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ENVIRONMENTAL STUDIES (722 journals)            First | 1 2 3 4 5 6 7 8     

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: 5)
Management of Environmental Quality: An International Journal     Hybrid Journal   (Followers: 4)
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: 12)
Materials for Renewable and Sustainable Energy     Open Access   (Followers: 8)
Mathematical and Computational Forestry & Natural-Resource Sciences     Free  
Mathematical Population Studies: An International Journal of Mathematical Demography     Hybrid Journal   (Followers: 2)
Medio Ambiente y Urbanizacion     Full-text available via subscription  
Membranes     Open Access   (Followers: 4)
Michigan Journal of Sustainability     Open Access  
Midwest Studies In Philosophy     Hybrid Journal   (Followers: 10)
Mine Water and the Environment     Hybrid Journal   (Followers: 6)
Mitigation and Adaptation Strategies for Global Change     Hybrid Journal   (Followers: 12)
Modern Asian Studies     Hybrid Journal   (Followers: 7)
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: 301)
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  
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 1)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 6)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 3)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (Followers: 1)
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access  
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 7)
Ocean Acidification     Open Access  
Ochrona Srodowiska i Zasobów Naturalnych     Open Access  
Oecologia     Hybrid Journal   (Followers: 29)
Oikos     Hybrid Journal   (Followers: 33)
Open Journal of Ecology     Open Access   (Followers: 11)
Open Journal of Marine Science     Open Access   (Followers: 6)
Open Journal of Modern Hydrology     Open Access   (Followers: 3)
Our Nature     Open Access   (Followers: 2)
Oxford Journal of Legal Studies     Hybrid Journal   (Followers: 18)
Pace Environmental Law Review     Open Access   (Followers: 4)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 3)
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: 9)
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: 11)
Plant Knowledge Journal     Open Access   (Followers: 2)
Plant, Cell & Environment     Hybrid Journal   (Followers: 4)
Polar Journal     Hybrid Journal   (Followers: 1)
Policy Studies     Hybrid Journal   (Followers: 8)
Policy Studies Journal     Hybrid Journal   (Followers: 5)
Polish Polar Research     Open Access   (Followers: 4)
Political Studies     Hybrid Journal   (Followers: 24)
Political Studies Review     Hybrid Journal   (Followers: 14)
Population and Environment     Hybrid Journal   (Followers: 6)
Population Ecology     Hybrid Journal   (Followers: 9)
Population Studies: A Journal of Demography     Hybrid Journal   (Followers: 8)
Postcolonial Studies     Hybrid Journal   (Followers: 9)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (Followers: 2)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (Followers: 1)
Presidential Studies Quarterly     Hybrid Journal   (Followers: 4)
Procedia Environmental Sciences     Open Access   (Followers: 2)
Proceedings of ICE, Waste and Resource Management     Hybrid Journal   (Followers: 2)
Proceedings of the Institution of Mechanical Engineers Part M: Journal of Engineering for the Maritime Environment     Hybrid Journal   (Followers: 1)
Proceedings of the International Academy of Ecology and Environmental Sciences     Open Access   (Followers: 4)
Process Safety and Environmental Protection     Hybrid Journal   (Followers: 5)
Progress in Industrial Ecology, An International Journal     Hybrid Journal   (Followers: 4)
Psychological Assessment     Full-text available via subscription   (Followers: 5)
Public Money & Management     Hybrid Journal   (Followers: 5)
Public Works Management & Policy     Hybrid Journal   (Followers: 6)
Qatar Foundation Annual Research Forum Proceedings     Open Access   (Followers: 3)
Radioactivity in the Environment     Full-text available via subscription   (Followers: 3)
Regional Environmental Change     Hybrid Journal   (Followers: 4)
Regional Studies     Hybrid Journal   (Followers: 6)
Religious Studies     Hybrid Journal   (Followers: 10)
RELP - Renewable Energy Law and Policy     Full-text available via subscription   (Followers: 4)
Remediation Journal     Hybrid Journal   (Followers: 5)
Remote Sensing Letters     Hybrid Journal   (Followers: 9)
Renaissance Studies     Hybrid Journal   (Followers: 15)

  First | 1 2 3 4 5 6 7 8     

Journal Cover   Toxicology and Applied Pharmacology
  [SJR: 1.328]   [H-I: 110]   [14 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2589 journals]
  • Contents
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2

      PubDate: 2015-03-04T14:51:26Z
  • Chemical allergens stimulate human epidermal keratinocytes to produce
           lymphangiogenic vascular endothelial growth factor
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Ok-Nam Bae , Seyeon Ahn , Sun Hee Jin , Soo Hyun Hong , Jinyoung Lee , Eun-Sun Kim , Tae Cheon Jeong , Young-Jin Chun , Ai-Young Lee , Minsoo Noh
      Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • MAPK pathway activation by chronic lead-exposure increases vascular
           reactivity through oxidative stress/cyclooxygenase-2-dependent pathways
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Maylla Ronacher Simões , Andrea Aguado , Jonaína Fiorim , Edna Aparecida Silveira , Bruna Fernandes Azevedo , Cindy Medice Toscano , Olha Zhenyukh , Ana María Briones , María Jesús Alonso , Dalton Valentim Vassallo , Mercedes Salaices
      Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100g; subsequent doses: 0.125μg/100g, intramuscular, 30days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20μg/dL) were used. Lead blood levels of treated rats attained 21.7±2.38μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension.

      PubDate: 2015-03-04T14:51:26Z
  • Genistein modulates the expression of NF-κB and MAPK (p-38 and
           ERK1/2), thereby attenuating d-Galactosamine induced fulminant hepatic
           failure in Wistar rats
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Ajaz A. Ganai , Athar A. Khan , Zainul A. Malik , Humaira Farooqi
      Genistein is an isoflavanoid abundantly found in soy. It has been found to play an important role in the prevention of various chronic diseases including cancer. In this study, we evaluated potential therapeutic properties of Genistein against d-Galactosamine (d-GalN) induced inflammation and hepatotoxicity in male Wistar rats. Fulminant hepatic failure (FHF) was induced in rats by intraperitoneal injection of d-GalN (700mg/kgBW). Genistein (5mg/kgBW/day) was given as pre-treatment for 30days via intra-gastric route followed by d-GalN (700mg/kgBW) injection. The hepatoprotective and curative effects of Genistein were evident from a significant decrease in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as prevention of histological damage by pre-treatment of Genistein. Genistein pre-treatment significantly inhibited the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing nitric oxide (NO) and prostaglandin-E2 (PGE) levels, respectively. In addition Genistein significantly suppressed the production of d-GalN-induced proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. These inhibitory effects were associated with the suppression of nuclear factor-kappa B (NF-ĸB) activation, IKKα/β and Mitogen activated protein kinase (MAPK) phosphorylation by Genistein in d-GalN-treated animals. In conclusion, our results suggest that Genistein may serve as a potential supplement in the prevention of hepatic and inflammatory diseases. Furthermore Genistein is able to maintain the redox potential and strengthens the antioxidant defense system of a cell.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates
           later-life Notch1-mediated T cell development and leukemogenesis
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Lori S. Ahrenhoerster , Tess C. Leuthner , Everett R. Tate , Peter A. Lakatos , Michael D. Laiosa
      Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively active Notch1 transgene (NotchICN-TG). Following exposure of adult NotchICN-TG mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed NotchICN-TG offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed NotchICN-TG offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression.

      PubDate: 2015-03-04T14:51:26Z
  • Diethylstilbestrol can effectively accelerate
           estradiol-17-O-glucuronidation, while potently inhibiting
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Liangliang Zhu , Ling Xiao , Yangliu Xia , Kun Zhou , Huili Wang , Minyi Huang , Guangbo Ge , Yan Wu , Ganlin Wu , Ling Yang
      This in vitro study investigates the effects of diethylstilbestrol (DES), a widely used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-O) glucuronidation, via culturing human liver microsomes (HLMs) or recombinant UDP-glucuronosyltransferases (UGTs) with DES and E2. DES can potently inhibit E2-3-O-glucuronidation in HLM, a probe reaction for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive inhibition mechanism, with the Ki value of 2.1±0.3μM, which is less than the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation, the acceleration is observed on E2-17-O-glucuronidation in HLM, in which cholestatic E2-17-O-glucuronide is generated. In the presence of DES (0–6.25μM), Km values for E2-17-O-glucuronidation are located in the range of 7.2–7.4μM, while Vmax values range from 0.38 to 1.54nmol/min/mg. The mechanism behind the activation in HLM is further demonstrated by the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing E2-17-O-glucuronidation. The presence of DES (2μM) can elevate Vmax from 0.016 to 0.81nmol/min/mg, while lifting Km in a much lesser extent from 4.4 to 11μM. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with KA, α, and β values of 0.077±0.18μM, 3.3±1.1 and 104±56, respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation are not observed in liver microsomes from several common experimental animals. In summary, this study issues new potential toxic mechanisms for DES: potently inhibiting the activity of UGT1A1 and powerfully accelerating the formation of cholestatic E2-17-O-glucuronide by UGT1A4.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Role of p53–fibrinolytic system cross-talk in the regulation of
           quartz-induced lung injury
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Yashodhar P. Bhandary , Shwetha K. Shetty , Amarnath S. Marudamuthu , Jian Fu , Barbara M. Pinson , Jeffrey Levin , Sreerama Shetty
      Silica is the major component of airborne dust generated by wind, manufacturing and/or demolition. Chronic occupational inhalation of silica dust containing crystalline quartz is by far the predominant form of silicosis in humans. Silicosis is a progressive lung disease that typically arises after a very long latency and is a major occupational concern with no known effective treatment. The mechanism of silicosis is not clearly understood. However, silicosis is associated with increased cell death, expression of redox enzymes and pro-fibrotic cytokines and chemokines. Since alveolar epithelial cell (AEC) death and disruption of alveolar fibrinolysis is often associated with both acute and chronic lung injuries, we explored whether p53-mediated changes in the urokinase-type plasminogen activator (uPA) system contributes to silica-induced lung injury. We further sought to determine whether caveolin-1 scaffolding domain peptide (CSP), which inhibits p53 expression, mitigates lung injury associated with exposure to silica. Lung tissues and AECs isolated from wild-type (WT) mice exposed to silica exhibit increased apoptosis, p53 and PAI-1, and suppression of uPA expression. Treatment of WT mice with CSP inhibits PAI-1, restores uPA expression and prevents AEC apoptosis by suppressing p53, which is otherwise induced in mice exposed to silica. The process involves CSP-mediated inhibition of serine-15 phosphorylation of p53 by inhibition of protein phosphatase 2A-C (PP2A-C) interaction with silica-induced caveolin-1 in AECs. These observations suggest that changes in the p53–uPA fibrinolytic system cross-talk contribute to lung injury caused by inhalation of silica dust containing crystalline quartz and is protected by CSP by targeting this pathway.

      PubDate: 2015-03-04T14:51:26Z
  • Topological, functional, and dynamic properties of the protein interaction
           networks rewired by benzo(a)pyrene
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Qian Ba , Junyang Li , Chao Huang , Jingquan Li , Ruiai Chu , Yongning Wu , Hui Wang
      Benzo(a)pyrene is a common environmental and foodborne pollutant that has been identified as a human carcinogen. Although the carcinogenicity of benzo(a)pyrene has been extensively reported, its precise molecular mechanisms and the influence on system-level protein networks are not well understood. To investigate the system-level influence of benzo(a)pyrene on protein interactions and regulatory networks, a benzo(a)pyrene-rewired protein interaction network was constructed based on 769 key proteins derived from more than 500 literature reports. The protein interaction network rewired by benzo(a)pyrene was a scale-free, highly-connected biological system. Ten modules were identified, and 25 signaling pathways were enriched, most of which belong to the human diseases category, especially cancer and infectious disease. In addition, two lung-specific and two liver-specific pathways were identified. Three pathways were specific in short and medium-term networks (<48h), and five pathways were enriched only in the medium-term network (6h–48h). Finally, the expression of linker genes in the network was validated by Western blotting. These findings establish the overall, tissue- and time-specific benzo(a)pyrene-rewired protein interaction networks and provide insights into the biological effects and molecular mechanisms of action of benzo(a)pyrene.

      PubDate: 2015-03-04T14:51:26Z
  • Molecular basis of carcinogenicity of tungsten alloy particles
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Robert M. Harris , Tim D. Williams , Rosemary H. Waring , Nikolas J. Hodges
      The tungsten alloy of 91% tungsten, 6% nickel and 3% cobalt (WNC 91–6–3) induces rhabdomyosarcoma when implanted into a rat thigh muscle. To investigate whether this effect is species-specific human HSkMc primary muscle cells were exposed to WNC 91–6–3 particles and responses were compared with those from a rat skeletal muscle cell line (L6-C11). Toxicity was assessed by the adenylate kinase assay and microscopy, DNA damage by the Comet assay. Caspase 3 enzyme activity was measured and oligonucleotide microarrays were used for transcriptional profiling. WNC 91–6–3 particles caused toxicity in cells adjacent to the particles and also increased DNA strand breaks. Inhibition of caspase 3 by WNC 91–6–3 occurred in rat but not in human cells. In both rat and human cells, the transcriptional response to WNC 91–6–3 showed repression of transcripts encoding muscle-specific proteins with induction of glycolysis, hypoxia, stress responses and transcripts associated with DNA damage and cell death. In human cells, genes encoding metallothioneins were also induced, together with genes related to angiogenesis, dysregulation of apoptosis and proliferation consistent with pre-neoplastic changes. An alloy containing iron, WNF 97–2–1, which is non-carcinogenic in vivo in rats, did not show these transcriptional changes in vitro in either species while the corresponding cobalt-containing alloy, WNC 97–2–1 elicited similar responses to WNC 91–6–3. Tungsten alloys containing both nickel and cobalt therefore have the potential to be carcinogenic in man and in vitro assays coupled with transcriptomics can be used to identify alloys, which may lead to tumour formation, by dysregulation of biochemical processes.

      PubDate: 2015-03-04T14:51:26Z
  • Editorial Board
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2

      PubDate: 2015-03-04T14:51:26Z
  • Evaluation of the interindividual human variation in bioactivation of
           methyleugenol using physiologically based kinetic modeling and Monte Carlo
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Ala′ A.A. Al-Subeihi , Wasma Alhusainy , Reiko Kiwamoto , Bert Spenkelink , Peter J. van Bladeren , Ivonne M.C.M. Rietjens , Ans Punt
      The present study aims at predicting the level of formation of the ultimate carcinogenic metabolite of methyleugenol, 1′-sulfooxymethyleugenol, in the human population by taking variability in key bioactivation and detoxification reactions into account using Monte Carlo simulations. Depending on the metabolic route, variation was simulated based on kinetic constants obtained from incubations with a range of individual human liver fractions or by combining kinetic constants obtained for specific isoenzymes with literature reported human variation in the activity of these enzymes. The results of the study indicate that formation of 1′-sulfooxymethyleugenol is predominantly affected by variation in i) P450 1A2-catalyzed bioactivation of methyleugenol to 1′-hydroxymethyleugenol, ii) P450 2B6-catalyzed epoxidation of methyleugenol, iii) the apparent kinetic constants for oxidation of 1′-hydroxymethyleugenol, and iv) the apparent kinetic constants for sulfation of 1′-hydroxymethyleugenol. Based on the Monte Carlo simulations a so-called chemical-specific adjustment factor (CSAF) for intraspecies variation could be derived by dividing different percentiles by the 50th percentile of the predicted population distribution for 1′-sulfooxymethyleugenol formation. The obtained CSAF value at the 90th percentile was 3.2, indicating that the default uncertainty factor of 3.16 for human variability in kinetics may adequately cover the variation within 90% of the population. Covering 99% of the population requires a larger uncertainty factor of 6.4. In conclusion, the results showed that adequate predictions on interindividual human variation can be made with Monte Carlo-based PBK modeling. For methyleugenol this variation was observed to be in line with the default variation generally assumed in risk assessment.

      PubDate: 2015-03-04T14:51:26Z
  • Arsenic responsive microRNAs in vivo and their potential involvement in
           arsenic-induced oxidative stress
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Xuefeng Ren , Daniel P. Gaile , Zhihong Gong , Wenting Qiu , Yichen Ge , Chuanwu Zhang , Chenping Huang , Hongtao Yan , James R. Olson , Terrance J. Kavanagh , Hongmei Wu
      Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100mg/L) for 60days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate–cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress.

      PubDate: 2015-03-04T14:51:26Z
  • A precisely substituted benzopyran targets androgen refractory prostate
           cancer cells through selective modulation of estrogen receptors
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Rajeev Kumar , Vikas Verma , Vikas Sharma , Ashish Jain , Vishal Singh , Amit Sarswat , Jagdamba P. Maikhuri , Vishnu L. Sharma , Gopal Gupta
      Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Alisol B 23-acetate protects against ANIT-induced hepatotoxity and
           cholestasis, due to FXR-mediated regulation of transporters and enzymes
           involved in bile acid homeostasis
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Qiang Meng , Xin-li Chen , Chang-yuan Wang , Qi Liu , Hui-jun Sun , Peng-yuan Sun , Xiao-kui Huo , Zhi-hao Liu , Ji-hong Yao , Ke-xin Liu
      Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Bile acid-induced necrosis in primary human hepatocytes and in patients
           with obstructive cholestasis
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Benjamin L. Woolbright , Kenneth Dorko , Daniel J. Antoine , Joanna I. Clarke , Parviz Gholami , Feng Li , Sean C. Kumer , Timothy M. Schmitt , Jameson Forster , Fang Fan , Rosalind E. Jenkins , B. Kevin Park , Bruno Hagenbuch , Mojtaba Olyaee , Hartmut Jaeschke
      Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Tunicamycin-induced unfolded protein response in the developing mouse
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      Author(s): Haiping Wang , Xin Wang , Zun-Ji Ke , Ashley L. Comer , Mei Xu , Jacqueline A. Frank , Zhuo Zhang , Xianglin Shi , Jia Luo
      Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1–CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress.

      PubDate: 2015-03-04T14:51:26Z
  • Blackberry extract inhibits UVB-induced oxidative damage and inflammation
           through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Sasidharan Padmaja Divya , Xin Wang , Poyil Pratheeshkumar , Young-Ok Son , Ram Vinod Roy , Donghern Kim , Jin Dai , John Andrew Hitron , Lei Wang , Padmaja Asha , Xianglin Shi , Zhuo Zhang
      Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100mJ/cm2) on alternate days for 10weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways.

      PubDate: 2015-03-04T14:51:26Z
  • Green tea polyphenol (−)-epigallocatechin-3-gallate triggered
           hepatotoxicity in mice: Responses of major antioxidant enzymes and the
           Nrf2 rescue pathway
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Dongxu Wang , Yijun Wang , Xiaochun Wan , Chung S. Yang , Jinsong Zhang
      (−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity.

      PubDate: 2015-03-04T14:51:26Z
  • Contents
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1

      PubDate: 2015-03-04T14:51:26Z
  • A novel synthetic derivative of melatonin,
           5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory
           responses via regulation of TRIF-dependent signaling and inflammasome
    • Abstract: Publication date: Available online 14 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Do-Wan Shim , Hee Jae Shin , Ji-Won Han , Young-Eun Ji , Cheol-Hun Jang , Sushruta Koppula , Tae-Bong Kang , Kwang-Ho Lee
      Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Individual bile acids have differential effects on bile acid signaling in
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Peizhen Song , Cheryl E. Rockwell , Julia Yue Cui , Curtis D. Klaassen
      Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In the liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and pharmacological concentrations of BAs.

      PubDate: 2015-03-04T14:51:26Z
  • Motoneuron axon pathfinding errors in zebrafish: Differential effects
           related to concentration and timing of nicotine exposure
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Evdokia Menelaou , Latoya T. Paul , Surangi N. Perera , Kurt R. Svoboda
      Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window.

      PubDate: 2015-03-04T14:51:26Z
  • Permanent uncoupling of male-specific CYP2C11 transcription/translation by
           perinatal glutamate
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Sarmistha Banerjee , Rajat Kumar Das , Kelly A. Giffear , Bernard H. Shapiro
      Perinatal exposure of rats and mice to the typically reported 4mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2mg/g bd wt on alternate days for the first 9days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible.

      PubDate: 2015-03-04T14:51:26Z
  • Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by
           modulating HMGB1/RAGE pathway
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Liang Zhang , Yunxia Ji , Zechun Kang , Changjun Lv , Wanglin Jiang
      An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway.

      PubDate: 2015-03-04T14:51:26Z
  • Lineage-related cytotoxicity and clonogenic profile of
           1,4-benzoquinone-exposed hematopoietic stem and progenitor cells
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Paik Wah Chow , Zariyantey Abdul Hamid , Kok Meng Chan , Salmaan Hussain Inayat-Hussain , Nor Fadilah Rajab
      Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p <0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e+ cells but reduced the total counts of Sca-1+, CD11b+, Gr-1+, and CD45+ cells at 7 and 12μM (p <0.05). Furthermore, the CFU assay showed reduced (p <0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage.

      PubDate: 2015-03-04T14:51:26Z
  • Early life exposure to allergen and ozone results in altered development
           in adolescent rhesus macaque lungs
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): M.J. Herring , L.F. Putney , J.A. St. George , M.V. Avdalovic , E.S. Schelegle , L.A. Miller , D.M. Hyde
      In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O3) or HDMA/ozone (HDMA+O3) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA+O3 alters the development process in the lung alveoli.

      PubDate: 2015-03-04T14:51:26Z
  • Sympathetic activity induced by naloxone-precipitated morphine withdrawal
           is blocked in genetically engineered mice lacking functional CRF1 receptor
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Juan-Antonio García-Carmona , Elena Martínez-Laorden , María-Victoria Milanés , María-Luisa Laorden
      There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction.

      PubDate: 2015-03-04T14:51:26Z
  • Improving in vitro to in vivo extrapolation by incorporating toxicokinetic
           measurements: A case study of lindane-induced neurotoxicity
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Edward L. Croom , Timothy J. Shafer , Marina V. Evans , William R. Mundy , Chris R. Eklund , Andrew F.M. Johnstone , Cina M. Mack , Rex A. Pegram
      Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans. Time- and concentration-dependent lindane dosimetry was determined in primary cultures of rat cortical neurons in vitro using “faux” (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from rat to human. The previously determined EC50 for increased firing rates in primary cultures of cortical neurons was 0.6μg/ml. Media and cell lindane concentrations at the EC50 were 0.4μg/ml and 7.1μg/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. Rat blood and brain lindane levels during seizures were 1.7–1.9μg/ml and 5–11μg/ml, respectively. Brain lindane levels associated with seizures in rats and those predicted for humans (average=7μg/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC50 dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of rat and human neurotoxicity.

      PubDate: 2015-03-04T14:51:26Z
  • Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces
           atresia, and inhibits steroid hormone production in cultured mouse antral
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Patrick R. Hannon , Katherine E. Brannick , Wei Wang , Rupesh K. Gupta , Jodi A. Flaws
      Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1–100μg/ml) for 24–96h to establish the temporal effects of DEHP on the follicle. Following 24–96h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis.

      PubDate: 2015-03-04T14:51:26Z
  • Quinacrine induces apoptosis in human leukemia K562 cells via p38
           MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated
           BCL2L1 expression
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Jung-Jung Changchien , Ying-Jung Chen , Chia-Hui Huang , Tian-Lu Cheng , Shinne-Ren Lin , Long-Sen Chang
      Although previous studies have revealed the anti-cancer activity of quinacrine, its effect on leukemia is not clearly resolved. We sought to explore the cytotoxic effect and mechanism of quinacrine action in human leukemia K562 cells. Quinacrine induced K562 cell apoptosis accompanied with ROS generation, mitochondrial depolarization, and down-regulation of BCL2L1 and BCL2. Upon exposure to quinacrine, ROS-mediated p38 MAPK activation and ERK inactivation were observed in K562 cells. Quinacrine-induced cell death and mitochondrial depolarization were suppressed by the p38MAPK inhibitor SB202190 and constitutively active MEK1 over-expression. Activation of p38 MAPK was shown to promote BCL2 degradation. Further, ERK inactivation suppressed c-Jun-mediated transcriptional expression of BCL2L1. Over-expression of BCL2L1 and BCL2 attenuated quinacrine-evoked mitochondrial depolarization and rescued the viability of quinacrine-treated cells. Taken together, our data indicate that quinacrine-induced K562 cell apoptosis is mediated through mitochondrial alterations triggered by p38 MAPK-mediated BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.

      PubDate: 2015-03-04T14:51:26Z
  • Celecoxib, but not indomethacin, ameliorates the hypertensive and
           perivascular fibrotic actions of cyclosporine in rats: Role of endothelin
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      Author(s): Mahmoud M. El-Mas , Maged W. Helmy , Rabab M. Ali , Hanan M. El-Gowelli
      The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ETA/ETB) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20mgkg−1 day−1, 10days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renal perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ETA (increases) and ETB (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5mgkg−1 day−1), celecoxib (10mgkg−1 day−1) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ETA/ETB receptor expressions. Selective blockade of ETA receptors by atrasentan (5mgkg−1 day−1) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ETB receptor blocker, 0.1mgkg−1 day−1) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ETA downregulation and ETB upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Editorial Board
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1

      PubDate: 2015-03-04T14:51:26Z
  • Preferential cytotoxicity of bortezomib toward highly malignant human
           liposarcoma cells via suppression of MDR1 expression and function
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): Yamei Hu , Lingxian Wang , Lu Wang , Xuefeng Wu , Xudong Wu , Yanhong Gu , Yongqian Shu , Yang Sun , Yan Shen , Qiang Xu
      Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SW872-S cells compared with its parental SW872 cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo. Treatment of cells with Jun-N-terminal kinase (JNK) inhibitor SP60015 or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. Bortezomib inhibited MDR1 expression and function more effectively in SW872-S cells than in SW872 cells, indicating that the increased cytotoxicity relies on the degree of proteasome inhibition. Furthermore, the pharmacological or genetic inhibition of sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2, which is highly expressed in SW872-S cells, resulted in partial reversal of cell growth inhibition and increase of MDR1 expression in bortezomib-treated SW872-S cells. These results show that bortezomib exhibits preferential cytotoxicity toward SW872-S cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma.

      PubDate: 2015-03-04T14:51:26Z
  • Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast
           carcinogenesis and adduct formation in human breast cells by inhibiting
           the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway
    • Abstract: Publication date: Available online 16 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Zaid H. Maayah , Hazem Ghebeh , Abdulqader A. Alhaider , Ayman O.S. El-Kadi , Anatoly A. Soshilov , Michael S. Denison , Mushtaq Ahmad Ansari , Hesham M. Korashy
      Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Quaternary and tertiary aldoxime antidotes for organophosphate exposure in
           a zebrafish model system
    • Abstract: Publication date: Available online 17 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Hayden R. Schmidt , Zoran Radić , Palmer Taylor , Erica A. Fradinger
      The zebrafish is rapidly becoming an important model system for screening of new therapeutics. Here we evaluated the zebrafish as a potential pharmacological model for screening novel oxime antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE). The ki values determined for chlorpyrifos oxon (CPO) and dichlorvos (DDVP) showed that CPO was a more potent inhibitor of both human and zebrafish AChE, but overall zebrafish AChE was less sensitive to OP inhibition. In contrast, aldoxime antidotes, the quaternary ammonium 2-PAM and tertiary amine RS-194B, showed generally similar overall reactivation kinetics, kr, in both zebrafish and human AChE. However, differences between the Kox and k2 constants suggest that zebrafish AChE associates more tightly with oximes, but has a slower maximal reactivation rate than human AChE. Homology modeling suggests that these kinetic differences result from divergences in the amino acids lining the entrance to the active site gorge. Although 2-PAM had the more favorable in vitro reactivation kinetics, RS-194B was more effective antidote in vivo. In intact zebrafish embryos, antidotal treatment with RS-194B rescued embryos from OP toxicity, whereas 2-PAM had no effect. Dechorionation of the embryos prior to antidotal treatment allowed both 2-PAM and RS-194B to rescue zebrafish embryos from OP toxicity. Interestingly, RS-194B and 2-PAM alone increased cholinergic motor activity in dechorionated embryos possibly due to the reversible inhibition kinetics, Ki and αKi, of the oximes. Together these results demonstrate that the zebrafish at various developmental stages provides an excellent model for investigating membrane penetrant antidotes to OP exposure.

      PubDate: 2015-03-04T14:51:26Z
  • Combination effects of AHR agonists and Wnt/β-catenin modulators in
           zebrafish embryos: Implications for physiological and toxicological AHR
    • Abstract: Publication date: Available online 21 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Emma Wincent , John J. Stegeman , Maria E. Jönsson
      Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholine-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

      PubDate: 2015-03-04T14:51:26Z
  • Paradoxically, iron overload does not potentiate doxorubicin-induced
           cardiotoxicity in vitro in cardiomyocytes and in vivo in mice
    • Abstract: Publication date: Available online 21 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Charles Guenancia , Na Li , Olivier Hachet , Eve Rigal , Yves Cottin , Patrick Dutartre , Luc Rochette , Catherine Vergely
      Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15mg/kg) for 3weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

      PubDate: 2015-03-04T14:51:26Z
  • Regulation of ozone-induced lung inflammation and injury by the
           β-galactoside-binding lectin galectin-3
    • Abstract: Publication date: Available online 25 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Vasanthi R. Sunil , Mary Francis , Kinal N. Vayas , Jessica A. Cervelli , Hyejeong Choi , Jeffrey D. Laskin , Debra L. Laskin
      Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24–72h after exposure (3h) of WT and Gal-3-/- mice to air or 0.8ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3+, iNOS+) and anti-inflammatory (MR-1+) macrophages in the lungs. While accumulation of iNOS+ macrophages was attenuated in Gal-3-/- mice, increased numbers of enlarged MR-1+ macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b+ and consisted mainly (>97%) mature (F4/80+CD11c+) proinflammatory (Ly6G−Ly6Chi) and anti-inflammatory (Ly6G−Ly6Clo) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6Chi macrophages, with no effect on Ly6Clo macrophages. CD11b+Ly6G+Ly6C+ granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3-/- mice, the response of G-MDSC to ozone was attenuated, while the response of M-MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3-/- mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure.

      PubDate: 2015-03-04T14:51:26Z
  • The imperatorin derivative OW1, a new vasoactive compound, inhibits VSMC
           proliferation and extracellular matrix hyperplasia
    • Abstract: Publication date: Available online 26 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Nan Zhou , Yu Zhang , Tao Wang , Jianyu He , Huaizhen He , Langchong He
      Chronic hypertension induces vascular remodeling. The most important factor for hypertension treatment is reducing the risk of cardiovascular disease. OW1 is a novel imperatorin derivative that exhibits vasodilative activity and antihypertensive effects in two-kidney one-clip (2K1C) renovascular hypertensive rats. It also inhibited vascular remodeling of the thoracic aorta in a previous study. Here, the inhibitory effects and mechanisms of OW1 on arterial vascular remodeling were investigated in vitro and in 2K1C hypertensive rats in vivo. OW1 (20μM, 10μM, 5μM) inhibited Ang II-induced vascular smooth muscle cells (VSMCs) proliferation and ROS generation in vitro. OW1 also reversed the Ang II-mediated inhibition of α-SMA levels and stimulation of OPN levels. Histology results showed that treatment of 2K1C hypertensive rats with OW1 (20, 40, and 80mg/kg per day, respectively for 5weeks) in vivo significantly decreased the number of VSMCs, the aortic cross-sectional area (CSA), the media to lumen (M/L) ratio, and the content of collagen I and III in the mesenteric artery. Western blot results also revealed that OW1 stimulated the expression of α-SMA and inhibited the expression of collagen I and III on the thoracic aorta of 2K1C hypertensive rats. In mechanistic studies, OW1 acted as an ACE inhibitor and affected calcium channels. The suppression of MMP expression and the MAPK pathway may account for the effects of OW1 on vascular remodeling. OW1 attenuated vascular remodeling in vitro and in vivo. It could be a novel candidate for hypertension intervention.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA
           methyltransferase (dnmt) expression in zebrafish (Danio rerio)
    • Abstract: Publication date: Available online 27 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Neelakanteswar Aluru , Elaine Kuo , Lily W. Helfrich , Sibel I. Karchner , Elwood A. Linney , June E. Pais , Diana G. Franks
      DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5nM TCDD for 1h from 4 to 5h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns.

      PubDate: 2015-03-04T14:51:26Z
  • Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity:
           An in vitro model in mitochondria
    • Abstract: Publication date: Available online 27 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Dan Hu , Chun-qi Wu , Ze-jun Li , Yue Liu , Xing Fan , Quan-jun Wang , Ri-gao Ding
      Objective To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50μM) for 48h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p<0.05. Results Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles.

      PubDate: 2015-03-04T14:51:26Z
  • Honokiol activates the LKB1-AMPK signaling pathway and attenuates the
           lipid accumulation in hepatocytes
    • Abstract: Publication date: Available online 28 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Min Suk Seo , Jung Hwan Kim , Hye Jung Kim , Ki Churl Chang , Sang Won Park
      Honokiol is a bioactive neolignan compound isolated from the species of Magnolia. This study was designed to elucidate the cellular mechanism by which honokiol alleviates the development of non-alcoholic steatosis. HepG2 cells were treated with honokiol for 1 h, and then exposed to 1 mM free fatty acid (FFA) for 24 h to simulate non-alcoholic steatosis in vitro. C57BL/6 mice were fed with a high-fat diet for 28 days, and honokiol (10 mg/kg/day) was daily treated. Honokiol concentration-dependently attenuated intracellular fat overloading and triglyceride (TG) accumulation in FFA-exposed HepG2 cells. These effects were blocked by pretreatment with an AMP-activated protein kinase (AMPK) inhibitor. Honokiol significantly inhibited sterol regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) in FFA-exposed HepG2 cells, but these effects were blocked by pretreatment of an AMPK inhibitor. Honokiol induced AMPK phosphorylation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, which were inhibited by genetic deletion of liver kinase B1 (LKB1). Honokiol stimulated LKB1 phosphorylation, and genetic deletion of LKB1 blocked the effect of honokiol on SREBP-1c maturation and the induction of SCD-1 and FAS proteins in FFA-exposed HepG2 cells. Honokiol attenuated the increases in hepatic TG and lipogenic protein levels and fat accumulation in the mice fed with high-fat diet, while significantly induced LKB1 and AMPK phosphorylation. Taken together, our findings suggest that honokiol has an anti-lipogenic effect in hepatocytes, and this effect may be mediated by the LKB1-AMPK signaling pathway, which induces ACC phosphorylation and inhibits SREBP-1c maturation in hepatocytes.
      Graphical abstract image

      PubDate: 2015-03-04T14:51:26Z
  • A rat model of nerve agent exposure applicable to the pediatric
           population: The anticonvulsant efficacies of atropine and GluK1
    • Abstract: Publication date: Available online 14 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Steven L. Miller , Vassiliki Aroniadou-Anderjaska , Taiza H. Figueiredo , Eric M. Prager , Camila P. Almeida-Suhett , James P. Apland , Maria F.M. Braga
      Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2mg/kg, administered 20min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/kg, given along with an oxime within 1min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1h post-exposure, prevents brain pathology and behavioral deficits.

      PubDate: 2015-03-04T14:51:26Z
  • Potential of Extracellular MicroRNAs as Biomarkers of Acetaminophen
           Toxicity in Children
    • Abstract: Publication date: Available online 21 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Xi Yang , William F. Salminen , Qiang Shi , James Greenhaw , Pritmohinder S. Gill , Sudeepa Bhattacharyya , Richard D. Beger , Donna L. Mendrick , William B. Mattes , Laura P. James
      Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, −375, −423-5p, −30d-5p, −125b-5p, −4732-5p, −204-5p, and −574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, −940, −9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p <0.01) followed by miR-375 (R=0.70; p =0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity.

      PubDate: 2015-02-27T19:35:17Z
  • Sex-related differences in murine hepatic transcriptional and proteomic
           responses to TCDD
    • Abstract: Publication date: Available online 20 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Stephenie D. Prokopec , John D. Watson , Jamie Lee , Raimo Pohjanvirta , Paul C. Boutros
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as amongst different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500μg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6hours following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144hours following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear.

      PubDate: 2015-02-22T22:14:43Z
  • MWCNT of different physicochemical properties causes similar inflammatory
           responses, but differences in transcriptional and histological markers of
           fibrosis in mouse lungs
    • Abstract: Publication date: Available online 29 December 2014
      Source:Toxicology and Applied Pharmacology
      Author(s): Sarah S. Poulsen , Anne T. Saber , Andrew Williams , Ole Andersen , Carsten Købler , Rambabu Atluri , Maria E. Pozzebon , Stefano P. Mucelli , Monica Simion , David Rickerby , Alicja Mortensen , Petra Jackson , Zdenka O. Kyjovska , Kristian Mølhave , Nicklas R. Jacobsen , Keld A. Jensen , Carole L. Yauk , Håkan Wallin , Sabina Halappanavar , Ulla Vogel
      Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162μg/mouse of a small, curled (CNTSmall, 0.8±0.1μm in length) or large, thick MWCNT (CNTLarge, 4±0.4μm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer–Emmett–Teller surface area analysis. Lung tissues were harvested 24h, 3days and 28days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNTSmall or CNTLarge were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNTLarge elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNTSmall. The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNTLarge, which may eventually lead to the different responses observed at day 28.

      PubDate: 2015-02-16T09:48:51Z
  • Environmental contaminants activate human and polar bear (Ursus maritimus)
           pregnane X receptors (PXR, NR1I2) differently
    • Abstract: Publication date: Available online 10 February 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Roger Lille-Langøy , Jared V. Goldstone , Marte Rusten , Matthew R. Milnes , Rune Male , John J. Stegeman , Bruce Blumberg , Anders Goksøyr
      Background Many persistent organic pollutants (POPs) accumulate readily in polar bears because of their position as apex predators in Arctic food webs. The pregnane X receptor (PXR, formally NR1I2, here proposed to be named promiscuous xenobiotic receptor) is a xenobiotic sensor that is directly involved in metabolizing pathways of a wide range of environmental contaminants. Objectives In the present study, we comparably assess the ability of 51 selected pharmaceuticals, pesticides and emerging contaminants to activate PXRs from polar bears and humans using an in vitro luciferase reporter gene assay. Results We found that polar bear PXR is activated by a wide range of our test compounds (68%) but has a slightly more narrow ligand specificity than human PXR that was activated by 86% of the 51 test compounds. The majority of the agonists identified (70%) produces a stronger induction of the reporter gene via human PXR than via polar bear PXR, however with some notable and environmentally relevant exceptions. Conclusions Due to the observed differences in activation of polar bear and human PXRs, exposure of each species to environmental agents is likely to induce biotransformation differently in the two species. Bioinformatics analyses and structural modelling studies suggests that amino acids that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation.

      PubDate: 2015-02-11T09:38:45Z
  • Changes in cholesterol homeostasis and acute phase response link pulmonary
           exposure to multi-walled carbon nanotubes to risk of cardiovascular
    • Abstract: Publication date: Available online 22 January 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Sarah S. Poulsen , Anne T. Saber , Alicja Mortensen , Józef Szarek , Dongmei Wu , Andrew Williams , Ole Andersen , Nicklas R. Jacobsen , Carole L. Yauk , Håkan Wallin , Sabina Halappanavar , Ulla Vogel
      Adverse lung effects following pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) are well documented in rodents. However, systemic effects are less understood. Epidemiological studies have shown increased cardiovascular disease risk after pulmonary exposure to airborne particles, which has led to concerns that inhalation exposure to MWCNTs might pose similar risks. We analyzed parameters related to cardiovascular disease, including plasma acute phase response (APR) proteins and plasma lipids, in female C57BL/6 mice exposed to a single intratracheal instillation of 0, 18, 54 or 162μg/mouse of small, entangled (CNTSmall, 0.8±0.1μm long) or large, thick MWCNTs (CNTLarge, 4±0.4μm long). Liver tissues and plasma were harvested 1, 3 and 28days post-exposure. In addition, global hepatic gene expression, hepatic cholesterol content and liver histology were used to assess hepatic effects. The two MWCNTs induced similar systemic responses despite their different physicochemical properties. APR proteins SAA3 and haptoglobin, plasma total cholesterol and low-density/very low-density lipoprotein were significantly increased following exposure to either MWCNTs. Plasma SAA3 levels correlated strongly with pulmonary Saa3 levels. Analysis of global gene expression revealed perturbation of the same biological processes and pathways in liver, including the HMG-CoA reductase pathway. Both MWCNTs induced similar histological hepatic changes, with a tendency towards greater response following CNTLarge exposure. Overall, we show that pulmonary exposure to two different MWCNTs induces similar systemic and hepatic responses, including changes in plasma APR, lipid composition, hepatic gene expression and liver morphology. The results link pulmonary exposure to MWCNTs with risk of cardiovascular disease.

      PubDate: 2015-01-26T08:18:10Z
  • Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural
           mesothelial cells
    • Abstract: Publication date: Available online 13 January 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Li-Jun Chen , Hong Ye , Qian Zhang , Feng-Zhi Li , Lin-Jie Song , Jie Yang , Qing Mu , Shan-Shan Rao , Peng-Cheng Cai , Fei Xiang , Jian-Chu Zhang , Yunchao Su , Jian-Bao Xin , Wan-Li Ma
      Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis.

      PubDate: 2015-01-17T08:05:39Z
  • Evaluation of the fate and pathological response in the lung and pleura of
           brake dust alone and in combination with added chrysotile compared to
           crocidolite asbestos following short-term inhalation exposure
    • Abstract: Publication date: Available online 2 January 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): D.M. Bernstein , R. Rogers , R. Sepulveda , P. Kunzendorf , B. Bellmann , H. Ernst , O. Creutzenberg , J. Phillips
      This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake-dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6h/day for 5days to either brake-dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake-dust or crocidolite asbestos. The chrysotile fibers were relatively biosoluble whereas the crocidolite asbestos fibers persisted through the life-time of the animal. This was reflected in the lung and the pleura where no significant pathological response was observed at any time point in the brake dust or chrysotile/brake dust exposure groups through 365days post exposure. In contrast, crocidolite asbestos produced a rapid inflammatory response in the lung parenchyma and the pleura, inducing a significant increase in fibrotic response in both of these compartments. Crocidolite fibers were observed embedded in the diaphragm with activated mesothelial cells immediately after cessation of exposure. While no chrysotile fibers were found in the mediastinal lymph nodes, crocidolite fibers of up to 35μm were observed. These results provide support that brake-dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung or the pleural cavity following short term inhalation.

      PubDate: 2015-01-02T19:13:04Z
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