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 - Meyer, Sören A1 - Matissek, M. A1 - Müller, Sandra Marie A1 - Taleshi, M. S. A1 - Ebert, Franziska A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - In vitro toxicological characterisation of three arsenic-containing hydrocarbons JF - Metallomics N2 - Arsenic-containing hydrocarbons are one group of fat-soluble organic arsenic compounds (arsenolipids) found in marine fish and other seafood. A risk assessment of arsenolipids is urgently needed, but has not been possible because of the total lack of toxicological data. In this study the cellular toxicity of three arsenic-containing hydrocarbons was investigated in cultured human bladder (UROtsa) and liver (HepG2) cells. Cytotoxicity of the arsenic-containing hydrocarbons was comparable to that of arsenite, which was applied as the toxic reference arsenical. A large cellular accumulation of arsenic, as measured by ICP-MS/MS, was observed after incubation of both cell lines with the arsenolipids. Moreover, the toxic mode of action shown by the three arsenic-containing hydrocarbons seemed to differ from that observed for arsenite. Evidence suggests that the high cytotoxic potential of the lipophilic arsenicals results from a decrease in the cellular energy level. This first in vitro based risk assessment cannot exclude a risk to human health related to the presence of arsenolipids in seafood, and indicates the urgent need for further toxicity studies in experimental animals to fully assess this possible risk. KW - cod-liver KW - human-cells KW - arsenolipids present KW - excision-repair KW - fatty-acids KW - marine oils KW - RP-HPLC KW - metabolites KW - identification KW - trivalent Y1 - 2014 U6 - https://doi.org/10.1039/c4mt00061g SN - 1756-591X SN - 1756-5901 VL - 2014 IS - 6 SP - 1023 EP - 1033 ER - TY - GEN A1 - Meyer, Sören A1 - Matissek, M. A1 - Müller, Sandra Marie A1 - Taleshi, M. S. A1 - Ebert, Franziska A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - In vitro toxicological characterisation of three arsenic-containing hydrocarbons N2 - Arsenic-containing hydrocarbons are one group of fat-soluble organic arsenic compounds (arsenolipids) found in marine fish and other seafood. A risk assessment of arsenolipids is urgently needed, but has not been possible because of the total lack of toxicological data. In this study the cellular toxicity of three arsenic-containing hydrocarbons was investigated in cultured human bladder (UROtsa) and liver (HepG2) cells. Cytotoxicity of the arsenic-containing hydrocarbons was comparable to that of arsenite, which was applied as the toxic reference arsenical. A large cellular accumulation of arsenic, as measured by ICP-MS/MS, was observed after incubation of both cell lines with the arsenolipids. Moreover, the toxic mode of action shown by the three arsenic-containing hydrocarbons seemed to differ from that observed for arsenite. Evidence suggests that the high cytotoxic potential of the lipophilic arsenicals results from a decrease in the cellular energy level. This first in vitro based risk assessment cannot exclude a risk to human health related to the presence of arsenolipids in seafood, and indicates the urgent need for further toxicity studies in experimental animals to fully assess this possible risk. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - paper 170 KW - cod-liver KW - human-cells KW - arsenolipids present KW - excision-repair KW - fatty-acids KW - marine oils KW - RP-HPLC KW - metabolites KW - identification KW - trivalent Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-74201 SP - 1023 EP - 1033 ER - TY - JOUR A1 - Unterberg, Marlies A1 - Leffers, Larissa A1 - Hübner, Florian A1 - Humpf, Hans-Ulrich A1 - Lepikhov, Konstantin A1 - Walter, Jörn A1 - Ebert, Franziska A1 - Schwerdtle, Tanja T1 - Toxicity of arsenite and thio-DMAV after long-term (21 days) incubation of human urothelial cells: cytotoxicity, genotoxicity and epigenetics JF - Toxicology Research N2 - This study aims to further mechanistically understand toxic modes of action after chronic inorganic arsenic exposure. Therefore long-term incubation studies in cultured cells were carried out, to display chronically attained changes, which cannot be observed in the generally applied in vitro short-term incubation studies. Particularly, the cytotoxic, genotoxic and epigenetic effects of an up to 21 days incubation of human urothelial (UROtsa) cells with pico- to nanomolar concentrations of iAsIII and its metabolite thio-DMAV were compared. After 21 days of incubation, cytotoxic effects were strongly enhanced in the case of iAsIII and might partly be due to glutathione depletion and genotoxic effects on the chromosomal level. These results are in strong contrast to cells exposed to thio-DMAV. Thus, cells seemed to be able to adapt to this arsenical, as indicated among others by an increase in the cellular glutathione level. Most interestingly, picomolar concentrations of both iAsIII and thio-DMAV caused global DNA hypomethylation in UROtsa cells, which was quantified in parallel by 5-medC immunostaining and a newly established, reliable, high resolution mass spectrometry (HRMS)-based test system. This is the first time that epigenetic effects are reported for thio-DMAV; iAsIII induced epigenetic effects occur in at least 8000 fold lower concentrations as reported in vitro before. The fact that both arsenicals cause DNA hypomethylation at really low, exposure-relevant concentrations in human urothelial cells suggests that this epigenetic effect might contribute to inorganic arsenic induced carcinogenicity, which for sure has to be further investigated in future studies. KW - induced malignant-transformation KW - genomic dna methylation KW - vitro toxicological characterization KW - thio-dimethylarsinic acid KW - bladder-cancer KW - methyltransferases dnmt3a KW - cytosine methylation KW - carcinogen exposure KW - mass-spectrometry KW - gene-expression Y1 - 2014 SN - 2045-4538 SN - 2045-452X VL - 3 IS - 6 SP - 456 EP - 464 PB - Royal Society of Chemistry CY - Cambridge ER - TY - GEN A1 - Unterberg, Marlies A1 - Leffers, Larissa A1 - Hübner, Florian A1 - Humpf, Hans-Ulrich A1 - Lepikhov, Konstantin A1 - Walter, Jörn A1 - Ebert, Franziska A1 - Schwerdtle, Tanja T1 - Toxicity of arsenite and thio-DMAV after long-term (21 days) incubation of human urothelial cells: cytotoxicity, genotoxicity and epigenetics N2 - This study aims to further mechanistically understand toxic modes of action after chronic inorganic arsenic exposure. Therefore long-term incubation studies in cultured cells were carried out, to display chronically attained changes, which cannot be observed in the generally applied in vitro short-term incubation studies. Particularly, the cytotoxic, genotoxic and epigenetic effects of an up to 21 days incubation of human urothelial (UROtsa) cells with pico- to nanomolar concentrations of iAsIII and its metabolite thio-DMAV were compared. After 21 days of incubation, cytotoxic effects were strongly enhanced in the case of iAsIII and might partly be due to glutathione depletion and genotoxic effects on the chromosomal level. These results are in strong contrast to cells exposed to thio-DMAV. Thus, cells seemed to be able to adapt to this arsenical, as indicated among others by an increase in the cellular glutathione level. Most interestingly, picomolar concentrations of both iAsIII and thio-DMAV caused global DNA hypomethylation in UROtsa cells, which was quantified in parallel by 5-medC immunostaining and a newly established, reliable, high resolution mass spectrometry (HRMS)-based test system. This is the first time that epigenetic effects are reported for thio-DMAV; iAsIII induced epigenetic effects occur in at least 8000 fold lower concentrations as reported in vitro before. The fact that both arsenicals cause DNA hypomethylation at really low, exposure-relevant concentrations in human urothelial cells suggests that this epigenetic effect might contribute to inorganic arsenic induced carcinogenicity, which for sure has to be further investigated in future studies. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 178 KW - induced malignant-transformation KW - genomic dna methylation KW - vitro toxicological characterization KW - thio-dimethylarsinic acid KW - bladder-cancer KW - methyltransferases dnmt3a KW - cytosine methylation KW - carcinogen exposure KW - mass-spectrometry KW - gene-expression Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-76239 SP - 456 EP - 464 ER - TY - JOUR A1 - Meyer, S. A1 - Raber, G. A1 - Ebert, Franziska A1 - Leffers, L. A1 - Müller, Sandra Marie A1 - Taleshi, M. S. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - In vitro toxicological characterisation of arsenic-containing fatty acids and three of their metabolites JF - Toxicology research N2 - Arsenic-containing fatty acids are a group of fat-soluble arsenic species (arsenolipids) which are present in marine fish and other seafood. Recently, it has been shown that arsenic-containing hydrocarbons, another group of arsenolipids, exert toxicity in similar concentrations comparable to arsenite although the toxic modes of action differ. Hence, a risk assessment of arsenolipids is urgently needed. In this study the cellular toxicity of a saturated (AsFA 362) and an unsaturated (AsFA 388) arsenic-containing fatty acid and three of their proposed metabolites (DMAV, DMAPr and thio-DMAPr) were investigated in human liver cells (HepG2). Even though both arsenic-containing fatty acids were less toxic as compared to arsenic-containing hydrocarbons and arsenite, significant effects were observable at μM concentrations. DMAV causes effects in a similar concentration range and it could be seen that it is metabolised to its highly toxic thio analogue thio-DMAV in HepG2 cells. Nevertheless, DMAPr and thio-DMAPr did not exert any cytotoxicity. In summary, our data indicate that risks to human health related to the presence of arsenic-containing fatty acids in marine food cannot be excluded. This stresses the need for a full in vitro and in vivo toxicological characterisation of these arsenolipids. Y1 - 2015 U6 - https://doi.org/10.1039/c5tx00122f SN - 2045-4538 VL - 5 IS - 4 SP - 1289 EP - 1296 PB - Royal Society of Chemistry CY - Cambridge ER - TY - GEN A1 - Meyer, S. A1 - Raber, G. A1 - Ebert, Franziska A1 - Leffers, L. A1 - Müller, Sandra Marie A1 - Taleshi, M. S. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - In vitro toxicological characterisation of arsenic-containing fatty acids and three of their metabolites N2 - Arsenic-containing fatty acids are a group of fat-soluble arsenic species (arsenolipids) which are present in marine fish and other seafood. Recently, it has been shown that arsenic-containing hydrocarbons, another group of arsenolipids, exert toxicity in similar concentrations comparable to arsenite although the toxic modes of action differ. Hence, a risk assessment of arsenolipids is urgently needed. In this study the cellular toxicity of a saturated (AsFA 362) and an unsaturated (AsFA 388) arsenic-containing fatty acid and three of their proposed metabolites (DMAV, DMAPr and thio-DMAPr) were investigated in human liver cells (HepG2). Even though both arsenic-containing fatty acids were less toxic as compared to arsenic-containing hydrocarbons and arsenite, significant effects were observable at μM concentrations. DMAV causes effects in a similar concentration range and it could be seen that it is metabolised to its highly toxic thio analogue thio-DMAV in HepG2 cells. Nevertheless, DMAPr and thio-DMAPr did not exert any cytotoxicity. In summary, our data indicate that risks to human health related to the presence of arsenic-containing fatty acids in marine food cannot be excluded. This stresses the need for a full in vitro and in vivo toxicological characterisation of these arsenolipids. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 199 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-82008 ER - TY - JOUR A1 - Pieper, Imke A1 - Wehe, Christoph A. A1 - Bornhorst, Julia A1 - Ebert, Franziska A1 - Leffers, Larissa A1 - Holtkamp, Michael A1 - Höseler, Pia A1 - Weber, Till A1 - Mangerich, Aswin A1 - Bürkle, Alexander A1 - Karst, Uwe A1 - Schwerdtle, Tanja T1 - Mechanisms of Hg species induced toxicity in cultured human astrocytes BT - genotoxicity and DNA-damage response JF - Metallomics N2 - The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co-genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl)ation contributes to organic Hg induced neurotoxicity. KW - cell-death KW - poly(ADP-ribose) polymerase-1 KW - neurodegenerative diseases KW - adduct formation KW - thimerosal KW - methylmercury KW - repair KW - neurotoxicity KW - manganese KW - exposure Y1 - 2014 U6 - https://doi.org/10.1039/c3mt00337j SN - 1756-591X SN - 1756-5901 VL - 2014 IS - 6 SP - 662 EP - 671 ER - TY - GEN A1 - Pieper, Imke A1 - Wehe, Christoph A. A1 - Bornhorst, Julia A1 - Ebert, Franziska A1 - Leffers, Larissa A1 - Holtkamp, Michael A1 - Höseler, Pia A1 - Weber, Till A1 - Mangerich, Aswin A1 - Bürkle, Alexander A1 - Karst, Uwe A1 - Schwerdtle, Tanja T1 - Mechanisms of Hg species induced toxicity in cultured human astrocytes BT - genotoxicity and DNA-damage response N2 - The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - paper 171 KW - adduct formation KW - cell-death KW - exposure KW - manganese KW - methylmercury KW - neurodegenerative diseases KW - neurotoxicity KW - poly(ADP-ribose) polymerase-1 KW - repair KW - thimerosal Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-74379 SP - 662 EP - 671 ER - TY - JOUR A1 - Crone, Barbara A1 - Aschner, Michael A. A1 - Schwerdtle, Tanja A1 - Karst, Uwe A1 - Bornhorst, Julia T1 - Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS JF - Metallomics N2 - cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 μm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00096c SN - 1756-591X SN - 1756-5901 VL - 2015 IS - 7 SP - 1189 EP - 1195 PB - Royal Society of Chemistry CY - Cambridge ER -