TY - JOUR A1 - Michaelis, Vivien A1 - Aengenheister, Leonie A1 - Tuchtenhagen, Max A1 - Rinklebe, Jörg A1 - Ebert, Franziska A1 - Schwerdtle, Tanja A1 - Buerki-Thurnherr, Tina A1 - Bornhorst, Julia T1 - Differences and interactions in placental manganese and iron transfer across an in vitro model of human villous trophoblasts JF - International journal of molecular sciences N2 - Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes. KW - manganese KW - iron KW - placental transfer KW - TE interactions KW - BeWo b30 KW - trophoblasts Y1 - 2022 U6 - https://doi.org/10.3390/ijms23063296 SN - 1422-0067 VL - 23 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Ijomone, Omamuyovwi M. A1 - Iroegbu, Joy D. A1 - Morcillo, Patricia A1 - Ayodele, Akinyemi J. A1 - Ijomone, Olayemi K. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael T1 - Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure JF - Environmental toxicology N2 - Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions. KW - brain KW - female KW - male KW - manganese KW - oxidative stress Y1 - 2022 U6 - https://doi.org/10.1002/tox.23583 SN - 1520-4081 SN - 1522-7278 VL - 37 IS - 9 SP - 2167 EP - 2177 PB - Wiley CY - New York, NY ER - TY - JOUR A1 - Kuhn, Eugênia Carla A1 - Tavares Jacques, Maurício A1 - Teixeira, Daniela A1 - Meyer, Sören A1 - Gralha, Thiago A1 - Roehrs, Rafael A1 - Camargo, Sandro A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia A1 - Ávila, Daiana Silva T1 - Ecotoxicological assessment of Uruguay River and affluents pre- and biomonitoring JF - Environmental science and pollution research : ESPR N2 - 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. KW - Heavy metals KW - Pesticides KW - Contamination KW - Arsenic KW - Environmental KW - pollution KW - Uruguay River Y1 - 2021 U6 - https://doi.org/10.1007/s11356-020-11986-4 SN - 0944-1344 SN - 1614-7499 VL - 28 IS - 17 SP - 21730 EP - 21741 PB - Springer CY - Berlin ; Heidelberg ER - TY - JOUR A1 - Pan, Yuanwei A1 - Ma, Xuehua A1 - Liu, Chuang A1 - Xing, Jie A1 - Zhou, Suqiong A1 - Parshad, Badri A1 - Schwerdtle, Tanja A1 - Li, Wenzhong A1 - Wu, Aiguo A1 - Haag, Rainer T1 - Retinoic acid-loaded dendritic polyglycerol-conjugated gold nanostars for targeted photothermal therapy in breast cancer stem cells JF - ACS nano N2 - The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse. KW - cancer stem cells KW - dendritic polyglycerol KW - gold nanostars KW - retinoic acid KW - photothermal therapy Y1 - 2021 U6 - https://doi.org/10.1021/acsnano.1c05452 SN - 1936-0851 SN - 1936-086X VL - 15 IS - 9 SP - 15069 EP - 15084 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Varão Moura, Alexandre A1 - Aparecido Rosini Silva, Alex A1 - Domingos Santo da Silva, José A1 - Aleixo Leal Pedroza, Lucas A1 - Bornhorst, Julia A1 - Stiboller, Michael A1 - Schwerdtle, Tanja A1 - Gubert, Priscila T1 - Determination of ions in Caenorhabditis elegans by ion chromatography JF - Journal of chromatography. B N2 - 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. KW - ion chromatography KW - C. elegans KW - method development KW - method validation KW - ion quantification Y1 - 2022 U6 - https://doi.org/10.1016/j.jchromb.2022.123312 SN - 1570-0232 SN - 1873-376X VL - 1204 PB - Elsevier CY - Amsterdam [u.a.] ER - TY - JOUR A1 - Nicolai, Merle Marie A1 - Witt, Barbara A1 - Friese, Sharleen A1 - Michaelis, Vivien A1 - Hölz-Armstrong, Lisa A1 - Martin, Maximilian A1 - Ebert, Franziska A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells JF - Food and chemical toxicology N2 - 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. KW - Manganese KW - Dopaminergic neurons KW - DNA integrity KW - DNA repair KW - Neurodegeneration KW - Oxidative stress KW - Genotoxicity Y1 - 2022 U6 - https://doi.org/10.1016/j.fct.2022.112822 SN - 0278-6915 SN - 1873-6351 VL - 161 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Volk, Christin A1 - Brandsch, Corinna A1 - Schlegelmilch, Ulf A1 - Wensch-Dorendorf, Monika A1 - Hirche, Frank A1 - Simm, Andreas A1 - Gargum, Osama A1 - Wiacek, Claudia A1 - Braun, Peggy G. A1 - Kopp, Johannes F. A1 - Schwerdtle, Tanja A1 - Treede, Hendrik A1 - Stangl, Gabriele I. T1 - Postprandial metabolic response to rapeseed protein in healthy subjects JF - Nutrients N2 - Plant proteins have become increasingly important for ecological reasons. Rapeseed is a novel source of plant proteins with high biological value, but its metabolic impact in humans is largely unknown. A randomized, controlled intervention study including 20 healthy subjects was conducted in a crossover design. All participants received a test meal without additional protein or with 28 g of rapeseed protein isolate or soy protein isolate (control). Venous blood samples were collected over a 360-min period to analyze metabolites; satiety was assessed using a visual analog scale. Postprandial levels of lipids, urea, and amino acids increased following the intake of both protein isolates. The postprandial insulin response was lower after consumption of the rapeseed protein than after intake of the soy protein (p< 0.05), whereas the postmeal responses of glucose, lipids, interleukin-6, minerals, and urea were comparable between the two protein isolates. Interestingly, the rapeseed protein exerted stronger effects on postprandial satiety than the soy protein (p< 0.05). The postmeal metabolism following rapeseed protein intake is comparable with that of soy protein. The favorable effect of rapeseed protein on postprandial insulin and satiety makes it a valuable plant protein for human nutrition. KW - rapeseed protein KW - soy protein KW - postprandial study KW - metabolic response KW - healthy subjects Y1 - 2020 U6 - https://doi.org/10.3390/nu12082270 SN - 2072-6643 VL - 12 IS - 8 PB - MDPI CY - Basel ER - TY - JOUR A1 - Knoche, Lisa A1 - Lisec, Jan A1 - Schwerdtle, Tanja A1 - Koch, Matthias T1 - LC-HRMS-Based identification of transformation products of the drug salinomycin generated by electrochemistry and liver microsome JF - Antibiotics N2 - The drug salinomycin (SAL) is a polyether antibiotic and used in veterinary medicine as coccidiostat and growth promoter. Recently, SAL was suggested as a potential anticancer drug. However, transformation products (TPs) resulting from metabolic and environmental degradation of SAL are incompletely known and structural information is missing. In this study, we therefore systematically investigated the formation and identification of SAL derived TPs using electrochemistry (EC) in an electrochemical reactor and rat and human liver microsome incubation (RLM and HLM) as TP generating methods. Liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) was applied to determine accurate masses in a suspected target analysis to identify TPs and to deduce occurring modification reactions of derived TPs. A total of 14 new, structurally different TPs were found (two EC-TPs, five RLM-TPs, and 11 HLM-TPs). The main modification reactions are decarbonylation for EC-TPs and oxidation (hydroxylation) for RLM/HLM-TPs. Of particular interest are potassium-based TPs identified after liver microsome incubation because these might have been overlooked or declared as oxidated sodium adducts in previous, non-HRMS-based studies due to the small mass difference between K and O + Na of 21 mDa. The MS fragmentation pattern of TPs was used to predict the position of identified modifications in the SAL molecule. The obtained knowledge regarding transformation reactions and novel TPs of SAL will contribute to elucidate SAL-metabolites with regards to structural prediction. KW - salinomycin KW - ionophore antibiotics KW - transformation product KW - electrochemistry KW - rat KW - human liver microsomes KW - HRMS Y1 - 2022 U6 - https://doi.org/10.3390/antibiotics11020155 SN - 2079-6382 VL - 11 IS - 2 PB - MDPI CY - Basel ER - TY - JOUR A1 - Witt, Barbara A1 - Stiboller, Michael A1 - Raschke, Stefanie A1 - Friese, Sharleen A1 - Ebert, Franziska A1 - Schwerdtle, Tanja T1 - Characterizing effects of excess copper levels in a human astrocytic cell line with focus on oxidative stress markers JF - Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS N2 - 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. KW - Copper KW - Astrocytes KW - Toxicity KW - Mitochondria KW - ROS KW - Trace elements Y1 - 2021 U6 - https://doi.org/10.1016/j.jtemb.2021.126711 SN - 1878-3252 VL - 65 PB - Elsevier CY - München ER - TY - JOUR A1 - Hackethal, Christin A1 - Kopp, Johannes Florian A1 - Sarvan, Irmela A1 - Schwerdtle, Tanja A1 - Lindtner, Oliver T1 - Total arsenic and water-soluble arsenic species in foods of the first German total diet study (BfR MEAL Study) JF - Food chemistry N2 - Arsenic can occur in foods as inorganic and organic forms. Inorganic arsenic is more toxic than most watersoluble organic arsenic compounds such as arsenobetaine, which is presumed to be harmless for humans. Within the first German total diet study, total arsenic, inorganic arsenic, arsenobetaine, dimethylarsinic acid and monomethylarsonic acid were analyzed in various foods. Highest levels of total arsenic were found in fish, fish products and seafood (mean: 1.43 mg kg(-1); n = 39; min-max: 0.01-6.15 mg kg(-1)), with arsenobetaine confirmed as the predominant arsenic species (1.233 mg kg 1; n = 39; min-max: 0.01-6.23 mg kg (1)). In contrast, inorganic arsenic was determined as prevalent arsenic species in terrestrial foods (0.02 mg kg (1); n = 38; min-max: 0-0.11 mg kg (1)). However, the toxicity of arsenic species varies and measurements are necessary to gain information about the composition and changes of arsenic species in foods due to household processing of foods. KW - Occurrence data KW - Food KW - Total arsenic KW - Arsenic speciation KW - Inductively KW - coupled plasma mass spectrometry Y1 - 2021 U6 - https://doi.org/10.1016/j.foodchem.2020.128913 SN - 0308-8146 SN - 1873-7072 VL - 346 PB - Elsevier CY - Amsterdam [u.a.] ER - TY - JOUR A1 - Nicolai, Merle Marie A1 - Baesler, Jessica A1 - Aschner, Michael A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Consequences of manganese overload in C. elegans BT - oxidative stress and DNA damage JF - Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie Y1 - 2020 U6 - https://doi.org/10.1007/s00210-020-01828-y SN - 0028-1298 SN - 1432-1912 VL - 393 IS - SUPPL 1 SP - 9 EP - 9 PB - Springer CY - New York ER - TY - JOUR A1 - Müller, Anke Katharina A1 - Helms, Ute A1 - Rohrer, Carsten A1 - Möhler, Monika A1 - Hellwig, Frank A1 - Glei, Michael A1 - Schwerdtle, Tanja A1 - Lorkowski, Stefan A1 - Dawczynski, Christine T1 - Nutrient composition of different hazelnut cultivars grown in Germany JF - Foods N2 - Hazelnuts are rarely cultivated in Germany, although they are a valuable source for macro- and micronutrients and can thus contribute to a healthy diet. Near the present, 15 varieties were cultivated in Thuringia, Germany, as a pilot study for further research. The aim of our study was to evaluate the micro- and macronutrient composition of representative, randomly mixed samples of the 15 different hazelnut cultivars. Protein, fat, and fiber contents were determined using established methods. Fatty acids, tocopherols, minerals, trace elements, and ultra-trace elements were analyzed using gas chromatography, high-performance liquid chromatography, and inductively coupled plasma triple quadrupole mass-spectrometry, respectively. We found that the different hazelnut varieties contained valuable amounts of fat, protein, dietary fiber, minerals, trace elements, and alpha-tocopherol, however, in different quantities. The variations in nutrient composition were independent of growth conditions, which were identical for all hazelnut varieties. Therefore, each hazelnut cultivar has its specific nutrient profile. KW - Corylus avellana L. KW - nutrient composition KW - hazelnut cultivars KW - minerals KW - tocopherols Y1 - 2020 U6 - https://doi.org/10.3390/foods9111596 SN - 2304-8158 VL - 9 IS - 11 PB - MDPI CY - Basel ER - TY - JOUR A1 - Dünkelberg, Sophie A1 - Maywald, Martina A1 - Schmitt, Anne Kristina A1 - Schwerdtle, Tanja A1 - Meyer, Sören A1 - Rink, Lothar T1 - The interaction of sodium and zinc in the priming of T cell subpopulations regarding Th17 and Treg cells JF - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology N2 - Scope: Nutrition is a critical determinant of a functional immune system. The aim of this study is to investigate the molecular mechanisms by which immune cells are influenced by zinc and sodium. Methods and Results: Mixed lymphocyte cultures and Jurkat cells are generated and incubated with zinc, sodium, or a combination of both for further tests. Zinc induces the number of regulatory T cells (Treg) and decreases T helper 17 cells (Th17), and sodium has the opposite effect. The transforming growth factor beta receptor signaling pathway is also enhanced by zinc and reduced by sodium as indicated by contrary phosphoSmad 2/3 induction. Antagonistic effects can also be seen on zinc transporter and metallothionein-1 (MT-1) mRNA expression: zinc declines Zip10 mRNA expression while sodium induces it, whereas MT-1 mRNA expression is induced by zinc while it is reduced by sodium. Conclusion: This data indicate that zinc and sodium display opposite effects regarding Treg and Th17 induction in MLC, respectively, resulting in a contrary effect on the immune system. Additionally, it reveals a direct interaction of zinc and sodium in the priming of T cell subpopulations and shows that Zip10 and MT-1 play a significant role in those differentiation pathways. KW - Foxp3 KW - regulatory T cells KW - sodium KW - T helper 17 cells KW - zinc Y1 - 2020 U6 - https://doi.org/10.1002/mnfr.201900245 SN - 1613-4133 VL - 64 IS - 2 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Kotthoff, Lisa A1 - O'Callaghan, Sarah-Louise A1 - Lisec, Jan A1 - Schwerdtle, Tanja A1 - Koch, Matthias T1 - Structural annotation of electro- and photochemically generated transformation products of moxidectin using high-resolution mass spectrometry JF - Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica N2 - Moxidectin (MOX) is a widely used anthelmintic drug for the treatment of internal and external parasites in food-producing and companion animals. Transformation products (TPs) of MOX, formed through metabolic degradation or acid hydrolysis, may pose a potential environmental risk, but only few were identified so far. In this study, we therefore systematically characterized electro- and photochemically generated MOX TPs using high-resolution mass spectrometry (HRMS). Oxidative electrochemical (EC) TPs were generated in an electrochemical reactor and photochemical (PC) TPs by irradiation with UV-C light. Subsequent HRMS measurements were performed to identify accurate masses and deduce occurring modification reactions of derived TPs in a suspected target analysis. In total, 26 EC TPs and 59 PC TPs were found. The main modification reactions were hydroxylation, (de-)hydration, and derivative formation with methanol for EC experiments and isomeric changes, (de-)hydration, and changes at the methoxime moiety for PC experiments. In addition, several combinations of different modification reactions were identified. For 17 TPs, we could predict chemical structures through interpretation of acquired MS/MS data. Most modifications could be linked to two specific regions of MOX. Some previously described metabolic reactions like hydroxylation or O-demethylation were confirmed in our EC and PC experiments as reaction type, but the corresponding TPs were not identical to known metabolites or degradation products. The obtained knowledge regarding novel TPs and reactions will aid to elucidate the degradation pathway of MOX which is currently unknown. KW - veterinary drug KW - moxidectin KW - transformation products KW - electrochemistry KW - photochemistry KW - LC KW - HRMS Y1 - 2020 U6 - https://doi.org/10.1007/s00216-020-02572-1 SN - 1618-2642 SN - 1618-2650 VL - 412 IS - 13 SP - 3141 EP - 3152 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Zhou, Suqiong A1 - Pan, Yuanwei A1 - Zhang, Jianguang A1 - Li, Yan A1 - Neumann, Falko A1 - Schwerdtle, Tanja A1 - Li, Wenzhong A1 - Haag, Rainer T1 - Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells JF - Nanoscale N2 - Nanomaterials play an important role in mimicking the biochemical and biophysical cues of the extracellular matrix in human mesenchymal stem cells (MSCs). Increasing studies have demonstrated the crucial impact of functional groups on MSCs, while limited research is available on how the functional group's density on nanoparticles regulates MSC behavior. Herein, the effects of dendritic polyglycerol (dPG)-conjugated gold nanostars (GNSs) with different densities of functional groups on the osteogenesis of MSCs are systematically investigated. dPG@GNS nanocomposites have good biocompatibility and the uptake by MSCs is in a functional group density-dependent manner. The osteogenic differentiation of MSCs is promoted by all dPG@GNS nanocomposites, in terms of alkaline phosphatase activity, calcium deposition, and expression of osteogenic protein and genes. Interestingly, the dPGOH@GNSs exhibit a slight upregulation in the expression of osteogenic markers, while the different charged densities of sulfate and amino groups show more efficacy in the promotion of osteogenesis. Meanwhile, the sulfated nanostars dPGS20@GNSs show the highest enhancement. Furthermore, various dPG@GNS nanocomposites exerted their effects by regulating the activation of Yes-associated protein (YAP) to affect osteogenic differentiation. These results indicate that dPG@GNS nanocomposites have functional group density-dependent influence on the osteogenesis of MSCs, which may provide a new insight into regulating stem cell fate. Y1 - 2020 U6 - https://doi.org/10.1039/d0nr06570f SN - 2040-3364 SN - 2040-3372 VL - 12 IS - 47 SP - 24006 EP - 24019 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Finke, Hannah A1 - Wandt, Viktoria Klara Veronika A1 - Ebert, Franziska A1 - Guttenberger, Nikolaus A1 - Glabonjat, Ronald A. A1 - Stiboller, Michael A1 - Francesconi, Kevin A. A1 - Raber, Georg A1 - Schwerdtle, Tanja T1 - Toxicological assessment of arsenic-containing phosphatidylcholines in HepG2 cells N2 - Arsenolipids include a wide range of organic arsenic species that occur naturally in seafood and thereby contribute to human arsenic exposure. Recently arsenic-containing phosphatidylcholines (AsPCs) were identified in caviar, fish, and algae. In this first toxicological assessment of AsPCs, we investigated the stability of both the oxo- and thioxo-form of an AsPC under experimental conditions, and analyzed cell viability, indicators of genotoxicity and biotransformation in human liver cancer cells (HepG2). Precise toxicity data could not be obtained owing to the low solubility in the cell culture medium of the thioxo-form, and the ease of hydrolysis of the oxo-form, and to a lesser degree the thioxo-form. Hydrolysis resulted amongst others in the respective constituent arsenic-containing fatty acid (AsFA). Incubation of the cells with oxo-AsPC resulted in a toxicity similar to that determined for the hydrolysis product oxo-AsFA alone, and there were no indices for genotoxicity. Furthermore, the oxo-AsPC was readily taken up by the cells resulting in high cellular arsenic concentrations (50 μM incubation: 1112 ± 146 μM As cellular), whereas the thioxo-AsPC was substantially less bioavailable (50 μM incubation: 293 ± 115 μM As cellular). Speciation analysis revealed biotransformation of the AsPCs to a series of AsFAs in the culture medium, and, in the case of the oxo-AsPC, to as yet unidentified arsenic species in cell pellets. The results reveal the difficulty of toxicity studies of AsPCs in vitro, indicate that their toxicity might be largely governed by their arsenic fatty acid content and suggest a multifaceted human metabolism of food derived complex arsenolipids. KW - Biochemistry KW - Biological Sciences KW - Science and Mathematics KW - Books KW - Journals Y1 - 2020 U6 - https://doi.org/10.1039/d0mt00073f VL - 12 IS - 7 SP - 1159 EP - 1170 PB - Oxford University CY - Cambridge ER - TY - JOUR A1 - Ebert, Franziska A1 - Ziemann, Vanessa A1 - Wandt, Viktoria Klara Veronika A1 - Witt, Barbara A1 - Müller, Sandra Marie A1 - Guttenberger, Nikolaus A1 - Bankoglu, Ezgi Eyluel A1 - Stopper, Helga A1 - Raber, Georg A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Cellular toxicological characterization of a thioxolated arsenic-containing hydrocarbon JF - Journal of trace elements in medicine and biology N2 - 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. Y1 - 2017 U6 - https://doi.org/10.1016/j.jtemb.2020.126563 VL - 61 PB - Elsevier CY - München ER - TY - JOUR A1 - Taylor, Vivien A1 - Goodale, Britton A1 - Raab, Andrea A1 - Schwerdtle, Tanja A1 - Reimer, Ken A1 - Conklin, Sean A1 - Karagas, Margaret R. A1 - Francesconi, Kevin A. T1 - Human exposure to organic arsenic species from seafood JF - The science of the total environment : an international journal for scientific research into the environment and its relationship with man N2 - Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be nontoxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge. KW - Organic arsenic KW - Seafood KW - Arsenosugar KW - Arsenolipid Y1 - 2017 U6 - https://doi.org/10.1016/j.scitotenv.2016.12.113 SN - 0048-9697 SN - 1879-1026 VL - 580 SP - 266 EP - 282 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Marschall, Talke Anu A1 - Kroepfl, Nina A1 - Jensen, Kenneth Bendix A1 - Bornhorst, Julia A1 - Meermann, B. A1 - Kühnelt, Doris A1 - Schwerdtle, Tanja T1 - Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites JF - Metallomics N2 - 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. Y1 - 2017 U6 - https://doi.org/10.1039/c6mt00300a SN - 1756-5901 SN - 1756-591X VL - 9 SP - 268 EP - 277 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Kröpfl, Nina A1 - Marschall, Talke A. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja A1 - Kuehnelt, Doris T1 - Quantitative determination of the sulfur-containing antioxidant ergothioneine by HPLC/ICP- QQQ-MS JF - Journal of Analytical Atomic Spectrometry N2 - Interest in the sulfur-containing antioxidant ergothioneine calls for reliable analytical methods for its quantification. In this work, a method based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled with elemental mass spectrometry detection in mass shift mode (inductively coupled plasma triple quadrupole mass spectrometry, ICP-QQQ-MS) using oxygen as the reaction gas was developed for the element-selective determination of ergothioneine in complex biological matrices. Application of an instrumental setup using a 6-port-valve and the introduction of a methanol gradient allowed the time-efficient analysis of samples containing strongly retained sulfur species besides ergothioneine without compromising ICPMS detection. In aqueous solution, limits of detection and quantification (LOD and LOQ) of the optimized method for m/z 32 -> 48 (SO+) were 0.23 mu g S per L and 0.80 mu g S per L, respectively; measurements in a complex matrix (human hepatocyte carcinoma cells, HepG2) resulted in an LOD of 0.6 mu g S per L and an LOQ of 2.3 mu g S per L. Recoveries of ergothioneine from cell pellets spiked with the analyte before cell lysis (97 +/- 3%) matched those obtained for cell culture medium spiked before syringe filtration (96 +/- 9%) demonstrating that sample preparation did not impair the quantitative determination of ergothioneine. When HepG2 cells were exposed to ergothioneine via the culture medium, they showed low absorption; approximately 3% of the added ergothioneine was found in cell lysates, while most of it (>= 85%) remained in the cell culture medium. The method is capable of separating ergothioneine from other biologically relevant sulfur-containing species and is expected to be of broad future use. Furthermore, the potential use for the simultaneous separation of selenium species, thereby extending the scope of possible applications, was demonstrated by applying it to water extracts of oyster mushrooms. Y1 - 2017 U6 - https://doi.org/10.1039/c7ja00030h SN - 0267-9477 SN - 1364-5544 VL - 32 SP - 1571 EP - 1581 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Meyer, Sören A1 - Lopez-Serrano, Aniceto A1 - Mitze, Hanna A1 - Jakubowski, Norbert A1 - Schwerdtle, Tanja T1 - Single-cell analysis by ICP-MS/MS as a fast tool for cellular bioavailability studies of arsenite JF - Metallomics : integrated biometal science N2 - Single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) has become a powerful and fast tool to evaluate the elemental composition at a single-cell level. In this study, the cellular bioavailability of arsenite (incubation of 25 and 50 mu M for 0-48 h) has been successfully assessed by SC-ICP-MS/MS for the first time directly after re-suspending the cells in water. This procedure avoids the normally arising cell membrane permeabilization caused by cell fixation methods (e.g. methanol fixation). The reliability and feasibility of this SC-ICP-MS/MS approach with a limit of detection of 0.35 fg per cell was validated by conventional bulk ICP-MS/MS analysis after cell digestion and parallel measurement of sulfur and phosphorus. Y1 - 2017 U6 - https://doi.org/10.1039/c7mt00285h SN - 1756-5901 SN - 1756-591X VL - 10 IS - 1 SP - 73 EP - 76 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Müller, Sandra Marie A1 - Ebert, Franziska A1 - Bornhorst, Julia A1 - Galla, Hans-Joachim A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Arsenic-containing hydrocarbons disrupt a model in vitro blood-cerebrospinal fluid barrier JF - Journal of trace elements in medicine and biology N2 - 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. KW - Arsenolipids KW - Blood-liquor barrier KW - Blood-cerebrospinal fluid barrier KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids Y1 - 2018 U6 - https://doi.org/10.1016/j.jtemb.2018.01.020 SN - 0946-672X VL - 49 SP - 171 EP - 177 PB - Elsevier GMBH CY - München ER - TY - JOUR A1 - Meyer, Sören A1 - Markova, Mariya A1 - Pohl, Gabriele A1 - Marschall, Talke Anu A1 - Pivovarova, Olga A1 - Pfeiffer, Andreas F. H. A1 - Schwerdtle, Tanja T1 - Development, validation and application of an ICP-MS/MS method to quantify minerals and (ultra-)trace elements in human serum JF - Journal of trace elements in medicine and biology N2 - Multi-element determination in human samples is very challenging. Especially in human intervention studies sample volumes are often limited to a few microliters and due to the high number of samples a high-throughput is indispensable. Here, we present a state-of-the-art ICP-MS/MS-based method for the analysis of essential (trace) elements, namely Mg, Ca, Fe, Cu, Zn, Mo, Se and I, as well as food-relevant toxic elements such as As and Cd. The developed method was validated regarding linearity of the calibration curves, method LODs and LOQs, selectivity and trueness as well as precision. The established reliable method was applied to quantify the element serum concentrations of participants of a human intervention study (LeguAN). The participants received isocaloric diets, either rich in plant protein or in animal protein. While the serum concentrations of Mg and Mo increased in participants receiving the plant protein-based diet (above all legumes), the Se concentration in serum decreased. In contrast, the animal protein-based diet, rich in meat and dairy products, resulted in an increased Se concentration in serum. KW - ICP-MS KW - Elemental blood serum concentration KW - Human nutritional intervention Y1 - 2018 U6 - https://doi.org/10.1016/j.jtemb.2018.05.012 SN - 0946-672X VL - 49 SP - 157 EP - 163 PB - Elsevier GMBH CY - München ER - TY - JOUR A1 - Müller, Sandra Marie A1 - Ebert, Franziska A1 - Raber, Georg A1 - Meyer, Sören A1 - Bornhorst, Julia A1 - Hüwel, Stephan A1 - Galla, Hans-Joachim A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Effects of arsenolipids on in vitro blood-brain barrier model JF - Archives of toxicology : official journal of EUROTOX N2 - 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. KW - Arsenolipids KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids KW - In vitro blood-brain barrier model Y1 - 2017 SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 2 SP - 823 EP - 832 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Finke, Hannah A1 - Winkelbeiner, Nicola Lisa A1 - Lossow, Kristina A1 - Hertel, Barbara A1 - Wandt, Viktoria Klara Veronika A1 - Schwarz, Maria A1 - Pohl, Gabriele A1 - Kopp, Johannes Florian A1 - Ebert, Franziska A1 - Kipp, Anna Patricia A1 - Schwerdtle, Tanja T1 - Effects of a Cumulative, Suboptimal Supply of Multiple Trace Elements in Mice BT - trace element status, genomic stability, inflammation, and epigenetics JF - Molecular nutrition & food research N2 - Scope: Trace element (TE) deficiencies often occur accumulated, as nutritional intake is inadequate for several TEs, concurrently. Therefore, the impact of a suboptimal supply of iron, zinc, copper, iodine, and selenium on the TE status, health parameters, epigenetics, and genomic stability in mice are studied. Methods and results: Male mice receive reduced or adequate amounts of TEs for 9 weeks. The TE status is analyzed mass‐spectrometrically in serum and different tissues. Furthermore, gene and protein expression of TE biomarkers are assessed with focus on liver. Iron concentrations are most sensitive toward a reduced supply indicated by increased serum transferrin levels and altered hepatic expression of iron‐related genes. Reduced TE supply results in smaller weight gain but higher spleen and heart weights. Additionally, inflammatory mediators in serum and liver are increased together with hepatic genomic instability. However, global DNA (hydroxy)methylation is unaffected by the TE modulation. Conclusion: Despite homeostatic regulation of most TEs in response to a low intake, this condition still has substantial effects on health parameters. It appears that the liver and immune system react particularly sensitive toward changes in TE intake. The reduced Fe status might be the primary driver for the observed effects. Y1 - 2020 U6 - https://doi.org/10.1002/mnfr.202000325 SN - 1613-4125 VL - 64 IS - 16 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Wandt, Viktoria Klara Veronika A1 - Winkelbeiner, Nicola Lisa A1 - Bornhorst, Julia A1 - Witt, Barbara A1 - Raschke, Stefanie A1 - Simon, Luise A1 - Ebert, Franziska A1 - Kipp, Anna Patricia A1 - Schwerdtle, Tanja T1 - A matter of concern BT - trace element dyshomeostasis and genomic stability in neurons JF - Redox Biology N2 - 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 Y1 - 2021 U6 - https://doi.org/10.1016/j.redox.2021.101877 VL - 41 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Müller, S. M. A1 - Finke, Hannah A1 - Ebert, Franziska A1 - Kopp, Johannes Florian A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Francesconi, Kevin A. A1 - Raber, G. A1 - Schwerdtle, Tanja T1 - Arsenic-containing hydrocarbons BT - effects on gene expression, epigenetics, and biotransformation in HepG2 cells JF - Archives of toxicology : official journal of EUROTOX N2 - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine-5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids. KW - Arsenolipids KW - Gene expression KW - Arsenic-containing hydrocarbons KW - Global DNA methylation KW - Arsenic speciation KW - Metabolism Y1 - 2018 U6 - https://doi.org/10.1007/s00204-018-2194-z SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 5 SP - 1751 EP - 1765 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Nowotny, Kerstin A1 - Castro, Jose Pedro A1 - Hugo, Martin A1 - Braune, Sabine A1 - Weber, Daniela A1 - Pignitter, Marc A1 - Somoza, Veronika A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Grune, Tilman T1 - Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - 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. KW - Advanced glycation end products KW - Aging KW - Apoptosis KW - Collagen KW - ER stress KW - Methylglyoxal KW - Redox homeostasis Y1 - 2018 U6 - https://doi.org/10.1016/j.freeradbiomed.2018.03.022 SN - 0891-5849 SN - 1873-4596 VL - 120 SP - 102 EP - 113 PB - Elsevier CY - New York ER - TY - JOUR A1 - Rohn, Isabelle A1 - Marschall, Talke Anu A1 - Kröpfl, Nina A1 - Jensen, Kenneth Bendix A1 - Aschner, Michael A1 - Tuck, Simon A1 - Kuehnelt, Doris A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans JF - Metallomics : integrated biometal science N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1039/c8mt00066b SN - 1756-5901 SN - 1756-591X VL - 10 IS - 6 SP - 818 EP - 827 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Maares, Maria A1 - Duman, Ayse A1 - Keil, Claudia A1 - Schwerdtle, Tanja A1 - Haase, Hajo T1 - The impact of apical and basolateral albumin on intestinal zinc resorption in the Caco-2/HT-29-MTX co-culture model JF - Metallomics : integrated biometal science N2 - The molecular mechanisms of intestinal zinc resorption and its regulation are still topics of ongoing research. To this end, the application of suitable in vitro intestinal models, optimized with regard to their cellular composition and medium constituents, is of crucial importance. As one vital aspect, the impact of cell culture media or buffer compounds, respectively, on the speciation and cellular availability of zinc has to be considered when investigating zinc resorption. Thus, the present study aims to investigate the impact of serum, and in particular its main constituent serum albumin, on zinc uptake and toxicity in the intestinal cell line Caco-2. Furthermore, the impact of serum albumin on zinc resorption is analyzed using a co-culture of Caco-2 cells and the mucin-producing goblet cell line HT-29-MTX. Apically added albumin significantly impaired zinc uptake into enterocytes and buffered its cytotoxicity. Yet, undigested albumin does not occur in the intestinal lumen in vivo and impairment of zinc uptake was abrogated by digestion of albumin. Interestingly, zinc uptake, as well as gene expression studies of mt1a and selected intestinal zinc transporters after zinc incubation for 24 h, did not show significant differences between 0 and 10% serum. Importantly, the basolateral application of serum in a transport study significantly enhanced fractional apical zinc resorption, suggesting that the occurrence of a zinc acceptor in the plasma considerably affects intestinal zinc resorption. This study demonstrates that the apical and basolateral medium composition is crucial when investigating zinc, particularly its intestinal resorption, using in vitro cell culture. Y1 - 2018 U6 - https://doi.org/10.1039/c8mt00064f SN - 1756-5901 SN - 1756-591X VL - 10 IS - 7 SP - 979 EP - 991 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Nicolai, Merle Marie A1 - Weishaupt, Ann-Kathrin A1 - Baesler, Jessica A1 - Brinkmann, Vanessa A1 - Wellenberg, Anna A1 - Winkelbeiner, Nicola Lisa A1 - Gremme, Anna A1 - Aschner, Michael A1 - Fritz, Gerhard A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Effects of manganese on genomic integrity in the multicellular model organism Caenorhabditis elegans JF - International Journal of Molecular Sciences N2 - Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms. KW - manganese KW - oxidative stress KW - DNA repair KW - DNA damage response KW - Caenorhabditis elegans Y1 - 2021 U6 - https://doi.org/10.3390/ijms222010905 SN - 1422-0067 VL - 22 IS - 20 PB - MDPI CY - Basel ER - TY - JOUR A1 - Duydu, Yalcin A1 - Basaran, Nursen A1 - Ustundag, Aylin A1 - Aydin, Sevtap A1 - Yalcin, Can Ozgur A1 - Anlar, Hatice Gul A1 - Bacanli, Merve A1 - Aydos, Kaan A1 - Atabekoglu, Cem Somer A1 - Golka, Klaus A1 - Ickstadt, Katja A1 - Schwerdtle, Tanja A1 - Werner, Matthias A1 - Meyer, Sören A1 - Bolt, Hermann M. T1 - Birth weights of newborns and pregnancy outcomes of environmentally boron-exposed females in Turkey JF - Archives of toxicology : official journal of EUROTOX N2 - Boric acid and sodium borates are currently classified as being toxic to reproduction under "Category 1B" with the hazard statement of "H360 FD" in the European CLP regulation. This has prompted studies on boron-mediated reprotoxic effects in male workers in boron mining areas and boric acid production plants. By contrast, studies on boron-mediated developmental effects in females are scarce. The present study was designed to fill this gap. Hundred and ninety nine females residing in Bandirma and Bigadic participated in this study investigating pregnancy outcomes. The participants constituted a study group covering blood boron from low (< 100 ng B/g blood, n = 143) to high (> 150 ng B/g blood, n = 27) concentrations. The mean blood boron concentration and the mean estimated daily boron exposure of the high exposure group was 274.58 (151.81-975.66) ng B/g blood and 24.67 (10.47-57.86) mg B/day, respectively. In spite of the high level of daily boron exposure, boron-mediated adverse effects on induced abortion, spontaneous abortion (miscarriage), stillbirth, infant death, neonatal death, early neonatal death, preterm birth, congenital anomalies, sex ratio and birth weight of newborns were not observed. KW - Boric acid KW - Boron exposure KW - Biological monitoring KW - Developmental toxicity KW - Pregnancy outcomes Y1 - 2018 U6 - https://doi.org/10.1007/s00204-018-2238-4 SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 8 SP - 2475 EP - 2485 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Ruszkiewicz, Joanna A. A1 - de Macedo, Gabriel Teixeira A1 - Miranda-Vizuete, Antonio A1 - Teixeira da Rocha, Joao B. A1 - Bowman, Aaron B. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael T1 - The cytoplasmic thioredoxin system in Caenorhabditis elegans affords protection from methylmercury in an age-specific manner JF - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system N2 - 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. KW - Methylmercury KW - Age KW - Development KW - C. elegans KW - Thioredoxin KW - Thioredoxin reductase Y1 - 2018 U6 - https://doi.org/10.1016/j.neuro.2018.08.007 SN - 0161-813X SN - 1872-9711 VL - 68 SP - 189 EP - 202 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Peres, Tanara Vieira A1 - Arantes, Leticia P. A1 - Miah, Mahfuzur R. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Bowman, Aaron B. A1 - Leal, Rodrigo B. A1 - Aschner, Michael T1 - Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity JF - Neurotoxicity Research N2 - 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. KW - Manganese . C. elegans KW - Signaling pathways KW - DAF-16 KW - Akt/PKB KW - SGK-1 Y1 - 2018 U6 - https://doi.org/10.1007/s12640-018-9915-1 SN - 1029-8428 SN - 1476-3524 VL - 34 IS - 3 SP - 584 EP - 596 PB - Springer CY - New York ER - TY - JOUR A1 - Duydu, Yalcin A1 - Basaran, Nursen A1 - Aydin, Sevtap A1 - Ustundag, Aylin A1 - Yalcin, Can Özgür A1 - Anlar, Hatice Gul A1 - Bacanli, Merve A1 - Aydos, Kaan A1 - Atabekoglu, Cem Somer A1 - Golka, Klaus A1 - Ickstadt, Katja A1 - Schwerdtle, Tanja A1 - Werner, Matthias A1 - Meyer, Sören A1 - Bolt, Hermann M. T1 - Evaluation of FSH, LH, testosterone levels and semen parameters in male boron workers under extreme exposure conditions JF - Archives of toxicology : official journal of EUROTOX N2 - Boric acid and sodium borates are currently classified in the EU-CLP regulation as "toxic to reproduction" under "Category 1B", with hazard statement of H360FD. However, so far field studies on male reproduction in China and in Turkey could not confirm such boron-associated toxic effects. As validation by another independent study is still required, the present study has investigated possible boron-associated effects on male reproduction in workers (n = 212) under different boron exposure conditions. The mean daily boron exposure (DBE) and blood boron concentration of workers in the extreme exposure group (n = 98) were 47.17 +/- 17.47 (7.95-106.8) mg B/day and 570.6 +/- 160.1 (402.6-1100) ng B/g blood, respectively. Nevertheless, boron-associated adverse effects on semen parameters, as well as on FSH, LH and total testosterone levels were not seen, even within the extreme exposure group. With this study, a total body of evidence has accumulated that allows to conclude that male reproductive effects are not relevant to humans, under any feasible and realistic conditions of exposure to inorganic boron compounds. KW - Boron exposure KW - Boric acid KW - Reproductive toxicity KW - FSH KW - LH KW - Testosterone KW - Semen parameters Y1 - 2018 U6 - https://doi.org/10.1007/s00204-018-2296-7 SN - 0340-5761 SN - 1432-0738 VL - 92 IS - 10 SP - 3051 EP - 3059 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Bornhorst, Julia A1 - Ebert, Franziska A1 - Meyer, Sören A1 - Ziemann, Vanessa A1 - Xiong, Chan A1 - Guttenberger, Nikolaus A1 - Raab, Andrea A1 - Baesler, Jessica A1 - Aschner, Michael A1 - Feldmann, Jörg A1 - Francesconi, Kevin A1 - Raber, Georg A1 - Schwerdtle, Tanja T1 - Toxicity of three types of arsenolipids BT - species-specific effects in Caenorhabditis elegans JF - Metallomics N2 - 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. Y1 - 2020 U6 - https://doi.org/https://doi.org/10.1039/d0mt00039f SN - 1756-591X SN - 1756-5901 VL - 12 IS - 5 SP - 794 EP - 798 PB - Oxford University Press CY - Cambridge ER - TY - JOUR A1 - Baesler, Jessica A1 - Michaelis, Vivien A1 - Stiboller, Michael A1 - Haase, Hajo A1 - Aschner, Michael A1 - Schwerdtle, Tanja A1 - Sturzenbaum, Stephen R. A1 - Bornhorst, Julia T1 - Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis JF - Molecular Nutrition and Food Research N2 - 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. KW - aging KW - C. elegans KW - homeostasis KW - manganese KW - zinc Y1 - 2021 U6 - https://doi.org/10.1002/mnfr.202001176 SN - 1613-4133 SN - 1613-4125 VL - 65 IS - 8 SP - 1 EP - 11 PB - Wiley-VCH GmbH CY - Weinheim ER - TY - JOUR A1 - Baesler, Jessica A1 - Kopp, Johannes Florian A1 - Pohl, Gabriele A1 - Aschner, Michael A1 - Haase, Hajo A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Zn homeostasis in genetic models of Parkinson’s disease in Caenorhabditis elegans JF - Journal of Trace Elements in Medicine and Biology N2 - 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. KW - Caenorhabditis elegans KW - Zinc KW - Zinc homeostasis KW - Parkinson disease KW - Labile zinc Y1 - 2019 U6 - https://doi.org/10.1016/j.jtemb.2019.05.005 VL - 55 SP - 44 EP - 49 PB - Elsevier CY - München ER - TY - JOUR A1 - Rausch, Ann-Kristin A1 - Brockmeyer, Robert A1 - Schwerdtle, Tanja T1 - Development and Validation of a QuEChERS-Based Liquid Chromatography Tandem Mass Spectrometry Multi-Method for the Determination of 38 Native and Modified Mycotoxins in Cereals JF - Journal of Agricultural and Food Chemistry N2 - Here, a reliable and sensitive method for the determination of 38 (modified) mycotoxins was developed. Using a QuEChERS-based extraction method [acetonitrile/water/formic acid (75:20:5, v/v/v)], followed by two runs of high performance liquid chromatography tandem mass spectrometry with different conditions, relevant mycotoxins in cereals were analyzed. The method was validated according to the performance criteria defined by the European Commission (EC) in Commission Decision no. 657/2002. Limits of quantification ranged from 0.05 to 150 μg/kg. Good linearity (R2 > 0.99), recovery (61–120%), repeatability (RSDr < 15%), and reproducibility (RSDR < 20%) were obtained for most mycotoxins. However, validation results for Alternaria toxins and fumonisins were unsatisfying. Matrix effects (−69 to +59%) were compensated for using standard addition. Application on reference materials gave correct results while analysis of samples from local retailers revealed contamination, especially with deoxynivalenol, deoxynivalenol-3-glucoside, fumonisins, and zearalenone, in concentrations up to 369, 58, 1002, and 21 μg/kg, respectively. KW - multi-mycotoxin analysis KW - modified mycotoxins KW - QuEChERS KW - LC−MS/MS KW - cereals KW - validation Y1 - 2020 U6 - https://doi.org/10.1021/acs.jafc.9b07491 SN - 0021-8561 VL - 68 IS - 16 SP - 4657 EP - 4669 PB - ACS Publications CY - Washington, DC ER - TY - JOUR A1 - Rausch, Ann-Kristin A1 - Brockmeyer, Robert A1 - Schwerdtle, Tanja T1 - Development, validation, and application of a multi-method for the determination of mycotoxins, plant growth regulators, tropane alkaloids, and pesticides in cereals by two-dimensional liquid chromatography tandem mass spectrometry JF - Analytical & bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica N2 - Mycotoxins and pesticides regularly co-occur in agricultural products worldwide. Thus, humans can be exposed to both toxic contaminants and pesticides simultaneously, and multi-methods assessing the occurrence of various food contaminants and residues in a single method are necessary. A two-dimensional high performance liquid chromatography tandem mass spectrometry method for the analysis of 40 (modified) mycotoxins, two plant growth regulators, two tropane alkaloids, and 334 pesticides in cereals was developed. After an acetonitrile/water/formic acid (79:20:1, v/v/v) multi-analyte extraction procedure, extracts were injected into the two-dimensional setup, and an online clean-up was performed. The method was validated according to Commission Decision (EC) no. 657/2002 and document N° SANTE/12682/2019. Good linearity (R2 > 0.96), recovery data between 70-120%, repeatability and reproducibility values < 20%, and expanded measurement uncertainties < 50% were obtained for a wide range of analytes, including very polar substances like deoxynivalenol-3-glucoside and methamidophos. However, results for fumonisins, zearalenone-14,16-disulfate, acid-labile pesticides, and carbamates were unsatisfying. Limits of quantification meeting maximum (residue) limits were achieved for most analytes. Matrix effects varied highly (−85 to +1574%) and were mainly observed for analytes eluting in the first dimension and early-eluting analytes in the second dimension. The application of the method demonstrated the co-occurrence of different types of cereals with 28 toxins and pesticides. Overall, 86% of the samples showed positive findings with at least one mycotoxin, plant growth regulator, or pesticide. KW - 2D-LC-MS/MS KW - Multi-method KW - Mycotoxins KW - Modified mycotoxins KW - Pesticides KW - Cereals Y1 - 2021 U6 - https://doi.org/10.1007/s00216-021-03239-1 SN - 1618-2650 SN - 1618-2642 VL - 413 IS - 11 SP - 3041 EP - 3054 PB - Springer CY - Berlin ER - TY - JOUR A1 - Rausch, Ann-Kristin A1 - Brockmeyer, Robert A1 - Schwerdtle, Tanja T1 - Development and validation of a liquid chromatography tandem mass spectrometry multi-method for the determination of 41 free and modified mycotoxins in beer JF - Food chemistry N2 - A fast high performance liquid chromatography tandem mass spectrometry multi-method based on an ACN-precipitation extraction was developed for the analysis of 41 (modified) mycotoxins in beer. Validation according to the performance criteria defined by the European Commission (EC) in Commission Decision no. 657/2002 revealed good linearity (R2 > 0.99), repeatability (RSDr < 15%), reproducibility (RSDR < 15%), and recovery (79–100%). Limits of quantification ranging from 0.04 to 75 µg/L were obtained. Matrix effects varied from −67 to +319% and were compensated for using standard addition. In total, 87 beer samples, produced worldwide, were analyzed for the presence of mycotoxins with a focus on modified mycotoxins, whereof 76% of the samples were contaminated with at least one mycotoxin. The most prevalent mycotoxins were deoxynivalenol-3-glucoside (63%), HT-2 toxin (15%), and tenuazonic acid (13%). Exposure estimates of deoxynivalenol and its metabolites for German beer revealed no significant contribution to intake of deoxynivalenol. KW - Multi-mycotoxin analysis KW - Modified mycotoxins KW - LC–MS/MS KW - Beer KW - Validation Y1 - 2020 U6 - https://doi.org/10.1016/j.foodchem.2020.127801 SN - 1873-7072 SN - 0308-8146 VL - 338 PB - Elsevier CY - New York, NY ER - TY - JOUR A1 - Turrini, Nikolaus G. A1 - Kroepfl, Nina A1 - Jensen, Kenneth Bendix A1 - Reiter, Tamara C. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja A1 - Kroutil, Wolfgang A1 - Kuehnelt, Doris T1 - Biosynthesis and isolation of selenoneine from genetically modified fission yeast JF - Metallomics : integrated biometal science N2 - Selenoneine, a naturally occurring form of selenium, is the selenium analogue of ergothioneine, a sulfur species with health relevance not only as a purported antioxidant but likely also beyond. Selenoneine has been speculated to exhibit similar effects. To study selenoneine's health properties as well as its metabolic transformation, the pure compound is required. Chemical synthesis of selenoneine, however, is challenging and biosynthetic approaches have been sought. We herein report the biosynthesis and isolation of selenoneine from genetically modified fission yeast Schizosaccharomyces pombe grown in a medium containing sodium selenate. After cell lysis and extraction with methanol, selenoneine was purified by three consecutive preparative reversed-phase HPLC steps. The product obtained at the mg level was characterised by high resolution mass spectrometry, NMR and HPLC/ICPMS. Biosynthesis was found to be a promising alternative to chemical synthesis, and should be suitable for upscaling to produce higher amounts of this important selenium species in the future. Y1 - 2018 U6 - https://doi.org/10.1039/c8mt00200b SN - 1756-5901 SN - 1756-591X VL - 10 IS - 10 SP - 1532 EP - 1538 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Kroepfl, Nina A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja A1 - Kuehnelt, Doris T1 - Selenoneine and ergothioneine in human blood cells determined simultaneously by HPLC/ICP-QQQ-MS JF - Journal of Analytical Atomic Spectrometry N2 - The possible relevance to human health of selenoneine and its sulfur-analogue ergothioneine has generated interest in their quantitative determination in biological samples. To gain more insight into the similarities and differences of these two species, a method for their simultaneous quantitative determination in human blood cells using reversed-phase high performance liquid chromatography (RP-HPLC) coupled to inductively coupled plasma triple quadrupole mass spectrometry (ICP-QQQ-MS) is presented. Spectral interferences hampering the determination of sulfur and selenium by ICPMS are overcome by introducing oxygen to the reaction cell. To access selenoneine and ergothioneine in the complex blood matrix, lysis of the cells with cold water followed by cut-off filtration (3000 Da) is performed. Recoveries based on blood cells spiked with selenoneine and ergothioneine were between 80% and 85%. The standard deviation of the method was around 0.10 mg S per L for ergothioneine (corresponding to relative standard deviations (RSD) between 10-1% for ergothioneine concentrations of 1-10 mg S per L) and 0.25 g Se per L for selenoneine (RSDs of 25-2% for concentrations of 1-10 g Se per L). The method was applied to blood cell samples from three volunteers which showed selenoneine and ergothioneine concentrations in the range of 3.25 to 7.35 g Se per L and 0.86 to 6.44 mg S per L, respectively. The method is expected to be of wide use in future studies investigating the dietary uptake of selenoneine and ergothioneine and their relevance in human health. Y1 - 2018 U6 - https://doi.org/10.1039/c8ja00276b SN - 0267-9477 SN - 1364-5544 VL - 34 IS - 1 SP - 127 EP - 134 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Ruszkiewicz, Joanna A. A1 - de Macedo, Gabriel Teixeira A1 - Miranda-Vizuete, Antonio A1 - Bowman, Aaron B. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Antunes Soares, Felix A. A1 - Aschner, Michael T1 - Sex-Specific response of caenorhabditis elegans to Methylmercury Toxicity JF - Neurotoxicity Research N2 - Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observedmales exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans. KW - Methylmercury KW - Sex KW - Male KW - C KW - elegans KW - Antioxidant KW - Thioredoxin Y1 - 2019 U6 - https://doi.org/10.1007/s12640-018-9949-4 SN - 1029-8428 SN - 1476-3524 VL - 35 IS - 1 SP - 208 EP - 216 PB - Springer CY - New York ER - TY - JOUR A1 - Peres, Tanara V. A1 - Horning, Kyle J. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Bowman, Aaron B. A1 - Aschner, Michael T1 - Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo JF - Biological Trace Element Research N2 - 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. KW - Small molecules KW - Manganese KW - Neurotoxicity KW - C. elegans KW - Dopamine Y1 - 2018 U6 - https://doi.org/10.1007/s12011-018-1531-7 SN - 0163-4984 SN - 1559-0720 VL - 188 IS - 1 SP - 127 EP - 134 PB - Human press inc. CY - Totowa ER - TY - JOUR A1 - Duydu, Yalcin A1 - Basaran, Nursen A1 - Yalcin, Can Özgür A1 - Ustundag, Aylin A1 - Aydin, Sevtap A1 - Anlar, Hatice Gul A1 - Bacanli, Merve A1 - Aydos, Kaan A1 - Atabekoglu, Cem Somer A1 - Golka, Klaus A1 - Ickstadt, Katja A1 - Schwerdtle, Tanja A1 - Werner, Matthias A1 - Bolt, Hermann M. T1 - Boron-exposed male workers in Turkey BT - no change in sperm Y:X chromosome ratio and in offspring's sex ratio JF - Archives of toxicology : official journal of EUROTOX N2 - 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. KW - Paternal exposure KW - Boron exposure KW - Y:X chromosome ratio KW - Sex ratio at birth Y1 - 2019 U6 - https://doi.org/10.1007/s00204-019-02391-z SN - 0340-5761 SN - 1432-0738 VL - 93 IS - 3 SP - 743 EP - 751 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Schutkowski, Alexandra A1 - König, Bettina A1 - Kluge, Holger A1 - Hirche, Frank A1 - Henze, Andrea A1 - Schwerdtle, Tanja A1 - Lorkowski, Stefan A1 - Dawczynski, Christine A1 - Gabel, Alexander A1 - Grosse, Ivo A1 - Stangl, Gabriele I. T1 - Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model JF - The journal of nutritional biochemistry N2 - Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved. KW - Lupin KW - Beef KW - Casein KW - Pig KW - Biomarker KW - Microbiome Y1 - 2019 U6 - https://doi.org/10.1016/j.jnutbio.2019.02.004 SN - 0955-2863 SN - 1873-4847 VL - 67 SP - 149 EP - 160 PB - Elsevier CY - New York ER - TY - JOUR A1 - Kotthoff, Lisa A1 - Lisec, Jan A1 - Schwerdtle, Tanja A1 - Koch, Matthias T1 - Prediction of transformation products of monensin by electrochemistry compared to microsomal assay and hydrolysis JF - Molecules N2 - The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation. KW - transformation products KW - monensin KW - veterinary drugs KW - electrochemistry KW - hydrolysis KW - LC/HRMS Y1 - 2019 U6 - https://doi.org/10.3390/molecules24152732 SN - 1420-3049 VL - 24 IS - 15 PB - MDPI CY - Basel ER - TY - JOUR A1 - Rohn, Isabelle A1 - Raschke, Stefanie A1 - Aschner, Michael A1 - Tuck, Simon A1 - Kuehnelt, Doris A1 - Kipp, Anna Patricia A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Treatment of caenorhabditis elegans with small selenium species enhances antioxidant defense systems JF - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology N2 - 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. KW - antioxidant defense systems KW - caenorhabditis elegans KW - selenium KW - oxidative stress KW - selenoproteins Y1 - 2019 U6 - https://doi.org/10.1002/mnfr.201801304 SN - 1613-4125 SN - 1613-4133 VL - 63 IS - 9 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Başaran, Nurşen A1 - Duydu, Yalçın A1 - Üstündağ, Aylin A1 - Taner, Gökçe A1 - Aydin Dilsiz, Sevtap A1 - Anlar, Hatice Gül A1 - Yalçin, Can Özgür A1 - Bacanli, Merve A1 - Golka, Klaus A1 - Schwerdtle, Tanja A1 - Bolt, Hermann M. T1 - Environmental boron exposure does not induce DNA damage in lymphocytes and buccal cells of females DNA damage in lymphocytes and buccal cells of boron exposed females JF - Journal of trace elements in medicine and biology N2 - Boron (B) compounds are essential for plants and animals and beneficial for humans in nutritional amounts. I animals and humans increasing evidence have shown beneficial effects on B compounds on nutrition and on antioxidant status. The genotoxic effects of environmental B exposure in women living in boron-rich and boronpoor areas was examined in this study. For this purpose, the DNA damage in the lymphocytes and buccal cells of females were assessed by Comet and micronucleus (MN) assays respectively. No significant difference was observed in the DNA damage of the lymphocytes of B exposed groups of female volunteers in Comet assay. Even buccal micronucleus (MN) frequency observed in the high exposure group was significantly lower than the low exposure group (p < 0.05). The results of this study came to the same conclusions of the previous studies that boron does not induce DNA damage even under extreme exposure conditions. KW - Boric acid KW - Boron exposure KW - DNA damage Y1 - 2019 U6 - https://doi.org/10.1016/j.jtemb.2019.03.004 SN - 0946-672X VL - 53 SP - 150 EP - 153 PB - Elsevier B.V. CY - München ER -