@article{WinkelbeinerWandtEbertetal.2020,
  author    = {Winkelbeiner, Nicola Lisa and Wandt, Viktoria Klara Veronika and Ebert, Franziska and Lossow, Kristina and Bankoglu, Ezgi E. and Martin, Maximilian and Mangerich, Aswin and Stopper, Helga and Bornhorst, Julia and Kipp, Anna Patricia and Schwerdtle, Tanja},
  title     = {A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {18},
  publisher = {Molecular Diversity Preservation International},
  address   = {Basel},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21186600},
  pages     = {19},
  year      = {2020},
  abstract  = {Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2'-deoxyguanosine (8-oxodG), 5-hydroxy-2'-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.},
  language  = {en}
}
@article{KoppMuellerPohletal.2019,
  author    = {Kopp, Johannes Florian and M{\"u}ller, Sandra Marie and Pohl, Gabriele and Lossow, Kristina and Kipp, Anna Patricia and Schwerdtle, Tanja},
  title     = {A quick and simple method for the determination of six trace elements in mammalian serum samples using ICP-MS/MS},
  series = {Journal of trace elements in medicine and biology},
  volume    = {54},
  journal   = {Journal of trace elements in medicine and biology},
  publisher = {Elsevier},
  address   = {M{\"u}nchen},
  issn      = {0946-672X},
  doi       = {10.1016/j.jtemb.2019.04.015},
  pages     = {221 -- 225},
  year      = {2019},
  abstract  = {In order to assess the individual trace element status of humans for either medical or scientific purposes, amongst others, blood serum levels are determined. Furthermore, animal models are used to study interactions of trace elements. Most published methods require larger amounts (500-1000 mu L) of serum to achieve a reliable determination of multiple trace elements. However, oftentimes, these amounts of serum cannot be dedicated to a single analysis and the amount available for TE-determination is much lower. Therefore, a published ICP-MS/MS method for trace element determination in serum was miniaturized, optimized and validated for the measurement of Mn, Fe, Cu Zn, I and Se in as little as 50 mu L of human and murine serum and is presented in this work. For validation, recoveries of multiple LOTs and levels from commercially available human reference serum samples were determined, infra- and inter-day variations were assessed and limits of detection and quantification determined. It is shown, that the method is capable of giving accurate and reproducible results for all six elements within the relevant concentration ranges for samples from humans living in central Europe as well as from laboratory mice. As a highlight, the achieved limits of detection and quantification for Mn were found to be at 0.02 mu g/L serum and 0.05 mu g/L serum, respectively, while using an alkaline diluent for the parallel determination of iodine.},
  language  = {en}
}
@article{MeyerRaberEbertetal.2015,
  author    = {Meyer, S{\"o}ren and Raber, Georg and Ebert, Franziska and Taleshi, Mojtaba S. and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Arsenic-containing hydrocarbons and arsenic-containing fatty acids: Transfer across and presystemic metabolism in the Caco-2 intestinal barrier model},
  series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology},
  volume    = {59},
  journal   = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology},
  number    = {10},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {1613-4125},
  doi       = {10.1002/mnfr.201500286},
  pages     = {2044 -- 2056},
  year      = {2015},
  abstract  = {Scope: Arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) represent two classes of arsenolipids occurring naturally in marine food. Toxicological data are yet scarce and an assessment regarding the risk to human health has not been possible. Here, we investigated the transfer and presystemic metabolism of five arsenolipids in an intestinal barrier model. Methods and results: Three AsHCs and two AsFAs were applied to the Caco-2 intestinal barrier model. Thereby, the short-chain AsHCs reached up to 50\% permeability. Transport is likely to occur via passive diffusion. The AsFAs showed lower intestinal bioavailability, but respective permeabilities were still two to five times higher as compared to arsenobetaine or arsenosugars. Interestingly, AsFAs were effectively biotransformed while passing the in vitro intestinal barrier, whereas AsHCs were transported to the blood-facing compartment essentially unchanged. Conclusion: AsFAs can be presystemically metabolised and the amount of transferred arsenic is lower than that for AsHCs. In contrast, AsHCs are likely to be highly intestinally bioavailable to humans. Since AsHCs exert strong toxicity in vitro and in vivo, toxicity studies with experimental animals as well as a human exposure assessment are needed to assess the risk to human health related to the presence of AsHCs in seafood.},
  language  = {en}
}
@article{MuellerEbertBornhorstetal.2018,
  author    = {M{\"u}ller, Sandra Marie and Ebert, Franziska and Bornhorst, Julia and Galla, Hans-Joachim and Francesconi, Kevin A. and Schwerdtle, Tanja},
  title     = {Arsenic-containing hydrocarbons disrupt a model in vitro blood-cerebrospinal fluid barrier},
  series = {Journal of trace elements in medicine and biology},
  volume    = {49},
  journal   = {Journal of trace elements in medicine and biology},
  publisher = {Elsevier GMBH},
  address   = {M{\"u}nchen},
  issn      = {0946-672X},
  doi       = {10.1016/j.jtemb.2018.01.020},
  pages     = {171 -- 177},
  year      = {2018},
  abstract  = {Lipid-soluble arsenicals, so-called arsenolipids, have gained a lot of attention in the last few years because of their presence in many seafoods and reports showing substantial cytotoxicity emanating from arsenic-containing hydrocarbons (AsHCs), a prominent subgroup of the arsenolipids. More recent in vivo and in vitro studies indicate that some arsenolipids might have adverse effects on brain health. In the present study, we focused on the effects of selected arsenolipids and three representative metabolites on the blood-cerebrospinal fluid barrier (B-CSF-B), a brain-regulating interface. For this purpose, we incubated an in vitro model of the B-CSF-B composed of porcine choroid plexus epithelial cells (PCPECs) with three AsHCs, two arsenic-containing fatty acids (AsFAs) and three representative arsenolipid metabolites (dimethylarsinic acid, thio/oxo-dimethylpropanoic acid) to examine their cytotoxic potential and impact on barrier integrity. The toxic arsenic species arsenite was also tested in this way and served as a reference substance. While AsFAs and the metabolites showed no cytotoxic effects in the conducted assays, AsHCs showed a strong cytotoxicity, being up to 1.5-fold more cytotoxic than arsenite. Analysis of the in vitro B-CSF-B integrity showed a concentration dependent disruption of the barrier within 72 h. The correlation with the decreased plasma membrane surface area (measured as capacitance) indicates cytotoxic effects. These findings suggest exposure to elevated levels of certain arsenolipids may have detrimental consequences for the central nervous system.},
  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{DuyduBasaranYalcinetal.2019,
  author    = {Duydu, Yalcin and Basaran, Nursen and Yalcin, Can {\"O}zg{\"u}r and Ustundag, Aylin and Aydin, Sevtap and Anlar, Hatice Gul and Bacanli, Merve and Aydos, Kaan and Atabekoglu, Cem Somer and Golka, Klaus and Ickstadt, Katja and Schwerdtle, Tanja and Werner, Matthias and Bolt, Hermann M.},
  title     = {Boron-exposed male workers in Turkey},
  series = {Archives of toxicology : official journal of EUROTOX},
  volume    = {93},
  journal   = {Archives of toxicology : official journal of EUROTOX},
  number    = {3},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0340-5761},
  doi       = {10.1007/s00204-019-02391-z},
  pages     = {743 -- 751},
  year      = {2019},
  abstract  = {Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 +/- 18.32 mg B/day, 1643.23 +/- 965.44 ng B/g semen and 553.83 +/- 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions.},
  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}
}
@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 Publ. 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}
}
@article{DraudeKoersgenPelsteretal.2015,
  author    = {Draude, Felix and K{\"o}rsgen, Martin and Pelster, Andreas and Schwerdtle, Tanja and M{\"u}thing, Johannes and Arlinghaus, Heinrich F.},
  title     = {Characterization of freeze-fractured epithelial plasma membranes on nanometer scale with ToF-SIMS},
  series = {Analytical \& bioanalytical chemistry},
  volume    = {407},
  journal   = {Analytical \& bioanalytical chemistry},
  number    = {8},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {1618-2642},
  doi       = {10.1007/s00216-014-8334-2},
  pages     = {2203 -- 2211},
  year      = {2015},
  abstract  = {Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to characterize the freeze-fracturing process of human epithelial PANC-1 and UROtsa cells. For this purpose, phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and phosphatidylserine standard samples were investigated to find specific signals with both high specificity and signal intensity. The results were used to investigate single cells of subconfluent cell layers prepared with a special silicon wafer sandwich preparation technique. This freeze-fracturing technique strips cell membranes off the cells, isolating them on opposing silicon wafer substrates. Criteria were found for defining regions with stripped off cell membranes and, on the opposing wafer, complementary regions with the remaining cells. Measured ethanolamine/choline and serine/choline ratios in these regions clearly showed that in the freeze-fracturing process, the lipid bilayer of the plasma membrane is split along its central zone. Accordingly, only the outer lipid monolayer is stripped off the cell, while the inner lipid monolayer remains attached to the cell on the opposing wafer, thus allowing detailed analysis of a single lipid monolayer. Furthermore, it could be shown that using different washing procedures did not influence the transmembrane lipid distribution. Under optimized preparation conditions, it became feasible to detect lipids with a lateral resolution of approximately 100 nm. The data indicate that ToF-SIMS would be a very useful technique to study with very high lateral resolution changes in lipid composition caused, for example, by lipid storage diseases or pharmaceuticals that interfere with the lipid metabolism.},
  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}
}