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  Subjects -> ENVIRONMENTAL STUDIES (Total: 766 journals)
    - ENVIRONMENTAL STUDIES (702 journals)
    - POLLUTION (22 journals)
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ENVIRONMENTAL STUDIES (702 journals)            First | 1 2 3 4 5 6 7 8     

Mathematical and Computational Forestry & Natural-Resource Sciences     Free  
Mathematical Population Studies: An International Journal of Mathematical Demography     Hybrid Journal   (Followers: 2)
Medieval Sermon Studies     Hybrid Journal   (Followers: 5)
Medio Ambiente y Urbanizacion     Full-text available via subscription  
Membranes     Open Access   (Followers: 4)
Michigan Journal of Sustainability     Open Access  
Midwest Studies In Philosophy     Hybrid Journal   (Followers: 10)
Mine Water and the Environment     Hybrid Journal   (Followers: 6)
Mitigation and Adaptation Strategies for Global Change     Hybrid Journal   (Followers: 12)
Modern Asian Studies     Hybrid Journal   (Followers: 4)
Modern Cartography Series     Full-text available via subscription   (Followers: 6)
Mountain Research and Development     Open Access   (Followers: 3)
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (Followers: 2)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (Followers: 8)
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 5)
Natural Areas Journal     Full-text available via subscription   (Followers: 7)
Natural Hazards     Hybrid Journal   (Followers: 177)
Natural Resources     Open Access  
Natural Resources and Environmental Issues     Open Access   (Followers: 5)
Nature and Culture     Full-text available via subscription   (Followers: 9)
NeuroToxicology     Hybrid Journal   (Followers: 1)
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 2)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 6)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 3)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (Followers: 1)
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access  
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 8)
Ocean Acidification     Open Access  
Oecologia     Hybrid Journal   (Followers: 24)
Oikos     Hybrid Journal   (Followers: 29)
Open Journal of Ecology     Open Access   (Followers: 10)
Open Journal of Marine Science     Open Access   (Followers: 6)
Open Journal of Modern Hydrology     Open Access   (Followers: 1)
Our Nature     Open Access   (Followers: 2)
Oxford Journal of Legal Studies     Hybrid Journal   (Followers: 16)
Pace Environmental Law Review     Open Access   (Followers: 4)
Packaging, Transport, Storage and Security of Radioactive Material     Hybrid Journal   (Followers: 2)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 3)
Papers on Global Change IGBP     Open Access   (Followers: 1)
Particle and Fibre Toxicology     Open Access   (Followers: 3)
Pastos y Forrajes     Open Access  
Pesquisa em Educação Ambiental     Open Access  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 5)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 1)
Philosophical Studies     Hybrid Journal   (Followers: 7)
Physio-Géo     Open Access   (Followers: 2)
Pittsburgh Journal of Environmental and Public Health Law     Open Access   (Followers: 1)
Planet     Open Access  
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (Followers: 6)
Plant Ecology & Diversity     Partially Free   (Followers: 9)
Plant Knowledge Journal     Open Access   (Followers: 2)
Plant, Cell & Environment     Hybrid Journal   (Followers: 4)
Polar Journal     Hybrid Journal   (Followers: 1)
Policy Studies     Hybrid Journal   (Followers: 7)
Policy Studies Journal     Hybrid Journal   (Followers: 5)
Polish Polar Research     Open Access   (Followers: 4)
Political Studies     Hybrid Journal   (Followers: 22)
Political Studies Review     Hybrid Journal   (Followers: 14)
Population and Environment     Hybrid Journal   (Followers: 6)
Population Ecology     Hybrid Journal   (Followers: 9)
Population Studies: A Journal of Demography     Hybrid Journal   (Followers: 4)
Postcolonial Studies     Hybrid Journal   (Followers: 5)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (Followers: 3)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (Followers: 1)
Presidential Studies Quarterly     Hybrid Journal   (Followers: 3)
Procedia Environmental Sciences     Open Access   (Followers: 2)
Proceedings of ICE, Waste and Resource Management     Hybrid Journal   (Followers: 3)
Proceedings of the Institution of Mechanical Engineers Part M: Journal of Engineering for the Maritime Environment     Hybrid Journal   (Followers: 1)
Proceedings of the International Academy of Ecology and Environmental Sciences     Open Access   (Followers: 4)
Process Safety and Environmental Protection     Hybrid Journal   (Followers: 3)
Progress in Industrial Ecology, An International Journal     Hybrid Journal   (Followers: 4)
Psychological Assessment     Full-text available via subscription   (Followers: 5)
Public Money & Management     Hybrid Journal   (Followers: 4)
Public Works Management & Policy     Hybrid Journal   (Followers: 5)
Qatar Foundation Annual Research Forum Proceedings     Open Access   (Followers: 3)
Radioactivity in the Environment     Full-text available via subscription   (Followers: 4)
Regional Environmental Change     Hybrid Journal   (Followers: 3)
Regional Studies     Hybrid Journal   (Followers: 6)
Religious Studies     Hybrid Journal   (Followers: 10)
RELP - Renewable Energy Law and Policy     Full-text available via subscription   (Followers: 4)
Remediation Journal     Hybrid Journal   (Followers: 5)
Remote Sensing Letters     Hybrid Journal   (Followers: 8)
Renaissance Studies     Hybrid Journal   (Followers: 13)
Rendiconti Lincei     Hybrid Journal  
Renewable Energy Focus     Full-text available via subscription   (Followers: 7)
Research & Reviews : Journal of Ecology     Full-text available via subscription  
Research and Practice for Persons with Severe Disabilities     Full-text available via subscription   (Followers: 3)
Research Journal of Environmental Sciences     Open Access   (Followers: 1)
Research Journal of Environmental Toxicology     Open Access   (Followers: 2)
ReSource     Full-text available via subscription  
Resources     Open Access  
Resources, Conservation and Recycling     Hybrid Journal   (Followers: 9)
Reuse/Recycle Newsletter     Hybrid Journal   (Followers: 2)
Review of English Studies     Hybrid Journal   (Followers: 7)
Review of Environmental Economics and Policy     Hybrid Journal   (Followers: 7)
Revista AIDIS de Ingeniería y Ciencias Ambientales. Investigación, desarrollo y práctica     Open Access   (Followers: 2)

  First | 1 2 3 4 5 6 7 8     

Journal Cover Toxicology and Applied Pharmacology
   [14 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
     Published by Elsevier Homepage  [2563 journals]   [SJR: 1.328]   [H-I: 110]
  • Rosiglitazone inhibits chlorpyrifos-induced apoptosis via modulation of
           the oxidative stress and inflammatory response in SH-SY5Y cells
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Jeong Eun Lee , Jae Hyeon Park , Sea Jeong Jang , Hyun Chul Koh
      Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-κB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, against CPF-induced neuronal cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-α. CPF also induced nuclear translocation of NF-κB and inhibitors of NF-κB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-κB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-κB.


      PubDate: 2014-06-05T09:41:47Z
       
  • Soy isoflavones interfere with thyroid hormone homeostasis in
           orchidectomized middle-aged rats
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Branka Šošić-Jurjević , Branko Filipović , Eva Katrin Wirth , Jasmina Živanović , Niko Radulović , Snežana Janković , Verica Milošević , Josef Köhrle
      We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh β, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T3-activated genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO-immunopositivity and immunofluorescence of T4 bound to Tg, determined thyroid T4 levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p<0.05) correlated with immunohistochemical staining results, and together with decreased serum total T4 levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p<0.05) gene in liver and kidney was up-regulated, and liver Dio 1 expression and activity (p<0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats.


      PubDate: 2014-06-05T09:41:47Z
       
  • Modulation of miR-203 and its regulators as a function of time during the
           development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors
           in presence or absence of the antitumor agents
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Prakash Tiwari , Krishna P. Gupta
      We investigated the chemopreventive effects of naturally occurring compounds like butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) individually or in combination in 7, 12-dimethylbenz [a] anthracene (DMBA) treated mouse skin at 4 and 16weeks, the time before and after the tumor development. DMBA application did not show any skin tumors at 4weeks but well defined tumors appeared at 16weeks. BA, NA or CAG prevented the tumor development significantly but the protection was highly enhanced when all these compounds were given together. In order to see the molecular changes progressing with tumors, we showed the downregulation of tumor suppressor miR-203 at 16weeks and upregulation of histone deacetylases (HDAC), DNA methyltransferase, promoter methylation of miR-203 at 4 or 16weeks. Regulators of micro RNA biogenesis such as DICER1 and Ago2 were also deregulated by DMBA. Proto-oncogene c-myc and BMI1 were upregulated and tumor suppressor gene p16 was downregulated by DMBA as a function of time. Effects of BA, NA or CAG were more pronounced after 16weeks as compared to 4weeks in preventing the tumor development and altered gene expression. Concomitant administration of BA, NA and CAG tried to prevent these alterations more effectively than that of individual compound possibly by regulating miR-203 status through epigenetic or biogenetic modulations before and after the tumor development. Study provides a rationale for chemoprevention by combination of different compounds targeting miR-203.


      PubDate: 2014-06-05T09:41:47Z
       
  • Triclosan exacerbates the presence of 14C-bisphenol A in tissues of female
           and male mice
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Tyler Pollock , Brandon Tang , Denys deCatanzaro
      Current human generations are commonly exposed to both triclosan (TCS), an antimicrobial agent, and bisphenol A (BPA), the monomer of polycarbonate plastics and epoxies. Both are readily absorbed into circulation and found distributed among diverse tissues. Potential interactions between TCS and BPA are largely unstudied. We investigated whether TCS exposure affects the distribution of ingested 14C-BPA in select tissues. CF-1 mice were each subcutaneously injected with TCS then orally administered 50μg/kg 14C-BPA. Females received 0, 0.2, 0.6, 1, 2, or 18mg TCS (equivalent respectively to 0, 6.3, 16.9, 30.1, 60.5, and 558.9mg/kg). Males received 0, 0.2, 2, or 18 mg TCS (equivalent respectively to 0, 5.3, 53.4, and 415.0mg/kg). Levels of radioactivity were measured through liquid scintillation counting in blood serum and brain, reproductive, and other tissues. Significantly elevated levels of radioactivity were observed following combined TCS and 14C-BPA administration, with minimally effective TCS doses being tissue-dependent (Females: lungs, 0.6mg; uterus, 1mg; heart, muscle, ovaries, and serum, 18mg. Males: serum, 0.2mg; epididymides, 2mg). Subsequently, we found that 2 or 6mg TCS increased radioactivity in the ovaries and serum of females orally given only 5μg/kg 14C-BPA. These data indicate that TCS can interact with BPA in vivo, magnifying its presence in certain tissues and serum. The data are consistent with evidence that TCS utilizes enzymes that are critical for metabolism and excretion of BPA. Further research should investigate the mechanisms through which these two chemicals interact at environmentally-relevant doses.


      PubDate: 2014-06-05T09:41:47Z
       
  • Contents Continued
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2




      PubDate: 2014-06-05T09:41:47Z
       
  • Contents
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2




      PubDate: 2014-06-05T09:41:47Z
       
  • Exposure to 9,10-phenanthrenequinone accelerates malignant progression of
           lung cancer cells through up-regulation of aldo-keto reductase 1B10
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Toshiyuki Matsunaga , Yoshifumi Morikawa , Mariko Haga , Satoshi Endo , Midori Soda , Keiko Yamamura , Ossama El-Kabbani , Kazuo Tajima , Akira Ikari , Akira Hara
      Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5μM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-l-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling.
      Graphical abstract image

      PubDate: 2014-06-05T09:41:47Z
       
  • Mechanisms of cisplatin-induced muscle atrophy
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Hiroyasu Sakai , Atsunobu Sagara , Kazuhiko Arakawa , Ryoto Sugiyama , Akiko Hirosaki , Kazuhide Takase , Ara Jo , Ken Sato , Yoshihiko Chiba , Mitsuaki Yamazaki , Motohiro Matoba , Minoru Narita
      Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue.
      Graphical abstract image

      PubDate: 2014-06-05T09:41:47Z
       
  • Alpha5 nicotinic acetylcholine receptor mediates nicotine-induced
           HIF-1α and VEGF expression in non-small cell lung cancer
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Xiaoli Ma , Yanfei Jia , Shanshan Zu , Ruisheng Li , Ying Jia , Yun Zhao , Dongjie Xiao , Ningning Dang , Yunshan Wang
      By binding to nicotinic acetylcholine receptors (nAChRs), nicotine induces the proliferation and apoptosis of non-small cell lung cancer (NSCLC). Previous studies have indicated that α5-nAChR is highly associated with lung cancer risk and nicotine dependence. However, the mechanisms through which α5-nAChRs may influence lung carcinogenesis are far from clear. In the present study, we investigated the roles of α5-nAChR in the nicotine-induced expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Immunohistochemistry was used to detect the expression of α5-nAChR and HIF-1α in 60 specimens of lung cancer and para-carcinoma tissue. The correlations between the expression levels of α5-nAChR and HIF-1α and other clinicopathological data were analyzed. In a cell line that highly expressed α5-nAChR, the loss of α5-nAChR function by siRNA was used to study whether α5-nAChR is involved in the nicotine-induced expression of HIF-1α and VEGF through the activation of the ERK1/2 and PI3K/Akt signaling pathways. Cell growth was detected using the cell counting kit-8 (CCK-8). α5-nAChR (78.3%) and HIF-1α (88.3%) were both overexpressed in NSCLC, and their expression levels were found to be correlated with each other (P<0.05). In the A549 cell line, α5-nAChR and HIF-1α were found to be expressed under normal conditions, and their expression levels were significantly increased in response to nicotine treatment. The silencing of α5-nAChR significantly inhibited the nicotine-induced cell proliferation compared with the control group and attenuated the nicotine-induced upregulation of HIF-1α and VEGF, and these effects required the cooperation of the ERK1/2 and PI3K/Akt signaling pathways. These results show that the α5-nAChR/HIF-1α/VEGF axis is involved in nicotine-induced tumor cell proliferation, which suggests that α5-nAChR may serve as a potential anticancer target in nicotine-associated lung cancer.


      PubDate: 2014-06-05T09:41:47Z
       
  • Interactive effects of cerium oxide and diesel exhaust nanoparticles on
           inducing pulmonary fibrosis
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Jane Y.C. Ma , Shih-Houng Young , Robert R. Mercer , Mark Barger , Diane Schwegler-Berry , Joseph K. Ma , Vincent Castranova
      Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO2) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO2 on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO2 and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO2 induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO2 and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO2, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP+CeO2 were significantly larger than CeO2 or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP+CeO2 reflects the combination of DEP-exposure plus CeO2-exposure. At 4weeks post-exposure, the histological features demonstrated that CeO2 induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO2 in the combined exposure. Using CeO2 as diesel fuel catalyst may cause health concerns.


      PubDate: 2014-06-05T09:41:47Z
       
  • Editorial Board
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2




      PubDate: 2014-06-05T09:41:47Z
       
  • Flavin-containing monooxygenase S-oxygenation of a series of thioureas and
           thiones
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Marilyn C. Henderson , Lisbeth K. Siddens , Sharon K. Krueger , J. Fred Stevens , Karen Kedzie , Wenkui K. Fang , Todd Heidelbaugh , Phong Nguyen , Ken Chow , Michael Garst , Daniel Gil , David E. Williams
      Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC–MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2–7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with K m s ranging from 7 to 160μM and turnover numbers of 30–40min−1. The product formed was identified by LC–MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.


      PubDate: 2014-06-05T09:41:47Z
       
  • Effects of oral exposure to naturally-occurring and synthetic
           deoxynivalenol congeners on proinflammatory cytokine and chemokine mRNA
           expression in the mouse
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): Wenda Wu , Kaiyu He , Hui-Ren Zhou , Franz Berthiller , Gerhard Adam , Yoshiko Sugita-Konishi , Maiko Watanabe , Anthony Krantis , Tony Durst , Haibin Zhang , James J. Pestka
      The foodborne mycotoxin deoxynivalenol (DON) induces a ribotoxic stress response in mononuclear phagocytes that mediate aberrant multi-organ upregulation of TNF-α, interleukins and chemokines in experimental animals. While other DON congeners also exist as food contaminants or pharmacologically-active derivatives, it is not known how these compounds affect expression of these cytokine genes in vivo. To address this gap, we compared in mice the acute effects of oral DON exposure to that of seven relevant congeners on splenic expression of representative cytokine mRNAs after 2 and 6h. Congeners included the 8-ketotrichothecenes 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), nivalenol (NIV), the plant metabolite DON-3-glucoside (D3G) and two synthetic DON derivatives with novel satiety-inducing properties (EN139528 and EN139544). DON markedly induced transient upregulation of TNF-α IL-1β, IL-6, CXCL-2, CCL-2 and CCL-7 mRNA expressions. The two ADONs also evoked mRNA expression of these genes but to a relatively lesser extent. FX induced more persistent responses than the other DON congeners and, compared to DON, was: 1) more potent in inducing IL-1β mRNA, 2) approximately equipotent in the induction of TNF-α and CCL-2 mRNAs, and 3) less potent at upregulating IL-6, CXCL-2, and CCL-2 mRNAs. EN139528's effects were similar to NIV, the least potent 8-ketotrichothecene, while D3G and EN139544 were largely incapable of eliciting cytokine or chemokine mRNA responses. Taken together, the results presented herein provide important new insights into the potential of naturally-occurring and synthetic DON congeners to elicit aberrant mRNA upregulation of cytokines associated with acute and chronic trichothecene toxicity.


      PubDate: 2014-06-05T09:41:47Z
       
  • The inhibition of human T cell proliferation by the caspase inhibitor
           z-VAD-FMK is mediated through oxidative stress
    • Abstract: Publication date: 15 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 2
      Author(s): T. Rajah , S.C. Chow
      The caspase inhibitor benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe)-fluoromethylketone (z-VAD-FMK) has recently been shown to inhibit T cell proliferation without blocking caspase-8 and caspase-3 activation in primary T cells. We showed in this study that z-VAD-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-mediated T cell proliferation induced by z-VAD-FMK was abolished by the presence of low molecular weight thiols such as GSH, N-acetylcysteine (NAC) and l-cysteine, whereas d-cysteine which cannot be metabolised to GSH has no effect. These results suggest that the depletion of intracellular GSH is the underlying cause of z-VAD-FMK-mediated inhibition of T cell activation and proliferation. The presence of exogenous GSH also attenuated the inhibition of anti-CD3-induced CD25 and CD69 expression mediated by z-VAD-FMK. However, none of the low molecular weight thiols were able to restore the caspase-inhibitory properties of z-VAD-FMK in activated T cells where caspase-8 and caspase-3 remain activated and processed into their respective subunits in the presence of the caspase inhibitor. This suggests that the inhibition of T cell proliferation can be uncoupled from the caspase-inhibitory properties of z-VAD-FMK. Taken together, the immunosuppressive effects in primary T cells mediated by z-VAD-FMK are due to oxidative stress via the depletion of GSH.


      PubDate: 2014-06-05T09:41:47Z
       
  • Mechanisms of Acetaminophen-induced Cell Death in Primary Human
           Hepatocytes
    • Abstract: Publication date: Available online 3 June 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuchao Xie , Mitchell R. McGill , Kenneth Dorko , Sean C. Kumer , Timothy M. Schmitt , Jameson Forster , Hartmut Jaeschke
      Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP over a period of 48hours and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24h and 48h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6hours after APAP and a partial protection when given at 15h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic.


      PubDate: 2014-06-03T14:42:46Z
       
  • Editorial Board
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1




      PubDate: 2014-06-03T14:42:46Z
       
  • Cover 3--TOC (Cont'd)
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1




      PubDate: 2014-06-03T14:42:46Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1




      PubDate: 2014-06-03T14:42:46Z
       
  • Zinc oxide nanoparticles induce migration and adhesion of monocytes to
           endothelial cells and accelerate foam cell formation
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Yuka Suzuki , Saeko Tada-Oikawa , Gaku Ichihara , Masayuki Yabata , Kiyora Izuoka , Masako Suzuki , Kiyoshi Sakai , Sahoko Ichihara
      Metal oxide nanoparticles are widely used in industry, cosmetics, and biomedicine. However, the effects of exposure to these nanoparticles on the cardiovascular system remain unknown. The present study investigated the effects of nanosized TiO2 and ZnO particles on the migration and adhesion of monocytes, which are essential processes in atherosclerogenesis, using an in vitro set-up of human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cells (THP-1). We also examined the effects of exposure to nanosized metal oxide particles on macrophage cholesterol uptake and foam cell formation. The 16-hour exposure to ZnO particles increased the level of monocyte chemotactic protein-1 (MCP-1) and induced the migration of THP-1 monocyte mediated by increased MCP-1. Exposure to ZnO particles also induced adhesion of THP-1 cells to HUVECs. Moreover, exposure to ZnO particles, but not TiO2 particles, upregulated the expression of membrane scavenger receptors of modified LDL and increased cholesterol uptake in THP-1 monocytes/macrophages. In the present study, we found that exposure to ZnO particles increased macrophage cholesterol uptake, which was mediated by an upregulation of membrane scavenger receptors of modified LDL. These results suggest that nanosized ZnO particles could potentially enhance atherosclerogenesis and accelerate foam cell formation.


      PubDate: 2014-05-12T04:53:18Z
       
  • Testicular distribution and toxicity of a novel LTA4H inhibitor in rats
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): P.D. Ward , D. La
      JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the Tmax of M1 was 48h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed.


      PubDate: 2014-05-12T04:53:18Z
       
  • Contents
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3




      PubDate: 2014-05-12T04:53:18Z
       
  • SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human
           keratinocytes
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Katharine J. Herbert , Anthony L. Cook , Elizabeth T. Snow
      Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested. Through use of RNAi, miRNA target site blocking oligonucleotides and small molecule inhibitors, this study explored the influence of p53 mutational status, SIRT1 activity and miR-34a levels on apoptotic sensitivity in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines. SIRT1 and p53 are overexpressed in p53-mutated keratinocytes, whilst miR-34a levels are 90% less in HaCaT cells. HaCaTs have impaired responses to p53/SIRT1/miR-34a axis manipulation which enhanced survival during exposure to the chemotherapeutic agent, camptothecin. Inhibition of SIRT1 activity in this cell line increased p53 acetylation and doubled camptothecin-induced cell death. Our results demonstrate that p53 mutations increase apoptotic resistance in keratinocytes by interfering with miR-34a-mediated regulation of SIRT1 expression. Thus, SIRT1 inhibitors may have a therapeutic potential for overcoming apoptotic resistance during skin cancer treatment.
      Graphical abstract image

      PubDate: 2014-05-12T04:53:18Z
       
  • Persistent modification of Nav1.9 following chronic exposure to
           insecticides and pyridostigmine bromide
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Thomas J. Nutter , Brian Y. Cooper
      Many veterans of the 1991 Gulf War (GW) returned from that conflict with a widespread chronic pain affecting deep tissues. Recently, we have shown that a 60day exposure to the insecticides permethrin, chlorpyrifos, and pyridostigmine bromide (NTPB) had little influence on nociceptor action potential forming Nav1.8, but increased Kv7 mediated inhibitory currents 8weeks after treatment. Using the same exposure regimen, we used whole cell patch methods to examine whether the influences of NTPB could be observed on Nav1.9 expressed in muscle and vascular nociceptors. During a 60day exposure to NTPB, rats exhibited lowered muscle pain thresholds and increased rest periods, but these measures subsequently returned to normal levels. Eight and 12weeks after treatments ceased, DRG neurons were excised from the sensory ganglia. Whole cell patch studies revealed little change in voltage dependent activation and deactivation of Nav1.9, but significant increases in the amplitude of Nav1.9 were observed 8weeks after exposure. Cellular studies, at the 8week delay, revealed that NTPB also significantly prolonged action potential duration and afterhyperpolarization (22°C). Acute application of permethrin (10μM) also increased the amplitude of Nav1.9 in skin, muscle and vascular nociceptors. In conclusion, chronic exposure to Gulf War agents produced long term changes in the amplitude of Nav1.9 expressed in muscle and vascular nociceptors. The reported increases in Kv7 amplitude may have been an adaptive response to increased Nav1.9, and effectively suppressed behavioral pain measures in the post treatment period. Factors that alter the balance between Nav1.9 and Kv7 could release spontaneous discharge and produce chronic deep tissue pain.


      PubDate: 2014-05-12T04:53:18Z
       
  • Bleomycin-induced epithelial–mesenchymal transition in sclerotic
           skin of mi Possible role of oxidative stress in the pathogenesis
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Cheng-Fan Zhou , Deng-Chuan Zhou , Jia-Xiang Zhang , Feng Wang , Wan-Sheng Cha , Chang-Hao Wu , Qi-Xing Zhu
      Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100mg/kg body weight/day) injected daily for 3weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice.


      PubDate: 2014-05-12T04:53:18Z
       
  • 1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane and tris(methylphenyl)
           phosphate cause significant effects on development, mRNA expression, and
           circulating bile acid concentrations in chicken embryos
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Doug Crump , Emily Porter , Caroline Egloff , Kim L. Williams , Robert J. Letcher , Lewis T. Gauthier , Sean W. Kennedy
      1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane (DBE-DBCH; formerly abbreviated as TBECH) and tris(methylphenyl) phosphate (TMPP; formerly abbreviated as TCP) are additive flame retardants that are detected in the environment and biota. A recent avian in vitro screening study of 16 flame retardants identified DBE-DBCH and TMPP as important chemicals for follow-up in ovo evaluation based on their effects on cytotoxicity and mRNA expression in avian hepatocytes. In this study, technical mixtures of DBE-DBCH and TMPP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 54,900ng/g and from 0 to 261,400ng/g, respectively, to determine effects on pipping success, development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations. Both compounds were detectable in embryos at pipping and the β-DBE-DBCH isomer was depleted more rapidly than the α-isomer in tissue samples. DBE-DBCH had limited effects on the endpoints measured, with the exception of the up-regulation of two phase I metabolizing enzymes, CYP3A37 and CYP2H1. TMPP exposure caused embryonic deformities, altered growth, increased liver somatic index (LSI) and plasma bile acid concentrations, and altered mRNA expression levels of genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Overall, TMPP elicited more adverse molecular and phenotypic effects than DBE-DBCH albeit at concentrations several orders of magnitude greater than those detected in the environment. The increase in plasma bile acid concentrations was a useful phenotypic anchor as it was associated with a concomitant increase in LSI, discoloration of the liver tissue, and modulation of hepatic genes involved with xenobiotic and lipid metabolism.


      PubDate: 2014-05-12T04:53:18Z
       
  • Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced
           NF-κB activation and caspase inhibition
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Changjiang Liu , Jixin Yang , Wenjuan Fu , Suqin Qi , Chenmin Wang , Chao Quan , Kedi Yang
      Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10μM) for 24h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity.


      PubDate: 2014-05-12T04:53:18Z
       
  • 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside confers
           neuroprotection in cell and animal models of ischemic stroke through
           calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Shu Yu , Qiong Cheng , Lu Li , Mei Liu , Yumin Yang , Fei Ding
      Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (named SalA-4g), has been synthesized in our lab. In this study, we showed that SalA-4g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4g was more neuroprotective than salidroside. We further found that SalA-4g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemic brain. Signaling analysis revealed that SalA-4g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4g. Moreover, SalA-4g was noted to inhibit intracellular Ca2+ influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway.
      Graphical abstract image

      PubDate: 2014-05-12T04:53:18Z
       
  • Metabolism and physiologically based pharmacokinetic modeling of
           flumioxazin in pregnant animals
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): Tomoyuki Takaku , Hirohisa Nagahori , Yoshihisa Sogame
      A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000mg/kg). The data on flumioxazin concentration in pregnant rats (30mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-14C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000mg/kg in rats was low (12.3%) by summing up 14C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000mg/kg po was 0.86μg/mL and 0.68μg/mL, respectively, which is much lower than Km (202.4μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments.


      PubDate: 2014-05-12T04:53:18Z
       
  • Editorial Board
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3




      PubDate: 2014-05-12T04:53:18Z
       
  • Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via
           steroidogenic factor 1 (SF-1) deacetylation
    • Abstract: Publication date: 15 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 3
      Author(s): You-e Yan , Lian Liu , Jian-fei Wang , Fang Liu , Xiao-hai Li , Hai-quan Qin , Hui Wang
      This study aimed to investigate the suppressive effect of nicotine on fetal adrenal steroidogenesis and to explore the potential role of epigenetic modification of steroidogenic factor-1 (SF-1) transcriptional activity in this process. Nicotine was intragastrically administered to pregnant rats and NCI-H295A cells were treated with nicotine or trichostatin A (TSA). The pathomorphology of fetal adrenals, steroid hormone levels, the expression of SF-1 and its target genes, and histone deacetylase (HDAC) mRNA were analyzed. Histone modification and DNA methylation of the SF-1 promoter region were assessed using chromatin immunoprecipitation (ChIP) and bisulfite sequencing PCR. The interaction between SF1 and its target genes was observed. Prenatal nicotinic exposure decreased fetal body weight, increased the IUGR rate and caused detrimental changes in fetal adrenal. In addition, the levels of corticosterone, the expression of SF-1 and its target genes were decreased while HDAC2 expression was enhanced. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels while there was no effect on the methylation frequency on the SF-1 promoter region. Furthermore, in nicotine-treated NCI-H295A cells, lower levels of steroidogenic synthesis, lower expression of SF-1 and its target genes were observed while the expression of HDACs was enhanced. The interaction between SF1 and StAR decreased with nicotine treatment. Nicotine treatment decreased histone H3K9 and H3K14 acetylation levels, and addition of TSA reversed the inhibition of nicotine-mediated SF-1 and its partial target genes. Thus, nicotine-mediated reduction of SF-1 expression resulted in an inhibitory effect on the expression of its target genes and steroid production via histone deacetylation.


      PubDate: 2014-05-12T04:53:18Z
       
  • Exploring the potential role of tungsten carbide cobalt (WC-Co)
           nanoparticle internalization in observed toxicity toward lung epithelial
           cells in vitro
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Andrea L. Armstead , Christopher B. Arena , Bingyun Li
      Tungsten carbide cobalt (WC-Co) has been recognized as a workplace inhalation hazard in the manufacturing, mining and drilling industries by the National Institute of Occupational Safety and Health. Exposure to WC-Co is known to cause “hard metal lung disease” but the relationship between exposure, toxicity and development of disease remain poorly understood. To better understand this relationship, the present study examined the role of WC-Co particle size and internalization on toxicity using lung epithelial cells. We demonstrated that nano- and micro-WC-Co particles exerted toxicity in a dose- and time-dependent manner and that nano-WC-Co particles caused significantly greater toxicity at lower concentrations and shorter exposure times compared to micro-WC-Co particles. WC-Co particles in the nano-size range (not micron-sized) were internalized by lung epithelial cells, which suggested that internalization may play a key role in the enhanced toxicity of nano-WC-Co particles over micro-WC-Co particles. Further exploration of the internalization process indicated that there may be multiple mechanisms involved in WC-Co internalization such as actin and microtubule based cytoskeletal rearrangements. These findings support our hypothesis that WC-Co particle internalization contributes to cellular toxicity and suggest that therapeutic treatments inhibiting particle internalization may serve as prophylactic approaches for those at risk of WC-Co particle exposure.


      PubDate: 2014-05-12T04:53:18Z
       
  • Short-term effects of electronic and tobacco cigarettes on exhaled nitric
           oxide
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Sara Marini , Giorgio Buonanno , Luca Stabile , Giorgio Ficco
      The objective of this study was to compare the short-term respiratory effects due to the inhalation of electronic and conventional tobacco cigarette-generated mainstream aerosols through the measurement of the exhaled nitric oxide (eNO). To this purpose, twenty-five smokers were asked to smoke a conventional cigarette and to vape an electronic cigarette (with and without nicotine), and an electronic cigarette without liquid (control session). Electronic and tobacco cigarette mainstream aerosols were characterized in terms of total particle number concentrations and size distributions. On the basis of the measured total particle number concentrations and size distributions, the average particle doses deposited in alveolar and tracheobronchial regions of the lungs for a single 2-s puff were also estimated considering a subject performing resting (sitting) activity. Total particle number concentrations in the mainstream resulted equal to 3.5±0.4×109, 5.1±0.1×109, and 3.1±0.6×109 part. cm−3 for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively. The corresponding alveolar doses for a resting subject were estimated equal to 3.8×1010, 5.2×1010 and 2.3×1010 particles. The mean eNO variations measured after each smoking/vaping session were equal to 3.2ppb, 2.7ppb and 2.8ppb for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively; whereas, negligible eNO changes were measured in the control session. Statistical tests performed on eNO data showed statistically significant differences between smoking/vaping sessions and the control session, thus confirming a similar effect on human airways whatever the cigarette smoked/vaped, the nicotine content, and the particle dose received.


      PubDate: 2014-05-12T04:53:18Z
       
  • Availability of human induced pluripotent stem cell-derived cardiomyocytes
           in assessment of drug potential for QT prolongation
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Yumiko Nozaki , Yayoi Honda , Shinji Tsujimoto , Hitoshi Watanabe , Takeshi Kunimatsu , Hitoshi Funabashi
      Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K+ channel and Ca2+ channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca2+ channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential.


      PubDate: 2014-05-12T04:53:18Z
       
  • Pulmonary function responses to ozone in smokers with a limited smoking
           history
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Melissa L. Bates , Timothy M. Brenza , Abdellaziz Ben-Jebria , Rebecca Bascom , Marlowe W. Eldridge , James S. Ultman
      In non-smokers, ozone (O3) inhalation causes decreases in forced expiratory volume (FEV1) and dead space (VD) and increases the slope of the alveolar plateau (SN). We previously described a population of smokers with a limited smoking history that had enhanced responsiveness to brief O3 boluses and aimed to determine if responsiveness to continuous exposure was also enhanced. Thirty smokers (19M, 11F, 24±4years, 6±4 total years smoking,4±2packs/week) and 30 non-smokers (17M, 13F, 25±6years) exercised for 1h on a cycle ergometer while breathing 0.30ppm O3. Smokers and non-smokers were equally responsive in terms of FEV1 (−9.5±1.8% vs −8.7±1.9%). Smokers alone were responsive in terms of VD (−6.1±1.2%) and SN (9.1±3.4%). There was no difference in total delivered dose. Dead space ventilation (VD/VT) was not initially different between the two groups, but increased in the non-smokers (16.4±2.8%) during the exposure, suggesting that the inhaled dose may be distributed more peripherally in smokers. We also conclude that these cigarette smokers retain their airway responsiveness to O3 and, uniquely, experience changes in VD that lead to heterogeneity in airway morphometry and an increase in SN.


      PubDate: 2014-05-12T04:53:18Z
       
  • Generation and characterization of gsuα:EGFP transgenic zebrafish for
           evaluating endocrine-disrupting effects
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Xiaoxia Cheng , Xiaowen Chen , Xia Jin , Jiangyan He , Zhan Yin
      The glycoprotein subunit α (gsuα) gene encodes the shared α subunit of the three pituitary heterodimeric glycoprotein hormones: follicle-stimulating hormone β (Fshβ), luteinizing hormone β (Lhβ) and thyroid stimulating hormone β (Tshβ). In our current study, we identified and characterized the promoter region of zebrafish gsuα and generated a stable gsuα:EGFP transgenic line, which recapitulated the endogenous gsuα expression in the early developing pituitary gland. A relatively conserved regulatory element set is presented in the promoter regions of zebrafish and three other known mammalian gsuα promoters. Our results also demonstrated that the expression patterns of the gsuα:EGFP transgene were all identical to those expression patterns of the endogenous gsuα expression in the pituitary tissue when our transgenic fish were treated with various endocrine chemicals, including forskolin (FSK), SP600125, trichostatin A (TSA), KClO4, dexamethasone (Dex), β-estradiol and progesterone. Thus, this gsuα:EGFP transgenic fish reporter line provides another valuable tool for investigating the lineage development of gsuα-expressing gonadotrophins and the coordinated regulation of various glycoprotein hormone subunit genes. These reporter fish can serve as a novel platform to perform screenings of endocrine-disrupting chemicals (EDCs) in vivo as well.
      Graphical abstract image

      PubDate: 2014-05-12T04:53:18Z
       
  • Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl
           hydrocarbon receptor (AhR)
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Xingguo Cheng , Saurabh G. Vispute , Jie Liu , Christine Cheng , Alexei Kharitonenkov , Curtis D. Klaassen
      The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (−105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.


      PubDate: 2014-05-12T04:53:18Z
       
  • Acute chlorine gas exposure produces transient inflammation and a
           progressive alteration in surfactant composition with accompanying
           mechanical dysfunction
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Christopher B. Massa , Pamela Scott , Elena Abramova , Carol Gardner , Debra L. Laskin , Andrew J. Gow
      Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60ppm-hour Cl2 dose, and were euthanized 3, 24 and 48h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24h. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3 − or NO2 −. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation.


      PubDate: 2014-05-12T04:53:18Z
       
  • DNA damage in internal organs after cutaneous exposure to sulphur mustard
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Mohamed Batal , Isabelle Boudry , Stéphane Mouret , Cécile Cléry-Barraud , Julien Wartelle , Izabel Bérard , Thierry Douki
      Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target.
      Graphical abstract image

      PubDate: 2014-05-12T04:53:18Z
       
  • The effect of doxycycline treatment on the postvaccinal immune response in
           pigs
    • Abstract: Publication date: 1 July 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 1
      Author(s): Małgorzata Pomorska-Mól , Krzysztof Kwit , Iwona Markowska-Daniel , Zygmunt Pejsak
      The effect of a seven-day antibiotic therapy with doxycycline was investigated on the postvaccinal humoral and cellular immune response in pigs. The selected parameters of non-specific immunity were also studied. Fifty pigs were used (control not vaccinated (C, n=10), control vaccinated (CV, n=20), and experimental — received doxycycline (DOXY, n=20)). For vaccination live-attenuated vaccine against pseudorabies (PR) was used. From day −1 to day 5 pigs from DOXY group received doxycycline orally with drinking water, at the recommended dose. Pigs from DOXY and CV groups were vaccinated at 8 and 10weeks of age. The results of the present study showed that cell-mediated postvaccinal immune response can be modulated by oral treatment with doxycycline. Significantly lower values of stimulation index were observed after PRV restimulation in doxycycline-treated pigs. Moreover, in the DOXY group a significant decrease in IFN-γ production after PRV restimulation was noted. The significantly lower number of CD4+CD8+ cells was also observed in doxy-treated, vaccinated pigs, 2weeks after final vaccination. Simultaneously, specific humoral response was not disturbed. This study demonstrated the importance of defining the immune modulatory activity of doxycycline because it may alter the immune responses to vaccines. The exact mechanism of T-cell response suppression by doxycycline remains to be elucidated, however the influence of doxycycline on the secretion of various cytokines, including IFN-γ, may be considered as a possible cause. The present observations should prompt further studies on the practical significance of such phenomena in terms of clinical implications.


      PubDate: 2014-05-12T04:53:18Z
       
  • Editorial Board
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2




      PubDate: 2014-05-06T23:19:10Z
       
  • Oleanolic acid supplement attenuates liquid fructose-induced adipose
           tissue insulin resistance through the insulin receptor
           substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Ying Li , Jianwei Wang , Tieguang Gu , Johji Yamahara , Yuhao Li
      Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25mg/kg, once daily, by oral gavage) over 10weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid.


      PubDate: 2014-04-27T05:18:49Z
       
  • Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro
           and in vivo
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Lijuan Wang , Changyuan Wang , Jinyong Peng , Qi Liu , Qiang Meng , Huijun Sun , Xiaokui Huo , Pengyuan Sun , Xiaobo Yang , Yuhong Zhen , Kexin Liu
      The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen.


      PubDate: 2014-04-27T05:18:49Z
       
  • Effect of various antibiotics on modulation of intestinal microbiota and
           bile acid profile in mice
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Youcai Zhang , Pallavi B. Limaye , Helen J. Renaud , Curtis D. Klaassen
      Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin+imipenem and cephalothin+neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin+imipenem but stimulated by cephalothin+neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism.


      PubDate: 2014-04-27T05:18:49Z
       
  • Aspirin-triggered resolvin D1 down-regulates inflammatory responses and
           protects against endotoxin-induced acute kidney injury
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Jiao Chen , Sreerama Shetty , Ping Zhang , Rong Gao , Yuxin Hu , Shuxia Wang , Zhenyu Li , Jian Fu
      The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.


      PubDate: 2014-04-27T05:18:49Z
       
  • Perfluorinated chemicals: Differential toxicity, inhibition of aromatase
           activity and alteration of cellular lipids in human placental cells
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Eva Gorrochategui , Elisabet Pérez-Albaladejo , Josefina Casas , Sílvia Lacorte , Cinta Porte
      The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA>PFOS≫PFNA>PFOA>PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells.


      PubDate: 2014-04-27T05:18:49Z
       
  • Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress
           responses in the lungs of hepatic alcohol dehydrogenase deficient deer
           mice after chronic ethanol feeding
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Lata Kaphalia , Nahal Boroumand , Ju Hyunsu , Bhupendra S. Kaphalia , William J. Calhoun
      Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3months. Blood ethanol concentration was 180mg% in ethanol fed mice, compared to <1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6μg/g in the lungs of ethanol-fed mice as compared to 1.5μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease.
      Graphical abstract image

      PubDate: 2014-04-27T05:18:49Z
       
  • Erlotinib promotes endoplasmic reticulum stress-mediated injury in the
           intestinal epithelium
    • Abstract: Publication date: Available online 24 April 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Lu Fan , Lingna Hu , Baofang Yang , Xianying Fang , Zhe Gao , Wanshuai Li , Yang Sun , Yan Shen , Xuefeng Wu , Yongqian Shu , Yanhong Gu , Xudong Wu , Qiang Xu
      Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependent manner induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients.
      Graphical abstract image

      PubDate: 2014-04-27T05:18:49Z
       
  • Investigation of the in vitro toxicological properties of the synthetic
           cannabimimetic drug CP-47,497-C8
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Verena J. Koller , Volker Auwärter , Tamara Grummt , Bjoern Moosmann , Miroslav Mišík , Siegfried Knasmüller
      Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥7.5μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥10μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.


      PubDate: 2014-04-27T05:18:49Z
       
  • Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates
           capacity of hematopoietic stem cells to undergo lymphocyte differentiation
           
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Lori S. Ahrenhoerster , Everett R. Tate , Peter A. Lakatos , Xuexia Wang , Michael D. Laiosa
      The process of hematopoiesis, characterized by long-term self-renewal and multi-potent lineage differentiation, has been shown to be regulated in part by the ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous contaminant and the most potent AHR agonist, also modulates regulation of adult hematopoietic stem and progenitor cell (HSC/HPC) homeostasis. However, the effect of developmental TCDD exposure on early life hematopoiesis has not been fully explored. Given the inhibitory effects of TCDD on hematopoiesis and lymphocyte development, we hypothesized that in utero exposure to TCDD would alter the functional capacity of fetal HSC/HPCs to complete lymphocyte differentiation. To test this hypothesis, we employed a co-culture system designed to facilitate the maturation of progenitor cells to either B or T lymphocytes. Furthermore, we utilized an innovative limiting dilution assay to precisely quantify differences in lymphocyte differentiation between HSC/HPCs obtained from fetuses of dams exposed to 3μg/kg TCDD or control. We found that the AHR is transcribed in yolk sac hematopoietic cells and is transcriptionally active as early as gestational day (GD) 7.5. Furthermore, the number of HSC/HPCs present in the fetal liver on GD 14.5 was significantly increased in fetuses whose mothers were exposed to TCDD throughout pregnancy. Despite this increase in HSC/HPC cell number, B and T lymphocyte differentiation is decreased by approximately 2.5 fold. These findings demonstrate that inappropriate developmental AHR activation in HSC/HPCs adversely impacts lymphocyte differentiation and may have consequences for lymphocyte development in the bone marrow and thymus later in life.


      PubDate: 2014-04-27T05:18:49Z
       
  • Liver biomarker and in vitro assessment confirm the hepatic origin of
           aminotransferase elevations lacking histopathological correlate in beagle
           dogs treated with GABAA receptor antagonist NP260
    • Abstract: Publication date: 1 June 2014
      Source:Toxicology and Applied Pharmacology, Volume 277, Issue 2
      Author(s): Alison H. Harrill , John S. Eaddy , Kelly Rose , John M. Cullen , Lakshmi Ramanathan , Stephen Wanaski , Stephen Collins , Yu Ho , Paul B. Watkins , Edward L. LeCluyse
      NP260 was designed as a first-in-class selective antagonist of α4-subtype GABAA receptors that had promising efficacy in animal models of pain, epilepsy, psychosis, and anxiety. However, development of NP260 was complicated following a 28-day safety study in dogs in which pronounced elevations of serum aminotransferase levels were observed, although there was no accompanying histopathological indication of hepatocellular injury. To further investigate the liver effects of NP260, we assayed stored serum samples from the 28-day dog study for liver specific miRNA (miR-122) as well as enzymatic biomarkers glutamate dehydrogenase and sorbitol dehydrogenase, which indicate liver necrosis. Cytotoxicity assessments were conducted in hepatocytes derived from dog, rat, and human liver samples to address the species specificity of the liver response to NP260. All biomarkers, except ALT, returned toward baseline by Day 29 despite continued drug treatment, suggesting adaptation to the initial injury. In vitro analysis of the toxicity potential of NP260 to primary hepatocytes indicated a relative sensitivity of dog>human>rat, which may explain, in part, why the liver effects were not evident in the rodent safety studies. Taken together, the data indicate that a diagnostic biomarker approach, coupled with sensitive in vitro screening strategies, may facilitate interpretation of toxicity potential when an adaptive event masks the underlying toxicity.


      PubDate: 2014-04-27T05:18:49Z
       
 
 
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