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  - 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  - 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  - GEN
A1  - Kumar, Kevin K.
A1  - Goodwin, Cody R.
A1  - Uhouse, Michael A.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael A.
A1  - McLean, John A.
A1  - Bowman, Aaron B.
T1  - Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status
N2  - Manganese (Mn) is an essential micronutrient for development and function of the nervous system. Deficiencies in Mn transport have been implicated in the pathogenesis of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by loss of medium spiny neurons of the striatum. Brain Mn levels are highest in striatum and other basal ganglia structures, the most sensitive brain regions to Mn neurotoxicity. Mouse models of HD exhibit decreased striatal Mn accumulation and HD striatal neuron models are resistant to Mn cytotoxicity. We hypothesized that the observed modulation of Mn cellular transport is associated with compensatory metabolic responses to HD pathology. Here we use an untargeted metabolomics approach by performing ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) on control and HD immortalized mouse striatal neurons to identify metabolic disruptions under three Mn exposure conditions, low (vehicle), moderate (non-cytotoxic) and high (cytotoxic). Our analysis revealed lower metabolite levels of pantothenic acid, and glutathione (GSH) in HD striatal cells relative to control cells. HD striatal cells also exhibited lower abundance and impaired induction of isobutyryl carnitine in response to increasing Mn exposure. In addition, we observed induction of metabolites in the pentose shunt pathway in HD striatal cells after high Mn exposure. These findings provide metabolic evidence of an interaction between the HD genotype and biologically relevant levels of Mn in a striatal cell model with known HD by Mn exposure interactions. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathobiology of both HD and Mn neurotoxicity.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 232 
KW  - cells
KW  - coenzyme-a
KW  - database
KW  - energy-metabolism
KW  - glutathione
KW  - hallervorden-spatz-syndrome
KW  - mobility-mass spectrometry
KW  - model
KW  - neurodegeneration
KW  - neurotoxicity
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-94314
SP  - 363
EP  - 370
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  -