@article{ChenBornhorstAschner2018,
  author    = {Chen, Pan and Bornhorst, Julia and Aschner, Michael},
  title     = {Manganese metabolism in humans},
  series = {Frontiers in Bioscience-Landmark},
  volume    = {23},
  journal   = {Frontiers in Bioscience-Landmark},
  number    = {9},
  publisher = {Frontiers in Bioscience INC},
  address   = {Irvine},
  issn      = {1093-9946},
  doi       = {10.2741/4665},
  pages     = {1655 -- 1679},
  year      = {2018},
  abstract  = {Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.},
  language  = {en}
}
@article{DrobyshevSolovyevGorokhovskiyetal.2018,
  author    = {Drobyshev, Evgenii J. and Solovyev, Nikolay D. and Gorokhovskiy, Boris M. and Kashuro, Vadim A.},
  title     = {Accumulation Patterns of Sub-chronic Aluminum Toxicity Model After Gastrointestinal Administration in Rats},
  series = {Biological Trace Element Research},
  volume    = {185},
  journal   = {Biological Trace Element Research},
  number    = {2},
  publisher = {Humana Press Inc.},
  address   = {Totowa},
  issn      = {0163-4984},
  doi       = {10.1007/s12011-018-1247-8},
  pages     = {384 -- 394},
  year      = {2018},
  abstract  = {Although aluminum chronic neurotoxicity is well documented, there are no well-established experimental protocols of Al exposure. In the current study, toxic effects of sub-chronic Al exposure have been evaluated in outbreed male rats (gastrointestinal administration). Forty animals were used: 10 were administered with AlCl3 water solution (2 mg/kg Al per day) for 1 month, 10 received the same concentration of AlCl3 for 3 month, and 20 (10 per observation period) saline as control. After 30 and 90 days, the animals underwent behavioral tests: open field, passive avoidance, extrapolation escape task, and grip strength. At the end of the study, the blood, liver, kidney, and brain were excised for analytical and morphological studies. The Al content was measured by inductively coupled plasma mass-spectrometry. Essential trace elements-Co, Cr, Cu, Fe, Mg, Mn, Mo, Se, and Zn-were measured in whole blood samples. Although no morphological changes were observed in the brain, liver, or kidney for both exposure terms, dose-dependent Al accumulation and behavioral differences (increased locomotor activity after 30 days) between treatment and control groups were indicated. Moreover, for 30 days exposure, strong positive correlation between Al content in the brain and blood for individual animals was established, which surprisingly disappeared by the third month. This may indicate neural barrier adaptation to the Al exposure or the saturation of Al transport into the brain. Notably, we could not see a clear neurodegeneration process after rather prolonged sub-chronic Al exposure, so probably longer exposure periods are required.},
  language  = {en}
}
@article{PeresHorningBornhorstetal.2019,
  author    = {Peres, Tanara V. and Horning, Kyle J. and Bornhorst, Julia and Schwerdtle, Tanja and Bowman, Aaron B. and Aschner, Michael},
  title     = {Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo},
  series = {Biological Trace Element Research},
  volume    = {188},
  journal   = {Biological Trace Element Research},
  number    = {1},
  publisher = {Human press inc.},
  address   = {Totowa},
  issn      = {0163-4984},
  doi       = {10.1007/s12011-018-1531-7},
  pages     = {127 -- 134},
  year      = {2019},
  abstract  = {Manganese (Mn) is essential for several species and daily requirements are commonly met by an adequate diet. Mn overload may cause motor and psychiatric disturbances and may arise from an impaired or not fully developed excretion system, transporter malfunction and/or exposure to excessive levels of Mn. Therefore, deciphering processes regulating neuronal Mn homeostasis is essential to understand the mechanisms of Mn neurotoxicity. In the present study, we selected two small molecules (with opposing effects on Mn transport) from a previous high throughput screen of 40,167 to test their effects on Mn toxicity parameters in vivo using Caenorhabditis elegans. We pre-exposed worms to VU0063088 and VU0026921 for 30min followed by co-exposure for 1h with Mn and evaluated Mn accumulation, dopaminergic (DAergic) degeneration and worm survival. Control worms were exposed to vehicle (DMSO) and saline only. In pdat-1::GFP worms, with GFP labeled DAergic neurons, we observed a decrease of Mn-induced DAergic degeneration in the presence of both small molecules. This effect was also observed in an smf-2 knockout strain. SMF-2 is a regulator of Mn transport in the worms and this strain accumulates higher Mn levels. We did not observe improved survival in the presence of small molecules. Our results suggest that both VU0063088 and VU0026921 may modulate Mn levels in the worms through a mechanism that does not require SMF-2 and induce protection against Mn neurotoxicity.},
  language  = {en}
}
@article{WittMeyerEbertetal.2017,
  author    = {Witt, Barbara and Meyer, S{\"o}ren and Ebert, Franziska and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons},
  series = {Archives of toxicology : official journal of EUROTOX},
  volume    = {91},
  journal   = {Archives of toxicology : official journal of EUROTOX},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0340-5761},
  doi       = {10.1007/s00204-017-1933-x},
  pages     = {3121 -- 3134},
  year      = {2017},
  abstract  = {Arsenolipids are lipid-soluble organoarsenic compounds, mainly occurring in marine organisms, with arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) representing two major subgroups. Recently, toxicity studies of several arsenolipids showed a high cytotoxic potential of those arsenolipids in human liver and bladder cells. Furthermore, feeding studies with Drosophila melanogaster indicated an accumulation of arsenolipids in the fruit fly's brain. In this study, the neurotoxic potential of three AsHCs, two AsFAs and three metabolites (dimethylarsinic acid, thio/oxo-dimethylarsenopropanoic acid) was investigated in comparison to the toxic reference arsenite (iAsIII) in fully differentiated human brain cells (LUHMES cells). Thereby, in the case of AsHCs both the cell number and cell viability were reduced in a low micromolar concentration range comparable to iAsIII, while AsFAs and the applied metabolites were less toxic. Mechanistic studies revealed that AsHCs reduced the mitochondrial membrane potential, whereas neither iAsIII nor AsFAs had an impact. Furthermore, neurotoxic mechanisms were investigated by examining the neuronal network. Here, AsHCs massively disturbed the neuronal network and induced apoptotic effects, while iAsIII and AsFAs showed comparatively lesser effects. Taking into account the substantial in vitro neurotoxic potential of the AsHCs and the fact that they could transfer across the physiological barriers of the brain, a neurotoxic potential in vivo for the AsHCs cannot be excluded and needs to be urgently characterized.},
  language  = {en}
}
@misc{ChenBornhorstAschner2018,
  author    = {Chen, Pan and Bornhorst, Julia and Aschner, Michael A.},
  title     = {Manganese metabolism in humans},
  series = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe},
  number    = {711},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-42743},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-427432},
  pages     = {25},
  year      = {2018},
  abstract  = {Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.},
  language  = {en}
}
@article{PeresEyngLopesetal.2015,
  author    = {Peres, Tanara V. and Eyng, Helena and Lopes, Samantha C. and Colle, Dirleise and Goncalves, Filipe M. and Venske, Debora K. R. and Lopes, Mark W. and Ben, Juliana and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael A. and Farina, Marcelo and Prediger, Rui D. and Leal, Rodrigo B.},
  title     = {Developmental exposure to manganese induces lasting motor and cognitive impairment in rats},
  series = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system},
  volume    = {50},
  journal   = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0161-813X},
  doi       = {10.1016/j.neuro.2015.07.005},
  pages     = {28 -- 37},
  year      = {2015},
  abstract  = {Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum. (C) 2015 Elsevier Inc. All rights reserved.},
  language  = {en}
}