@misc{KumarGoodwinUhouseetal.2015,
  author    = {Kumar, Kevin K. and Goodwin, Cody R. and Uhouse, Michael A. and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael A. and McLean, John A. and Bowman, Aaron B.},
  title     = {Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-94314},
  pages     = {363 -- 370},
  year      = {2015},
  abstract  = {Manganese (Mn) is an essential micronutrient for development and function of the nervous system. Deficiencies in Mn transport have been implicated in the pathogenesis of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by loss of medium spiny neurons of the striatum. Brain Mn levels are highest in striatum and other basal ganglia structures, the most sensitive brain regions to Mn neurotoxicity. Mouse models of HD exhibit decreased striatal Mn accumulation and HD striatal neuron models are resistant to Mn cytotoxicity. We hypothesized that the observed modulation of Mn cellular transport is associated with compensatory metabolic responses to HD pathology. Here we use an untargeted metabolomics approach by performing ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) on control and HD immortalized mouse striatal neurons to identify metabolic disruptions under three Mn exposure conditions, low (vehicle), moderate (non-cytotoxic) and high (cytotoxic). Our analysis revealed lower metabolite levels of pantothenic acid, and glutathione (GSH) in HD striatal cells relative to control cells. HD striatal cells also exhibited lower abundance and impaired induction of isobutyryl carnitine in response to increasing Mn exposure. In addition, we observed induction of metabolites in the pentose shunt pathway in HD striatal cells after high Mn exposure. These findings provide metabolic evidence of an interaction between the HD genotype and biologically relevant levels of Mn in a striatal cell model with known HD by Mn exposure interactions. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathobiology of both HD and Mn neurotoxicity.},
  language  = {en}
}
@article{KumarGoodwinUhouseetal.2015,
  author    = {Kumar, Kevin K. and Goodwin, Cody R. and Uhouse, Michael A. and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael A. and McLean, John A. and Bowman, Aaron B.},
  title     = {Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status},
  series = {Metallomics},
  volume    = {7},
  journal   = {Metallomics},
  publisher = {RSC Publ.},
  address   = {Cambridge},
  issn      = {1756-591X},
  doi       = {10.1039/C4MT00223G},
  pages     = {363 -- 370},
  year      = {2015},
  abstract  = {Manganese (Mn) is an essential micronutrient for development and function of the nervous system. Deficiencies in Mn transport have been implicated in the pathogenesis of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by loss of medium spiny neurons of the striatum. Brain Mn levels are highest in striatum and other basal ganglia structures, the most sensitive brain regions to Mn neurotoxicity. Mouse models of HD exhibit decreased striatal Mn accumulation and HD striatal neuron models are resistant to Mn cytotoxicity. We hypothesized that the observed modulation of Mn cellular transport is associated with compensatory metabolic responses to HD pathology. Here we use an untargeted metabolomics approach by performing ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) on control and HD immortalized mouse striatal neurons to identify metabolic disruptions under three Mn exposure conditions, low (vehicle), moderate (non-cytotoxic) and high (cytotoxic). Our analysis revealed lower metabolite levels of pantothenic acid, and glutathione (GSH) in HD striatal cells relative to control cells. HD striatal cells also exhibited lower abundance and impaired induction of isobutyryl carnitine in response to increasing Mn exposure. In addition, we observed induction of metabolites in the pentose shunt pathway in HD striatal cells after high Mn exposure. These findings provide metabolic evidence of an interaction between the HD genotype and biologically relevant levels of Mn in a striatal cell model with known HD by Mn exposure interactions. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathobiology of both HD and Mn neurotoxicity.},
  language  = {en}
}
@article{KumarGoodwinUhouseetal.2015,
  author    = {Kumar, Kevin K. and Goodwin, Cody R. and Uhouse, Michael A. and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael A. and McLean, John A. and Bowman, Aaron B.},
  title     = {Untargeted metabolic profiling identifies interactions between},
  series = {Metallomics : integrated biometal science},
  volume    = {7},
  journal   = {Metallomics : integrated biometal science},
  number    = {2},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1756-5901},
  doi       = {10.1039/c4mt00223g},
  pages     = {363 -- 370},
  year      = {2015},
  language  = {en}
}
@article{GubertPuntelLehmenetal.2016,
  author    = {Gubert, Priscila and Puntel, Bruna and Lehmen, Tassia and Bornhorst, Julia and Avila, Daiana Silva and Aschner, Michael A. and Soares, Felix A. A.},
  title     = {Reversible reprotoxic effects of manganese through DAF-16 transcription factor activation and vitellogenin downregulation in Caenorhabditis elegans},
  series = {Life sciences : molecular, cellular and functional basis of therapy},
  volume    = {151},
  journal   = {Life sciences : molecular, cellular and functional basis of therapy},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0024-3205},
  doi       = {10.1016/j.lfs.2016.03.016},
  pages     = {218 -- 223},
  year      = {2016},
  abstract  = {Aims Vitellogenesis is the yolk production process which provides the essential nutrients for the developing embryos. Yolk is a lipoprotein particle that presents lipids and lipid-binding proteins, referred to as vitellogenins (VIT). The Caenorhabditis elegans nematode has six genes encoding VIT lipoproteins. Several pathways are known to regulate vitellogenesis, including the DAF-16 transcription factor. Some reports have shown that heavy metals, such as manganese (Mn), impair brood size in C. elegans; however the mechanisms associated with this effect have yet to be identified. Our aim was to evaluate Mn\&\#8242;s effects on C. elegans reproduction and better understand the pathways related to these effects. Main methods. Young adult larval stage worms were treated for 4 h with Mn in 85 mM NaCl and Escherichia coli OP50 medium. Key findings. Mn reduced egg-production and egg-laying during the first 24 h after the treatment, although the total number of progenies were indistinguishable from the control group levels. This delay may have occurred due to DAF-16 activation, which was noted only after the treatment and was not apparent 24 h later. Moreover, the expression, protein levels and green fluorescent protein (GFP) fluorescence associated with VIT were decreased soon after Mn treatment and recovered after 24 h. Significance Combined, these data suggest that the delay in egg-production is likely regulated by DAF-16 and followed by the inhibition of VIT transport activity. Further studies are needed to clarify the mechanisms associated with Mn-induced DAF-16 activation.},
  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}
}
@misc{ChakrabortyChenBornhorstetal.2015,
  author    = {Chakraborty, Sudipta and Chen, Pan and Bornhorst, Julia and Schwerdtle, Tanja and Schumacher, Fabian and Kleuser, Burkhard and Bowman, Aaron B. and Aschner, Michael A.},
  title     = {Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-99508},
  pages     = {10},
  year      = {2015},
  abstract  = {Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson's disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology.},
  language  = {en}
}
@article{ChakrabortyChenBornhorstetal.2015,
  author    = {Chakraborty, Sudipta and Chen, Pan and Bornhorst, Julia and Schwerdtle, Tanja and Schumacher, Fabian and Kleuser, Burkhard and Bowman, Aaron B. and Aschner, Michael A.},
  title     = {Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C-elegans},
  series = {Metallomics : integrated biometal science},
  volume    = {7},
  journal   = {Metallomics : integrated biometal science},
  number    = {5},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1756-5901},
  doi       = {10.1039/c5mt00052a},
  pages     = {847 -- 856},
  year      = {2015},
  language  = {en}
}
@article{AvilaBenedettoAuetal.2016,
  author    = {Avila, Daiana Silva and Benedetto, Alexandre and Au, Catherine and Bornhorst, Julia and Aschner, Michael A.},
  title     = {Involvement of heat shock proteins on Mn-induced toxicity in Caenorhabditis elegans},
  series = {Plant Methods},
  volume    = {17},
  journal   = {Plant Methods},
  publisher = {BioMed Central},
  address   = {London},
  issn      = {2050-6511},
  doi       = {10.1186/s40360-016-0097-2},
  pages     = {9},
  year      = {2016},
  abstract  = {Background: All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. Conclusions: Taken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans. Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal.},
  language  = {en}
}
@misc{AvilaBenedettoAuetal.2016,
  author    = {Avila, Daiana Silva and Benedetto, Alexandre and Au, Catherine and Bornhorst, Julia and Aschner, Michael A.},
  title     = {Involvement of heat shock proteins on Mn-induced toxicity in Caenorhabditis elegans},
  series = {BMC pharmacology and toxicology},
  journal   = {BMC pharmacology and toxicology},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-407286},
  pages     = {9},
  year      = {2016},
  abstract  = {Background: All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein ( hsp ) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. Methods: We exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survi val, protein carbonylation (as a marker of oxidative stress) and Parkinson ' s disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05. Results: We verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1 , a gene that has been linked to Parkinson ' sdisease. Conclusions: Taken together, our data suggest that Mn exposu re modulates heat shock protein expression, particularly HSP-70, in C. elegans .Furthermore,lossof hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus pot entially exacerbating the v ulnerability to this metal.},
  language  = {en}
}
@misc{AschnerPalinskiSperlingetal.2017,
  author    = {Aschner, Michael A. and Palinski, Catherine and Sperling, Michael and Karst, U. and Schwerdtle, Tanja and Bornhorst, Julia},
  title     = {Imaging metals in Caenorhabditis elegans},
  series = {Metallomics : integrated biometal science},
  volume    = {9},
  journal   = {Metallomics : integrated biometal science},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1756-5901},
  doi       = {10.1039/c6mt00265j},
  pages     = {357 -- 364},
  year      = {2017},
  abstract  = {Systemic trafficking and storage of essential metal ions play fundamental roles in living organisms by serving as essential cofactors in various cellular processes. Thereby metal quantification and localization are critical steps in understanding metal homeostasis, and how their dyshomeostasis might contribute to disease etiology and the ensuing pathologies. Furthermore, the amount and distribution of metals in organisms can provide insight into their underlying mechanisms of toxicity and toxicokinetics. While in vivo studies on metal imaging in mammalian experimental animals are complex, time- and resource-consuming, the nematode Caenorhabditis elegans (C. elegans) provides a suitable comparative and complementary model system. Expressing homologous genes to those inherent to mammals, including those that regulate metal homeostasis and transport, C. elegans has become a powerful tool to study metal homeostasis and toxicity. A number of recent technical advances have been made in the development and application of analytical methods to visualize metal ions in C. elegans. Here, we briefly summarize key findings and challenges of the three main techniques and their application to the nematode, namely sensing fluorophores, microbeam synchrotron radiation X-ray fluorescence as well as laser ablation ( LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS).},
  language  = {en}
}