Documents published in Scipedia

• Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases

  L. Takser, N. Benachour, B. Husk, H. Cabana, D. Gris

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN), microcystin-LR (MC-LR), and anatoxin-a (ATX-a), individually as well as their mixture. In addition, we studied the neurotoxins β-N -methylamino-l -alanine (BMAA) and its isomer 2, 4-diaminobutyric acid (DAB), as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food.

  Abstract
  Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study [...]

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• Food safety risk assessment for estimating dietary intake of sulfites in the Taiwanese population

  K. Lien, D. Hsieh, H. Huang, C. Wu, S. Ni, M. Ling

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  The purpose of this study was to assess the health risk associated with dietary intake of sulfites for Taiwanese general consumers by conducting a total diet study (TDS). We evaluated the exposure of Taiwanese to sulfites in the diet and its associated health risk. This study used a list of 128 food items representing 83% of the total daily diet. Among the 128 food items, 59 items may contain sulfites. Samples of the 59 food items were collected and subjected to chemical analysis to determine the sulfur dioxide concentration. Health risk was assessed by calculating the ratio of exposure level to the acceptable daily intake (ADI) level of the analyte. For high-intake consumers, the HI of sulfites was 19.7% ADI for males over the age of three years at the 95th percentile, whereas for females over the age of 66, the HI was 17.8% ADI. The HI for high-intake consumers was above 10% ADI. This suggests that regulatory actions must be continued and that consumers should be advised to be aware of processed foods with relatively high contamination to avoid excessive exposure.

  Abstract
  The purpose of this study was to assess the health risk associated with dietary intake of sulfites for Taiwanese general consumers by conducting a total diet study (TDS). [...]

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• Sequencing the exposome: A call to action

  D. Jones

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures and behaviors, and cumulative integration of associated biologic responses. As such, the concept is both refreshingly simple and dauntingly complex. This article reviews high-resolution metabolomics (HRM) as an affordable approach to routinely analyze samples for a broad spectrum of environmental chemicals and biologic responses. HRM has been successfully used in multiple exposome research paradigms and is suitable to implement in a prototype universal exposure surveillance system. Development of such a structure for systematic monitoring of environmental exposures is an important step toward sequencing the exposome because it builds upon successes of exposure science, naturally connects external exposure to body burden and partitions the exposome into workable components. Practical results would be repositories of quantitative data on chemicals according to geography and biology. This would support new opportunities for environmental health analysis and predictive modeling. Complementary approaches to hasten development of exposome theory and associated biologic response networks could include experimental studies with model systems, analysis of archival samples from longitudinal studies with outcome data and study of relatively short-lived animals, such as household pets (dogs and cats) and non-human primates (common marmoset). International investment and cooperation to sequence the human exposome will advance scientific knowledge and also provide an important foundation to control adverse environmental exposures to sustain healthy living spaces and improve prediction and management of disease.

  Abstract
  The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures [...]

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• Sodium sulfite promotes the assembly and secretion of very low-density lipoprotein in HL-7702 hepatocytes

  J. Bai, P. Lei, C. Zhao, Y. Wang, D. Yan, S. Yang

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  This study investigated the effects of Na2 SO3 on the fat metabolism in human normal diploid HL-7702 (referred as L-02) hepatocytes. After 24 h and 48 h, treatment with different concentrations of Na2 SO3, the intra and extra-hepatocellular triglyceride (TG) contents of L-02 were determined using chemical-enzymatic method. The contents of very low-density lipoprotein (VLDL) and apolipoprotein B100 (apoB100) in the culture supernatants were determined using enzyme-linked immunosorbent assay (ELISA). Western blot was applied to detect the expressions of fatty acid oxidation and fat synthesis related proteins, VLDL assembly and secretion in L-02 cells. Na2 SO3 treatment (10 mM, 24 h/48 h) significantly increased the intra TG level in the hepatocytes. Different concentrations of Na2 SO3 increased the extra-hepatocellular TG content. After 24 h exposure, the extracellular VLDL levels and secretions of apoB100 in 0.1–10 mM Na2 SO3 groups were significantly higher than that of the negative control (P < 0.05). Meanwhile, the expression of CPT1 and SREBP1 protein were significantly reduced by Na2 SO3 . MTP and TGH protein expressions were significantly elevated in each Na2 SO3 treatment group. The expression level of LDLR in hepatocytes was reduced by Na2 SO3 . Na2 SO3 exposure may promote the hepatocellular VLDL assembly and secretion, through increasing of MTP and TGH expressions and inhibiting the uptake of extracelluar VLDL.

  Abstract
  This study investigated the effects of Na2 SO3 on the fat metabolism in human normal diploid HL-7702 (referred as L-02) hepatocytes. After 24 h and 48 h, treatment with different [...]

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• Cytotoxic effects of nickel nanowires in human fibroblasts

  L. Felix, J. Perez, M. Contreras, T. Ravasi, J. Kosel

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  The increasing interest in the use of magnetic nanostructures for biomedical applications necessitates rigorous studies to be carried out in order to determine their potential toxicity. This work attempts to elucidate the cytotoxic effects of nickel nanowires (NWs) in human fibroblasts WI-38 by a colorimetric assay (MTT) under two different parameters: NW concentration and exposure time. This was complemented with TEM and confocal images to assess the NWs internalization and to identify any changes in the cell morphology. Ni NWs were fabricated by electrodeposition using porous alumina templates. Energy dispersive X-ray analysis, scanning electron microscopy and transmission electron microscopy imaging were used for NW characterization. The results showed decreased cell metabolic activity for incubation times longer than 24 h and no negative effects for exposure times shorter than that. The cytotoxicity effects for human fibroblasts were then compared with those reported for HCT 116 cells, and the findings point out that it is relevant to consider the cellular size. In addition, the present study compares the toxic effects of equivalent amounts of nickel in the form of its salt to those of NWs and shows that the NWs are more toxic than the salts. Internalized NWs were found in vesicles inside of the cells where their presence induced inflammation of the endoplasmic reticulum.

  Abstract
  The increasing interest in the use of magnetic nanostructures for biomedical applications necessitates rigorous studies to be carried out in order to determine their potential [...]

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• Dose- and time-dependent changes in tissue levels of tetrabromobisphenol A (TBBPA) and its sulfate and glucuronide conjugates following repeated administration to female Wistar Han Rats

  S. Borghoff, D. Wikoff, S. Harvey, L. Haws

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Tetrabromobisphenol A (TBBPA), a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA) for these tumors involves an increase in the bioavailability of estradiol as a result of TBBPA inhibiting estrogen sulfotransferases (ES), the enzymes responsible for inactivating and enhancing the elimination of estradiol. The objective of this study was to evaluate the effect of dose and repeated administration of TBBPA on the level of TBBPA, TBBPA-glucuronide (GA) and TBBPA-sulfate (S) conjugates in plasma, liver and uterus of female Wistar Han rats administered TBBPA (50, 100, 250, 500 or 1000 mg/kg) for 28 consecutive days. In accordance with this objective, TBBPA sulfation was used as a surrogate for evaluating the potential for estradiol sulfation to be limited at high dose levels of TBBPA. Blood samples were collected at 4 and 8 h post-dosing on study day 7, 14, and 28, while liver and uterus were collected at the same time points following 28 days of dosing. Tissue samples were analyzed for TBBPA, TBBPA-GA and TBBPA-S by LC–MS/MS. A dose-related increase in the concentration of all three analytes occurred in plasma (day 7, 14, and 28) as well as liver and uterus tissue (day 28) at both 4 and 8 h post dose. The plasma concentration of TBBPA-GA and TBBPA-S was higher in animals dosed for 28 days compared to those dosed for 7 or 14 days showing an increase in systemic circulation of these conjugates with repeated administration. The balance of these conjugates was also different in tissues with TBBPA-S > TBBPA-GA at high doses in the liver and TBBPA-GA > TBBPA-S in both plasma and uterus. In all three tissues the ratio of TBBPA-S/TBBPA-GA showed a decreasing trend with dose, suggesting that at high TBBPA dose levels sulfation of TBBPA becomes limited. This effect was most apparent in the liver and plasma at 28 days of administration. Together these data show that administration of high doses of TBBPA associated with the induction of uterine tumors, results in a disruption in the balance of conjugates reflected by a decrease in the TBBPA-S/TBBPA-GA ratio. A limitation in the sulfation of TBBPA in vivo supports in vitro data defining TBBPA as an inhibitor of ES activity, thus providing further support that the proposed MoA occurs under conditions of high dose, chronic TBBPA administration to Wistar Han rats. Given that the uterine tumors observed in rats (250–1000 mg/kg-day) only occur at very high doses that perturb homeostatic control, it is unlikely such effects would occur in humans given that current TBBPA exposure levels are approximately eight orders of magnitude lower than these doses that are associated with exceeding the capacity of conjugation pathways in animal studies.

  Abstract
  Tetrabromobisphenol A (TBBPA), a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA) for these tumors involves an increase [...]

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• The possible role of intravenous lipid emulsion in the treatment of chemical warfare agent poisoning

  A. Eisenkraft, A. Falk

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, without proper and early antidotal treatment, death. Most of these compounds are highly lipophilic. Sulfur mustard is a toxic lipophilic alkylating agent, exerting its damage through alkylation of cellular macromolecules (e.g., DNA, proteins) and intense activation of pro-inflammatory pathways. Currently approved antidotes against OPs include the peripheral anticholinergic drug atropine and an oxime that reactivates the inhibited cholinesterase. Benzodiazepines are used to stop organophosphate-induced seizures. Despite these approved drugs, efforts have been made to introduce other medical countermeasures in order to attenuate both the short-term and long-term clinical effects following exposure. Currently, there is no antidote against sulfur mustard poisoning. Intravenous lipid emulsions are used as a source of calories in parenteral nutrition. In recent years, efficacy of lipid emulsions has been shown in the treatment of poisoning by fat-soluble compounds in animal models as well as clinically in humans. In this review we discuss the usefulness of intravenous lipid emulsions as an adjunct to the in-hospital treatment of chemical warfare agent poisoning.

  Abstract
  Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, [...]

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• Nrf2 activators as potential modulators of injury in human kidney cells

  A. Atilano-Roque, X. Wen, L. Aleksunes, M. Joy

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Cisplatin is a chemotherapeutic agent used in the treatment of solid tumors, with clinical use often complicated by kidney toxicity. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) is a transcription factor involved in kidney protectant effects. The purpose of this study was to determine whether the Nrf2 activators oltipraz, sulforaphane, and oleanolic acid could protect human kidney cells against cisplatin-induced injury and to compare the protective effects between three Nrf2 activators. Human proximal tubule cells (hPTC) and human embryonic kidney 293 cells (HEK293) were exposed to cisplatin doses in the absence and presence of Nrf2 activators. Pre- and delayed-cisplatin and Nrf2 activator exposures were also assessed. Cell viability was enhanced with Nrf2 activator exposures, with differences detected between pre- and delayed-treatments. Both sulforaphane and oltipraz increased the expression of anti-oxidant genes GCLC and NQO1. These findings suggest potential human kidney protective benefits of Nrf2 activators with planned exposures to cisplatin.

  Abstract
  Cisplatin is a chemotherapeutic agent used in the treatment of solid tumors, with clinical use often complicated by kidney toxicity. Nuclear factor (erythroid-derived-2)-like [...]

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• Vanillin abrogates ethanol induced gastric injury in rats via modulation of gastric secretion, oxidative stress and inflammation

  A. Asmari, H. Shahrani, N. Masri, A. Faraidi, I. Elfaki, M. Arshaduddin

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Vanillin is commonly used as an additive in food, medicine and cosmetics, but its effect has not yet been studied in gastric injury. Therefore the effect of vanillin was studied in experimental gastric ulcer. Gastric secretion and acidity were studied in pylorus ligated rats. Ulcer index, levels of gastric mucus, malondialdehyde (MDA), myeloperoxidase activity (MPO), expression of nuclear factor kappa B (NF-κB) p65, and histopathological changes were determined in ethanol induced gastric ulcer. Pre treatment with vanillin significantly reduced gastric secretion (P < 0.001) and acidity (P < 0.0001) and gastric ulcer index scores (P < 0.001). and augmented the gastric mucosal defense. Vanillin significantly restored the depleted gastric wall mucus levels (P < 0.0001) induced by ethanol and also significantly attenuated ethanol induced inflammation and oxidative stress by the suppression of gastric MPO activity (P < 0.001), reducing the expression of NF-κB p65 and the increased MDA levels (P < 0.001). Vanillin was also effective in alleviating the damage to the histological architecture and the activation of mast cells induced by ethanol. Together the results of this study highlight the gastroprotective activity of vanillin in gastric ulcers of rats through multiple actions that include inhibition of gastric secretion and acidity, reduction of inflammation and oxidative stress, suppression of expression of NF-κB, and restoration of the histological architecture.

  Abstract
  Vanillin is commonly used as an additive in food, medicine and cosmetics, but its effect has not yet been studied in gastric injury. Therefore the effect of vanillin was studied [...]

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• Visibilidad y enunciabilidad en la larga duración de la violencia política: La sombra azul de Sergio Schmucler 1

  G. Villanueva

  Acta Poética (2017).

  
  

  Abstract

  Una historia de vida, eje fundamental de un film, es la discursividad que hemos indagado para percibir sentidos nuevos en la relación cine, memoria y violencia en la zona amplia de los discursos producidos sobre el terrorismo de estado en Argentina. La sombra azul, con guión y dirección de Sergio Schmucler, irrumpe para desbaratar conciencias. Nuestro trabajo, filiado en el Análisis del Discurso, se ha detenido en la indagación de tres dispositivos: las visibilidades, las enunciabilidades y las temporalidades, superpuestas, fragmentarias a veces, otras omnipresentes, deslizadas en la larga duración de una memoria social. Estos dispositivos, elaborados por Foucault para blandir discursividades exasperantes de órdenes impuestos, constituyen un camino privilegiado para llegar, a través de su desgranamiento, a una verdad intolerable forjada en este film. En La sombra azul la larga duración de la violencia de estado, la impunidad de los represores durante la democracia y, fundamentalmente, un sobreviviente —a la tortura, la prisión, el exilio, perteneciente a la fuerza policial de una de las provincias más castigadas por la dictadura— son cincelados, en la heteroglosia, en el diálogo y en el antagonismo, con otras voces. Este sobreviviente, devenido en re-viviente señala cómo un marco ético, capaz de valorar la tragedia humana, lo erige en un don para dotar de verdad, para esclarecer a una sociedad que, en muchos espacios, aún permanece en sombra. Este recorrido discursivo señala cómo, desde la indecibilidad original de un sujeto doliente, irrumpen visibilidades y enunciabilidades capaces de decir verdad y así proseguir con una memoria que nunca cesa.

  Abstract
  Una historia de vida, eje fundamental de un film, es la discursividad que hemos indagado para percibir sentidos nuevos en la relación cine, memoria y violencia en la zona [...]

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