@article{BaeslerKoppPohletal.2019, author = {Baesler, Jessica and Kopp, Johannes Florian and Pohl, Gabriele and Aschner, Michael and Haase, Hajo and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Zn homeostasis in genetic models of Parkinson's disease in Caenorhabditis elegans}, series = {Journal of Trace Elements in Medicine and Biology}, volume = {55}, journal = {Journal of Trace Elements in Medicine and Biology}, publisher = {Elsevier}, address = {M{\"u}nchen}, doi = {10.1016/j.jtemb.2019.05.005}, pages = {44 -- 49}, year = {2019}, abstract = {While the underlying mechanisms of Parkinson's disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD.}, language = {en} } @article{BaeslerKoppPohletal.2019, author = {Baesler, Jessica and Kopp, Johannes F. and Pohl, Gabriele and Aschner, Michael and Haase, Hajo and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Zn homeostasis in genetic models of Parkinson's disease in Caenorhabditis elegans}, series = {Journal of trace elements in medicine and biology}, volume = {55}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier GMBH}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.05.005}, pages = {44 -- 49}, year = {2019}, 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} } @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}, 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{RohnRaschkeAschneretal.2019, author = {Rohn, Isabelle and Raschke, Stefanie and Aschner, Michael and Tuck, Simon and Kuehnelt, Doris and Kipp, Anna Patricia and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Treatment of caenorhabditis elegans with small selenium species enhances antioxidant defense systems}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {63}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {9}, publisher = {Wiley}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201801304}, pages = {9}, year = {2019}, abstract = {ScopeSmall selenium (Se) species play a key role in Se metabolism and act as dietary sources of the essential trace element. However, they are redox-active and trigger pro- and antioxidant responses. As health outcomes are strongly species-dependent, species-specific characteristics of Se compounds are tested in vivo. Methods and resultsIn the model organism Caenorhabditis elegans (C. elegans), immediate and sustained effects of selenite, selenomethionine (SeMet), and Se-methylselenocysteine (MeSeCys) are studied regarding their bioavailability, incorporation into proteins, as well as modulation of the cellular redox status. While all tested Se compounds are bioavailable, only SeMet persistently accumulates and is non-specifically incorporated into proteins. However, the protection toward chemically-induced formation of reactive species is independent of the applied Se compound. Increased thioredoxin reductase (TXNRD) activity and changes in mRNA expression levels of antioxidant proteins indicate the activation of cellular defense mechanisms. However, in txnrd-1 deletion mutants, no protective effects of the Se species are observed anymore, which is also reflected by differential gene expression data. ConclusionSe species protect against chemically-induced reactive species formation. The identified immediate and sustained systemic effects of Se species give rise to speculations on possible benefits facing subsequent periods of inadequate Se intake.}, language = {en} } @article{MarschallKroepflJensenetal.2017, author = {Marschall, Talke Anu and Kroepfl, Nina and Jensen, Kenneth Bendix and Bornhorst, Julia and Meermann, B. and K{\"u}hnelt, Doris and Schwerdtle, Tanja}, title = {Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites}, series = {Metallomics}, volume = {9}, journal = {Metallomics}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c6mt00300a}, pages = {268 -- 277}, year = {2017}, abstract = {Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species-and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-beta- D-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely gamma-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-) toxification modes of Se metabolism and require further investigation.}, language = {en} } @article{BornhorstEbertMeyeretal.2020, author = {Bornhorst, Julia and Ebert, Franziska and Meyer, S{\"o}ren and Ziemann, Vanessa and Xiong, Chan and Guttenberger, Nikolaus and Raab, Andrea and Baesler, Jessica and Aschner, Michael and Feldmann, J{\"o}rg and Francesconi, Kevin and Raber, Georg and Schwerdtle, Tanja}, title = {Toxicity of three types of arsenolipids}, series = {Metallomics}, volume = {12}, journal = {Metallomics}, number = {5}, publisher = {Oxford University Press}, address = {Cambridge}, issn = {1756-591X}, doi = {https://doi.org/10.1039/d0mt00039f}, pages = {794 -- 798}, year = {2020}, abstract = {Although fish and seafood are well known for their nutritional benefits, they contain contaminants that might affect human health. Organic lipid-soluble arsenic species, so called arsenolipids, belong to the emerging contaminants in these food items; their toxicity has yet to be systematically studied. Here, we apply the in vivo model Caenorhabditis elegans to assess the effects of two arsenic-containing hydrocarbons (AsHC), a saturated arsenic-containing fatty acid (AsFA), and an arsenic-containing triacylglyceride (AsTAG) in a whole organism. Although all arsenolipids were highly bioavailable in Caenorhabditis elegans, only the AsHCs were substantially metabolized to thioxylated or shortened metabolic products and induced significant toxicity, affecting both survival and development. Furthermore, the AsHCs were several fold more potent as compared to the toxic reference arsenite. This study clearly indicates the need for a full hazard identification of subclasses of arsenolipids to assess whether they pose a risk to human health.}, language = {en} } @article{StrehlauWeberLuerenbaumetal.2017, author = {Strehlau, Jenny and Weber, Till and Luerenbaum, Constantin and Bornhorst, Julia and Galla, Hans-Joachim and Schwerdtle, Tanja and Winter, Martin and Nowak, Sascha}, title = {Towards quantification of toxicity of lithium ion battery electrolytes - development and validation of a liquid-liquid extraction GC-MS method for the determination of organic carbonates in cell culture materials}, series = {Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica}, volume = {409}, journal = {Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica}, publisher = {Springer}, address = {Heidelberg}, issn = {1618-2642}, doi = {10.1007/s00216-017-0549-6}, pages = {6123 -- 6131}, year = {2017}, abstract = {A novel method based on liquid-liquid extraction with subsequent gas chromatography separation and mass spectrometric detection (GC-MS) for the quantification of organic carbonates in cell culture materials is presented. Method parameters including the choice of extraction solvent, of extraction method and of extraction time were optimised and the method was validated. The setup allowed for determination within a linear range of more than two orders of magnitude. The limits of detection (LODs) were between 0.0002 and 0.002 mmol/L and the repeatability precisions were in the range of 1.5-12.9\%. It could be shown that no matrix effects were present and recovery rates between 98 and 104\% were achieved. The methodology was applied to cell culture models incubated with commercial lithium ion battery (LIB) electrolytes to gain more insight into the potential toxic effects of these compounds. The stability of the organic carbonates in cell culture medium after incubation was studied. In a porcine model of the blood-cerebrospinal fluid (CSF) barrier, it could be shown that a transfer of organic carbonates into the brain facing compartment took place.}, language = {en} } @article{CramerTackeBornhorstetal.2014, author = {Cramer, Sandra and Tacke, Sebastian and Bornhorst, Julia and Klingauf, J{\"u}rgen and Schwerdtle, Tanja and Galla, Hans-Joachim}, title = {The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro}, series = {Journal of Nanomedicine \& Nanotechnology}, volume = {5}, journal = {Journal of Nanomedicine \& Nanotechnology}, number = {5}, issn = {2157-7439}, doi = {10.4172/2157-7439.1000225}, pages = {12}, year = {2014}, abstract = {The use of silver nanoparticles in medical and consumer products such as wound dressings, clothing and cosmetic has increased significantly in recent years. Still, the influence of these particles on our health and especially on our brain, has not been examined adequately up to now. We studied the influence of AgEO- (Ethylene Oxide) and AgCitrate-Nanoparticles (NPs) on the protective barriers of the brain, namely the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (blood-CSF) barrier in vitro. The NPs toxicity was evaluated by examining changes in membrane integrity, cell morphology, barrier properties, oxidative stress and inflammatory reactions. AgNPs decreased cell viability, disturbed barrier integrity and tight junctions and triggered oxidative stress and DNA strand breaks. However, all mentioned effects were, at least partly, suppressed by a Citrate-coating and were most pronounced in the cells of the BBB as compared to the epithelial cells representing the blood-CSF barrier. AgEO- but not AgCitrate-NPs also triggered an inflammatory reaction in porcine brain capillary endothelial cells (PBCEC), which represent the BBB. Our data indicate that AgNPs may cause adverse effects within the barriers of the brain, but their toxicity can be reduced by choosing an appropriate coating material.}, language = {en} } @article{RuszkiewiczdeMacedoMirandaVizueteetal.2018, author = {Ruszkiewicz, Joanna A. and de Macedo, Gabriel Teixeira and Miranda-Vizuete, Antonio and Teixeira da Rocha, Joao B. and Bowman, Aaron B. and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael}, title = {The cytoplasmic thioredoxin system in Caenorhabditis elegans affords protection from methylmercury in an age-specific manner}, series = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system}, volume = {68}, 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.2018.08.007}, pages = {189 -- 202}, year = {2018}, abstract = {Methylmercury (MeHg) is an environmental pollutant linked to many neurological defects, especially in developing individuals. The thioredoxin (TRX) system is a key redox regulator affected by MeHg toxicity, however the mechanisms and consequences of MeHg-induced dysfunction are not completely understood. This study evaluated the role of the TRX system in C. elegans susceptibility to MeHg during development. Worms lacking or overexpressing proteins from the TRX family were exposed to MeHg for 1 h at different developmental stage: L1, L4 and adult. Worms without cytoplasmic thioredoxin system exhibited age-specific susceptibility to MeHg when compared to wild-type (wt). This susceptibility corresponded partially to decreased total glutathione (GSH) levels and enhanced degeneration of dopaminergic neurons. In contrast, the overexpression of the cytoplasmic system TRX-1/TRXR-1 did not provide substantial protection against MeHg. Moreover, transgenic worms exhibited decreased protein expression for cytoplasmic thioredoxin reductase (TRXR-1). Both mitochondrial thioredoxin system TRX-2/TRXR-2, as well as other thioredoxin-like proteins: TRX-3, TRX-4, TRX-5 did not show significant role in C. elegans resistance to MeHg. Based on the current findings, the cytoplasmic thioredoxin system TRX-1/TRXR-1 emerges as an important age-sensitive protectant against MeHg toxicity in C. elegans.}, language = {en} } @misc{BornhorstKippHaaseetal.2018, author = {Bornhorst, Julia and Kipp, Anna P. and Haase, Hajo and Meyer, Soeren and Schwerdtle, Tanja}, title = {The crux of inept biomarkers for risks and benefits of trace elements}, series = {Trends in Analytical Chemistry}, volume = {104}, journal = {Trends in Analytical Chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0165-9936}, doi = {10.1016/j.trac.2017.11.007}, pages = {183 -- 190}, year = {2018}, abstract = {Nowadays, the role of trace elements (TE) is of growing interest because dyshomeostasis of selenium (Se), manganese (Mn), zinc (Zn), and copper (Cu) is supposed to be a risk factor for several diseases. Thereby, research focuses on identifying new biomarkers for the TE status to allow for a more reliable description of the individual TE and health status. This review mirrors a lack of well-defined, sensitive, and selective biomarkers and summarizes technical limitations to measure them. Thus, the capacity to assess the relationship between dietary TE intake, homeostasis, and health is restricted, which would otherwise provide the basis to define adequate intake levels of single TE in both healthy and diseased humans. Besides that, our knowledge is even more limited with respect to the real life situation of combined TE intake and putative interactions between single TE.}, language = {en} } @article{LohrenBornhorstGallaetal.2015, author = {Lohren, Hanna and Bornhorst, Julia and Galla, Hans-Joachim and Schwerdtle, Tanja}, title = {The blood-cerebrospinal fluid barrier - first evidence for an active transport of organic mercury compounds out of the brain}, series = {Metallomics : integrated biometal science}, volume = {7}, journal = {Metallomics : integrated biometal science}, number = {10}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c5mt00171d}, pages = {1420 -- 1430}, year = {2015}, abstract = {Exposure to organic mercury compounds promotes primarily neurological effects. Although methylmercury is recognized as a potent neurotoxicant, its transfer into the central nervous system (CNS) is not fully evaluated. While methylmercury and thiomersal pass the blood-brain barrier, limited data are available regarding the second brain regulating interface, the blood-cerebrospinal fluid (CSF) barrier. This novel study was designed to investigate the effects of organic as well as inorganic mercury compounds on, and their transfer across, a porcine in vitro model of the blood-CSF barrier for the first time. The barrier system is significantly more sensitive towards organic Hg compounds as compared to inorganic compounds regarding the endpoints cytotoxicity and barrier integrity. Whereas there are low transfer rates from the blood side to the CSF side, our results strongly indicate an active transfer of the organic mercury compounds out of the CSF. These results are the first to demonstrate an efflux of organic mercury compounds regarding the CNS and provide a completely new approach in the understanding of mercury compounds specific transport.}, 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{RohnKroepflBornhorstetal.2019, author = {Rohn, Isabelle and Kroepfl, Nina and Bornhorst, Julia and K{\"u}hnelt, Doris and Schwerdtle, Tanja}, title = {Side-directed transfer and presystemic metabolism of selenoneine in a human intestinal barrier model}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {63}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {12}, publisher = {Wiley}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201900080}, pages = {11}, year = {2019}, abstract = {Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfur-containing purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Se-methylselenocysteine (MeSeCys) and selenite are applied to the Caco-2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco-2 cells. Moreover, HPLC/MS-based Se speciation studies reveal a partial metabolism to Se-methylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carrier-mediated transport, is highly bioavailable to Caco-2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans.}, language = {en} } @article{RohnKroepflAschneretal.2019, author = {Rohn, Isabelle and Kroepfl, Nina and Aschner, Michael and Bornhorst, Julia and Kuehnelt, Doris and Schwerdtle, Tanja}, title = {Selenoneine ameliorates peroxide-induced oxidative stress in C. elegans}, series = {Journal of trace elements in medicine and biology}, volume = {55}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier GMBH}, address = {M{\"u}nchen}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2019.05.012}, pages = {78 -- 81}, year = {2019}, abstract = {Scope: Selenoneine (2-selenyl-N-alpha, N-alpha, N-alpha-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. Methods and results: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h posttreatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. Conclusion: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.}, language = {en} } @article{RohnMarschallKroepfletal.2018, author = {Rohn, Isabelle and Marschall, Talke Anu and Kr{\"o}pfl, Nina and Jensen, Kenneth Bendix and Aschner, Michael and Tuck, Simon and Kuehnelt, Doris and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans}, series = {Metallomics : integrated biometal science}, volume = {10}, journal = {Metallomics : integrated biometal science}, number = {6}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c8mt00066b}, pages = {818 -- 827}, year = {2018}, abstract = {The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and -glutamyl-MeSeCys (-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode.}, language = {en} } @article{PeresArantesMiahetal.2018, author = {Peres, Tanara Vieira and Arantes, Leticia P. and Miah, Mahfuzur R. and Bornhorst, Julia and Schwerdtle, Tanja and Bowman, Aaron B. and Leal, Rodrigo B. and Aschner, Michael}, title = {Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity}, series = {Neurotoxicity Research}, volume = {34}, journal = {Neurotoxicity Research}, number = {3}, publisher = {Springer}, address = {New York}, issn = {1029-8428}, doi = {10.1007/s12640-018-9915-1}, pages = {584 -- 596}, year = {2018}, abstract = {Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson's disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.}, 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} } @article{NowotnyCastroHugoetal.2018, author = {Nowotny, Kerstin and Castro, Jose Pedro and Hugo, Martin and Braune, Sabine and Weber, Daniela and Pignitter, Marc and Somoza, Veronika and Bornhorst, Julia and Schwerdtle, Tanja and Grune, Tilman}, title = {Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts}, series = {Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research}, volume = {120}, journal = {Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research}, publisher = {Elsevier}, address = {New York}, issn = {0891-5849}, doi = {10.1016/j.freeradbiomed.2018.03.022}, pages = {102 -- 113}, year = {2018}, abstract = {Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2 alpha pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.}, language = {en} } @misc{BaeslerMichaelisStibolleretal.2021, author = {Baesler, Jessica and Michaelis, Vivien and Stiboller, Michael and Haase, Hajo and Aschner, Michael and Schwerdtle, Tanja and Sturzenbaum, Stephen R. and Bornhorst, Julia}, title = {Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {8}, issn = {1866-8372}, doi = {10.25932/publishup-51499}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-514995}, pages = {13}, year = {2021}, abstract = {Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.}, language = {en} } @article{BaeslerMichaelisStibolleretal.2021, author = {Baesler, Jessica and Michaelis, Vivien and Stiboller, Michael and Haase, Hajo and Aschner, Michael and Schwerdtle, Tanja and Sturzenbaum, Stephen R. and Bornhorst, Julia}, title = {Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis}, series = {Molecular Nutrition and Food Research}, volume = {65}, journal = {Molecular Nutrition and Food Research}, number = {8}, publisher = {Wiley-VCH GmbH}, address = {Weinheim}, issn = {1613-4133}, doi = {10.1002/mnfr.202001176}, pages = {1 -- 11}, year = {2021}, abstract = {Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.}, language = {en} } @misc{WellenbergWeidesBornhorstetal.2019, author = {Wellenberg, Anna and Weides, L. and Bornhorst, Julia and Crone, Barbara and Karst, U. and Fritz, G. and Honnen, S.}, title = {Molecular and electrophysiological analysis of platinum-induced neurotoxicity using the model organism C. elegans}, series = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {392}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, doi = {10.1007/s00210-019-01621-6}, pages = {S63 -- S63}, year = {2019}, language = {en} } @article{GubertPuntelLehmenetal.2018, author = {Gubert, Priscila and Puntel, Bruna and Lehmen, Tassia and Fessel, Joshua P. and Cheng, Pan and Bornhorst, Julia and Trindade, Lucas Siqueira and Avila, Daiana S. and Aschner, Michael and Soares, Felix A. A.}, title = {Metabolic effects of manganese in the nematode Caenorhabditis elegans through DAergic pathway and transcription factors activation}, series = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system}, volume = {67}, 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.2018.04.008}, pages = {65 -- 72}, year = {2018}, abstract = {Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn's effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85 mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins.}, language = {en} } @article{NicolaiWittFrieseetal.2022, author = {Nicolai, Merle Marie and Witt, Barbara and Friese, Sharleen and Michaelis, Vivien and H{\"o}lz-Armstrong, Lisa and Martin, Maximilian and Ebert, Franziska and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells}, series = {Food and chemical toxicology}, volume = {161}, journal = {Food and chemical toxicology}, publisher = {Elsevier}, address = {Oxford}, issn = {0278-6915}, doi = {10.1016/j.fct.2022.112822}, pages = {10}, year = {2022}, abstract = {Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl2, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2'-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.}, language = {en} } @article{PieperWeheBornhorstetal.2014, author = {Pieper, Imke and Wehe, Christoph A. and Bornhorst, Julia and Ebert, Franziska and Leffers, Larissa and Holtkamp, Michael and Hoeseler, Pia and Weber, Till and Mangerich, Aswin and Buerkle, Alexander and Karst, Uwe and Schwerdtle, Tanja}, title = {Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and DNA-damage response}, series = {Metallomics : integrated biometal science}, volume = {6}, journal = {Metallomics : integrated biometal science}, number = {3}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c3mt00337j}, pages = {662 -- 671}, year = {2014}, abstract = {The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity.}, language = {en} } @misc{ChenBornhorstNeelyetal.2018, author = {Chen, Pan and Bornhorst, Julia and Neely, M. Diana and Avila, Daiana Silva}, title = {Mechanisms and disease pathogenesis underlying metal-induced oxidative stress}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {1045}, issn = {1866-8372}, doi = {10.25932/publishup-46786}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-467869}, pages = {5}, year = {2018}, language = {en} } @misc{ChenBornhorstNeelyetal.2018, author = {Chen, Pan and Bornhorst, Julia and Neely, M. Diana and Avila, Daiana Silva}, title = {Mechanisms and Disease Pathogenesis Underlying Metal-Induced Oxidative Stress}, series = {Oxidative Medicine and Cellular Longevity}, journal = {Oxidative Medicine and Cellular Longevity}, publisher = {Hindawi}, address = {London}, issn = {1942-0900}, doi = {10.1155/2018/7612172}, pages = {3}, year = {2018}, language = {en} } @article{BornhorstNustedeFudickar2019, author = {Bornhorst, Julia and Nustede, Eike Jannik and Fudickar, Sebastian}, title = {Mass Surveilance of C. elegans-Smartphone-Based DIY Microscope and Machine-Learning-Based Approach for Worm Detection}, series = {Sensors}, volume = {19}, journal = {Sensors}, number = {6}, publisher = {MDPI}, address = {Basel}, issn = {1424-8220}, doi = {10.3390/s19061468}, pages = {14}, year = {2019}, abstract = {The nematode Caenorhabditis elegans (C. elegans) is often used as an alternative animal model due to several advantages such as morphological changes that can be seen directly under a microscope. Limitations of the model include the usage of expensive and cumbersome microscopes, and restrictions of the comprehensive use of C. elegans for toxicological trials. With the general applicability of the detection of C. elegans from microscope images via machine learning, as well as of smartphone-based microscopes, this article investigates the suitability of smartphone-based microscopy to detect C. elegans in a complete Petri dish. Thereby, the article introduces a smartphone-based microscope (including optics, lighting, and housing) for monitoring C. elegans and the corresponding classification via a trained Histogram of Oriented Gradients (HOG) feature-based Support Vector Machine for the automatic detection of C. elegans. Evaluation showed classification sensitivity of 0.90 and specificity of 0.85, and thereby confirms the general practicability of the chosen approach.}, language = {en} } @inproceedings{MichaelisAengenheisterSchwerdtleetal.2021, author = {Michaelis, Vivien and Aengenheister, Leonie and Schwerdtle, Tanja and Buerki-Thurnherr, Tina and Bornhorst, Julia}, title = {Manganese translocation across an in vitro model of human villous trophoblast}, series = {Placenta}, volume = {112}, booktitle = {Placenta}, publisher = {Elsevier}, address = {Amsterdam [u.a.]}, issn = {0143-4004}, pages = {E63 -- E64}, year = {2021}, 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} } @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} } @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{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} } @misc{HonnenWellenbergWeidesetal.2018, author = {Honnen, S. and Wellenberg, Anna and Weides, L. and Bornhorst, Julia and Crone, B. and Karst, U. and Fritz, G.}, title = {Identification of potent drug candidates for the prevention of cisplatin-induced neurotoxicity in the model organism C. elegans}, series = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {391}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, doi = {10.1007/s00210-018-1477-5}, pages = {S4 -- S4}, year = {2018}, language = {en} } @article{SchumacherChakrabortyKleuseretal.2015, author = {Schumacher, Fabian and Chakraborty, Sudipta and Kleuser, Burkhard and Gulbins, Erich and Schwerdtle, Tanja and Aschner, Michael A. and Bornhorst, Julia}, title = {Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans}, series = {Talanta : the international journal of pure and applied analytical chemistry}, volume = {144}, journal = {Talanta : the international journal of pure and applied analytical chemistry}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0039-9140}, doi = {10.1016/j.talanta.2015.05.057}, pages = {71 -- 79}, year = {2015}, abstract = {Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C elegans to the monoamine oxidase B (MAOB) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and SRT system in order to identify compounds with neuroprotective or regenerative properties. (C) 2015 Elsevier B.V. All rights reserved.}, language = {en} } @article{RundHeylmannSeiwertetal.2019, author = {Rund, Katharina M. and Heylmann, Daniel and Seiwert, Nina and Wecklein, Sabine and Oger, Camille and Galano, Jean-Marie and Durand, Thierry and Chen, Rongjun and G{\"u}ler, Faikah and Fahrer, J{\"o}rg and Bornhorst, Julia and Schebb, Nils Helge}, title = {Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress}, series = {Prostaglandins \& Other Lipid Mediators}, volume = {144}, journal = {Prostaglandins \& Other Lipid Mediators}, publisher = {Elsevier}, address = {New York}, issn = {1098-8823}, doi = {10.1016/j.prostaglandins.2019.04.004}, pages = {10}, year = {2019}, abstract = {In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.}, language = {en} } @article{CroneAschnerSchwerdtleetal.2015, author = {Crone, Barbara and Aschner, Michael A. and Schwerdtle, Tanja and Karst, Uwe and Bornhorst, Julia}, title = {Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS}, series = {Metallomics : integrated biometal science}, volume = {7}, journal = {Metallomics : integrated biometal science}, number = {7}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c5mt00096c}, pages = {1189 -- 1195}, year = {2015}, abstract = {cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 mm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose) metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable.}, language = {en} } @article{LohrenBornhorstFitkauetal.2016, author = {Lohren, Hanna and Bornhorst, Julia and Fitkau, Romy and Pohl, Gabriele and Galla, Hans-Joachim and Schwerdtle, Tanja}, title = {Effects on and transfer across the blood-brain barrier in vitro-Comparison of organic and inorganic mercury species}, series = {BMC pharmacology \& toxicology}, volume = {17}, journal = {BMC pharmacology \& toxicology}, publisher = {BioMed Central}, address = {London}, issn = {2050-6511}, doi = {10.1186/s40360-016-0106-5}, pages = {422 -- 433}, year = {2016}, abstract = {Background: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain.}, language = {en} } @misc{LohrenBornhorstFitkauetal.2017, author = {Lohren, Hanna and Bornhorst, Julia and Fitkau, Romy and Pohl, Gabriele and Galla, Hans-Joachim and Schwerdtle, Tanja}, title = {Effects on and transfer across the blood-brain barrier in vitro}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-401776}, pages = {11}, year = {2017}, abstract = {Background: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain.}, language = {en} } @article{MuellerEbertRaberetal.2018, author = {M{\"u}ller, Sandra Marie and Ebert, Franziska and Raber, Georg and Meyer, S{\"o}ren and Bornhorst, Julia and H{\"u}wel, Stephan and Galla, Hans-Joachim and Francesconi, Kevin A. and Schwerdtle, Tanja}, title = {Effects of arsenolipids on in vitro blood-brain barrier model}, series = {Archives of toxicology : official journal of EUROTOX}, volume = {92}, journal = {Archives of toxicology : official journal of EUROTOX}, number = {2}, publisher = {Springer}, address = {Heidelberg}, issn = {0340-5761}, pages = {823 -- 832}, year = {2018}, abstract = {Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood-brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood-brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood-brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood-brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain.}, language = {en} } @article{KuhnTavaresJacquesTeixeiraetal.2021, author = {Kuhn, Eug{\^e}nia Carla and Tavares Jacques, Maur{\´i}cio and Teixeira, Daniela and Meyer, S{\"o}ren and Gralha, Thiago and Roehrs, Rafael and Camargo, Sandro and Schwerdtle, Tanja and Bornhorst, Julia and {\´A}vila, Daiana Silva}, title = {Ecotoxicological assessment of Uruguay River and affluents pre- and biomonitoring}, series = {Environmental science and pollution research : ESPR}, volume = {28}, journal = {Environmental science and pollution research : ESPR}, number = {17}, publisher = {Springer}, address = {Berlin ; Heidelberg}, issn = {0944-1344}, doi = {10.1007/s11356-020-11986-4}, pages = {21730 -- 21741}, year = {2021}, abstract = {Uruguay River is the most important river in western Rio Grande do Sul, separating Brazil from Argentina and Uruguay. However, its pollution is of great concern due to agricultural activities in the region and the extensive use of pesticides. In a long term, this practice leads to environmental pollution, especially to the aquatic system. The objective of this study was to analyze the physicochemical characteristics, metals and pesticides levels in water samples obtained before and after the planting and pesticides' application season from three sites: Uruguay River and two minor affluents, Mezomo Dam and Salso Stream. For biomonitoring, the free-living nematode Caenorhabditis elegans was used, which were exposed for 24 h. We did not find any significant alteration in physicochemical parameters. In the pre- and post-pesticides' samples we observed a residual presence of three pesticides (tebuconazole, imazethapyr, and clomazone) and metals which levels were above the recommended (As, Hg, Fe, and Mn). Exposure to both pre- and post-pesticides' samples impaired C. elegans reproduction and post-pesticides samples reduced worms' survival rate and lifespan. PCA analysis indicated that the presence of metals and pesticides are important variables that impacted C. elegans biological endpoints. Our data demonstrates that Uruguay River and two affluents are contaminated independent whether before or after pesticides' application season. In addition, it reinforces the usefulness of biological indicators, since simple physicochemical analyses are not sufficient to attest water quality and ecological safety.}, language = {en} } @article{MarschallBornhorstKuehneltetal.2016, author = {Marschall, Talke Anu and Bornhorst, Julia and Kuehnelt, Doris and Schwerdtle, Tanja}, title = {Differing cytotoxicity and bioavailability of selenite, methylselenocysteine, selenomethionine, selenosugar 1 and trimethylselenonium ion and their underlying metabolic transformations in human cells}, series = {Applied computing review : the publication of the ACM Special Interest Group on Applied Computing}, volume = {60}, journal = {Applied computing review : the publication of the ACM Special Interest Group on Applied Computing}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201600422}, pages = {2622 -- 2632}, year = {2016}, abstract = {Scope: The trace element selenium (Se) is an integral component of our diet. However, its metabolism and toxicity following elevated uptake are not fully understood. Since the either adverse or beneficial health effects strongly depend on the ingested Se species, five low molecular weight species were investigated regarding their toxicological effects, cellular bioavailability and species-specific metabolism in human cells. Methods and results: For the first time, the urinary metabolites methyl-2-acetamido-2-deoxy1- seleno-beta-D-galactopyranoside (selenosugar 1) and trimethylselenonium ion (TMSe) were toxicologically characterised in comparison to the food relevant species methylselenocysteine (MeSeCys), selenomethionine (SeMet) and selenite in human urothelial, astrocytoma and hepatoma cells. In all cell lines selenosugar 1 and TMSe showed no cytotoxicity. Selenite, MeSeCys and SeMet exerted substantial cytotoxicity, which was strongest in the urothelial cells. There was no correlation between the potencies of the respective toxic effects and the measured cellular Se concentrations. Se speciation indicated that metabolism of the respective species is likely to affect cellular toxicity. Conclusion: Despite being taken up, selenosugar 1 and TMSe are non-cytotoxic to urothelial cells, most likely because they are not metabolically activated. The absent cytotoxicity of selenosugar 1 and TMSe up to supra-physiological concentrations, support their importance as metabolites for Se detoxification.}, 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} } @article{VaraoMouraAparecidoRosiniSilvaDomingosSantodaSilvaetal.2022, author = {Var{\~a}o Moura, Alexandre and Aparecido Rosini Silva, Alex and Domingos Santo da Silva, Jos{\´e} and Aleixo Leal Pedroza, Lucas and Bornhorst, Julia and Stiboller, Michael and Schwerdtle, Tanja and Gubert, Priscila}, title = {Determination of ions in Caenorhabditis elegans by ion chromatography}, series = {Journal of chromatography. B}, volume = {1204}, journal = {Journal of chromatography. B}, publisher = {Elsevier}, address = {Amsterdam [u.a.]}, issn = {1570-0232}, doi = {10.1016/j.jchromb.2022.123312}, pages = {6}, year = {2022}, abstract = {The Caenorhabditis elegans (C. elegans) is a model organism that has been increasingly used in health and environmental toxicity assessments. The quantification of such elements in vivo can assist in studies that seek to relate the exposure concentration to possible biological effects. Therefore, this study is the first to propose a method of quantitative analysis of 21 ions by ion chromatography (IC), which can be applied in different toxicity studies in C. elegans. The developed method was validated for 12 anionic species (fluoride, acetate, chloride, nitrite, bromide, nitrate, sulfate, oxalate, molybdate, dichromate, phosphate, and perchlorate), and 9 cationic species (lithium, sodium, ammonium, thallium, potassium, magnesium, manganese, calcium, and barium). The method did not present the presence of interfering species, with R2 varying between 0.9991 and 0.9999, with a linear range from 1 to 100 mu g L-1. Limits of detection (LOD) and limits of quantification (LOQ) values ranged from 0.2319 mu g L-1 to 1.7160 mu g L-1 and 0.7028 mu g L-1 to 5.1999 mu g L-1, respectively. The intraday and interday precision tests showed an Relative Standard Deviation (RSD) below 10.0 \% and recovery ranging from 71.0 \% to 118.0 \% with a maximum RSD of 5.5 \%. The method was applied to real samples of C. elegans treated with 200 uM of thallium acetate solution, determining the uptake and bioaccumulated Tl+ content during acute exposure.}, language = {en} } @inproceedings{TidballKumarBryanetal.2015, author = {Tidball, Andrew M. and Kumar, Kevin K. and Bryan, Miles R. and Bichell, Terry Jo and Horning, Kyle and Uhouse, Michael A. and Goodwin, Cody R. and Bornhorst, Julia and Schwerdtle, Tanja and Neely, Maja Diana and McClean, John A. and Aschner, Michael A. and Bowman, Aaron B.}, title = {Deficits in neural responses to manganese exposure in Huntington's disease models}, series = {Neurotoxicology and teratology}, volume = {49}, booktitle = {Neurotoxicology and teratology}, publisher = {Elsevier}, address = {Oxford}, issn = {0892-0362}, doi = {10.1016/j.ntt.2015.04.022}, pages = {105 -- 105}, year = {2015}, language = {en} } @article{NicolaiBaeslerAschneretal.2020, author = {Nicolai, Merle Marie and Baesler, Jessica and Aschner, Michael and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Consequences of manganese overload in C. elegans}, series = {Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft f{\"u}r Experimentelle und Klinische Pharmakologie und Toxikologie}, volume = {393}, journal = {Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft f{\"u}r Experimentelle und Klinische Pharmakologie und Toxikologie}, number = {SUPPL 1}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, doi = {10.1007/s00210-020-01828-y}, pages = {9 -- 9}, year = {2020}, language = {en} } @article{HenzeHomannRohnetal.2016, author = {Henze, Andrea and Homann, Thomas and Rohn, Isabelle and Aschner, Michael A. and Link, Christopher D. and Kleuser, Burkhard and Schweigert, Florian J. and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin}, series = {Scientific reports}, volume = {6}, journal = {Scientific reports}, publisher = {Nature Publishing Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/srep37346}, pages = {12}, year = {2016}, abstract = {The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.}, language = {en} } @misc{HenzeHomannRohnetal.2016, author = {Henze, Andrea and Homann, Thomas and Rohn, Isabelle and Aschner, Michael A. and Link, Christopher D. and Kleuser, Burkhard and Schweigert, Florian J. and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-103674}, pages = {12}, year = {2016}, abstract = {The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.}, language = {en} }