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  Subjects -> ENVIRONMENTAL STUDIES (Total: 805 journals)
    - ENVIRONMENTAL STUDIES (736 journals)
    - POLLUTION (21 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (39 journals)
    - WASTE MANAGEMENT (9 journals)

ENVIRONMENTAL STUDIES (736 journals)            First | 1 2 3 4 5 6 7 8     

Knowledge Management Research & Practice     Hybrid Journal   (Followers: 20)
Koedoe : African Protected Area Conservation and Science     Open Access   (Followers: 7)
L1-Educational Studies in Language and Literature     Open Access   (Followers: 2)
Lake and Reservoir Management     Hybrid Journal   (Followers: 4)
Landscape Ecology     Hybrid Journal   (Followers: 30)
Landscapes     Hybrid Journal   (Followers: 20)
Large Marine Ecosystems     Full-text available via subscription  
Latin American and Caribbean Ethnic Studies     Hybrid Journal   (Followers: 4)
Latin American Journal of Management for Sustainable Development     Hybrid Journal  
Legal Studies     Hybrid Journal   (Followers: 4)
Letras Verdes. Revista Latinoamericana de Estudios Socioambientales     Open Access  
Leviathan : A Journal of Melville Studies     Full-text available via subscription   (Followers: 2)
Limnological Review     Open Access   (Followers: 6)
Living Reviews in Landscape Research     Open Access   (Followers: 2)
Local Environment: The International Journal of Justice and Sustainability     Hybrid Journal   (Followers: 7)
Low Carbon Economy     Open Access   (Followers: 4)
Luna Azul     Open Access  
M+A. Revista Electrónica de Medioambiente     Open Access  
Macquarie Journal of International and Comparative Environmental Law     Full-text available via subscription   (Followers: 8)
Madagascar Conservation & Development     Open Access  
Management International Review     Hybrid Journal   (Followers: 7)
Management of Environmental Quality: An International Journal     Hybrid Journal   (Followers: 5)
Management of Sustainable Development     Open Access   (Followers: 2)
Marine Ecology     Hybrid Journal   (Followers: 13)
Marine Environmental Research     Hybrid Journal   (Followers: 12)
Marine Pollution Bulletin     Hybrid Journal   (Followers: 11)
Materials for Renewable and Sustainable Energy     Open Access   (Followers: 9)
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: 3)
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: 11)
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: 8)
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: 7)
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 7)
Natural Areas Journal     Full-text available via subscription   (Followers: 7)
Natural Hazards     Hybrid Journal   (Followers: 112)
Natural Resources     Open Access  
Natural Resources and Environmental Issues     Open Access   (Followers: 5)
Nature and Culture     Full-text available via subscription   (Followers: 10)
NeuroToxicology     Hybrid Journal   (Followers: 2)
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 1)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 5)
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 Mapping     Open Access  
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access   (Followers: 2)
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 9)
Ocean Acidification     Open Access   (Followers: 1)
Ochrona Srodowiska i Zasobów Naturalnych : Environmental Protection and Natural Resources     Open Access  
Oecologia     Hybrid Journal   (Followers: 34)
Oikos     Hybrid Journal   (Followers: 34)
Open Journal of Ecology     Open Access   (Followers: 11)
Open Journal of Marine Science     Open Access   (Followers: 7)
Open Journal of Modern Hydrology     Open Access   (Followers: 3)
Our Nature     Open Access   (Followers: 3)
Oxford Journal of Legal Studies     Hybrid Journal   (Followers: 18)
Pace Environmental Law Review     Open Access   (Followers: 6)
Pace Environmental Law Review Online Companion     Open Access   (Followers: 1)
Packaging, Transport, Storage & Security of Radioactive Material     Hybrid Journal   (Followers: 1)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 4)
Particle and Fibre Toxicology     Open Access   (Followers: 2)
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: 8)
Physio-Géo     Open Access   (Followers: 2)
Pittsburgh Journal of Environmental and Public Health Law     Open Access   (Followers: 1)
Planet     Open Access   (Followers: 1)
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (Followers: 7)
Plant Ecology & Diversity     Partially Free   (Followers: 13)
Plant Knowledge Journal     Open Access   (Followers: 2)
Plant, Cell & Environment     Hybrid Journal   (Followers: 5)
Polar Journal     Hybrid Journal   (Followers: 1)
Policy Studies     Hybrid Journal   (Followers: 7)
Policy Studies Journal     Hybrid Journal   (Followers: 4)
Polish Polar Research     Open Access   (Followers: 4)
Political Studies     Hybrid Journal   (Followers: 23)
Political Studies Review     Hybrid Journal   (Followers: 15)
Population and Environment     Hybrid Journal   (Followers: 6)
Population Ecology     Hybrid Journal   (Followers: 10)
Population Studies: A Journal of Demography     Hybrid Journal   (Followers: 8)
Postcolonial Studies     Hybrid Journal   (Followers: 10)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (Followers: 2)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (Followers: 1)
Present Environment and Sustainable Development     Open Access  
Presidential Studies Quarterly     Hybrid Journal   (Followers: 3)
Procedia Environmental Sciences     Open Access   (Followers: 2)

  First | 1 2 3 4 5 6 7 8     

Journal Cover   Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [12 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2800 journals]
  • Gene expression and pathway analysis of human hepatocellular carcinoma
           cells treated with cadmium
    • Abstract: Publication date: Available online 24 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Laura Cartularo, Freda Laulicht, Hong Sun, Thomas Kluz, Jonathan H. Freedman, Max Costa
      Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the earth’s crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0μM Cd for 24hours; or chronically-treated with 0.01, 0.05, or 0.1μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, and cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24hours indicated a reduction in global levels of histone methylation and acetylation that persisted 72hours post-treatment.


      PubDate: 2015-08-25T10:31:28Z
       
  • Developmental neurotoxic effects of two pesticides: Behavior and
           biomolecular studies on chlorpyrifos and carbaryl
    • Abstract: Publication date: Available online 24 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Iwa Lee, Per Eriksson, Anders Fredriksson, Sonja Buratovic, Henrik Viberg
      In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. Westudied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlopyrifos (0.1, 1.0 or 5mg/kg body weight) or carbaryl(0.5, 5.0 or 20.0mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced, are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8-12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.


      PubDate: 2015-08-25T10:31:28Z
       
  • Resveratrol Via Sirtuin-1 Downregulates RE1-Silencing Transcription Factor
           (REST) Expression Preventing PCB-95-Induced Neuronal Cell Death
    • Abstract: Publication date: Available online 22 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Natascia Guida, Giusy Laudati, Serenella Anzilotti, Agnese Secondo, Paolo Montuori, Gianfranco Di Renzo, Lorella M.T. Canzoniero, Luigi Formisano
      Resveratrol (3,5,4'-trihydroxystilbene) (RSV), a polyphenol widely present in plants, exerts a neuroprotective function in several neurological conditions; it is an activator of class III histone deacetylase sirtuin1 (SIRT1), a crucial regulator in the pathophysiology of neurodegenerative diseases. By contrast, the RE1-silencing transcription factor (REST) is involved in the neurotoxic effects following exposure to polychlorinated biphenyl (PCB) mixture A1254. The present study investigated the effects of RSV-induced activation of SIRT1 on REST expression in SH-SY5Y cells. Further, we investigated the possible relationship between the non-dioxin-like (NDL) PCB-95 and REST through SIRT1 to regulate neuronal death in rat cortical neurons. Our results revealed that RSV significantly decreased REST gene and protein levels in a dose- and time-dependent manner. Interestingly, overexpression of SIRT1 reduced REST expression, whereas EX-527, an inhibitor of SIRT1, increased REST expression and blocked RSV-induced REST downregulation. These results suggest that RSV downregulates REST through SIRT1. In addition, RSV enhanced activator protein 1 (AP-1) transcription factor c-Jun expression and its binding to the REST promoter gene. Indeed, c-Jun knockdown reverted RSV-induced REST downregulation. Intriguingly, in SH-SY5Y cells and rat cortical neurons the NDL PCB-95 induced necrotic cell death in a concentration-dependent manner by increasing REST mRNA and protein expression. In addition, SIRT1 knockdown blocked RSV-induced neuroprotection in rat cortical neurons treated with PCB-95. Collectively, these results indicate that RSV via SIRT1 activates c-Jun, thereby reducing REST expression in SH-SY5Y cells under physiological conditions and blocks PCB-95-induced neuronal cell death by activating the same SIRT1/c-Jun/REST pathway.


      PubDate: 2015-08-25T10:31:28Z
       
  • Methamphetamine and HIV-Tat Alter Murine Cardiac DNA Methylation and Gene
           Expression
    • Abstract: Publication date: Available online 22 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Christopher A. Koczor, Earl Fields, Mark J. Jedrzejczak, Zhe Jiao, Tomika Ludaway, Rodney Russ, Joan Shang, Rebecca A. Torres, William Lewis
      This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects.


      PubDate: 2015-08-25T10:31:28Z
       
  • Nonclinical evaluation of the potential for mast cell activation by an
           erythropoietin analog
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): James L. Weaver, Michael Boyne, Eric Pang, Krishna Chimalakonda, Kristina E. Howard
      The erythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. The adverse events occurred rapidly following the first ever administration of the drug with most affected patients becoming symptomatic in less than 30min. This is most consistent with an anaphylactoid reaction due to direct activation of mast cells. Laboratory evaluation was undertaken using rat peritoneal mast cells as the model system. Initial studies showed that high concentrations of the formulated drug as well as formulated vehicle alone could cause mast cell degranulation as measured by histamine release. The purified active drug was not able to cause histamine release whereas the vehicle filtrate and lab created drug vehicle were equally potent at causing histamine release. Individual formulations of vehicle leaving one component out showed that histamine release was due to phenol. Dose response studies with phenol showed a very sharp dose response curve that was similar in three buffer systems. Cellular analysis by flow cytometry showed that the histamine release was not due to cell death, and that changes in light scatter parameters consistent with degranulation were rapidly observed. Limited testing with primary human mast cells showed a similar dose response of histamine release with exposure to phenol. To provide in vivo confirmation, rats were injected with vehicle formulated with various concentrations of phenol via a jugular vein cannula. Significant release of histamine was detected in blood samples taken 2min after dosing at the highest concentrations tested.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Embryonic catalase protects against ethanol embryopathies in acatalasemic
           mice and transgenic human catalase-expressing mice in embryo culture
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Lutfiya Miller-Pinsler, Peter G. Wells
      Reactive oxygen species (ROS) have been implicated in the mechanism of ethanol (EtOH) teratogenicity, but the protective role of the embryonic antioxidative enzyme catalase is unclear, as embryonic activity is only about 5% of maternal levels. We addressed this question in a whole embryo culture model. C57BL/6 mouse embryos expressing human catalase (hCat) or their wild-type (C57BL/6 WT) controls, and C3Ga.Cg-Catb /J catalase-deficient, acatalasemic (aCat) mouse embryos or their wild-type C3HeB/FeJ (C3H WT) controls, were explanted on gestational day (GD) 9 (plug=GD 1), exposed for 24h to 2 or 4mg/mL EtOH or vehicle, and evaluated for functional and morphological changes. hCat and C57BL/6 WT vehicle-exposed embryos developed normally, while EtOH was embryopathic in C57BL/6 WT embryos, evidenced by decreases in anterior neuropore closure, somites developed, turning and head length, whereas hCat embryos were protected (p<0.001). Maternal pretreatment of C57BL/6 WT dams with 50kU/kg PEG-catalase (PEG-cat) 8h prior to embryo culture, which increases embryonic catalase activity, blocked all EtOH embryopathies (p<0.001). Vehicle-exposed aCat mouse embryos had lower yolk sac diameters compared to WT controls, suggesting that endogenous ROS are embryopathic. EtOH was more embryopathic in aCat embryos than WT controls, evidenced by reduced head length and somite development (p<0.01), and trends for reduced anterior neuropore closure, turning and crown–rump length. Maternal pretreatment of aCat dams with PEG-Cat blocked all EtOH embryopathies (p<0.05). These data suggest that embryonic catalase is a determinant of risk for EtOH embryopathies.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to
           study heavy metals induced carcinogenesis
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Youn-hee Park, Donghern Kim, Jin Dai, Zhuo Zhang
      Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG→TCG) at codon 47 and the codon 72 polymorphism (CGC→CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer.


      PubDate: 2015-08-21T10:30:47Z
       
  • Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid
           axis and its association with airways symptoms
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Julia M. Broström, Zhi-wei Ye, Anna Axmon, Margareta Littorin, Håkan Tinnerberg, Christian H. Lindh, Huiyuan Zheng, Aram Ghalali, Ulla Stenius, Bo A.G. Jönsson, Johan Högberg
      Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to <5ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose–response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting “sneezing”, the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Preclinical and first-in-human evaluation of PRX-105, a PEGylated,
           plant-derived, recombinant human acetylcholinesterase-R
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Jacob Atsmon, Einat Brill-Almon, Carmit Nadri-Shay, Raul Chertkoff, Sari Alon, Dimitri Shaikevich, Inna Volokhov, Kirsten Y. Haim, Daniel Bartfeld, Avidor Shulman, Ilya Ruderfer, Tehila Ben-Moshe, Orit Shilovitzky, Hermona Soreq, Yoseph Shaaltiel
      PRX-105 is a plant-derived recombinant version of the human ‘read-through’ acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50nmol/kg PRX-105, 2min before being exposed to 1.33×LD50 and 1.5×LD50 of toxin and 10min after exposure to 1.5×LD50 survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t½) in mice was 994 (±173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t½ in humans was substantially longer than in mice (average 26.7h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation.


      PubDate: 2015-08-21T10:30:47Z
       
  • Cuprizone decreases intermediate and late-stage progenitor cells in
           hippocampal neurogenesis of rats in a framework of 28-day oral dose
           toxicity study
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Hajime Abe, Takeshi Tanaka, Masayuki Kimura, Sayaka Mizukami, Fumiyo Saito, Nobuya Imatanaka, Yumi Akahori, Toshinori Yoshida, Makoto Shibutani
      Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3+ apoptotic cells. At ≥120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB+ interneurons, although the number of reelin+ interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells.


      PubDate: 2015-08-21T10:30:47Z
       
  • Solubility shift and SUMOylaltion of promyelocytic leukemia (PML) protein
           in response to arsenic(III) and fate of the SUMOylated PML
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Seishiro Hirano, Mihoko Tadano, Yayoi Kobayashi, Osamu Udagawa, Ayaka Kato
      Promyelocytic leukemia (PML), which is a tumor suppressor protein that nevertheless plays an important role in the maintenance of leukemia initiating cells, is known to be biochemically modified by As3+. We recently developed a simple method to evaluate the modification of PML by As3+ resulting in a change in solubility and the covalent binding of small ubiquitin-like modifier (SUMO). Here we semi-quantitatively investigated the SUMOylation of PML using HEK293 cells which were stably transfected with PML-VI (HEK-PML). Western blot analyses indicated that PML became insoluble in cold RadioImmunoPrecipitation Assay (RIPA) lysis buffer and was SUMOylated by both SUMO2/3 and SUMO1 by As3+. Surprisingly SUMO1 monomers were completely utilized for the SUMOylation of PML. Antimony (Sb3+) but not bismuth (Bi3+), Cu2+, or Cd2+ biochemically modified PML similarly. SUMOylated PML decreased after removal of As3+ from the culture medium. However, unSUMOylated PML was still recovered in the RIPA-insoluble fraction, suggesting that SUMOylation is not requisite for changing the RIPA-soluble PML into the RIPA-insoluble form. Immunofluorescence staining of As3+-exposed cells indicated that SUMO2/3 was co-localized with PML in the nuclear bodies. However, some PML protein was present in peri-nuclear regions without SUMO2/3. Functional Really Interesting New Gene (RING)-deleted mutant PML neither formed PML nuclear bodies nor was biochemically modified by As3+. Conjugation with intracellular glutathione may explain the accessibility of As3+ and Sb3+ to PML in the nuclear region evading chelation and entrapping by cytoplasmic proteins such as metallothioneins.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Editorial Board
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3




      PubDate: 2015-08-21T10:30:47Z
       
  • Hormone-dependence of sarin lethality in rats: Sex differences and stage
           of the estrous cycle
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Carl D. Smith, Linnzi K.M. Wright, Gregory E. Garcia, Robyn B. Lee, Lucille A. Lumley
      Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity.


      PubDate: 2015-08-21T10:30:47Z
       
  • Lipid rafts regulate PCB153-induced disruption of occludin and brain
           endothelial barrier function through protein phosphatase 2A and matrix
           metalloproteinase-2
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Sung Yong Eum, Dima Jaraki, Ibolya E. András, Michal Toborek
      Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.


      PubDate: 2015-08-21T10:30:47Z
       
  • Staphylococcal enterotoxin A regulates bone marrow granulocyte trafficking
           during pulmonary inflammatory disease in mice
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): W.M. Takeshita, V.O. Gushiken, A.P. Ferreira-Duarte, A.S. Pinheiro-Torres, I.A. Roncalho-Buck, D.M. Squebola-Cola, G.C. Mello, G.F. Anhê, E. Antunes, I.A. DeSouza
      Pulmonary neutrophil infiltration produced by Staphylococcal enterotoxin A (SEA) airway exposure is accompanied by marked granulocyte accumulation in bone marrow (BM). Therefore, the aim of this study was to investigate the mechanisms of BM cell accumulation, and trafficking to circulating blood and lung tissue after SEA airway exposure. Male BALB/C mice were intranasally exposed to SEA (1μg), and at 4, 12 and 24h thereafter, BM, circulating blood, bronchoalveolar lavage (BAL) fluid and lung tissue were collected. Adhesion of BM granulocytes and flow cytometry for MAC-1, LFA1-α and VLA-4 and cytokine and/or chemokine levels were assayed after SEA-airway exposure. Prior exposure to SEA promoted a marked PMN influx to BAL and lung tissue, which was accompanied by increased counts of immature and/or mature neutrophils and eosinophils in BM, along with blood neutrophilia. Airway exposure to SEA enhanced BM neutrophil MAC-1 expression, and adhesion to VCAM-1 and/or ICAM-1-coated plates. Elevated levels of GM-CSF, G-CSF, INF-γ, TNF-α, KC/CXCL-1 and SDF-1α were detected in BM after SEA exposure. SEA exposure increased production of eosinopoietic cytokines (eotaxin and IL-5) and BM eosinophil VLA-4 expression, but it failed to affect eosinophil adhesion to VCAM-1 and ICAM-1. In conclusion, BM neutrophil accumulation after SEA exposure takes place by integrated action of cytokines and/or chemokines, enhancing the adhesive responses of BM neutrophils and its trafficking to lung tissues, leading to acute lung injury. BM eosinophil accumulation in SEA-induced acute lung injury may occur via increased eosinopoietic cytokines and VLA-4 expression.


      PubDate: 2015-08-21T10:30:47Z
       
  • Ginsenoside-Rg1 induces angiogenesis by the inverse regulation of MET
           tyrosine kinase receptor expression through miR-23a
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Hoi-Hin Kwok, Lai-Sheung Chan, Po-Ying Poon, Patrick Ying-Kit Yue, Ricky Ngok-Shun Wong
      Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. Ginsenoside-Rg1 (Rg1), one of the most abundant active components of ginseng, has been demonstrated as an angiogenesis-stimulating compound in different models. There is increasing evidence implicating microRNAs (miRNAs), a group of non-coding RNAs, as important regulators of angiogenesis, but the role of microRNAs in Rg1-induced angiogenesis has not been fully explored. In this report, we found that stimulating endothelial cells with Rg1 could reduce miR-23a expression. In silico experiments predicted hepatocyte growth factor receptor (MET), a well-established mediator of angiogenesis, as the target of miR-23a. Transfection of the miR-23a precursor or inhibitor oligonucleotides validated the inverse relationship of miR-23a and MET expression. Luciferase reporter assays further confirmed the interaction between miR-23a and the MET mRNA 3′-UTR. Intriguingly, ginsenoside-Rg1 was found to increase MET protein expression in a time-dependent manner. We further demonstrated that ginsenoside-Rg1-induced angiogenic activities were indeed mediated through the down-regulation of miR-23a and subsequent up-regulation of MET protein expression, as confirmed by gain- and loss-of-function angiogenic experiments. In summary, our results demonstrated that ginsenoside-Rg1 could induce angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. This study has broadened our understanding of the non-genomic effects of ginsenoside-Rg1, and provided molecular evidence that warrant further development of natural compound as novel angiogenesis-promoting therapy.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Estrogen modulation of the ethanol-evoked myocardial oxidative stress and
           dysfunction via DAPK3/Akt/ERK activation in male rats
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Mahmoud M. El-Mas, Abdel A. Abdel-Rahman
      Evidence suggests that male rats are protected against the hypotensive and myocardial depressant effects of ethanol compared with females. We investigated whether E2 modifies the myocardial and oxidative effects of ethanol in male rats. Conscious male rats received ethanol (0.5, 1 or 1.5g/kg i.v.) 30-min after E2 (1μg/kg i.v.) or its vehicle (saline), and hearts were collected at the conclusion of hemodynamic measurements for ex vivo molecular studies. Ethanol had no effect in vehicle-treated rats, but it caused dose-related reductions in LV developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of rise in LV pressure (dP/dtmax) and systolic (SBP) and diastolic (DBP) blood pressures in E2-pretreated rats. These effects were associated with elevated (i) indices of reactive oxygen species (ROS), (ii) malondialdehyde (MDA) protein adducts, and (iii) phosphorylated death-associated protein kinase-3 (DAPK3), Akt, and extracellular signal-regulated kinases (ERK1/2). Enhanced myocardial anti-oxidant enzymes (heme oxygenase-1, catalase and aldehyde dehydrogenase 2) activities were also demonstrated. In conclusion, E2 promotes ethanol-evoked myocardial oxidative stress and dysfunction in male rats. The present findings highlight the risk of developing myocardial dysfunction in men who consume alcohol while receiving E2 for specific medical conditions.


      PubDate: 2015-08-21T10:30:47Z
       
  • An evaluation of in vivo models for toxicokinetics of hexavalent chromium
           in the stomach
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): A.F. Sasso, P.M. Schlosser
      Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses.


      PubDate: 2015-08-21T10:30:47Z
       
  • Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in
           rheumatoid arthritis synovial fibroblasts by ASK1 regulation
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Sadiq Umar, Omar Hedaya, Anil K. Singh, Salahuddin Ahmed
      Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine produced by monocytes/macrophage that plays a pathological role in rheumatoid arthritis (RA). In this study, we investigate the effect of thymoquinone (TQ), a phytochemical found in Nigella sativa, in regulating TNF-α-induced RA synovial fibroblast (RA-FLS) activation. Treatment with TQ (1–5μM) had no marked effect on the viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-α-induced interleukin-6 (IL-6) and IL-8 production and ICAM-1, VCAM-1, and cadherin-11 (Cad-11) expression in RA-FLS (p<0.01). Evaluation of the signaling events showed that TQ inhibited TNF-α-induced phospho-p38 and phospho-JNK expression, but had no inhibitory effect on NF-κB pathway, in RA-FLS (p<0.05; n=4). Interestingly, we observed that selective down-regulation of TNF-α-induced phospho-p38 and phospho-JNK activation by TQ is elicited through inhibition of apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-α selectively induced phosphorylation of ASK1 at Thr845 residue in RA-FLS, which was inhibited by TQ pretreatment in a dose dependent manner (p<0.01). Pre-treatment of RA-FLS with ASK1 inhibitor (TC ASK10), blocked TNF-α induced expression of ICAM-1, VCAM-1, and Cad-11. Our results suggest that TNF-α-induced ASK1-p38/JNK pathway is an important mediator of cytokine synthesis and enhanced expression of adhesion molecule in RA-FLS and TQ, by selectively inhibiting this pathway, may have a potential therapeutic value in regulating tissue destruction observed in RA.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Metallothionein deficiency aggravates depleted uranium-induced
           nephrotoxicity
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3
      Author(s): Yuhui Hao, Jiawei Huang, Ying Gu, Cong Liu, Hong Li, Jing Liu, Jiong Ren, Zhangyou Yang, Shuangqing Peng, Weidong Wang, Rong Li
      Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT−/−) and corresponding wild-type (MT+/+) mice was investigated to determine any associations with MT. Each MT−/− or MT+/+ mouse was pretreated with a single dose of DU (10mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT−/− mice significantly increased than in MT+/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT−/− mice. The apoptosis rate in MT−/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT−/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT−/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression.


      PubDate: 2015-08-21T10:30:47Z
       
  • Contents
    • Abstract: Publication date: 15 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 3




      PubDate: 2015-08-21T10:30:47Z
       
  • Anti-inflammatory effects of methylthiouracil in vitro and in vivo
    • Abstract: Publication date: Available online 20 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Sae-Kwang Ku, Moon-Chang Baek, Jong-Sup Bae
      The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Here, methylthiouracil (MTU), an antithyroid drug, was examined for its effects on lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, human neutrophil adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells and mice. We found that post-treatment with MTU inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of human neutrophils to human endothelial cells. MTU induced potent inhibition of LPS-induced endothelial cell protein C receptor (EPCR) shedding. It also suppressed LPS-induced hyperpermeability and neutrophil migration in vivo. Furthermore, MTU suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, and the activation of nuclear factor-κB (NF-κB) and extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, post-treatment with MTU resulted in reduced LPS-induced lethal endotoxemia. These results suggest that MTU exerts anti-inflammatory effects by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Identification of protein expression alterations in gefitinib-resistant
           human lung adenocarcinoma: PCNT and mPR play key roles in the development
           of gefitinib-associated resistance
    • Abstract: Publication date: Available online 20 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Chi-Chen Lin, Jing-Ting Chen, Meng-Wei Lin, Chia-Hao Chan, Yueh-Feng Wen, Shin-Bei Wu, Ting-Wen Chung, Kevin W. Lyu, Hsiu-Chuan Chou, Hong-Lin Chan
      Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC.
      Graphical abstract image

      PubDate: 2015-08-21T10:30:47Z
       
  • Butylated Hydroxyanisole Induces Distinct Expression Patterns of Nrf2 and
           Detoxification Enzymes in the Liver and Small Intestine of C57BL/6 Mice
    • Abstract: Publication date: Available online 18 August 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Lin Luo, Yeru Chen, Deqi Wu, Jiafeng Shou, Shengcun Wang, Jie Ye, Xiuwen Tang, Xiu Jun Wang
      Butylated hydroxyanisole (BHA) is widely used as an antioxidant and preservative in food, food packaging and medicines. Its chemopreventive properties are attributing to its ability to activate the transcription factor NF-E2 p45-related factor 2 (Nrf2), which directs central genetic programs of detoxification and protection against oxidative stress. This study was to investigate the histological changes of Nrf2 and its regulated Phase II enzymes Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2 −/− mice induced by BHA. The mice were given a 200mg/kg oral dose of BHA daily for three days. Immunohistochemistry revealed that, in the liver from WT mice, BHA increased Nqo1 staining in hepatocytes, predominately in the pericentral region. In contrast, the induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located almost exclusively in Kupffer cells. In the small intestine from WT mice, the inducible expression patterns of Nqo1 and AKR1B8 were nearly identical to that of Nrf2, with more intense staining in the villus than that the crypt. Conversely, Keap1 was more highly expressed in the crypt, where the proliferative cells reside. Our study demonstrates that BHA elicited differential expression patterns of phase II-detoxifying enzymes in the liver and small intestine from WT but not Nrf2 −/− mice, demonstrating a cell type specific response to BHA in vivo.


      PubDate: 2015-08-21T10:30:47Z
       
  • Low functional programming of renal AT2R mediates the developmental origin
           of glomerulosclerosis in adult offspring induced by prenatal caffeine
           exposure
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Ying Ao, Zhaoxia Sun, Shuangshuang Hu, Na Zuo, Bin Li, Shuailong Yang, Liping Xia, Yong Wu, Linlong Wang, Zheng He, Hui Wang
      Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis.


      PubDate: 2015-08-11T12:48:44Z
       
  • Extrapolation of systemic bioavailability assessing skin absorption and
           epidermal and hepatic metabolism of aromatic amine hair dyes in vitro
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): John Manwaring, Helga Rothe, Cindy Obringer, David J. Foltz, Timothy R. Baker, John A. Troutman, Nicola J. Hewitt, Carsten Goebel
      Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis–Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte Km and Vmax values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and Cmax was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers.


      PubDate: 2015-08-11T12:48:44Z
       
  • Contents
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2




      PubDate: 2015-08-11T12:48:44Z
       
  • Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of
           protein kinase A signaling pathway and toxicological relevance
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Maite Rocío Arana, Guillermo Nicolás Tocchetti, Pablo Domizi, Agostina Arias, Juan Pablo Rigalli, María Laura Ruiz, Marcelo Gabriel Luquita, Claudia Banchio, Aldo Domingo Mottino, Silvina Stella Maris Villanueva
      The cAMP pathway is a universal signaling pathway regulating many cellular processes including metabolic routes, growth and differentiation. However, its effects on xenobiotic biotransformation and transport systems are poorly characterized. The effect of cAMP on expression and activity of GST and MRP2 was evaluated in Caco-2 cells, a model of intestinal epithelium. Cells incubated with the cAMP permeable analog dibutyryl cyclic AMP (db-cAMP: 1,10,100μM) for 48h exhibited a dose–response increase in GST class α and MRP2 protein expression. Incubation with forskolin, an activator of adenylyl cyclase, confirmed the association between intracellular cAMP and upregulation of MRP2. Consistent with increased expression of GSTα and MRP2, db-cAMP enhanced their activities, as well as cytoprotection against the common substrate 1-chloro-2,4-dinitrobenzene. Pretreatment with protein kinase A (PKA) inhibitors totally abolished upregulation of MRP2 and GSTα induced by db-cAMP. In silico analysis together with experiments consisting of treatment with db-cAMP of Caco-2 cells transfected with a reporter construct containing CRE and AP-1 sites evidenced participation of these sites in MRP2 upregulation. Further studies involving the transcription factors CREB and AP-1 (c-JUN, c-FOS and ATF2) demonstrated increased levels of total c-JUN and phosphorylation of c-JUN and ATF2 by db-cAMP, which were suppressed by a PKA inhibitor. Co-immunoprecipitation and ChIP assay studies demonstrated that db-cAMP increased c-JUN/ATF2 interaction, with further recruitment to the region of the MRP2 promoter containing CRE and AP-1 sites. We conclude that cAMP induces GSTα and MRP2 expression and activity in Caco-2 cells via the PKA pathway, thus regulating detoxification of specific xenobiotics.


      PubDate: 2015-08-11T12:48:44Z
       
  • Taxifolin protects against cardiac hypertrophy and fibrosis during
           biomechanical stress of pressure overload
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Haipeng Guo, Xin Zhang, Yuqian Cui, Heng Zhou, Dachun Xu, Tichao Shan, Fan Zhang, Yuan Guo, Yuguo Chen, Dawei Wu
      Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis.


      PubDate: 2015-08-11T12:48:44Z
       
  • Telomere length in children environmentally exposed to low-to-moderate
           levels of lead
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Natalia Pawlas, Anna Płachetka, Agnieszka Kozłowska, Karin Broberg, Sławomir Kasperczyk
      Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007–2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR. The geometric mean of B-Pb was 3.28μg/dl (range: 0.90–14.2), and the geometric mean of rTL was 1.08 (range: 0.49–2.09). B-Pb was significantly inversely associated with rTL in the children (rS =−0.25, p=0.013; in further analyses both log-transformed-univariate regression analysis β=−0.13, p=0.026, and R2adj 4%; and β=−0.12, p=0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R2adj 12%, p=0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N=87, rS =−0.24, p=0.024; in further analyses, β=−0.13, p=0.029, and R2adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances). Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment.


      PubDate: 2015-08-11T12:48:44Z
       
  • Lung inflammation biomarkers and lung function in children chronically
           exposed to arsenic
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Edgar Olivas-Calderón, Rogelio Recio-Vega, A. Jay Gandolfi, R. Clark Lantz, Tania González-Cortes, Cesar Gonzalez-De Alba, John R. Froines, Jorge A. Espinosa-Fematt
      Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases.


      PubDate: 2015-08-11T12:48:44Z
       
  • Risk of death from cardiovascular disease associated with low-level
           arsenic exposure among long-term smokers in a US population-based study
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Shohreh F. Farzan, Yu Chen, Judy R. Rees, M. Scot Zens, Margaret R. Karagas
      High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic's effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, in relation to natural-log transformed toenail arsenic concentrations. In this US population, although we observed no overall association, arsenic exposure measured from toenail clipping samples was related to an increased risk of ischemic heart disease mortality among long-term smokers (as reported at baseline), with increased hazard ratios among individuals with ≥31 total smoking years (HR: 1.52, 95% CI: 1.02, 2.27), ≥ 30 pack-years (HR: 1.66, 95% CI: 1.12, 2.45), and among current smokers (HR: 1.69, 95% CI: 1.04, 2.75). These results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality.


      PubDate: 2015-08-11T12:48:44Z
       
  • Dehydroeffusol effectively inhibits human gastric cancer cell-mediated
           vasculogenic mimicry with low toxicity
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Wenming Liu, Mei Meng, Bin Zhang, Longsheng Du, Yanyan Pan, Ping Yang, Zhenlun Gu, Quansheng Zhou, Zhifei Cao
      Accumulated data has shown that various vasculogenic tumor cells, including gastric cancer cells, are able to directly form tumor blood vessels via vasculogenic mimicry, supplying oxygen and nutrients to tumors, and facilitating progression and metastasis of malignant tumors. Therefore, tumor vasculogenic mimicry is a rational target for developing novel anticancer therapeutics. However, effective antitumor vasculogenic mimicry-targeting drugs are not clinically available. In this study, we purified 2,7-dihydroxyl-1-methyl-5-vinyl-phenanthrene, termed dehydroeffusol, from the traditional Chinese medicinal herb Juncus effusus L., and found that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry in vitro and in vivo with very low toxicity. Dehydroeffusol significantly suppressed gastric cancer cell adhesion, migration, and invasion. Molecular mechanistic studies revealed that dehydroeffusol markedly inhibited the expression of a vasculogenic mimicry master gene VE-cadherin and reduced adherent protein exposure on the cell surface by inhibiting gene promoter activity. In addition, dehydroeffusol significantly decreased the expression of a key vasculogenic gene matrix metalloproteinase 2 (MMP2) in gastric cancer cells, and diminished MMP2 protease activity. Together, our results showed that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry with very low toxicity, suggesting that dehydroeffusol is a potential drug candidate for anti-gastric cancer neovascularization and anti-gastric cancer therapy.


      PubDate: 2015-08-11T12:48:44Z
       
  • Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin
           carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract,
           
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): Lisbeth K. Siddens, Kristi L. Bunde, Tod A. Harper, Tammie J. McQuistan, Christiane V. Löhr, Lisa M. Bramer, Katrina M. Waters, Susan C. Tilton, Sharon K. Krueger, David E. Williams, William M. Baird
      FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators.
      Graphical abstract image

      PubDate: 2015-08-11T12:48:44Z
       
  • Editorial Board
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2




      PubDate: 2015-08-11T12:48:44Z
       
  • Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated
           allergic inflammation through suppression of IκB kinase complex
    • Abstract: Publication date: 1 September 2015
      Source:Toxicology and Applied Pharmacology, Volume 287, Issue 2
      Author(s): In-Gyu Je, Hyun Gyu Choi, Hui-Hun Kim, Soyoung Lee, Jin Kyeong Choi, Sung-Wan Kim, Duk-Sil Kim, Taeg Kyu Kwon, Tae-Yong Shin, Pil-Hoon Park, Dongwoo Khang, Sang-Hyun Kim
      As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines.
      Graphical abstract image

      PubDate: 2015-08-11T12:48:44Z
       
  • Prenatal ethanol exposure-induced adrenal developmental abnormality of
           male offspring rats and its possible intrauterine programming mechanisms
    • Abstract: Publication date: 1 October 2015
      Source:Toxicology and Applied Pharmacology, Volume 288, Issue 1
      Author(s): Hegui Huang, Zheng He, Chunyan Zhu, Lian Liu, Hao Kou, Lang Shen, Hui Wang
      Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a “two-programming” mechanism for PEE-induced adrenal developmental toxicity: “the first programming” is a lower functional programming of adrenal steroidogenesis, and “the second programming” is GC-metabolic activation system-related GC-IGF1 axis programming.


      PubDate: 2015-08-04T03:22:52Z
       
  • Gene-arsenic interaction in longitudinal changes of blood pressure:
           Findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in
           Bangladesh
    • Abstract: Publication date: Available online 26 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Shohreh F. Farzan, Margaret R. Karagas, Jieying Jiang, Fen Wu, Mengling Liu, Jonathan D. Newman, Farzana Jasmine, Muhammad G. Kibriya, Rachelle Paul-Brutus, Faruque Parvez, Maria Argos, Molly Scannell Bryan, Mahbub Eunus, Alauddin Ahmed, Tariqul Islam, Muhammad Rakibuz-Zaman, Rabiul Hasan, Golam Sarwar, Vesna Slavkovich, Joseph Graziano, Habibul Ahsan, Yu Chen
      Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and mounting evidence indicates that toxicant exposures can profoundly impact on CVD risk. Epidemiologic studies have suggested that arsenic (As) exposure is positively related to increases in blood pressure (BP), a primary CVD risk factor. However, evidence of whether genetic susceptibility can modify the association between As and BP are lacking. In this study, we used mixed effects models adjusted for potential confounders to examine the interaction between As exposure from well water and potential genetic modifiers on longitudinal change in BP over approximately 7years of follow-up in 1137 subjects selected from the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in Bangladesh. Genotyping was conducted for 235 SNPs in 18 genes related to As metabolism, oxidative stress and endothelial function. We observed interactions between 44 SNPs with well water As for one or more BP outcome measures (systolic, diastolic, or pulse pressure (PP)) over the course of follow-up. The interaction between CYBA rs3794624 and well water As on annual PP remained statistically significant after correction for multiple comparisons (FDR-adjusted p for interaction=0.05). Among individuals with the rs3794624 variant genotype, well water As was associated with a 2.23mmHg (95% CI: 1.14-3.32) greater annual increase in PP, while among those with the wild type, well water As was associated with a 0.13mmHg (95% CI: 0.02-0.23) greater annual increase in PP. Our results suggest that genetic variability may contribute to As-associated increases in BP over time.


      PubDate: 2015-07-26T18:26:16Z
       
  • 2D-DIGE and MALDI TOF/TOF MS analysis reveal that small GTPase signaling
           pathways may play an important role in cadmium-induced colon cell
           malignant transformation
    • Abstract: Publication date: Available online 26 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Jian Lu, Zhongping Zhou, Jianzhou Zheng, Zhuyi Zhang, Rongzhu Lu, Hanqing Liu, Haifeng Shi, Zhigang Tu
      Cadmium is a toxic heavy metal present in the environment and in industrial materials. Cadmium has demonstrated carcinogenic activity that induces cell transformation, but how this occurs is unclear. We used 2D-DIGE and MALDI TOF/TOF MS combined with bioinformatics and immunoblotting to investigate the molecular mechanism of cadmium transformation. We found that small GTPases were critical for transformation. Additionally, proteins involved in mitochondrial transcription, DNA repair, and translation also had altered expression patterns in cadmium treated cells. Collectively, our results suggest that activation of small GTPases contributes to cadmium-induced transformation of colon cells.


      PubDate: 2015-07-26T18:26:16Z
       
  • Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated
           metabolism and inhibits parathion intoxication
    • Abstract: Publication date: Available online 23 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Yi-Hua Jan, Jason R. Richardson, Angela B. Baker, Vladimir Mishin, Diane E. Heck, Debra L. Laskin, Jeffrey D. Laskin
      Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation.
      Graphical abstract image

      PubDate: 2015-07-26T18:26:16Z
       
  • Malignant human cell transformation of Marcellus Shale gas drilling flow
           back water
    • Abstract: Publication date: Available online 22 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Yixin Yao, Tingting Chen, Steven S. Shen, Yingmei Niu, Thomas L. DesMarais, Reka Linn, Eric Saunders, Zhihua Fan, Paul Lioy, Thomas Kluz, Lung-Chi Chen, Zhuangchun Wu, Max Costa
      The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining.


      PubDate: 2015-07-22T18:18:30Z
       
  • Exploring possible mechanisms of action for the nanotoxicity and protein
           binding of decorated nanotubes: Interpretation of physicochemical
           properties from optimal QSAR models
    • Abstract: Publication date: Available online 19 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Emilio Xavier Esposito, Anton J. Hopfinger, Chi-Yu Shao, Bo-Han Su, Sing-Zuo Chen, Yufeng Jane Tseng
      Carbon nanotubes have become widely used in a variety of applications including biosensors and drug carriers. Therefore, the issue of carbon nanotube toxicity is increasingly an area of focus and concern. While previous studies have focused on the gross mechanisms of action relating to nanomaterials interacting with biological entities, this study proposes detailed mechanisms of action, relating to nanotoxicity, for a series of decorated (functionalized) carbon nanotube complexes based on previously reported QSAR models. Possible mechanisms of nanotoxicity for six endpoints (bovine serum albumin, carbonic anhydrase, chymotrypsin, hemoglobin along with cell viability and nitrogen oxide production) have been extracted from the corresponding optimized QSAR models. The molecular features relevant to each of the endpoint respective mechanism of action for the decorated nanotubes are also discussed. Based on the molecular information contained within the optimal QSAR models for each nanotoxicity endpoint, either the decorator attached to the nanotube is directly responsible for the expression of a particular activity, irrespective of the decorator's 3D-geometry and independent of the nanotube, or those decorators having structures that place the functional groups of the decorators as far as possible from the nanotube surface most strongly influence the biological activity. These molecular descriptors are further used to hypothesize specific interactions involved in the expression of each of the six biological endpoints.
      Graphical abstract image

      PubDate: 2015-07-22T18:18:30Z
       
  • Effects of amorphous silica coating on cerium oxide nanoparticles induced
           pulmonary responses
    • Abstract: Publication date: Available online 22 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Jane Ma, Robert R. Mercer, Mark Barger, Diane Schwegler-Berry, Joel M. Cohen, Philip Demokritou, Vincent Castranova
      Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO2) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO2 by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague–Dawley rats were exposed to CeO2 or CeO2 coated with a nano layer of amorphous SiO2 (aSiO2/CeO2) by a single IT and sacrificed at various times post-exposure to assess potential protective effects of the aSiO2 coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15mg/kg), CeO2 but not aSiO2/CeO2 exposure, induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1day post-exposure. Morphological analysis of lung showed increased inflammation, surfactant and collagen fibers after CeO2 (high dose at 3.5mg/kg) treatment at 28days post-exposure. aSiO2 coating significantly reduced CeO2-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive x-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO2/CeO2-exposed lungs up to 3days after exposure, suggesting that aSiO2 dissolved off the CeO2 core, and some of the CeO2 was transformed to CePO4 with time. These results demonstrate that aSiO2 coating reduce CeO2-induced inflammation, phospholipidosis and fibrosis.


      PubDate: 2015-07-22T18:18:30Z
       
  • Melittin induces PTCH1 expression by down-regulating MeCP2 in human
           hepatocellular carcinoma SMMC-7721 cells
    • Abstract: Publication date: Available online 17 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiaoqin Wu, Bin Zhao, Yahui Cheng, Yang Yang, Cheng Huang, Xiaoming Meng, Baoming Wu, Lei Zhang, Xiongwen Lv, Jun Li
      Hepatocellular carcinoma (HCC) has a high mortality rate worldwide and still remains to be a noticeable public health problem. Therefore, new remedies are urgently needed. Melittin, a major component of bee venom, is known to suppress cell growth in various cancers including HCC. However, the mechanism of the anticancer effect of melittin on HCC has not been fully elucidated. It has been reported that Methyl-CpG binding protein 2 (MeCP2) plays a key role in tumor proliferation, apoptosis, migration and invasion. In the present study, we found the high expression of MeCP2 in human HCC tissues and in SMMC-7721 cell line. MeCP2 silencing inhibited cell proliferation, while over-expression of MeCP2 promoted cell growth in SMMC-7721 cells. It indicates that MeCP2 may be an attractive target for human HCC. We further found that melittin could inhibit cell proliferation by reducing MeCP2 expression in vitro. Interestingly, the inhibitory effect of melittin on cell proliferation was due to a delay in G0/G1 cell cycle progression, without influencing cell apoptosis. Next, we investigated the potential molecular mechanisms and found that MeCP2 could modulate Shh signaling in SMMC-7721 cells. Further study indicates that melittin may induce the demethylation of PTCH1 promoter, resulting in the increased expression of PTCH1. Furthermore, the expression of Shh and GLI1 was significantly lowered upon treatment of melittin. These results suggest that melittin can block Shh signaling in vitro. In short, these results indicate that melittin inhibits cell proliferation by down-regulating MeCP2 through Shh signaling in SMMC-7721 cells.


      PubDate: 2015-07-19T10:40:28Z
       
  • Developmental exposure to 50 parts-per-billion arsenic influences histone
           modifications and associated epigenetic machinery in a region- and
           sex-specific manner in the adult mouse brain
    • Abstract: Publication date: Available online 17 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Christina R. Tyler, Alexander K. Hafez, Elizabeth R. Solomon, Andrea M. Allan
      Epidemiological studies report that arsenic exposure via drinking water adversely impacts cognitive development in children and, in adults, can lead to greater psychiatric disease susceptibility, among other conditions. While it is known that arsenic toxicity alters the epigenome, very few studies have investigated its effects on chromatin architecture in the brain. We have previously demonstrated that exposure to a low level of arsenic (50ppb) during all three trimesters of fetal/neonatal development induces deficits in adult hippocampal neurogenesis in the dentate gyrus (DG), depressive-like symptoms, and alterations in gene expression in the adult mouse brain. As epigenetic processes control these outcomes, here we assess the impact of our developmental arsenic exposure (DAE) paradigm on global histone posttranslational modifications and expression of associated chromatin-modifying proteins in the dentate gyrus and frontal cortex (FC) of adult male and female mice. DAE influenced histone 3K4 trimethylation with increased levels in the male DG and FC and decreased levels in the female DG (no change in female FC). The histone methyltransferase MLL exhibited a similar sex- and region- specific expression profile as H3K4me3 levels, while histone demethylase KDM5B expression trended in the opposite direction. DAE increased histone 3K9 acetylation levels in the male DG along with histone acetyltransferase (HAT) expression of GCN5 and decreased H3K9ac levels in the male FC along with decreased HAT expression of GCN5 and PCAF. DAE decreased expression of histone deacetylase enzymes HDAC1 and HDAC2, which were concurrent with increased H3K9ac levels but only in the female DG. Levels of H3 and H3K9me3 were not influenced by DAE in either brain region of either sex. These findings suggest that exposure to a low, environmentally relevant level of arsenic during development induces alterations in the adult brain via histone modifications and chromatin modifiers a sex- and region-specific manner.


      PubDate: 2015-07-19T10:40:28Z
       
  • Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of
           miR-122 targets in liver
    • Abstract: Publication date: Available online 11 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuliya A. Kazantseva , Andrei A. Yarushkin , Lyudmila A. Mostovich , Yuliya A. Pustylnyak , Vladimir O. Pustylnyak
      MiR-122 is a major hepatic microRNA, accounting for more than 70% of total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates expression via interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α-CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α-CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments.


      PubDate: 2015-07-14T13:06:55Z
       
  • Low concentrations of methylmercury inhibit neural progenitor cell
           proliferation associated with up-regulation of glycogen synthase kinase
           3β and subsequent degradation of cyclin E in rats
    • Abstract: Publication date: Available online 13 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Masatake Fujimura , Fusako Usuki
      Methylmercury (MeHg) is an environmental neurotoxicant. The developing nervous system is susceptible to low concentrations of MeHg; however, the effect of MeHg on neural progenitor cell (NPC) proliferation, a key stage of neurogenesis during development, remains to be clarified. In this study, we investigated the effect of low concentrations of MeHg on NPCs by using a primary culture system developed using embryonic rat cerebral cortex. NPC proliferation was suppressed 48h after exposure to 10 nM MeHg, but cell death was not observed. Western blot analyses for cyclins A, B, D1, and E demonstrated that MeHg down-regulated cyclin E, a promoter of the G1/S cell cycle transition. Cyclin E has been shown to be degraded following the phosphorylation by glycogen synthase kinase 3β (GSK-3β). The time course study showed that GSK-3β was up-regulated 3h after exposure to 10 nM MeHg, and cyclin E degradation 48h after MeHg exposure. We further demonstrated that GSK-3β inhibitors, lithium and SB-415286, suppressed MeHg-induced inhibition of NPC proliferation by preventing cyclin E degradation. These results suggest that the inhibition of NPC proliferation induced by low concentration of MeHg was associated with up-regulation of GSK-3β at the early stage and subsequent degeneration of cyclin E.


      PubDate: 2015-07-14T13:06:55Z
       
  • Differential cellular responses in healthy mice and in mice with
           established airway inflammation when exposed to hematite nanoparticles
    • Abstract: Publication date: Available online 7 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Åsa Gustafsson , Ulrika Bergström , Lina Ågren , Lars Österlund , Thomas Sandström , Anders Bucht
      The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.


      PubDate: 2015-07-09T12:58:35Z
       
  • Tungsten-induced carcinogenesis in human bronchial epithelial cells
    • Abstract: Publication date: Available online 9 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Freda Laulicht , Jason Brocato , Laura Cartularo , Joshua Vaughan , Feng Wu , Thomas Kluz , Hong Sun , Betul Akgol Oksuz , Steven Shen , Massimilano Paena , Serenella Medici , Maria Antonietta Zoroddu , Max Costa
      Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten’s ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer related pathways in transformed clones as determined by RNA seq. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data shows the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans.


      PubDate: 2015-07-09T12:58:35Z
       
  • Metabolic activation of hepatotoxic drugs (benzbromarone) induce
           mitochondrial membrane permeability transition
    • Abstract: Publication date: Available online 3 July 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Maho Shirakawa , Shuichi Sekine , Ayaka Tanaka , Toshiharu Horie , Kousei Ito
      The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeable transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1’,6-(OH)2 BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites.
      Graphical abstract image

      PubDate: 2015-07-05T12:57:52Z
       
 
 
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