@article{EbertThomannWittetal.2016,
  author    = {Ebert, Franziska and Thomann, Marlies and Witt, Barbara and M{\"u}ller, Sandra Marie and Meyer, S{\"o}ren and Weber, Till and Christmann, Markus and Schwerdtle, Tanja},
  title     = {Evaluating long-term cellular effects of the arsenic species thio-DMA(V): qPCR-based gene expression as screening tool},
  series = {Journal of trace elements in medicine and biology},
  volume    = {37},
  journal   = {Journal of trace elements in medicine and biology},
  publisher = {Yokohama Publishers},
  address   = {Jena},
  issn      = {0946-672X},
  doi       = {10.1016/j.jtemb.2016.06.004},
  pages     = {78 -- 84},
  year      = {2016},
  abstract  = {Thio-dimethylarsinic acid (thio-DMA(V)) is a human urinary metabolite of the class 1 human carcinogen inorganic arsenic as well as of arsenosugars. Thio-DMA(V) exerts strong cellular toxicity, whereas its toxic modes of action are not fully understood. For the first time, this study characterises the impact of a long-term (21 days) in vitro incubation of thio-DMA(V) on the expression of selected genes related to cell death, stress response, epigenetics and DNA repair. The observed upregulation of DNMT1 might be a cellular compensation to counterregulate the in a very recent study observed massive global DNA hypomethylation after chronic thio-DMAv incubation. Moreover, our data suggest that chronic exposure towards subcytotoxic, pico- to nanomolar concentrations of thio-DMA(V) causes a stress response in human urothelial cells. The upregulation of genes encoding for proteins of DNA repair (Apex1,Lig1, XRCC1,DDB2, XPG, ATR) as well as damage response (GADD45A, GADD45G, Trp53) indicate a potential genotoxic risk emanating from thio-DMA(V) after long-term incubation. (C) 2016 Elsevier GmbH. All rights reserved.},
  language  = {en}
}
@article{EbertZiemannWandtetal.2020,
  author    = {Ebert, Franziska and Ziemann, Vanessa and Wandt, Viktoria Klara Veronika and Witt, Barbara and M{\"u}ller, Sandra Marie and Guttenberger, Nikolaus and Bankoglu, Ezgi Eyluel and Stopper, Helga and Raber, Georg and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Cellular toxicological characterization of a thioxolated arsenic-containing hydrocarbon},
  series = {Journal of trace elements in medicine and biology},
  volume    = {61},
  journal   = {Journal of trace elements in medicine and biology},
  publisher = {Elsevier},
  address   = {M{\"u}nchen},
  doi       = {10.1016/j.jtemb.2020.126563},
  year      = {2020},
  abstract  = {Arsenolipids, especially arsenic-containing hydrocarbons (AsHC), are an emerging class of seafood originating contaminants. Here we toxicologically characterize a recently identified oxo-AsHC 332 metabolite, thioxo-AsHC 348 in cultured human liver (HepG2) cells. Compared to results of previous studies of the parent compound oxo-AsHC 332, thioxo-AsHC 348 substantially affected cell viability in the same concentration range but exerted about 10-fold lower cellular bioavailability. Similar to oxo-AsHC 332, thioxo-AsHC 348 did not substantially induce oxidative stress nor DNA damage. Moreover, in contrast to oxo-AsHC 332 mitochondria seem not to be a primary subcellular toxicity target for thioxo-AsHC 348. This study indicates that thioxo-AsHC 348 is at least as toxic as its parent compound oxo-AsHC 332 but very likely acts via a different mode of toxic action, which still needs to be identified.},
  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{WandtWinkelbeinerBornhorstetal.2021,
  author    = {Wandt, Viktoria Klara Veronika and Winkelbeiner, Nicola Lisa and Bornhorst, Julia and Witt, Barbara and Raschke, Stefanie and Simon, Luise and Ebert, Franziska and Kipp, Anna Patricia and Schwerdtle, Tanja},
  title     = {A matter of concern},
  series = {Redox Biology},
  volume    = {41},
  journal   = {Redox Biology},
  publisher = {Elsevier},
  address   = {Amsterdam},
  doi       = {10.1016/j.redox.2021.101877},
  pages     = {13},
  year      = {2021},
  abstract  = {Neurons are post-mitotic cells in the brain and their integrity is of central importance to avoid neurodegeneration. Yet, the inability of self-replenishment of post-mitotic cells results in the need to withstand challenges from numerous stressors during life. Neurons are exposed to oxidative stress due to high oxygen consumption during metabolic activity in the brain. Accordingly, DNA damage can occur and accumulate, resulting in genome instability. In this context, imbalances in brain trace element homeostasis are a matter of concern, especially regarding iron, copper, manganese, zinc, and selenium. Although trace elements are essential for brain physiology, excess and deficient conditions are considered to impair neuronal maintenance. Besides increasing oxidative stress, DNA damage response and repair of oxidative DNA damage are affected by trace elements. Hence, a balanced trace element homeostasis is of particular importance to safeguard neuronal genome integrity and prevent neuronal loss. This review summarises the current state of knowledge on the impact of deficient, as well as excessive iron, copper, manganese, zinc, and selenium levels on neuronal genome stability},
  language  = {en}
}
@phdthesis{Witt2017,
  author    = {Witt, Barbara},
  title     = {Toxicological characterization of lipid-soluble arsenic species in human brain cells},
  school      = {Universit{\"a}t Potsdam},
  pages     = {118, V},
  year      = {2017},
  language  = {en}
}
@article{WittEbertMeyeretal.2017,
  author    = {Witt, Barbara and Ebert, Franziska and Meyer, S{\"o}ren and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Assessing neurodevelopmental effects of arsenolipids in pre-differentiated human neurons},
  series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology},
  volume    = {61},
  journal   = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1613-4125},
  doi       = {10.1002/mnfr.201700199},
  pages     = {10},
  year      = {2017},
  abstract  = {Scope: In the general population exposure to arsenic occurs mainly via diet. Highest arsenic concentrations are found in seafood, where arsenic is present predominantly in its organic forms including arsenolipids. Since recent studies have provided evidence that arsenolipids could reach the brain of an organism and exert toxicity in fully differentiated human neurons, this work aims to assess the neurodevelopmental toxicity of arsenolipids. Methods and results: Neurodevelopmental effects of three arsenic-containing hydrocarbons (AsHC), two arsenic-containing fatty acids (AsFA), arsenite and dimethylarsinic acid (DMA(V)) were characterized in pre-differentiated human neurons. AsHCs and arsenite caused substantial cytotoxicity in a similar, low concentration range, whereas AsFAs and DMA(V) were less toxic. AsHCs were highly accessible for cells and exerted pronounced neurodevelopmental effects, with neurite outgrowth and the mitochondrial membrane potential being sensitive endpoints; arsenite did not substantially decrease those two endpoints. In fully differentiated neurons, arsenite and AsHCs caused neurite toxicity. Conclusion: These results indicate for a neurodevelopmental potential of AsHCs. Taken into account the possibility that AsHCs might easily reach the developing brain when exposed during early life, neurotoxicity and neurodevelopmental toxicity cannot be excluded. Further studies are needed in order to progress the urgently needed risk assessment.},
  language  = {en}
}
@article{WittMeyerEbertetal.2017,
  author    = {Witt, Barbara and Meyer, S{\"o}ren and Ebert, Franziska and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons},
  series = {Archives of toxicology : official journal of EUROTOX},
  volume    = {91},
  journal   = {Archives of toxicology : official journal of EUROTOX},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0340-5761},
  doi       = {10.1007/s00204-017-1933-x},
  pages     = {3121 -- 3134},
  year      = {2017},
  abstract  = {Arsenolipids are lipid-soluble organoarsenic compounds, mainly occurring in marine organisms, with arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) representing two major subgroups. Recently, toxicity studies of several arsenolipids showed a high cytotoxic potential of those arsenolipids in human liver and bladder cells. Furthermore, feeding studies with Drosophila melanogaster indicated an accumulation of arsenolipids in the fruit fly's brain. In this study, the neurotoxic potential of three AsHCs, two AsFAs and three metabolites (dimethylarsinic acid, thio/oxo-dimethylarsenopropanoic acid) was investigated in comparison to the toxic reference arsenite (iAsIII) in fully differentiated human brain cells (LUHMES cells). Thereby, in the case of AsHCs both the cell number and cell viability were reduced in a low micromolar concentration range comparable to iAsIII, while AsFAs and the applied metabolites were less toxic. Mechanistic studies revealed that AsHCs reduced the mitochondrial membrane potential, whereas neither iAsIII nor AsFAs had an impact. Furthermore, neurotoxic mechanisms were investigated by examining the neuronal network. Here, AsHCs massively disturbed the neuronal network and induced apoptotic effects, while iAsIII and AsFAs showed comparatively lesser effects. Taking into account the substantial in vitro neurotoxic potential of the AsHCs and the fact that they could transfer across the physiological barriers of the brain, a neurotoxic potential in vivo for the AsHCs cannot be excluded and needs to be urgently characterized.},
  language  = {en}
}
@misc{WittSchaumloeffelSchaumloeffeletal.2020,
  author    = {Witt, Barbara and Schauml{\"o}ffel, Dirk and Schauml{\"o}ffel, Dirk and Schwerdtle, Tanja},
  title     = {Subcellular Localization of Copper},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {862},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-45954},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-459544},
  pages     = {27},
  year      = {2020},
  abstract  = {As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer's disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.},
  language  = {en}
}
@article{WittSchaumloeffelSchwerdtle2020,
  author    = {Witt, Barbara and Schauml{\"o}ffel, Dirk and Schwerdtle, Tanja},
  title     = {Subcellular Localization of Copper},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {7},
  publisher = {Molecular Diversity Preservation International},
  address   = {Basel},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21072341},
  pages     = {25},
  year      = {2020},
  abstract  = {As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer's disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.},
  language  = {en}
}
@article{WittStibollerRaschkeetal.2021,
  author    = {Witt, Barbara and Stiboller, Michael and Raschke, Stefanie and Friese, Sharleen and Ebert, Franziska and Schwerdtle, Tanja},
  title     = {Characterizing effects of excess copper levels in a human astrocytic cell line with focus on oxidative stress markers},
  series = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS},
  volume    = {65},
  journal   = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS},
  publisher = {Elsevier},
  address   = {M{\"u}nchen},
  issn      = {1878-3252},
  doi       = {10.1016/j.jtemb.2021.126711},
  pages     = {9},
  year      = {2021},
  abstract  = {Background: Being an essential trace element, copper is involved in diverse physiological processes. However, excess levels might lead to adverse effects. Disrupted copper homeostasis, particularly in the brain, has been associated with human diseases including the neurodegenerative disorders Wilson and Alzheimer?s disease. In this context, astrocytes play an important role in the regulation of the copper homeostasis in the brain and likely in the prevention against neuronal toxicity, consequently pointing them out as a potential target for the neurotoxicity of copper. Major toxic mechanisms are discussed to be directed against mitochondria probably via oxidative stress. However, the toxic potential and mode of action of copper in astrocytes is poorly understood, so far. Methods: In this study, excess copper levels affecting human astrocytic cell model and their involvement in the neurotoxic mode of action of copper, as well as, effects on the homeostasis of other trace elements (Mn, Fe, Ca and Mg) were investigated. Results: Copper induced substantial cytotoxic effects in the human astrocytic cell line following 48 h incubation (EC30: 250 ?M) and affected mitochondrial function, as observed via reduction of mitochondrial membrane potential and increased ROS production, likely originating from mitochondria. Moreover, cellular GSH metabolism was altered as well. Interestingly, not only cellular copper levels were affected, but also the homeostasis of other elements (Ca, Fe and Mn) were disrupted. Conclusion: One potential toxic mode of action of copper seems to be effects on the mitochondria along with induction of oxidative stress in the human astrocytic cell model. Moreover, excess copper levels seem to interact with the homeostasis of other essential elements such as Ca, Fe and Mn. Disrupted element homeostasis might also contribute to the induction of oxidative stress, likely involved in the onset and progression of neurodegenerative disorders. These insights in the toxic mechanisms will help to develop ideas and approaches for therapeutic strategies against copper-mediated diseases.},
  language  = {en}
}