TY  - JOUR
A1  - Peres, Tanara V.
A1  - Eyng, Helena
A1  - Lopes, Samantha C.
A1  - Colle, Dirleise
A1  - Goncalves, Filipe M.
A1  - Venske, Debora K. R.
A1  - Lopes, Mark W.
A1  - Ben, Juliana
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael A.
A1  - Farina, Marcelo
A1  - Prediger, Rui D.
A1  - Leal, Rodrigo B.
T1  - Developmental exposure to manganese induces lasting motor and cognitive impairment in rats
JF  - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system
N2  - Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum. (C) 2015 Elsevier Inc. All rights reserved.
KW  - Manganese
KW  - Neurotoxicity
KW  - Development
KW  - Motor coordination
KW  - Cognition
Y1  - 2015
U6  - https://doi.org/10.1016/j.neuro.2015.07.005
SN  - 0161-813X
SN  - 1872-9711
VL  - 50
SP  - 28
EP  - 37
PB  - Elsevier
CY  - Amsterdam
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  - 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  - 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 : integrated biometal science
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
PB  - Royal Society of Chemistry
CY  - Cambridge
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  - Rohn, Isabelle
A1  - Kroepfl, Nina
A1  - Aschner, Michael
A1  - Bornhorst, Julia
A1  - Kuehnelt, Doris
A1  - Schwerdtle, Tanja
T1  - Selenoneine ameliorates peroxide-induced oxidative stress in C. elegans
JF  - Journal of trace elements in medicine and biology
N2  - Scope: Selenoneine (2-selenyl-N-alpha, N-alpha, N-alpha-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. Methods and results: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h posttreatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. Conclusion: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.
KW  - Selenoneine
KW  - Caenorhabditis elegans
KW  - Selenium
KW  - Oxidative stress
Y1  - 2019
U6  - https://doi.org/10.1016/j.jtemb.2019.05.012
SN  - 0946-672X
VL  - 55
SP  - 78
EP  - 81
PB  - Elsevier GMBH
CY  - München
ER  - 
TY  - JOUR
A1  - Rohn, Isabelle
A1  - Kroepfl, Nina
A1  - Bornhorst, Julia
A1  - Kühnelt, Doris
A1  - Schwerdtle, Tanja
T1  - Side-directed transfer and presystemic metabolism of selenoneine in a human intestinal barrier model
JF  - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology
N2  - Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfur-containing purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Se-methylselenocysteine (MeSeCys) and selenite are applied to the Caco-2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco-2 cells. Moreover, HPLC/MS-based Se speciation studies reveal a partial metabolism to Se-methylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carrier-mediated transport, is highly bioavailable to Caco-2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans.
KW  - bioavailability
KW  - Caco-2 intestinal barrier model
KW  - presystemic metabolism
KW  - selenoneine
KW  - Se-methylselenoneine
Y1  - 2019
U6  - https://doi.org/10.1002/mnfr.201900080
SN  - 1613-4125
SN  - 1613-4133
VL  - 63
IS  - 12
PB  - Wiley
CY  - Hoboken
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  - 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  - Rund, Katharina M.
A1  - Heylmann, Daniel
A1  - Seiwert, Nina
A1  - Wecklein, Sabine
A1  - Oger, Camille
A1  - Galano, Jean-Marie
A1  - Durand, Thierry
A1  - Chen, Rongjun
A1  - Güler, Faikah
A1  - Fahrer, Jörg
A1  - Bornhorst, Julia
A1  - Schebb, Nils Helge
T1  - Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress
JF  - Prostaglandins & Other Lipid Mediators
N2  - In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.
KW  - Isoprostane
KW  - Trans-epoxy-fatty acid
KW  - Oxidative stress
KW  - Biomarker
KW  - Oxylipin
KW  - Eicosanoid
Y1  - 2019
U6  - https://doi.org/10.1016/j.prostaglandins.2019.04.004
SN  - 1098-8823
SN  - 2212-196X
VL  - 144
PB  - Elsevier
CY  - New York
ER  -