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1.
J Trace Elem Med Biol ; 68: 126848, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34479099

ABSTRACT

BACKGROUND: Thallium (Tl) is a toxic metalloid and an emerging pollutant due to electronic devices and dispersal nearby base-metal mining. Therefore, Tl poses a threat to human health and especially the long-term impact on younger individuals exposed is still unknown. This study aimed to evaluate the toxic effects of thallium acetate in C. elegans in early larval stages, considering physiological and behavioral endpoints, as well as the Tl absorption and bioaccumulation. METHODS: Caenorhabditis elegans (C. elegans) was exposed to Thallium acetate (50, 100, 150, 200, 250, 500, and 1000 µM) in the L1 larval stage, with the purpose to observe the toxic effects invoked until adulthood. Transgenic worms strains were transported GFP, reporters to DAF-16 and were used to verify the antioxidant response. ICP-MS quantified total Tl+ concentration to evidence Tl uptake and bioaccumulation. RESULTS: Thallium acetate caused a significant reduction in the number of living worms (p < 0.0001 in 100-1000 µM), a delay in larval development (p < 0.01; p < 0.001 and p < 0.0001 in 100-1000 µM) through the larval stages, and egg production in the worm's uterus was reduced. Thallium acetate also induced behavioral changes. Additionally, thallium acetate activated antioxidant pathway responses in C. elegans by translocating the DAF-16 transcription factor and activation of SOD-3::GFP expression. The Tl+ quantification in worms showed its absorption in the L1 larval stage and bioaccumulation in the body after development. CONCLUSIONS: Thallium acetate reduced survival, delayed development, caused behavioral changes, induced responses inherent to oxidative stress, and serious damage to the worm's reproduction. In addition, C. elegans absorbed and bioaccumulated Tl+. Together, our results highlight the impacts of Tl+ exposure in the early stages of life, even for a short period.


Subject(s)
Organometallic Compounds/toxicity , Toxicity Tests, Acute , Animals , Antioxidants , Caenorhabditis elegans , Larva , Nematoda , Thallium/toxicity
2.
Arch Toxicol ; 92(5): 1751-1765, 2018 05.
Article in English | MEDLINE | ID: mdl-29602950

ABSTRACT

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.


Subject(s)
Arsenic/toxicity , Epigenesis, Genetic/drug effects , Gene Expression Regulation/drug effects , Hydrocarbons/toxicity , Arsenic/pharmacokinetics , Biotransformation , Chromatography, High Pressure Liquid , Culture Media/analysis , Culture Media/chemistry , DNA Methylation/drug effects , DNA Repair/drug effects , DNA Repair/genetics , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Hydrocarbons/administration & dosage , Hydrocarbons/chemistry , Hydrocarbons/pharmacokinetics , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry
3.
J Trace Elem Med Biol ; 49: 171-177, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29449109

ABSTRACT

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.


Subject(s)
Arsenic/chemistry , Cerebrospinal Fluid/metabolism , Hydrocarbons/chemistry , Animals , Arsenicals/chemistry , Blotting, Western , Cell Line , Fatty Acids/chemistry , Immunohistochemistry , Swine
4.
Metallomics ; 10(1): 73-76, 2018 01 24.
Article in English | MEDLINE | ID: mdl-29292446

ABSTRACT

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 µM 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.


Subject(s)
Arsenites/metabolism , Single-Cell Analysis/methods , Tandem Mass Spectrometry/methods , A549 Cells , Arsenites/analysis , Biological Availability , Humans , Phosphorus/analysis , Sulfur/analysis
5.
Arch Toxicol ; 92(2): 823-832, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29058019

ABSTRACT

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.


Subject(s)
Arsenicals/pharmacokinetics , Blood-Brain Barrier/drug effects , Endothelial Cells/drug effects , Fatty Acids/toxicity , Animals , Brain/blood supply , Capillaries/cytology , Fatty Acids/pharmacokinetics , Primary Cell Culture , Swine , Toxicity Tests
6.
Metallomics ; 9(5): 442-446, 2017 05 24.
Article in English | MEDLINE | ID: mdl-28436502

ABSTRACT

Arsenic-containing hydrocarbons (AsHCs), natural products found in seafood, have recently been shown to exert toxic effects in human neurons. In this study we assessed the toxicity of three AsHCs in cultured human astrocytes. Due to the high cellular accessibility and substantial toxicity observed astrocytes were identified as further potential brain target cells for arsenolipids. Thereby, the AsHCs exerted a 5-19-fold higher cytotoxicity in astrocytes as compared to arsenite. Next we compared the toxicity of the arsenicals in a co-culture model of the respective human astrocytes and neurons. Notably the AsHCs did not show any substantial toxic effects in the co-culture, while arsenite did. The arsenic accessibility studies indicated that in the co-culture astrocytes protect neurons against cellular arsenic accumulation especially after incubation with arsenolipids. In summary, these data underline the importance of the glial-neuron interaction when assessing the in vitro neurotoxicity of new unclassified metal species.


Subject(s)
Arsenic Poisoning/etiology , Arsenicals/chemistry , Astrocytes/drug effects , Lipids/chemistry , Lipids/toxicity , Arsenic Poisoning/metabolism , Arsenicals/metabolism , Astrocytes/cytology , Astrocytes/metabolism , Cell Culture Techniques , Cell Line , Cell Survival/drug effects , Coculture Techniques , Humans , Lipid Metabolism , Neurons/cytology , Neurons/drug effects , Neurons/metabolism
7.
Metallomics ; 9(3): 268-277, 2017 03 22.
Article in English | MEDLINE | ID: mdl-28184394

ABSTRACT

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-ß-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 γ-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.


Subject(s)
Cysteine/analogs & derivatives , Liver/drug effects , Organoselenium Compounds/metabolism , Selenium Compounds/analysis , Selenium Compounds/pharmacology , Cell Death/drug effects , Chromatography, High Pressure Liquid , Cysteine/metabolism , Hep G2 Cells , Humans , Liver/metabolism , Spectrometry, Mass, Electrospray Ionization
8.
Metallomics ; 9(4): 357-364, 2017 04 19.
Article in English | MEDLINE | ID: mdl-28054081

ABSTRACT

Systemic trafficking and storage of essential metal ions play fundamental roles in living organisms by serving as essential cofactors in various cellular processes. Thereby metal quantification and localization are critical steps in understanding metal homeostasis, and how their dyshomeostasis might contribute to disease etiology and the ensuing pathologies. Furthermore, the amount and distribution of metals in organisms can provide insight into their underlying mechanisms of toxicity and toxicokinetics. While in vivo studies on metal imaging in mammalian experimental animals are complex, time- and resource-consuming, the nematode Caenorhabditis elegans (C. elegans) provides a suitable comparative and complementary model system. Expressing homologous genes to those inherent to mammals, including those that regulate metal homeostasis and transport, C. elegans has become a powerful tool to study metal homeostasis and toxicity. A number of recent technical advances have been made in the development and application of analytical methods to visualize metal ions in C. elegans. Here, we briefly summarize key findings and challenges of the three main techniques and their application to the nematode, namely sensing fluorophores, microbeam synchrotron radiation X-ray fluorescence as well as laser ablation (LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS).


Subject(s)
Caenorhabditis elegans/chemistry , Metals/analysis , Animals , Mass Spectrometry/methods , Microscopy, Fluorescence/methods , Optical Imaging/methods
9.
Toxicol Res (Camb) ; 4(5): 1289-1296, 2015 Sep 18.
Article in English | MEDLINE | ID: mdl-26744620

ABSTRACT

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.

10.
Metallomics ; 6(11): 2010-4, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25292248

ABSTRACT

Arsenic-containing hydrocarbons (AsHC) constitute one group of arsenolipids that have been identified in seafood. In this first in vivo toxicity study for AsHCs, we show that AsHCs exert toxic effects in Drosophila melanogaster in a concentration range similar to that of arsenite. In contrast to arsenite, however, AsHCs cause developmental toxicity in the late developmental stages of Drosophila melanogaster. This work illustrates the need for a full characterisation of the toxicity of AsHCs in experimental animals to finally assess the risk to human health related to the presence of arsenolipids in seafood.


Subject(s)
Arsenic/toxicity , Drosophila melanogaster/drug effects , Hydrocarbons/toxicity , Animals , Arsenic/chemistry , Female , Hydrocarbons/chemistry , Life Cycle Stages/drug effects , Male , Manganese , Models, Biological
11.
Metallomics ; 6(5): 1023-33, 2014 May.
Article in English | MEDLINE | ID: mdl-24718560

ABSTRACT

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.


Subject(s)
Arsenic/toxicity , Hydrocarbons/toxicity , Adenosine Triphosphate/metabolism , Arsenic/chemistry , Arsenic/pharmacokinetics , Biological Availability , Caspase 3/metabolism , Cell Line , DNA Damage , Humans , Hydrocarbons/chemistry , Hydrocarbons/pharmacokinetics , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Tandem Mass Spectrometry
12.
Mutat Res ; 558(1-2): 81-92, 2004 Mar 14.
Article in English | MEDLINE | ID: mdl-15036122

ABSTRACT

Human mesothelial cells (HMC), the progenitor cells of asbestos-induced mesothelioma, are particularly sensitive to the genotoxic effects of asbestos, although the molecular mechanisms by which asbestos induces injury in HMC are not well known. The high susceptibility of HMC to simian virus 40 (SV40)-mediated transformation is assumed to play a causative role in the pathogenesis of mesothelioma. The aim of this study was to investigate the asbestos-induced DNA damage in cultured HMC and SV40-transformed HMC (MeT-5A) compared with their malignant counterparts, i.e. human mesothelioma cells (MSTO). The time-dependent initiation of DNA-strand breaks as well as the induction of oxidative DNA base modifications were key factors for investigation. HMC, MeT-5A and MSTO cells were exposed to chrysotile and crocidolite asbestos (3 microg/cm2) during different time periods (1-72 h). DNA damage was investigated by use of the Comet assay and alkaline unwinding, the latter in combination with the Fpg protein. The P53 level was analyzed by immunofluorescence, and measurement of apoptosis was conducted by flow cytometry. We found a significant induction of DNA damage in asbestos-treated HMC already after an exposure time of 1.5 h. This effect could not be observed in treated MeT-5A and MSTO cells. Also, a time-dependent significant increase in DNA-strand breaks was observed by alkaline unwinding in asbestos-treated HMC, but not in treated MeT-5A and MSTO cells. In none of the three cell lines we could detect oxidative DNA damage recognized by the Fpg protein (e.g. 8-oxo-guanine), up to 24 h after exposure to asbestos. In contrast to what was found in HMC, P53 was over-expressed in untreated MeT-5A and MSTO. The induction of apoptosis by asbestos fibers was suppressed in MeT-5A and MSTO cells. Crocidolite fibers induced the higher genotoxic effects and chrysotile the more pronounced apoptotic effects. We conclude that asbestos induces DNA damage in HMC already after a very short exposure time in the absence of 8-oxo-guanine formation. The presence of SV40-Tag in MeT-5A and MSTO cells results in an increased expression of P53, but not in additive genotoxic effects after exposure to asbestos. The deregulation of the apoptotic pathway may lead to proliferation of genomically damaged cells and finally to the development of mesothelioma.


Subject(s)
Asbestos/toxicity , DNA Damage , DNA/drug effects , Epithelium/metabolism , Tumor Suppressor Protein p53/genetics , Cell Line, Transformed , Comet Assay , Epithelium/pathology , Fluorescent Antibody Technique , Humans , Simian virus 40/physiology
13.
Toxicology ; 193(1-2): 161-9, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14599775

ABSTRACT

Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.


Subject(s)
Arsenicals/pharmacology , DNA Repair/drug effects , Selenium Compounds/pharmacology , Animals , DNA Repair Enzymes/metabolism , Humans , Zinc Fingers/physiology
14.
Environ Health Perspect ; 110 Suppl 5: 797-9, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12426134

ABSTRACT

Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to humans and experimental animals. Even though their DNA-damaging potentials are rather weak, they interfere with the nucleotide and base excision repair at low, noncytotoxic concentrations. For example, both water-soluble Ni(II) and particulate black NiO greatly reduced the repair of DNA adducts induced by benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II), As(III), and Co(II) interfered with cell cycle progression and cell cycle control in response to ultraviolet C radiation. As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling were investigated. We observed an inactivation of the bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma pigmentosum group A protein (XPA), and the poly(adenosine diphosphate-ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III) deserves special attention, as it inactivated only PARP, but did so at very low concentrations starting from 10 nM. Because DNA is permanently damaged by endogenous and environmental factors, functioning processing of DNA lesions is an important prerequisite for maintaining genomic integrity; its inactivation by metal compounds may therefore constitute an important mechanism of metal-related carcinogenicity.


Subject(s)
Cell Cycle/drug effects , DNA Repair , Metals, Heavy/adverse effects , Zinc Fingers , Animals , DNA-Binding Proteins/pharmacology , DNA-Formamidopyrimidine Glycosylase , Humans , N-Glycosyl Hydrolases/pharmacology , Poly(ADP-ribose) Polymerases/pharmacology , Xeroderma Pigmentosum Group A Protein
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