A Manganese-Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat

Garcia, Stéphanie; Gellein, Kristin; Syversen, Tore; Aschner, Michael

doi:10.1093/toxsci/kfl017

Cited by 98 publications

(71 citation statements)

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“…An in vivo study by Garcia et al showed that DMT1 expression increases by ∼35% in the brains of rat pups nurtured by dams fed with high Mn diet. This elevation in DMT1 expression is not region-specific; nonetheless, the data directly relate the effect of an enhanced Mn diet with augmentation in DMT1 expression (Garcia et al, 2006). In addition, this correlation is supported by in vitro data where exposure to Mn for 24 and 48 hours has been shown to increase DMT1 expression in the immortalized choroidal epithelial Z310 cell line by 45% and 78% respectively (Wang et al, 2006).…”

Section: Manganese and Dmt1mentioning

confidence: 57%

Manganese transport in eukaryotes: The role of DMT1

2008

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Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson's disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia (Calne et al., 1994;Dobson et al., 2004).Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans, and the baker's yeast, Saccharomyces cerevisiae. Keywords DMT1; Manganese; NRAMP-2; Transport ManganeseMn is one of the most abundant naturally occurring elements in the earth's crust; it does not occur naturally in a pure state. Oxides, carbonates and silicates are the most important Mncontaining minerals (Post, 1999). Depending on its oxidation state, Mn is utilized in countless industrial processes, such as the production of dry cell batteries, steel (Post, 1999; Saric, 1986), fuel oil additives and antiknock agents (Pfeifer et al., 2004;Ressler et al., 1999;Rollin et al., 2005). *Corresponding Author: Michael Aschner, PhD, 2215-B Garland Avenue, 11425 MRB IV, Vanderbilt University Medical Center, Nashville, michael.aschner@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2009 July 1. Published in final edited form as:Neurotoxicology. 2008 July ; 29(4): 569-576. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe major source of Mn in humans is through dietary ingestion. Approximately 3-5% of ingested Mn is absorbed across the intestinal wall, and the remainder is excreted in feces, representing tight homeostatic control over Mn absorption. Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al., 1991...

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Section: Manganese and Dmt1mentioning

confidence: 57%

Manganese transport in eukaryotes: The role of DMT1

2008

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“…Mn exposure has been shown to affect tissue concentrations in a differential manner depending upon species and type of exposure. A significant increase in striatal GABA due to Mn exposure was found in rats (Garcia et al 2006(Garcia et al , 2007Gwiazda et al 2002); while a marginally significant (P < 0.1) decrease in pallidal GABA concentrations in monkeys exposed to airborne MnSO4 has been reported (Struve et al 2007); and no statistical difference was found in brain regional GABA concentrations in primates injected with Mn intravenously (Burton et al 2009). While tissue GABA concentrations can capture the overall status of GABA biology in an organism, it does not fully reflect the extracellular concentrations which are critical for neurotransmission.…”

Section: Effects Of Mn On γ-Aminobutyric Acidmentioning

confidence: 90%

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

et al. 2009

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Abstract: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).

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“…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.…”

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 90%

“…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.…”

Section: Direction For Future Researchmentioning

confidence: 99%

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Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

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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/m 3 ) 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.

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A Manganese-Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat

Cited by 98 publications

References 45 publications

Manganese transport in eukaryotes: The role of DMT1

Manganese transport in eukaryotes: The role of DMT1

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

Manganese neurotoxicity: A focus on the neonate

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