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Archives of Toxicology (v.83, #10)
Expression and function of Oat1 and Oat3 in rat kidney exposed to mercuric chloride by Gisela Di Giusto; Naohiko Anzai; María L. Ruiz; Hitoshi Endou; Adriana M. Torres (pp. 887-897).
This study was designed to evaluate the expression and function of the organic anion transporters, Oat1 and Oat3, in rats exposed to a nephrotoxic dose of HgCl2. Oat1 protein expression increased in renal homogenates and decreased in renal basolateral membranes from HgCl2 rats, while Oat3 protein abundance decreased in both kidney homogenates and basolateral membranes. The lower protein levels of Oat1 and Oat3 in basolateral membranes explain the lower uptake capacity for p-aminohippurate (in vitro assays) and the diminution of the systemic clearance of this organic anion (in vivo studies) observed in treated rats. Since both transporters mediate mercury access to the renal cells, their down-regulation in basolateral membranes might be a defensive mechanism developed by the cell to protect itself against mercury injury. The pharmacological modulation of the expression and/or the function of Oat1 and Oat3 might be an effective therapeutic strategy for reducing the nephrotoxicity of mercury.
Keywords: Oat1; Oat3; Organic anions uptake; Nephrotoxicity; Mercury; Rat; Kidney
Arsenic induces mitochondria-dependent apoptosis by reactive oxygen species generation rather than glutathione depletion in Chang human hepatocytes by Yi Wang; Yuanyuan Xu; Huihui Wang; Peng Xue; Xin Li; Bing Li; Quanmei Zheng; Guifan Sun (pp. 899-908).
This study was conducted to evaluate the possible involvement of mitochondrial pathway in NaAsO2-induced apoptosis and the role of reactive oxygen species (ROS) and reduced glutathione (GSH) in the apoptotic effect in Chang human hepatocytes. The MTT assay demonstrated that sodium arsenite (NaAsO2) treatment for 24 h caused a dose-dependent decrease of cell viability. NaAsO2 treatment (0–30 μM) was also found to induce phosphatidylserine externalization, a hallmark of apoptosis; to disrupt the mitochondrial membrane potential (Δψ m ); to cause the release of cytochrome c into the cytosol, and to trigger cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in a dose-dependent manner. All these changes were accompanied with the enhanced generation of intracellular ROS and malondialdehyde (MDA). Increase of intracellular GSH also coincided unexpectedly. Moreover, the extracellular addition of N-acetyl-l-cysteine (NAC, 5 mM) effectively reduced the generation of ROS and MDA, and rescued the cells from NaAsO2 induced apoptosis and related alteration of mitochondria. These data suggest that the arsenic-induced cell apoptosis occurs though the mitochondrial pathway, and is mostly dependent on generation of ROS rather than GSH depletion in Chang human hepatocytes.
Keywords: Arsenic; Reactive oxygen species; Glutathione; Apoptosis; Mitochondria
Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats by Wei Xie; Qian Wu; Izabela Kania-Korwel; Job C. Tharappel; Sanjay Telu; Mitchell C. Coleman; Howard P. Glauert; Kurunthachalam Kannan; S. V. S. Mariappan; Douglas R. Spitz; Jamie Weydert; Hans-Joachim Lehmler (pp. 909-924).
Perfluorooctanesulfonamides, such as N-ethyl perfluorooctanesulfonamidoethanol (N-EtFOSE), are large scale industrial chemicals but their disposition and toxicity are poorly understood despite significant human exposure. The hypothesis that subacute exposure to N-EtFOSE, a weak peroxisome proliferator, causes a redox imbalance in vivo was tested using the known peroxisome proliferator, ciprofibrate, as a positive control. Female Sprague–Dawley rats were treated orally with N-EtFOSE, ciprofibrate or corn oil (vehicle) for 21 days, and levels of N-EtFOSE and its metabolites as well as markers of peroxisome proliferation and oxidative stress were assessed in serum, liver and/or uterus. The N-EtFOSE metabolite profile in liver and serum was in good agreement with reported in vitro biotransformation pathways in rats and the metabolite levels decreasing in the order perfluorooctanesulfonate ≫ perfluorooctanesulfonamide ~ N-ethyl perfluorooctanesulfonamidoacetate ≫ perfluorooctanesulfonamidoethanol ~ N-EtFOSE. Although N-EtFOSE treatment significantly decreased the growth rate, increased relative liver weight and activity of superoxide dismutases (SOD) in liver and uterus (total SOD, CuZnSOD and MnSOD), a metabolic study revealed no differences in the metabolome in serum from N-EtFOSE-treated and control animals. Ciprofibrate treatment increased liver weight and peroxisomal acyl Co-A oxidase activity in the liver and altered antioxidant enzyme activities in the uterus and liver. According to NMR metabolomic studies, ciprofibrate treated animals had altered serum lipid profiles compared to N-EtFOSE-treated and control animals, whereas putative markers of peroxisome proliferation in serum were not affected. Overall, this study demonstrates the biotransformation of N-EtFOSE to PFOS in rats that is accompanied by N-EtFOSE-induced alterations in antioxidant enzyme activity.
Keywords: Metabolomics; Perfluorooctanesulfonamides; Perfluorooctanesulfonate; Peroxisomal acyl Co-A oxidase; Superoxide dismutase
Identification of a novel M-superfamily conotoxin with the ability to enhance tetrodotoxin sensitive sodium currents by Lei Wang; Junliang Liu; Canhui Pi; Xiayun Zeng; Maojun Zhou; Xiaoyu Jiang; Shangwu Chen; Zhenghua Ren; Anlong Xu (pp. 925-932).
In this work, a novel M-superfamily conotoxin, designated lt3a, was purified from the crude venom of Conus litteratus. Combined with peptide sequencing, MALDI-TOF mass spectrometry and cDNA cloning techniques, the amino acid sequence of lt3a was supposed to be DγCCγ OQWCDGACDCCS, where O is hydroxyproline and γ is carboxyglutamate. The Cys framework of lt3a (–CC–C–C–CC–) is similar to that of ψ-, μ-, κM-conotoxins, which are representatives of M-conotoxins. Peptide lt3a is categorized into M1 branch based on the number of residues in the last Cys loop. Whole cell patch-clamp study on adult rat dorsal root ganglion neurons indicated that lt3a could enhance tetrodotoxin-sensitive sodium currents. This is a previously unknown function of M-superfamily conotoxins.
Keywords: Conus litteratus ; M-superfamily conotoxin; Tetrodotoxin-sensitive sodium channels; Rat dorsal root ganglion neurons; Post-translational modification
Appraisal of the sensitising potential of orally and dermally administered Mercaptobenzothiazol by a biphasic protocol of the local lymph node assay by Varun Ahuja; Reinhard Wanner; Thomas Platzek; Ralf Stahlmann (pp. 933-939).
Mercaptobenzothiazole (MBT) is used while manufacturing natural rubber products. Our study deals with assessing its allergenic potential following dermal and oral routes of exposure, using a biphasic local lymph node assay (LLNA). Female Balb/c mice were treated with MBT (dermally 3, 10, 30% concentrations in DMSO; orally 1, 10, 100 mg/kg doses in corn oil) on the back (dermal study) or through oral administration (oral study) on days 1–3 followed by auricular application of 3, 10 and 30% concentrations, respectively, on days 15–17. End points determined on day 19 included ear thickness, ear punch weight, lymph node weight, lymph node cell count, and lymphocyte subpopulations (CD4+, CD8+, CD45+). After dermal application of 3% or 10% solution, a significant increase in cell count and lymph node weight along with significant decrease in CD8+ cells was observed. After initial oral administration of 1 mg/kg, we noticed a significant amplification in cell count. Following oral administration of 10 mg/kg, we observed a similar increase in cell count and lymph node weight. The results of our study show that the modified biphasic LLNA protocol can be used to study the sensitising potential of a compound also following the oral route of exposure.
Keywords: Mercaptobenzothiazole; MBT; LLNA; Allergic contact dermatitis
Effects of chronic 4-n-nonylphenol treatment on aortic vasoconstriction and vasorelaxation in rats by Chi-Ying Hsieh; Chang-Ling Miaw; Chien-Cheng Hsieh; Hui-Ching Tseng; Yuan-Han Yang; Chia-Hung Yen (pp. 941-946).
4-Nonylphenol (para-nonylphenol, 4-NP), metabolites including linear and branched isoforms of nonylphenol (n-NP and t-NP, respectively), has been considered an endocrine disrupting substance resulting in reproductive dysfunction and increasing reactive oxygen species production in testis, liver, kidney, and brain. However, to date, whether vasculature is susceptible to NP exposure remains to be unclear. In this study, we have investigated the effects of chronic in vivo 4-n-NP exposure on vasoconstriction and vasorelaxation in male rats. After a 20-week 4-n-NP treatment orally at the dosage of 10 and 50 μM in the drinking water, phenylephrine- and potassium chloride-induced concentration-dependent responsiveness assessed by wire myograph were both significantly higher in aorta isolated from 4-n-NP-treated rats compared with control rats, but acetylcholine-induced vasorelaxation was similar between these two groups. In addition, systemic oxidative stress and vascular, but not intestinal, oxidant enzyme activities assessed by lucigenin-amplified chemiluminescence were all markedly higher in 4-n-NP-treated rats. In conclusion, our results suggested that chronic in vivo 4-n-NP exposure augments vascular contractile responsiveness through enhanced vascular oxidant enzyme activity.
Keywords: Nonylphenol; Vascular function; Oxidative stress
Occupational exposure to polycyclic aromatic hydrocarbons and DNA damage by industry: a nationwide study in Germany by Boleslaw Marczynski; Beate Pesch; Michael Wilhelm; Bernd Rossbach; Ralf Preuss; Jens-Uwe Hahn; Sylvia Rabstein; Monika Raulf-Heimsoth; Albrecht Seidel; Hans-Peter Rihs; Ansgar Adams; Michael Scherenberg; Anja Erkes; Beate Engelhardt; Kurt Straif; Heiko Udo Käfferlein; Jürgen Angerer; Thomas Brüning (pp. 947-957).
Exposure to polycyclic aromatic hydrocarbons (PAH) and DNA damage were analyzed in coke oven (n = 37), refractory (n = 96), graphite electrode (n = 26), and converter workers (n = 12), whereas construction workers (n = 48) served as referents. PAH exposure was assessed by personal air sampling during shift and biological monitoring in urine post shift (1-hydroxypyrene, 1-OHP and 1-, 2 + 9-, 3-, 4-hydroxyphenanthrenes, ΣOHPHE). DNA damage was measured by 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks in blood post shift. Median 1-OHP and ΣOHPHE were highest in converter workers (13.5 and 37.2 μg/g crea). The industrial setting contributed to the metabolite concentrations rather than the air-borne concentration alone. Other routes of uptake, probably dermal, influenced associations between air-borne concentrations and levels of PAH metabolites in urine making biomonitoring results preferred parameters to assess exposure to PAH. DNA damage in terms of 8-oxo-dGuo and DNA strand breaks was higher in exposed workers compared to referents ranking highest for graphite-electrode production. The type of industry contributed to genotoxic DNA damage and DNA damage was not unequivocally associated to PAH on the individual level most likely due to potential contributions of co-exposures.
Keywords: Polycyclic aromatic hydrocarbons; Occupational exposure; DNA damage; Biological monitoring; PAH industries