated brain Mn influx and diffusion-mediated efflux, slow brain Mn clearance and brain Mn accumulation with repeated excess exposure would be predicted, and have been reported. This may render the brain susceptible to Mn-induced neurotoxicity from excessive Mn exposure.


References

Aschner, J. L. and M. Aschner (2005). "Nutritional aspects of manganese homeostasis." Mol Aspects Med 26(4-5): 353-62.

Aschner, M., K. M. Erikson, et al. (2009). "Manganese and its role in Parkinson's disease: from transport to neuropathology." Neuromolecular Med 11(4): 252-66.

Barlow, P. J. and P. E. Sylvester (1983). "Hip dislocation and manganese deficiency." Lancet 2(8351): 685.

Beath, S. V., S. Gopalan, et al. (1996). "Manganese toxicity and parenteral nutrition." Lancet 347(9017): 1773-4.

Bertinet, D. B., M. Tinivella, et al. (2000). "Brain manganese deposition and blood levels in patients undergoing home parenteral nutrition." JPEN J Parenter Enteral Nutr 24(4): 223-7.

Dickerson, R. N. (2001). "Manganese intoxication and parenteral nutrition." Nutrition 17(7-8): 689-93.

Erikson, K. M. and M. Aschner (2006). "Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter." Neurotoxicology 27(1): 125-30.

Fell, J. M., A. P. Reynolds, et al. (1996). "Manganese toxicity in children receiving long-term parenteral nutrition." Lancet 347(9010): 1218-21.

Finley, J. W. and C. D. Davis (1999). "Manganese deficiency and toxicity: are high or low dietary amounts of manganese cause for concern?" Biofactors 10(1): 15-24.

Finley, J. W. and C. D. Davis (2001). "Manganese absorption and retention in rats is affected by the type of dietary fat." Biol Trace Elem Res 82(1-3): 143-58.

Foglieni, C., M. Cavarelli, et al. (2011). "Mn bioavailability by polarized Caco-2 cells: comparison between Mn gluconate and Mn oxyprolinate." Nutr J 10: 77.

Hardy, G. (2009). "Manganese in parenteral nutrition: who, when, and why should we supplement?" Gastroenterology 137(5 Suppl): S29-35.

Hardy, I. J., L. Gillanders, et al. (2008). "Is manganese an essential supplement for parenteral nutrition?" Curr Opin Clin Nutr Metab Care 11(3): 289-96.

Holley, A. K., S. K. Dhar, et al. (2010). "Manganese superoxide dismutase vs. p53: regulation of mitochondrial ROS." Mitochondrion 10(6): 649-61.

Kim, Y., J. K. Park, et al. (2005). "Blood manganese concentration is elevated in iron deficiency anemia patients, whereas globus pallidus signal intensity is minimally affected." Neurotoxicology 26(1): 107-11.

Louis, E. D., L. M. Applegate, et al. (2004). "Essential tremor: occupational exposures to manganese and organic solvents." Neurology 63(11): 2162-4.

Santamaria, A. B. and S. I. Sulsky (2010). "Risk assessment of an essential element: manganese." J Toxicol Environ Health A 73(2): 128-55.

Tong, M., M. Dong, et al. (2009). "Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity." J Alzheimers Dis 16(3): 585-99.

Yokel, R. A. (2006). "Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration." J Alzheimers Dis 10(2-3): 223-53.

Yokel, R. A. (2009). "Manganese flux across the blood-brain barrier." Neuromolecular Med 11(4): 297-310.