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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pharmacol Ther. Author manuscript; available in PMC 2008 February 1.
Published in final edited form as:
PMCID: PMC1852452
NIHMSID: NIHMS18017

Manganese Neurotoxicity: A Focus on the Neonate

Abstract

Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m3) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate.

This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

Keywords: manganese, neurotoxicity, neonate, brain, blood-brain barrier

Introduction

Manganese (Mn), a common naturally-occurring element, is second only to iron in terms of prevalence in the environment. It is considered an essential nutrient and is crucial for maintaining the proper function and regulation of many biological processes such as producing ATP and blood clotting. More prominently, Mn is a constituent of many enzymes involved in carbohydrate (pyruvate carboxylase) and protein (arginase) metabolism, is utilized by various antioxidant enzymes such as superoxide dismutase (MnSOD), and activates the glycosyltransferase necessary for the mucopolysaccharides utilized by cartilage, bone and other connective tissues (For a more detailed review, see: Hurley and Keen). The first reported cases of Mn deficiency were in chickens suffering from perosis, which later was discovered to be due to inadequate glycosyltransferase activity causing the malformed bones. This symptom of Mn deficiency manifests itself during the formation and growth of bones and connective tissues during development. In adult animals, including humans, Mn deficiency, which is extremely rare, is characterized by weight loss and blood clotting problems. Therefore, in humans pathologies associated with abnormal Mn biology revolve around exposure to excessive Mn and not its deficiency.

Mn is used in numerous industries including steel production, formulating gasoline anti-knock additives (methylcyclopentadienyl manganese tricarbonyl; MMT), mining, welding, battery assembly and glass and ceramics manufacturing. Considering this wide-spread use of Mn, it is important to identify populations that may be vulnerable to Mn intoxication, particularly since chronic Mn overexposure results in the onset of a neurological phenotype, known as manganism, which present with motor symptoms resembling those of Parkinson's disease (Aschner and Aschner, 1991; Pal et al., 1999; Lee, 2000). Generally, airborne Mn is considered to be the most relevant route of exposure in occupational settings (Dorman et al., 2002; Dobson et al., 2003; Erikson et al., 2004a; Aschner et al., 2005; Erikson et al., 2005). However, dystonia and movement disorders have been described in case reports of adults and children receiving prolonged total parenteral nutrition (TPN) and have been associated with magnetic resonance imaging (MRI) abnormalities suggesting Mn-associated changes in the basal ganglia.

Mn deposition in the brain has potentially important implications for long-term neurodevelopmental outcome in exposed infants. In monkeys and rats, a correlation exists between the severity of central nervous system (CNS) symptoms and Mn brain concentrations, with both the rate and extent of Mn transport into the CNS influencing the clinical outcome (Suzuki et al., 1975; Roels et al., 1997). In neonatal rats, high dietary Mn intake resulted in developmental deficits (Tran et al, 2002). It has been observed that infants who require prolonged parenteral nutrition during their early neonatal course have worse developmental outcomes than gestational age-matched control infants, even after correcting for confounders such as respiratory complications and socioeconomic status (Morris et al., 1999). While the explanation for this discrepancy in developmental outcomes is undoubtedly complex and multi-factorial, the potential contribution of Mn toxicity to the poor outcomes of infants dependent for an extended time on parenteral nutrition has not been fully acknowledged or studied. Neither is information available on the contribution of co-morbidities such as iron deficiency and cholestasis to the ability of the neonatal brain to regulate Mn uptake. It is known that increases in blood and brain Mn levels have been reported in persons with liver disease (Spahr et al., 1996; Rose et al., 1999); and data suggest that iron (Fe) deficiency may be a risk factor for Mn neurotoxicity (Ellingsen et al., 2003; Erikson et al., 2002a; Erikson et al., 2004a). This last point is especially relevant considering the prevalency of Fe deficiency throughout the world (approximately 2 billion people are affected).

This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn-exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will conclude with a discussion of ripe areas for research in this underreported area.

Manganese Transport into Brain

Transferrin/transferrin receptor in Mn transport

Little is also known about transport mechanisms of Mn during the developmental period. Putative transport mechanisms in the adult include the divalent metal transporter 1 (DMT-1) and the transferrin receptor (TfR). Protein expression of DMT-1 and TfR is seen as early as postnatal day 5 (PN5) and increases through PN15 in all regions examined (cortex, hippocampus, striatum) (Siddappa et al., 2002; Garcia et al., 2006), verifying that DMT-1 and TfR are present in the developing brain; however, whether functional, remains unknown.

A series of studies has shown that Mn influx to the brain, but not efflux, is carrier mediated (Crossgrove et al., 2003; Yokel et al., 2003). In plasma, Mn is bound to small molecular weight carriers such as albumin and citrate or proteins like transferrin. Transferrin (Tf) is the primary iron binding/transport protein in plasma and is also known to bind Mn. Mn does not avidly complex with sulfhydryl (-SH) groups or amines, and it shows little variation in its stability constants for endogenous complexing ligands such as glycine, cysteine, riboflavin, and guanosine. In the absence of Fe, the binding sites of Tf can accommodate a number of other metals raising the possibility that Tf functions in vivo as a transport agent for many of these metals. Mn binding to Tf is time-dependent (Keefer et al., 1970; Scheuhammer and Cherian, 1985; Aschner and Aschner, 1990). When complexed with Tf, Mn is exclusively present in the trivalent oxidation state, with 2 metal ions tightly bound to each Tf molecule (Aisen et al., 1969). At normal plasma Fe concentrations (0.9-2.8 μg/ml), normal iron binding capacity (2.5-4 μg/ml), and at normal Tf concentration in plasma, 3 mg/ml, with 2 metal-ion-binding sites per molecule (Mr 77000) of which only 30% are occupied by Fe+3, Tf has available 50 μ mole of unoccupied Mn3+ binding sites per liter (Aschner and Aschner, 1990).

Since Tf receptors are present on the surface of the cerebral capillaries (Fishman et al., 1985; Jeffries et al., 1984; Partridge et al., 1987) and endocytosis of Tf is known to occur in these capillaries (Partridge et al., 1987), it has been suggested that Mn (in the trivalent oxidation state) enters the endothelial cells complexed with Tf. Mn is then released from the complex in the endothelial cell interior by endosomal acidification and the apo-Tf Tf complex is returned to the luminal surface (Morris et al., 1992a; Morris et al., 1992b) without the assistance of DMT1 (Divalent Metal Transporter-1) (Moos et al., 2006). Mn released within the endothelial cells is subsequently transferred to the abluminal cell surface for release into the extracellular fluid. The endothelial Mn is delivered to brain-derived Tf for extracellular transport and the manganese subsequently taken up by neurons that posses both transferrin receptors and DMT1 (Moos and Morgan, 2002). A recent study by Moos et al. (2006) indicates that Tf-bound metal gains access to the brain through the blood-CSF barrier where the metal then diffuses into neurons form the ventricles and subarachnoid space. Support for receptor-mediated endocytosis of a Mn-Tf complex in cultured neuroblastoma cells (SHSY5Y) was recently demonstrated by Suarez and Eriksson (1993). Sloot and Gramsbergen (1994) have demonstrated anterograde axonal transport of 54Mn in both nigrostriatal and striatonigral pathways. Furthermore, in vivo, intravenous administration of ferric-hydroxide dextran complex significantly inhibits Mn brain uptake, and high Fe intake reduces CNS Mn concentrations, corroborating a relationship between Fe and Mn transport (Aschner and Aschner, 1990; Diez-Ewald et al., 1968).

It is noteworthy to mention the distribution of Tf receptors in relationship to CNS Mn accumulation. Pallidum, thalamic nuclei, and substantia nigra contain the highest Mn concentrations (Barbeau et al., 1976). Interestingly, Fe concentrations in these structures are the highest as well (Hill and Switzer, 1984). Although the areas with dense Tf distribution (Hill et al., 1985) do not correspond to the distribution of Mn (or Fe), the fact that Mn-accumulating areas are efferent to areas of high Tf receptor density suggests that these sites may accumulate Mn through neuronal transport (Sloot and Gramsbergen, 1994). For example, the Mn rich areas of the ventral-pallidum, globus pallidus, and substantia nigra receive input from the nucleus accumbens and the caudate-putamen (Walaas and Fonnum, 1979; Nagy et al., 1978) - two areas abundantly rich in Tf receptors.

Experiments examining Tf's role in Mn transport are often conducted with Mn-bound Tf complexes. However, experiments using the hypotransferrinemic mouse, which lacks functional Tf, has shown that Mn transport to the brain is not affected indicating that transferrin is not necessary for brain Mn acquisition across the blood-brain barrier (Malecki et al., 1999). Tf gains access to the cell by binding to its receptor, the TfR, where then the complex is endocytosed. Divalent metal transporter (DMT1) is a component of the endosome and functions to acidify the endosome to allow for release of Tf bound metal and then functions to pump the metal into the cytosol. Presumed is that Mn also is released from Tf-Mn complexes by the same mechanism (Roth and Garrick, 2003; Gunter et al., 2006) however more studies are needed. This mechanism was elucidated in reticulocytes where TfR is abundant and Tf-Fe complexes (and perhaps Tf-Mn complexes) were able to enter cells but the metal could not be released into the cytosol (Garrick et al., 1993). Several in vitro studies have shown that Mn3+ does not accumulate intracellularly to any significant amount to lead to neurotoxicity. Gunter et al., (2005) found no evidence of stabilization of Mn3+ complexes in human neuroteratocarcinoma (NT2) cells and primarly rat astrocyte cultures or in nerve growth factor treated PC12 cells (Gunter et al., 2005). The cause of manganese neurotoxicity is suggested to by due to Mn2+ inhibition of Ca2+ activation and control of ATP production (Gunter et al., 2006).

Divalent Metal Transporter (DMT1) in Mn transport

The plasma and transmembrane transport of Fe and Mn are thought to share common mechanisms. Divalent Metal Transporter-1 (DMT1/Nramp2/SLC11A2) has been suggested to be the Mn transporter in the duodenum in the adult. Conflicting arguments exist over whether Tf receptors are present or absent in the entrerocyte (Parmley et al., 1985; Pietrangelo et al., 1992 (Oates et al., 2000). Studies by Conrad et al. indicate that Mn shares the ferrous iron transport mechanism (DMT1) but no the ferric pathway (β3-integran and mobilferrin) (Conrad et al., 2000).

DMT1 is a divalent-metal transporter that functions in a pH-dependent fashion stimulated by acidic pH, which is suggestive of a proton/metal-symport mechanism. DMT1 is expressed at the duodenum brush border in mice, where it is responsible for transferrin-independent uptake of dietary iron from the intestinal lumen. DMT1 also colocalizes with transferrin in the recycling endosomes of many cell types, including reticulocytes, where it transports iron from the acidified lumen of the endosomes into the cytoplasm. Two animal models exist, mk (microcytic anemic) mouse and the Belgrade rat (b/b) (Canonne-Hergaux et al., 2001; Fleming et al., 1998). Both animals are anemic from birth and require iron supplementation to survive. The Belgrade rat has also been shown to have impaired Mn metabolism (Chua & Morgan, 1997) and has been the model used in several Mn transport studies. Interestingly, it is also known that mutations in NRAMP2 homologues in bacteria and yeast disrupt Mn transport (Kehres & Maguire, 2003; Portnoy et al., 2002; Rosakis & Koster, 2004; Rosakis & Koster, 2005).

Chua and Morgan found that Mn and iron shared similar transport mechanisms in the erythroid tissue, duodenal mucosa, kidney and blood-brain barrier where Mn and iron transport were reduced in these tissues in the Belgrade homozygous rat (b/b) (Chua & Morgan, 1997). Transport of Mn to reticulocyes was altered only when Tf-Mn was the form of Mn however and not under low-affinity conditions. Interestingly, Mn liver levels were higher in the b/b rat suggesting an alternate uptake pathway for non-Tf bound Mn. Tf mediate process seems to decline as rats mature due to changes in the rate of growth and proliferation. Crossgrove and Yokel have studies the transport of Mn across the BBB using the Belgrade rat. They found no difference between b/b rats and control rats suggesting that DMT1 does not play a role in uptake of Mn in the adult animal. Neuronal expression of transferrin receptors and DMT1 in adult rats implies that neurons at this age acquire iron by receptor-mediated endocytosis of transferrin followed by iron transport out of endosomes mediated by DMT1. The existence of the mutated DMT1 molecule in neurons suggests that the low cerebral iron uptake in b/b rats derives from a reduced neuronal uptake rather than an impaired iron transport through the blood-brain barrier (Moos & Morgan, 2004). Kidney studies remain to show the importance of DMT1 as well as different isoforms (Abouhamed et al., 2006; Canonne-Hergaux & Gros, 2002; Wareing et al., 2003; Ferguson et al., 2003). Pharmacokinetic studies show that iron status can alter lung Mn transport to circulation (Brain et al., 2006; Heilig et al., 2005; Thompson et al., 2006) DMT1 is not the transporter involved (Heilig et al., 2006). Recently is has been verified that the b/b Belgrade rat lacks transport mechanisms for divalent metals in its small intestine (Knopfel et al., 2005). It seems clear that duodenal absorption of metals is DMT1 regulated. However, while present early in postnatal development, it does not appear to be iron-regulated until adulthood (Leong, et al., 2003a; 2003b).

Other potential transporters of brain Mn

As mentioned the mechanism in which Mn is transported across the BBB has recently come to light. It appears that facilitated diffusion (Rabin et al., 1993), active transport (Murphy et al., 1991; Aschner and Gannon, 1993; Rabin et al., 1993), DMT-1-mediated transport (Erikson et al., 2004a; Garrick et al., 2003), ZIP8-, store-operated calcium channels as well as transferrin (Tf)-dependent transport (Aschner and Gannon, 1993) mechanisms are all involved in shuttling Mn across the BBB. Although non-protein-bound Mn enters the brain more rapidly than Tf-bound Mn (Murphy et al., 1991; Rabin et al., 1993), it is unclear as to which form represents the predominant mechanism of transport in situ.

A small fraction of Mn is found in plasma as Mn-citrate (Crossgrove et al., 2003; Yokel and Crossgrove, 2004). The same authors have suggested that a Mn citrate tridentate complex with a non-coordinated central carboxylate recognition moiety is likely a substrate for the organic anion transporter or a monocarboxylate transporter (MCT). Candidates for transport of Mn citrate may include MCT and/or members of the organic anion transporter polypeptide (OATP) or ATP-binding cassette (ABC) superfamilies.

A couple of recent studies suggest that calcium channels may be another potential transport mode for cellular Mn transport. The first study showed that Mn transport into the brain was not dependent on DMT-1 but rather another transport mode such as calcium channels {Crossgrove et al., 2005) (Yokel et al., 2003). The other study looked at 54Mn uptake in the human alveolar cell (A549) and found that calcium channel blockers significantly inhibited Mn uptake (Heilig et al., 2006). Pharmacological studies of 54Mn uptake by A549 cells, a human alveolar cell line, suggest that metal uptake by type II alveolar epithelial cells is associated with activities of both L-type Ca(2+) channels and TRPM7, a member of the transient receptor potential melastatin subfamily. Their results demonstrate that Fe and Mn are absorbed by the pulmonary epithelium through different pathways and reveal the potential role for calcium channels in lung metal clearance. The difference in transport between Fe and Mn has also been noted in the olfactory pathway. Where inhaled Mn was transported to the brain, Fe was not readily transported by the olfactory tract (Rao et al., 2003). In other studies using Mn enhanced MRI (MEMRI) to trace odor pathways in the brain, Pautler & Koretsky were able to inhibit the transport of Mn transport via the olfactory neurons using the calcium channel blocker diltiazem in conjunctions with MnCl2 administered directly into the naris and verified using MRI (Pautler & Koretsky, 2002).

Finally, recent evidence implies a role for the ZIP transporter proteins in Mn transport, though whether functional at the BBB has yet to be determined. The ZIP transporter proteins, members of the solute-carrier-39 (SLC39) metal-transporter family, having 14 members-highly conserved orthologs-between mouse and human (Eide et al., 2004). Zip proteins have been originally divided into two subfamilies, referred to as subfamily I, consisting mostly of fungal and plant sequences, and subfamily II, which consists of insect, nematode, and mammalian sequences. More recently, PSI-BLAST(position-specific iterative-basic local alignment search tool) analysis uncovered two additional subfamilies, referred to as gufA and the LIV-1 or LIV-1 subfamily of ZIP transporters (LZT). In plants, several ZIP proteins have been implicated in divalent metal transport, including zinc (Zn), Fe, and Mn. A recent in vitro study (He et al., 2006) in mouse fetal fibroblast cultures established that ZIP8 is a high affinity for Mn. The Km of 2.2 μM for Mn2+ is close to physiological concentrations and within the same range determined in many cell lines or tissues. However, whether Slc39 and organic transporters function in Mn transport remains to be examined under physiologically relevant conditions. Definitive studies to assess other protein functions (Slc39, MCT) in physiological roles are needed.

Modes of Manganese Exposure

Diet and water

The most important source of Mn for the population at large is diet, with most daily intakes falling below 5 mg Mn/kg. Adult dietary intake of Mn is estimated to be between 0.9 to 10 mg Mn/day (ATSDR, 2000; Finley and Davis, 1999). Based on the Total Diet Study, grains, beverages (tea), and vegetables provide approximately 33, 20, and 18% of dietary Mn in adult males, respectively (Pennington and Young, 1991).

Levels of Mn in excess of 30 mg/kg can be found in certain foods, such as grain, rice and nuts. Levels of Mn are also high in tea; a cup of tea may contain as much as 0.4 to 1.3 mg Mn (ATSDR, 2000). Another important source of dietary Mn intake is Mn-containing dietary supplements. Many of these contain Mn levels of 5–20 mg (NAS, 2001). Water concentrations of Mn typically range from 1 to 100 μg/L with most values below 10 μg/L (Keen and Zidenberg-Cherr, 1994). Greater than 60% of the nation's drinking water has been systematically assessed since 1991 to determine the quality of sources of drinking water in the US. The analysis, conducted by the National Water-Quality Assessment Program (NAWQA) of the U.S. Geological Survey (USGS, 2005), suggests that roughly 6% of domestic wells contain high levels of Mn in drinking water in the range of 300 μg/L. This level of Mn exposure has recently been shown to be associated with reduced Full-Scale, Performance, and Verbal raw scores in children in Bangladesh (Wasserman et al., 2006).

Milk and infant formulas

Human milk is generally low in Mn content (1.8-27.5 μg/L); however, Mn concentrations in infant formulas can vary dramatically (33-300 μg/L) (Keen and Zidenberg-Cherr, 1994; Murthy et al., 1971; Stastny et al., 1984; Vaughan et al., 1979). In human (and animal) milk Mn concentrations are associated with the stage of lactation (Casey et al., 1985; Stastny et al., 1984; Vaughan et al., 1979; Krachler and Rossipal, 2000; Table 1). For example Stastny and coworkers (1984) reported that mean (± SD) human milk Mn concentrations in the fourth week of lactation were 6.6 ± 4.7 μg/L and these levels were significantly higher than those collected during the 12th week of lactation (3.5 ± 1.4 μg/L). Notably, in human milk Mn is in the trivalent oxidation state where it is bound to lactoferrin, the major iron-binding protein in milk. Receptors for this protein are abundant in the brush border membranes of epithelial cells throughout the length of the small intestine, thus allowing for regulation of the uptake of Mn across the gastrointestinal tract. Since in formula Mn is in the divalent oxidation state, absorption through the GI tract cannot be regulated by lactoferrin receptors. Accordingly, Mn transport of infant formula-derived Mn is likely governed by mechanisms different from those from Mn in human breast milk.

Table 1
Manganese concentration in human milk and select infant formulas

In general, infant formulas contain much higher Mn concentrations compared to those observed in human milk (Table 1). Given the risk posed by high Mn concentrations in infant formulas (Golub et al., 2005) their composition has significantly changed over the last 20 years. For example, Enfamil (Mead Johnson and Company) contained 1289 μg Mn/L in 1983; levels dropped to 105 μg/L shortly thereafter (Stastny et al., 1984). It has been suggested that consumption of soy-based infant formulas is a potential area of concern for human infants as levels of 200-300 μgMn/L are common (Lonnerdal 1994).

Parenteral exposure

Risk for Mn neurotoxicity is associated with total parenteral nutrition (TPN), as these nutritional solutions are commonly formulated to include Mn along with other essential trace metals and they can contain Mn as a contaminant (Hambidge et al., 1989; Kurkus et al., 1984). A report by Wilson et al. (1992) found that Mn concentrations in TPN solutions ranged from 5.6 to 8.9 μg/L, in the absence of any supplementation.

Few studies have addressed Mn kinetics upon TPN administration (Takagi et al., 2002). Furthermore, no clear standard has been recommended for the daily dose of parenteral Mn, with the published literature indicating a broad, 200-fold range in the recommended daily Mn dose for adults on TPN ranging from a low dose of 0.18–0.91 μmol (0.01-0.05 mg) to a high dose of 40 μmol (2.2 mg). It should be acknowledged that infants, especially premature infants, receiving TPN, may not have intact or mature homeostatic control of the metal. In addition to bypassing the homeostatic barrier of the gastrointestinal tract where Mn absorption is normally tightly regulated (Davidsson et al., 1989), many infants and children on TPN solutions suffer from hepatic dysfunction and cholestasis, compromising their biliary excretion of Mn. Finally, further risk of Mn-induced toxicity is associated with the overall neurophysiological immaturity of the developing brain, perhaps allowing entrance for more Mn than would occur in the adult brain.

Mn intoxication associated with TPN solutions providing ≥ 0.1 mg Mn/day is well established (Bertinet et al., 2000; Nagatomo et al., 1999; Ono et al., 1995). These patients developed elevated serum Mn levels (Takagi et al., 2002), and they exhibit symmetrical high intensity MRI lesions in the globus pallidus consistent with the preferential accumulation of Mn at this site, in association with characteristic psychiatric symptoms and clinical signs of Mn-induced parkinsonism-like syndrome. Withdrawal from the TPN solutions significantly decreases Mn levels in both the blood and CNS (Bertinet et al., 2000). In children chronically receiving TPN high Mn blood levels and abnormal neurological signs have been reported, along with MRI findings indicative of Mn deposition in the brain (Kafritsa et al., 1998). Once removed from Mn supplemented TPN, Mn brain levels tend to decline over time, blood Mn levels normalize and some case reports suggest a good prognosis without long-lasting neurodevelopmental sequelae (Kafritsa et al., 1998).

Mechanisms of Mn Neurotoxicity

Oxidative Stress

Oxidative stress has been implicated as a contributing mechanism by which Mn may be cytotoxic (Aschner, 1997). The oxidation of dopamine by Mn is a potential mechanism by which Mn-induced oxidative stress may occur, especially since Mn can accumulate in dopamine-rich brain regions of rodents and primates (e.g., basal ganglia) following prolonged exposure (Sloot et al., 1996). Another possible mechanism is that Mn, through its sequestration in mitochondria (Galvani et al., 1995), interferes with proper respiration, thereby leading to excessive production of reactive oxygen species. One laboratory reported inhibition of complex I of the electron transport chain after treatment of PC12 cell cultures with Mn chloride (Brouillet et al., 1993). Another laboratory showed evidence suggesting that the ATPase complex is inhibited at very low levels of mitochondrial Mn, and that complex I is inhibited only at higher concentrations (Gavin et al., 1999). Although, trivalent Mn is more effective at inhibiting complex I (Archibald and Tyree, 1987; Ali et al., 1995; Chen et al., 2001), the divalent form is by far the predominant species within cells and is largely bound to ATP (Ali et al., 1995; Gunter et al., 2002). Nevertheless, in biological media, Mn of any valence will spontaneously give rise to small amounts of trivalent Mn. Interestingly, HaMai et al. (2001) demonstrated that even trace amounts of trivalent Mn can cause formation of reactive oxygen species (ROS) (HaMai et al., 2001).

Glutamate excitotoxicity

It has been shown that ROS will interfere with glutamate removal by inhibiting the high affinity glutamate transporters (Trotti et al., 1998). The ensuing increase in extracellular glutamate levels is potentially excitotoxic to neurons, representing a cause of Mn neurotoxicity. Glutamate uptake is attenuated in astrocytes that are exposed to Mn (Hazell and Norenberg, 1997; Erikson and Aschner, 2002b; Erikson et al., 2002c) and that GLAST gene expression is significantly decreased due to that exposure (Erikson and Aschner, 2002b; Erikson et al., 2002c). However, little data exist on the in vivo effects of Mn exposure on glutamate transporter gene expression and protein levels. Information that is critical for fully evaluating the neurotoxicity of Mn.

Neurotoxicity Studies using a neonatal model

Research projects that examine these putative mechanisms of Mn neurotoxicity in the neonatal brain are scant. Recently, our laboratory has shown that rats exposed to airborne Mn during gestation and during post-natal days 1-19 had significantly decreased glutathione (a prevalent endogenous antioxidant) levels as well as decreased gene expression of metallothionein and glutamine synthetase (two markers of oxidative stress) in the striatum (Erikson et al., 2006). It should be noted that compared to older rats, the neonatal rat striatum was impacted by Mn exposure to a greater degree (Erikson et al., 2004b; 2006). The striatum is also a brain region where marked changes in dopamine (Tran et al., 2002) and GABA metabolism have been observed in Mn exposed rat pups. Overall, it appears that the striatum is a vulnerable brain region in terms of Mn neurotoxicity in the neonate. This is in contrast to the adult brain in which other regions such as hippocampus, midbrain and olfactory bulb in addition to the striatum, have increased Mn concentrations (Dorman et al., 2003; 2004), altered neurotransmitter levels (Erikson et al., 2002a) and oxidative stress (Dobson et al., 2004; Erikson et al., 2005; 2006) due to Mn-exposure.

Direction for Future Research

Understanding the mechanisms in which Mn is transported into the neonatal brain is important when trying to dissect normal transport mechanisms from abnormal ones (i.e., during toxicity). To date it appears that the neonatal brain handles excessive Mn (via DMT-1 upregulation and to a lesser extent Tf/TfR) similarly to the adult brain (Garcia et al., 2006). In terms of neurochemical alterations associated with Mn-exposure in early life, both dopamine (Tran et al., 2002) and GABA (Garcia et al., 2006) have been implicated. One thing that remains unknown is the reversibility of these changes. In our recent study described in the previous paragraph, some of these developing rats were allowed to recover from Mn exposure for three and half weeks and upon termination (PND 45) many of the biomarkers did not normalize despite Mn levels returning to normal (Erikson et al., 2005). No data are available in terms of assessing the neurological effects of Mn-exposure during early life and long term consequences of this exposure. Specifically, does Mn-exposure during early development increase the risk for developing neurodegenerative diseases in later life? It is known that changes in Mn-containing proteins have been observed in many neurodegenerative diseases, including Alzheimer's disease (Markesbery, 1997), amyotrophic lateral sclerosis, and Parkinsonian-like syndrome (Pal et al., 1999; Malecki, 2001), as well neurobehavioral deficits (May, 2000; Normandin et al., 2002) are associated with Mn-exposure. Therefore longitudinal studies that examine both markers of oxidative stress and neurotransmitter biology in subjects who have a history of Mn exposure during critical neurodevelopmental periods are necessary. These studies could include recovery periods ranging from several weeks to months after exposure to high manganese levels and ultimately will expedite the development of therapies for affected individuals.

Acknowledgements

This review was partially supported by grants from NIEHS 10563 and DoD W81XWH-05-1-0239 (MA).

Footnotes

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References

  • Abbott N. Astrocyte-endothelial interactions and blood-brain barrier permeability. J. Anat. 2002;200:629–638. [PubMed]
  • Abouhamed M, Gburek J, Liu W, Torchalski B, Wilhelm A, Wolff NA, Christensen EI, Thevenod F, Smith CP. Divalent metal transporter 1 in the kidney proximal tubule is expressed in late endosomes/lysosomal membranes: implications for renal handling of protein-metal complexes. Am. J. Physiol. Renal. Physiol. 2006;290:F1525–1533. [PubMed]
  • Aisen P, Aasa R, Redfield AG. The chromium, manganese, and cobalt complexes of transferrin. J. Biol. Chem. 1969;244:4628–4633. [PubMed]
  • Al-Awadi FM, Srikumar TS. Trace-element status in milk and plasma of Kuwaiti and non-Kuwaiti lactating mothers. Nutrition. 2000;16:1069–1073. [PubMed]
  • Ali SF, Duhart HM, Newport GD, Lipe GW, Slikke W. Manganese-induced reactive oxygen species: Comparison between Mn+2 and Mn+3. Neurodegeneration. 1995;4:329–334. [PubMed]
  • Archibald FS, Tyree C. Manganese poisoning and the attack of trivalent manganese upon catecholamines. Arch Biochem Biophys. 1987;256:638–650. [PubMed]
  • Aschner M, Aschner JL. Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain Res. Bull. 1990;24:857–860. [PubMed]
  • Aschner M, Aschner J. Manganese neurotoxicity: Cellular effects and blood-brain barrier transport. Neurosci Biobehav Rev. 1991;15:333–340. [PubMed]
  • Aschner M, Gannon M. Manganese (Mn) transport across the blood-brain barrier: Saturable and transferrin-dependent transport mechanisms. Brain Res. Bull. 1994;33:345–349. [PubMed]
  • Aschner M. Manganese neurotoxicity and oxidative damage. In: Connor JR, editor. Metals and Oxidative Damage in Neurological Disorders. Plenum Press; New York: 1997. pp. 77–93.
  • Aschner M. Blood-brain barrier: physiological and functional considerations. In: Slikker W Jr, Chang L, editors. Handbook of developmental neurotoxicology. Academic Press; San Diego: 1998. pp. 339–351.
  • Aschner M, Erikson KM, Dorman DC. Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol. 2005;35:1–32. [PubMed]
  • ATSDR (Agency for Toxic Substances and Disease Registry) Toxicological Profile for Manganese. U.S. Department of Health and Human Services Public Health Service; 2000. (available at http://www.atsdr.cdc.gov/toxprofiles/tp151.html)
  • Barbeau A, Inoué N, Cloutier T. Role of manganese in dystonia. Adv. Neurol. 1976;14:339–352. [PubMed]
  • Bertinet DB, Tinivella M, Balzola FA, de Francesco A, Davini O, Rizzo L, Massarenti P, Leonardi MA, Balzola F. Brain manganese deposition and blood levels in patients undergoing home parenteral nutrition. J Parent Enter Nutr. 2000;24:223–227. [PubMed]
  • Boado R, Wang L, Pardridge W. Enhanced expression of the blood-brain barrier GLUT1 glucose transporter gene by brain-derived factors. Mol. Brain Res. 1994;22:259–267. [PubMed]
  • Brain JD, Heilig E, Donaghey TC, Knutson MD, Wessling-Resnick M, Molina RM. Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. Am J Respir Cell Mol Biol. 2006;34(3):330–337. [PMC free article] [PubMed]
  • Brightman M. Implication of astroglia in the blood-brain barrier. Ann. N.Y. Acad. Sci. 1991;633:343–347. [PubMed]
  • Brouillet EP, Shinobu L, McGarvey U, Hochberg F, Beal MF. Manganese injection into the rat striatum produces excitotoxic lesions by impairing energy metabolism. Exp. Neurol. 1993;120:89–94. [PubMed]
  • Canonne-Hergaux F, Zhang AS, Ponka P, Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood. 2001;98(13):3823–3830. [PubMed]
  • Canonne-Hergaux F, Gros P. Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice. Kidney In.t. 2002;62:147–156. [PubMed]
  • Casey CE, Hambidge KM, Neville MC. Studies in human lactation: zinc, copper, manganese and chromium in human milk in the first month of lactation. Am J Clin Nutr. 1985;41:1193–1200. [PubMed]
  • Chen JY, Tsao GC, Zhao Q, Zheng W. Differential cytotoxicity of Mn(II) and Mn(III): Special reference to mitochondrial [Fe-S] containing enzymes. Toxicol Appl Pharmacol. 2001;175:160–168. [PubMed]
  • Chua AC, Morgan EH. Manganese metabolism is impaired in the Belgrade laboratory rat. J Comp Physiol [B] 1997;167(5):361–369. [PubMed]
  • Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Porubcin M, Simovich MJ, et al. Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol. 2000;279(4):G767–774. [PubMed]
  • Conrad M,E, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis. 2002;29:336–55. [PubMed]
  • Cotzias GC, Horiuchi K, Fuenzalida S, Mena I. Chronic manganese poisoning: Clearance of tissue manganese concentrations with persistence of the neurological picture. Neurology. 1968;18:376–382. [PubMed]
  • Crossgrove JS, Allen DD, Bukaveckas BL, Rhineheimer SS, Yokel RA. Manganese distribution across the blood-brain barrier. I. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin. Neurotoxicology. 2003;24(1):3–13. [PubMed]
  • Crossgrove J, Yokel R. Manganese distribution across the blood-brain barrier III. The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake. Neurotoxicology. 2004;25:451–460. [PubMed]
  • Davidsson L, Cederblad A, Lonnerdal B, Sandstrom B. Manganese retention in man: a method for estimating manganese absorption. Am. J. Clin. Nutr. 1989;49:170–179. [PubMed]
  • Diez-Ewald M, Weintraub LR, Crosby WH. Inter relationship of iron and manganese metabolism. Proc. Soc. Exp. Biol. Med. 1968;129:448–151. [PubMed]
  • Dobson AW, Weber S, Dorman DC, Lash LK, Erikson KM, Aschner M. Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate. Biol Trace Elem Res. 2003;93:113–126. [PubMed]
  • Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann N Y Acad Sci. 2004;1012:115–28. [PubMed]
  • Dorman DC, Brenneman KA, McElveen AM, Lynch SE, Roberts KC, Wong BA. Olfactory transport: a direct route of delivery of inhaled manganese phosphate to the rat brain. J Toxicol Environ Health A. 2002;65:1493–1511. [PubMed]
  • Eide DJ. The SLC39 family of metal ion transporters. Pflueg. Arch. Eur. J. Physiol. 2004;447:796–800. [PubMed]
  • Ellingsen DG, Haug E, Ulvik RJ, Thomassen Y. Iron status in manganese alloy production workers. J Appl Toxicol. 2003;23:239–247. [PubMed]
  • Engelhardt B. Development of the blood-brain barrier. Cell Tissue Res. 2003;314:119–129. [PubMed]
  • Erikson KM, Shihabi ZK, Aschner JL, Aschner M. Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations. Biol Trace Elem Res. 2002a;87:143–156. [PubMed]
  • Erikson KM, Aschner M. Manganese causes differential regulation of glutamate transporter (GLAST), taurine transporter, and metallothionein in cultured rat astrocytes. Neurtoxicology. 2002b;23:595–602. [PubMed]
  • Erikson KM, Suber RL, Aschner M. Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate. Neurotoxicology. 2002c;23:281–288. [PubMed]
  • Erikson KM, Syversen T, Steinnes E, Aschner M. Globus pallidus: a target brain region for divalent metal accumulation associated with dietary iron deficiency. J Nutr Biochem. 2004a;15:335–341. [PubMed]
  • Erikson KM, Dorman DC, Lash LH, Dobson AW, Aschner M. Airborne manganese exposure differentially affects end points of oxidative stress in an age- and sex-dependent manner. Biol Trace Elem Res. 2004b;100:49–62. [PubMed]
  • Erikson KM, Dorman DC, Lash LH, Aschner M. Persistent alterations in biomarkers of oxidative stress resulting from combined in utero and neonatal manganese inhalation. Biol Trace Elem Res. 2005;104:151–163. [PubMed]
  • Erikson KM, Dorman DC, Fitsanakis V, Lash LH, Aschner M. In utero and neonatal airborne manganese exposure causes alterations in biomarkers of oxidative stress primarily in striatum of rat pup brains. Biol Trace Elem Res. 2006 in press. [PubMed]
  • Ferguson CJ, Wareing M, Delannoy M, Fenton R, McLarnon SJ, Ashton N, Cox AG, McMahon RF, Garrick LM, Green R, Smith CP, Riccardi D. Iron handling and gene expression of the divalent metal transporter, DMT1, in the kidney of the anemic Belgrade (b) rat. Kidney Int. 2003;64:1755–1764. [PubMed]
  • Finley JW, Davis CD. Manganese deficiency and toxicity: are high or low dietary amounts of manganese cause for concern? Biofactors. 1999;10:15–24. [PubMed]
  • Fishman JB, Handrahan JB, Rubir JB, Connor JR, Fine RE. Receptor-mediated trancytosis of transferrin across the blood-brain barrier. J. Cell. Biol. 1985;101:423A.
  • Fitsanakis VA, Piccola G, Aschner JL, Aschner M. Manganese (Mn) transport in rat brain endothelial cell (RBE4) monolayers cultured in the presence of astrocyte conditioned media (ACM) is an active process. J. Neurosci. Res. 2005;81:235–243. [PubMed]
  • Fleming MD, Trenor CC, III, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC. Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet. 1997;16:383–386. [PubMed]
  • Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U S A. 1998;95(3):1148–1153. [PubMed]
  • Forbes JR, Gros P. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood. 2003;102(5):1884–1892. [PubMed]
  • Galvani P, Fumagalli P, Santagostino A. Vulnerability of mitochondrial complex I in PC12 cells exposed to manganese. Eur J Pharmacol. 1995;293:377–383. [PubMed]
  • Garcia SJ, Gellein K, Syversen T, Aschner MA. Manganese Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat. Toxicol Sci. 2006 [Epub ahead of print] [PubMed]
  • Garrick MD, Gniecko K, Liu Y, Cohan DS, Garrick LM. Transferrin and the transferrin cycle in Belgrade rat reticulocytes. J Biol Chem. 1993;268(20):14867–14874. [PubMed]
  • Garrick M, Dolan K, Horbinski C, Ghio A, Higgins D, Porubcin M, Moore E, Hainsworth L, Umbreit J, Conrad M, Feng L, Lis A, Roth J, Singleton S, Garrick L. DMT1: A mammalian transporter for multiple metals. Biometals. 2003;16:41–54. [PubMed]
  • Gavin CE, Gunter KK, Gunter TE. Manganese and calcium transport in mitochondria: Implications for manganese toxicity. Neurotoxicology. 1999;20:445–453. [PubMed]
  • Golub MS, Hogrefe CE, Germann SL, Tran TT, Beard JL, Crinella FM, Lonnerdal B. Neurobehavioral evaluation of rhesus monkey infants fed cow's milk formula, soy formula or soy formula with added manganese. Neurotoxicol. Teratol. 2005;27:615–627. [PubMed]
  • Gunter KK, Miller LM, Aschner M, Eliseev R, Depuis D, Gavin CE, Gunter TE. XANES spectroscopy: A promising tool for toxicology: A tutorial. Neurotoxicology. 2002;23:127–146. [PubMed]
  • Gunter KK, Aschner M, Miller LM, Eliseev R, Salter J, Anderson K, Hammond S, Gunter TE. Determining the oxidation states of manganese in PC12 and nerve growth factor-induced PC12 cells. Free Radic Biol Med. 2005;39:164–181. [PubMed]
  • Gunter KK, Aschner M, Miller LM, Eliseev R, Salter J, Anderson K, Gunter TE. Determining the oxidation states of manganese in NT2 cells and cultured astrocytes. Neurobiol Aging (epub) 2005 Nov. 11 [PubMed]
  • Gunter TE, Gavin CE, Aschner M, Gunter KK. Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity. Neurotoxicology. 2006;27:765–776. [PubMed]
  • HaMai D, Campbell A, Bondy SC. Modulation of oxidative events by multivalent manganese complexes in brain tissue. Free Rad Biol Med. 2001;31:763–768. [PubMed]
  • Hambidge KM, Sokol RJ, Fidanza SJ, Goodall MA. Plasma manganese concentrations in infants and children receiving parenteral nutrition. J Parenter Enteral Nutr. 1989;13:168–171. [PubMed]
  • He L, Girijashanker K, Dalton TP, Reed J, Li H, Soleimani M, Nebert DW. ZIP8, Member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol. Pharmacol. 2006;70:171–80. [PubMed]
  • Heilig E, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L887–893. [PubMed]
  • Heilig EA, Thompson KJ, Molina RM, Ivanov AR, Brain JD, Wessling-Resnick M. Manganese and iron transport across pulmonary epithelium. Am J Physiol Lung Cell Mol Physiol. 2006;290(6):L1247–1259. [PubMed]
  • Hill JM, Switzer RC., III The regional distribution and cellular localization of iron in the rat brain. Neuroscience. 1984;11:595–603. [PubMed]
  • Hill JM, Ruff MR, Weber RJ. Transferrin receptors in rat brain: Neuropeptide-like pattern and relationship to iron distribution. Proc. Natl. Acad. Sci. USA. 1985;82:4553–4557. [PubMed]
  • Holash J, Noden D, Stewart P. Re-evaluating the role of astrocytes in blood-brain barrier induction. Dev. Dyn. 1993;197:14–25. [PubMed]
  • Holash J, Stewart P. The relationship of astrocyte-like cells to the vessels that contribute to the blood-ocular barriers. Brain Res. 1993;629:218–224. [PubMed]
  • Hurley LS, Keen CL. Manganese. In: Underwood E, Mertz W, editors. Trace Elements in Human Health and Animal Nutrition. Academic Press; New York: 1987. pp. 185–223.
  • Janzer R, Raff M. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature. 1987;325:253–257. [PubMed]
  • Janzer R. The blood-brain barrier: cellular basis. J. Inherit. Metab. Dis. 1993;16:639–647. [PubMed]
  • Jeffries WA, Brandon MR, Hunt SV, Williams AF, Mason DY. Transferrin receptor on endothelium of brain capillaries. Nature. 1984;132:162–163. [PubMed]
  • Kafritsa Y, Fell J, Long S, Bynevelt M, Taylor W, Milla P. Long-term outcome of brain manganese deposition in patients on home parenteral nutrition. Arch Dis Child. 1998;79:263–265. [PMC free article] [PubMed]
  • Keefer RC, Barak AJ, Boyett JD. Binding of manganese and transferrin in rat serum. Biochim. Biophys. Acta. 1970;221:390–393. [PubMed]
  • Keen CL, Zidenberg-Cherr S. Manganese toxicity in humans and experimental animals. In: Klimis-Tavantzis DJ, editor. Manganese in Health and Disease. CRC Press; Boca Raton, FL: 1994. pp. 193–205.
  • Keen CL. Overview of manganese toxicity. In: Velazquez S, Liaison EPA, editors. Proceedings of the Workshop on the Bioavailability and Oral Toxicity of Manganese. US EPA, Environmental Criteria and Assessment Office; 1995. pp. 3–11.
  • Kehres D, Maguire M. Emerging themes in manganese transport, biochemistry and pathogenesis in bacteria. FEMS Microbiol. Rev. 2003;27:263–90. [PubMed]
  • Kniesel U, Risau W, Wolburg H. Development of blood-brain barrier tight junctions in the rat cortex. Dev. Brain Res. 1996;96:229–240. [PubMed]
  • Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell. Mol. Neurobiol. 2000;20:57–76. [PubMed]
  • Knopfel M, Zhao L, Garrick MD. Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. Biochemistry. 2005;44(9):3454–3465. [PubMed]
  • Krachler M, Rossipal E. Concentrations of trace elements in extensively hydrolysed infant formulae and their estimated daily intakes. Ann Nutr Metab. 2000;44:68–74. [PubMed]
  • Kurkus J, Alcock NW, Shils ME. Manganese content of large-volume parenteral solutions and of nutrient additives. J Parenter Enteral Nutr. 1984;8:254–257. [PubMed]
  • Lee J. Manganese intoxication. Arch Neurol. 2000;57:597–599. [PubMed]
  • Leong WI, Bowlus CL, Tallkvist J, Lonnerdal B. DMT1 and FPN1 expression during infancy: developmental regulation of iron absorption. Am J Physiol Gastrointest Liver Physiol. 2003a;285(6):G1153–1161. [PubMed]
  • Leong WI, Bowlus CL, Tallkvist J, Lonnerdal B. Iron supplementation during infancy--effects on expression of iron transporters, iron absorption, and iron utilization in rat pups. Am J Clin Nutr. 2003b;78(6):1203–1211. [PubMed]
  • London RE, Toney G, Gabel SA, Funk A. Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride. Brain Res. Bull. 1989;23:229–235. [PubMed]
  • Lonnerdal B. Nutritional aspects of soy formula. Acta Paediatr Suppl. 1994;402:105–108. [PubMed]
  • Mackenzie B, Hediger M. Slc11 family of H+-coupled metal-ion transporters NRAMP1 and DMT. Pflug. Arch. 2004;447:571–579. [PubMed]
  • Malecki EA, Cook BM, Devenyi AG, Beard JL, Connor JR. Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain. J Neurol Sci. 1999;170(2):112–118. [PubMed]
  • Malecki E. Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons. Brain Res Bull. 2001;55:225–8. [PubMed]
  • Markesbery W. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997;23:134–47. [PubMed]
  • May M. Disturbing behavior: Neurotoxic effects in children. Environ Health Perspect. 2000;108:A262–267. [PMC free article] [PubMed]
  • Moos T, Morgan EH. A morphological study of the developmentally regulated transport of iron into the brain. Dev. Neurosci. 2002;24:99–105. [PubMed]
  • Moos T, Morgan EH. The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J Neurochem. 2004;88(1):233–245. [PubMed]
  • Moos T, Skjoerringe T, Gosk S, Morgan EH. Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J. Neurochem. 2006 [Epub ahead of print] [PubMed]
  • Morris CM, Keith AB, Edwardson JA, Pullen RGL. Uptake and distribution of iron and transferrin in the adult brain. J. Neurochem. 1992a;59:300–306. [PubMed]
  • Morris CM, Candy JM, Keith AB, Oakley A, Taylor G, Pullen RGL, Bloxham CA, Gocht A, Edwardson JA. Brain iron homeostasis. J. Inorganic Biochem. 1992b;47:257–265. [PubMed]
  • Morris BH, Miller-Loncar CL, Landry SH, Smith KE, Swank PR, Denson SE. Feeding, medical factors, and developmental outcome in premature infants. Clin Pediatr. 1999;38:451–457. [PubMed]
  • Murphy VA, Wadhwani KC, Smith QR, Rapoport SI. Saturable transport of manganese (II) across the rat blood-brain barrier. J. Neurochem. 1991;57:948–954. [PubMed]
  • Murthy GK, Rhea US. Cadmium, copper, iron, lead, manganese, and zinc in evaporated milk, infant products, and human milk. J Dairy Sci. 1971;54:1001–1005. [PubMed]
  • Nagatomo S, Umehara F, Hanada K, Nobuhara Y, Takenaga S, Arimura K, Osame M. Manganese intoxication during total parenteral nutrition: report of two cases and review of the literature. J Neurol Sci. 1999;162:102–105. [PubMed]
  • Nagy JI, Carter DA, Fibiger HC. Evidence for a GABA-containing projection from the enopenduncular nucleus to the lateral habenula in the rat. Brain Res. 1978;145:360–364. [PubMed]
  • National Academy of Sciences Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. 2001. Available at www.nap.edu/books/0309072794/html/ [PubMed]
  • Normandin L, Carrier G, Gardiner P, Kennedy G, Hazell A, Mergler D, et al. Assessment of bioaccumulation, neuropathology, and neurobehavior following subchronic (90 days) inhalation in Sprague-Dawley rats exposed to manganese phosphate. Toxicol Appl Pharmacol. 2002;183:135–145. [PubMed]
  • Oates PS, Thomas C, Morgan EH. Transferrin receptor activity and localisation in the rat duodenum. Pflugers Arch. 2000;440:116–124. [PubMed]
  • Ono J, Harada K, Kodaka R, Sakurai K, Tajiri H, Takagi Y, et al. Manganese deposition in the brain during long-term total parenteral nutrition. J Parenter Enteral Nutr. 1995;19:310–312. [PubMed]
  • Pal P, Samii A, Calne D. Manganese neurotoxicity: A review of clinical features, imaging and pathology. Neurotoxicology. 1999;20:227–38. [PubMed]
  • Parmley RT, Barton JC, Conrad ME. Ultrastructural localization of transferrin, transferrin receptor, and iron-binding sites on human placental and duodenal microvilli. Br J Haematol. 1985;60(1):81–89. [PubMed]
  • Partridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism. 1987;36:892–895. [PubMed]
  • Pautler RG, Koretsky AP. Tracing odor-induced activation in the olfactory bulbs of mice using manganese-enhanced magnetic resonance imaging. Neuroimage. 2002;16:441–448. [PubMed]
  • Pennington JA, Schoen SA. Total diet study: estimated dietary intakes of nutritional elements, 1982-1991. Int J Vitam Nutr Res. 1996;66:350–362. [PubMed]
  • Pietrangelo A, Rocchi E, Casalgrandi G, Rigo G, Ferrari A, Perini M, et al. Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum. Gastroenterology. 1992;102(3):802–809. [PubMed]
  • Portnoy M, Jenesn L, Culotta V. The distinct methods by which manganese and iron regulate the NRAMP transporters in yeast. Biochem. J. 2002;362:110–24. [PubMed]
  • Rabin O, Hegedus L, Bourre JM, Smith QR. Rapid brain uptake of manganese(II) across the blood-brain barrier. J. Neurochem. 1993;61:509–517. [PubMed]
  • Rao DB, Wong BA, McManus BE, McElveen AM, James AR, Dorman DC. Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway. Toxicol Appl Pharmacol. 2003;193:116–126. [PubMed]
  • Roels H, Meiers G, Delos M, Ortega I, Lauwerys R, Buchet JP, Lison D. Influence of the route of administration and the chemical form (MnCl2, MnO2) on the absorption and cerebral distribution of manganese in rats. Arch. Toxicol. 1997;71:223–230. [PubMed]
  • Rosakis A, Koster W. Transition metal transport in the green microalga Chlamydomonas reinhardtii-genomic sequence analysis. Res. Microbiol. 2004;155:201–210. [PubMed]
  • Rosakis A, Koster W. Divalent metal transport in the green microalga chlamydomonas reinhardtii is mediated by a protein similar to prokaryotic nramp homologues. Biometals. 2005;18:107–120. [PubMed]
  • Rose C, Butterworth RF, Zayed J, Normandin L, Todd K, Michalak A, Spahr L, Huet PM, Pomier-Layrargues G. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999;117:640–644. [PubMed]
  • Roth JA, Garrick MD. Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. Biochem. Pharmacol. 2003;66:1–13. [PubMed]
  • Rutten M, Hoover R, Karnovsky M. Electrical resistance and macromolecular permeability of brain endothelial monolayer cultures. Brain Res. 1987;425:301–310. [PubMed]
  • Scheuhammer AM, Cherian MG. Binding of manganese in human and rat plasma. Biochim. Biophys. Acta. 1985;840:163–169. [PubMed]
  • Siddappa AJM, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci. Res. 2002;68:761–775. [PubMed]
  • Sloot WN, Gramsbergen JB. Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res. 1994;657:124–132. [PubMed]
  • Sloot WN, Korf J, Koster JF, DeWit LEA, Gramsbergen JBP. Manganese-induced hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron chelation in vivo. Exp Neurol. 1996;138:236–245. [PubMed]
  • Spahr L, Butterworth RF, Fontaine S, Bui L, Therrien G, Milette PC, Lebrun LH, Zayed J, Leblanc A, Pomier-Layrargues G. Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology. 1996;24:1116–1120. [PubMed]
  • Stastny D, Vogel RS, Picciano MF. Manganese intake and serum manganese concentration of human milk-fed and formula-fed infants. Am J Clin Nutr. 1984;39:872–878. [PubMed]
  • Suarez N, Eriksson H. Receptor-mediated endocytosis of a manganese complex of transferrin into neuroblastoma (SHSY5Y) cells in culture. J. Neurochem. 1993;61:127–131. [PubMed]
  • Suzuki Y, Mouri T, Suzuki Y, Nishiyama K, Fujii N. Study of subacute toxicity of manganese dioxide in monkeys. Tokushima J. Exp. Med. 1975;22:5–10. [PubMed]
  • Takagi Y, Okada A, Sando K, Wasa M, Yoshida H, Hirabuki N. Evaluation of indexes of in vivo manganese status and the optimal intravenous dose for adult patients undergoing home parenteral nutrition. Am J Clin Nutr. 2002;75:112–118. [PubMed]
  • Takeda A, Akiyama T, Sawashita J, Okada S. Brain uptake of trace metals, zinc and manganese, in rats. Brain Res. 1994;640:341–344. [PubMed]
  • Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. The influence of high iron diet on rat lung manganese absorption. Toxicol Appl Pharmacol. 2006;210(12):17–23. [PubMed]
  • Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B. Effect of high dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine levels, and neurodevelopmental status. Neurotoxicology. 2002;23:635–643. [PubMed]
  • Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci. 1998;19:328–334. [PubMed]
  • USEPA Health Assessment Document for Manganese. United States Environmental Protection Agency; 1984. EPA 600/8-83-013F.
  • United States Geological Services National Water-Quality Assessment Program. U.S. Geological Survey; Reston, VA: 2005. Available: http://water.usgs.gov/nawqa/
  • Vaughan LA, Weber CW, Kemberling SR. Longitudinal changes in the mineral content of human milk. Am J Clin Nutr. 1979;32:2301–2306. [PubMed]
  • Walaas I, Fonnum F. The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions. Brain Res. 1979;177:325–336. [PubMed]
  • Wareing M, Ferguson CJ, Delannoy M, Cox AG, McMahon RF, Green R, Riccardi D, Smith CP. Altered dietary iron intake is a strong modulator of renal DMT1 expression. Am. J. Physiol. Renal. Physiol. 2003;285:F1050–1059. [PubMed]
  • Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor-Litvak P, et al. Water manganese exposure and children's intellectual function in Araihazar, Bangladesh. Environ. Health Perspect. 2006;114:124–129. [PMC free article] [PubMed]
  • Wilson DC, Tubman TR, Halliday HL, McMaster D. Plasma manganese levels in the very low birth weight infant are high in early life. Biol Neonate. 1992;61:42–46. [PubMed]
  • Wolburg H, Lippoldt A. Tight junctions of the blood-brain barrier: Development. composition and regulation. Vascul. Pharmacol. 2002;38:323–337. [PubMed]
  • Yokel RA, Crossgrove JS, Bukaveckas BL. Manganese distribution across the blood-brain barrier. II. Manganese efflux from the brain does not appear to be carrier mediated. Neurotoxicology. 2003;24(1):15–22. [PubMed]