@article{ZhouPanZhangetal.2020, author = {Zhou, Suqiong and Pan, Yuanwei and Zhang, Jianguang and Li, Yan and Neumann, Falko and Schwerdtle, Tanja and Li, Wenzhong and Haag, Rainer}, title = {Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells}, series = {Nanoscale}, volume = {12}, journal = {Nanoscale}, number = {47}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2040-3364}, doi = {10.1039/d0nr06570f}, pages = {24006 -- 24019}, year = {2020}, abstract = {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.}, language = {en} } @article{EbertZiemannWandtetal.2020, author = {Ebert, Franziska and Ziemann, Vanessa and Wandt, Viktoria Klara Veronika and Witt, Barbara and M{\"u}ller, Sandra Marie and Guttenberger, Nikolaus and Bankoglu, Ezgi Eyluel and Stopper, Helga and Raber, Georg and Francesconi, Kevin A. and Schwerdtle, Tanja}, title = {Cellular toxicological characterization of a thioxolated arsenic-containing hydrocarbon}, series = {Journal of trace elements in medicine and biology}, volume = {61}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier}, address = {M{\"u}nchen}, doi = {10.1016/j.jtemb.2020.126563}, year = {2020}, abstract = {Arsenolipids, especially arsenic-containing hydrocarbons (AsHC), are an emerging class of seafood originating contaminants. Here we toxicologically characterize a recently identified oxo-AsHC 332 metabolite, thioxo-AsHC 348 in cultured human liver (HepG2) cells. Compared to results of previous studies of the parent compound oxo-AsHC 332, thioxo-AsHC 348 substantially affected cell viability in the same concentration range but exerted about 10-fold lower cellular bioavailability. Similar to oxo-AsHC 332, thioxo-AsHC 348 did not substantially induce oxidative stress nor DNA damage. Moreover, in contrast to oxo-AsHC 332 mitochondria seem not to be a primary subcellular toxicity target for thioxo-AsHC 348. This study indicates that thioxo-AsHC 348 is at least as toxic as its parent compound oxo-AsHC 332 but very likely acts via a different mode of toxic action, which still needs to be identified.}, language = {en} } @article{KotthoffO'CallaghanLisecetal.2020, author = {Kotthoff, Lisa and O'Callaghan, Sarah-Louise and Lisec, Jan and Schwerdtle, Tanja and Koch, Matthias}, title = {Structural annotation of electro- and photochemically generated transformation products of moxidectin using high-resolution mass spectrometry}, series = {Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica}, volume = {412}, journal = {Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica}, number = {13}, publisher = {Springer}, address = {Heidelberg}, issn = {1618-2642}, doi = {10.1007/s00216-020-02572-1}, pages = {3141 -- 3152}, year = {2020}, abstract = {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.}, language = {en} } @article{RauschBrockmeyerSchwerdtle2020, author = {Rausch, Ann-Kristin and Brockmeyer, Robert and Schwerdtle, Tanja}, title = {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}, series = {Journal of Agricultural and Food Chemistry}, volume = {68}, journal = {Journal of Agricultural and Food Chemistry}, number = {16}, publisher = {ACS Publications}, address = {Washington, DC}, issn = {0021-8561}, doi = {10.1021/acs.jafc.9b07491}, pages = {4657 -- 4669}, year = {2020}, abstract = {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.}, language = {en} } @article{DuenkelbergMaywaldSchmittetal.2020, author = {D{\"u}nkelberg, Sophie and Maywald, Martina and Schmitt, Anne Kristina and Schwerdtle, Tanja and Meyer, S{\"o}ren and Rink, Lothar}, title = {The interaction of sodium and zinc in the priming of T cell subpopulations regarding Th17 and Treg cells}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {64}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {2}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1613-4133}, doi = {10.1002/mnfr.201900245}, pages = {10}, year = {2020}, abstract = {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.}, language = {en} } @article{FinkeWandtEbertetal.2020, author = {Finke, Hannah and Wandt, Viktoria Klara Veronika and Ebert, Franziska and Guttenberger, Nikolaus and Glabonjat, Ronald A. and Stiboller, Michael and Francesconi, Kevin A. and Raber, Georg and Schwerdtle, Tanja}, title = {Toxicological assessment of arsenic-containing phosphatidylcholines in HepG2 cells}, volume = {12}, number = {7}, publisher = {Oxford University}, address = {Cambridge}, doi = {10.1039/d0mt00073f}, pages = {1159 -- 1170}, year = {2020}, abstract = {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.}, language = {en} } @article{FinkeWinkelbeinerLossowetal.2020, author = {Finke, Hannah and Winkelbeiner, Nicola Lisa and Lossow, Kristina and Hertel, Barbara and Wandt, Viktoria Klara Veronika and Schwarz, Maria and Pohl, Gabriele and Kopp, Johannes Florian and Ebert, Franziska and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {Effects of a Cumulative, Suboptimal Supply of Multiple Trace Elements in Mice}, series = {Molecular nutrition \& food research}, volume = {64}, journal = {Molecular nutrition \& food research}, number = {16}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1613-4125}, doi = {10.1002/mnfr.202000325}, year = {2020}, abstract = {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.}, language = {en} } @article{MuellerHelmsRohreretal.2020, author = {M{\"u}ller, Anke Katharina and Helms, Ute and Rohrer, Carsten and M{\"o}hler, Monika and Hellwig, Frank and Glei, Michael and Schwerdtle, Tanja and Lorkowski, Stefan and Dawczynski, Christine}, title = {Nutrient composition of different hazelnut cultivars grown in Germany}, series = {Foods}, volume = {9}, journal = {Foods}, number = {11}, publisher = {MDPI}, address = {Basel}, issn = {2304-8158}, doi = {10.3390/foods9111596}, pages = {11}, year = {2020}, abstract = {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.}, language = {en} } @article{WittSchaumloeffelSchwerdtle2020, author = {Witt, Barbara and Schauml{\"o}ffel, Dirk and Schwerdtle, Tanja}, title = {Subcellular Localization of Copper}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {7}, publisher = {Molecular Diversity Preservation International}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms21072341}, pages = {25}, year = {2020}, abstract = {As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer's disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.}, language = {en} } @article{MuellerDawczynskiWiestetal.2020, author = {M{\"u}ller, Sandra and Dawczynski, Christine and Wiest, Johanna and Lorkowski, Stefan and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {Functional Biomarkers for the Selenium Status in a Human Nutritional Intervention Study}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {3}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu12030676}, pages = {14}, year = {2020}, abstract = {Soils in Germany are commonly low in selenium; consequently, a sufficient dietary supply is not always ensured. The extent of such provision adequacy is estimated by the optimal effect range of biomarkers, which often reflects the physiological requirement. Preceding epidemiological studies indicate that low selenium serum concentrations could be related to cardiovascular diseases. Inter alia, risk factors for cardiovascular diseases are physical inactivity, overweight, as well as disadvantageous eating habits. In order to assess whether these risk factors can be modulated, a cardio-protective diet comprising fixed menu plans combined with physical exercise was applied in the German MoKaRi (modulation of cardiovascular risk factors) intervention study. We analyzed serum samples of the MoKaRi cohort (51 participants) for total selenium, GPx activity, and selenoprotein P at different timepoints of the study (0, 10, 20, 40 weeks) to explore the suitability of these selenium-associated markers as indicators of selenium status. Overall, the time-dependent fluctuations in serum selenium concentration suggest a successful change in nutritional and lifestyle behavior. Compared to baseline, a pronounced increase in GPx activity and selenoprotein P was observed, while serum selenium decreased in participants with initially adequate serum selenium content. SELENOP concentration showed a moderate positive monotonic correlation (r = 0.467, p < 0.0001) to total Se concentration, while only a weak linear relationship was observed for GPx activity versus total Se concentration (r = 0.186, p = 0.021). Evidently, other factors apart from the available Se pool must have an impact on the GPx activity, leading to the conclusion that, without having identified these factors, GPx activity should not be used as a status marker for Se}, language = {en} } @article{VolkBrandschSchlegelmilchetal.2020, author = {Volk, Christin and Brandsch, Corinna and Schlegelmilch, Ulf and Wensch-Dorendorf, Monika and Hirche, Frank and Simm, Andreas and Gargum, Osama and Wiacek, Claudia and Braun, Peggy G. and Kopp, Johannes F. and Schwerdtle, Tanja and Treede, Hendrik and Stangl, Gabriele I.}, title = {Postprandial metabolic response to rapeseed protein in healthy subjects}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {8}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu12082270}, pages = {22}, year = {2020}, abstract = {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.}, language = {en} } @article{BornhorstEbertMeyeretal.2020, author = {Bornhorst, Julia and Ebert, Franziska and Meyer, S{\"o}ren and Ziemann, Vanessa and Xiong, Chan and Guttenberger, Nikolaus and Raab, Andrea and Baesler, Jessica and Aschner, Michael and Feldmann, J{\"o}rg and Francesconi, Kevin and Raber, Georg and Schwerdtle, Tanja}, title = {Toxicity of three types of arsenolipids}, series = {Metallomics}, volume = {12}, journal = {Metallomics}, number = {5}, publisher = {Oxford University Press}, address = {Cambridge}, issn = {1756-591X}, doi = {https://doi.org/10.1039/d0mt00039f}, pages = {794 -- 798}, year = {2020}, abstract = {Although fish and seafood are well known for their nutritional benefits, they contain contaminants that might affect human health. Organic lipid-soluble arsenic species, so called arsenolipids, belong to the emerging contaminants in these food items; their toxicity has yet to be systematically studied. Here, we apply the in vivo model Caenorhabditis elegans to assess the effects of two arsenic-containing hydrocarbons (AsHC), a saturated arsenic-containing fatty acid (AsFA), and an arsenic-containing triacylglyceride (AsTAG) in a whole organism. Although all arsenolipids were highly bioavailable in Caenorhabditis elegans, only the AsHCs were substantially metabolized to thioxylated or shortened metabolic products and induced significant toxicity, affecting both survival and development. Furthermore, the AsHCs were several fold more potent as compared to the toxic reference arsenite. This study clearly indicates the need for a full hazard identification of subclasses of arsenolipids to assess whether they pose a risk to human health.}, language = {en} } @article{NicolaiBaeslerAschneretal.2020, author = {Nicolai, Merle Marie and Baesler, Jessica and Aschner, Michael and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Consequences of manganese overload in C. elegans}, series = {Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft f{\"u}r Experimentelle und Klinische Pharmakologie und Toxikologie}, volume = {393}, journal = {Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft f{\"u}r Experimentelle und Klinische Pharmakologie und Toxikologie}, number = {SUPPL 1}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, doi = {10.1007/s00210-020-01828-y}, pages = {9 -- 9}, year = {2020}, language = {en} } @article{WinkelbeinerWandtEbertetal.2020, author = {Winkelbeiner, Nicola Lisa and Wandt, Viktoria Klara Veronika and Ebert, Franziska and Lossow, Kristina and Bankoglu, Ezgi E. and Martin, Maximilian and Mangerich, Aswin and Stopper, Helga and Bornhorst, Julia and Kipp, Anna Patricia and Schwerdtle, Tanja}, title = {A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {18}, publisher = {Molecular Diversity Preservation International}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms21186600}, pages = {19}, year = {2020}, abstract = {Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2'-deoxyguanosine (8-oxodG), 5-hydroxy-2'-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.}, language = {en} }