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Uruguay River is the most important river in western Rio Grande do Sul, separating Brazil from Argentina and Uruguay. However, its pollution is of great concern due to agricultural activities in the region and the extensive use of pesticides. In a long term, this practice leads to environmental pollution, especially to the aquatic system. The objective of this study was to analyze the physicochemical characteristics, metals and pesticides levels in water samples obtained before and after the planting and pesticides' application season from three sites: Uruguay River and two minor affluents, Mezomo Dam and Salso Stream. For biomonitoring, the free-living nematode Caenorhabditis elegans was used, which were exposed for 24 h. We did not find any significant alteration in physicochemical parameters. In the pre- and post-pesticides' samples we observed a residual presence of three pesticides (tebuconazole, imazethapyr, and clomazone) and metals which levels were above the recommended (As, Hg, Fe, and Mn). Exposure to both pre- and post-pesticides' samples impaired C. elegans reproduction and post-pesticides samples reduced worms' survival rate and lifespan. PCA analysis indicated that the presence of metals and pesticides are important variables that impacted C. elegans biological endpoints. Our data demonstrates that Uruguay River and two affluents are contaminated independent whether before or after pesticides' application season. In addition, it reinforces the usefulness of biological indicators, since simple physicochemical analyses are not sufficient to attest water quality and ecological safety.
The Caenorhabditis elegans (C. elegans) is a model organism that has been increasingly used in health and environmental toxicity assessments. The quantification of such elements in vivo can assist in studies that seek to relate the exposure concentration to possible biological effects.
Therefore, this study is the first to propose a method of quantitative analysis of 21 ions by ion chromatography (IC), which can be applied in different toxicity studies in C. elegans.
The developed method was validated for 12 anionic species (fluoride, acetate, chloride, nitrite, bromide, nitrate, sulfate, oxalate, molybdate, dichromate, phosphate, and perchlorate), and 9 cationic species (lithium, sodium, ammonium, thallium, potassium, magnesium, manganese, calcium, and barium).
The method did not present the presence of interfering species, with R2 varying between 0.9991 and 0.9999, with a linear range from 1 to 100 mu g L-1.
Limits of detection (LOD) and limits of quantification (LOQ) values ranged from 0.2319 mu g L-1 to 1.7160 mu g L-1 and 0.7028 mu g L-1 to 5.1999 mu g L-1, respectively.
The intraday and interday precision tests showed an Relative Standard Deviation (RSD) below 10.0 % and recovery ranging from 71.0 % to 118.0 % with a maximum RSD of 5.5 %.
The method was applied to real samples of C. elegans treated with 200 uM of thallium acetate solution, determining the uptake and bioaccumulated Tl+ content during acute exposure.
Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells
(2022)
Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl2, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2'-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.
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-beta- 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 gamma-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.
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.
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.
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.
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.
Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn’s effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85 mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins.