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  Subjects -> ENVIRONMENTAL STUDIES (Total: 793 journals)
    - ENVIRONMENTAL STUDIES (726 journals)
    - POLLUTION (21 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (38 journals)
    - WASTE MANAGEMENT (8 journals)

ENVIRONMENTAL STUDIES (726 journals)            First | 1 2 3 4 5 6 7 8     

Latin American Journal of Management for Sustainable Development     Hybrid Journal  
Legal Studies     Hybrid Journal   (Followers: 3)
Leviathan : A Journal of Melville Studies     Full-text available via subscription   (Followers: 2)
Limnological Review     Open Access   (Followers: 6)
Living Reviews in Landscape Research     Open Access   (Followers: 2)
Local Environment: The International Journal of Justice and Sustainability     Hybrid Journal   (Followers: 7)
Low Carbon Economy     Open Access   (Followers: 4)
Luna Azul     Open Access  
M+A. Revista Electrónica de Medioambiente     Open Access  
Macquarie Journal of International and Comparative Environmental Law     Full-text available via subscription   (Followers: 8)
Madagascar Conservation & Development     Open Access  
Management International Review     Hybrid Journal   (Followers: 5)
Management of Environmental Quality: An International Journal     Hybrid Journal   (Followers: 5)
Management of Sustainable Development     Open Access   (Followers: 2)
Marine Ecology     Hybrid Journal   (Followers: 13)
Marine Environmental Research     Hybrid Journal   (Followers: 12)
Marine Pollution Bulletin     Hybrid Journal   (Followers: 12)
Materials for Renewable and Sustainable Energy     Open Access   (Followers: 9)
Mathematical and Computational Forestry & Natural-Resource Sciences     Free  
Mathematical Population Studies: An International Journal of Mathematical Demography     Hybrid Journal   (Followers: 2)
Medieval Sermon Studies     Hybrid Journal   (Followers: 4)
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: 310)
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   (Followers: 1)
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)
Packaging, Transport, Storage and Security of Radioactive Material     Hybrid Journal   (Followers: 1)
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: 10)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription   (Followers: 2)
Presence Teleoperators & Virtual Environments     Hybrid Journal   (Followers: 1)
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)

  First | 1 2 3 4 5 6 7 8     

Journal Cover   Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [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  [2588 journals]
  • The neurotoxic effects of N-Methyl- N-nitrosourea on the
           electrophysiological property and visual signal transmission of
           rat’s retina
    • Abstract: Publication date: Available online 18 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Ye Tao , Tao Chen , Bei Liu , Guo Qing Yang , Guanghua Peng , Hua Zhang , Yi Fei Huang
      The neurotoxic effects of N-Methyl- N-nitrosourea(MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptors(PRs) degeneration. With the helping of MEA (multi electrodes array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retina were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PRs dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits has been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underling mechanism of human RP.
      Graphical abstract image

      PubDate: 2015-03-19T15:00:59Z
       
  • TG-interacting factor transcriptionally induced by AKT/FOXO3A is a
           negative regulator that antagonizes arsenic trioxide-induced cancer cell
           apoptosis
    • Abstract: Publication date: Available online 16 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Zi-Miao Liu , Hong-Yu Tseng , Ya-Ling Cheng , Bi-Wen Yeh , Wen-Jeng Wu , Huei-Sheng Huang
      Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK-induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21 WAF1/CIP1 ) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1–0.2μM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5–20μM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (−1486 to −1479bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20μM ATO-induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO.


      PubDate: 2015-03-19T15:00:59Z
       
  • Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic
           effects in mouse skin
    • Abstract: Publication date: Available online 16 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Anil K. Jain , Neera Tewari-Singh , Swetha Inturi , Dileep Kumar , David J. Orlicky , Chapla Agarwal , Carl W. White , Rajesh Agarwal
      Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants.


      PubDate: 2015-03-19T15:00:59Z
       
  • Curcumin attenuates glutamate neurotoxicity in the hippocampus by
           suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in
           a manner dependent on AMPK
    • Abstract: Publication date: Available online 16 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Ying Li , Jia Li , Shanshan Li , Yi Li , Xiangxiang Wang , Baolin Liu , Qiang Fu , Shiping Ma
      Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult.


      PubDate: 2015-03-19T15:00:59Z
       
  • Fumosorinone,a novel PTP1B inhibitor, activates insulin signaling in
           insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic
           KKAy mice
    • Abstract: Publication date: Available online 18 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhi-Qin Liu , Ting Liu , Chuan Chen , Ming-Yan Li , Zi-Yu Wang , Ruo-song Chen , Gui-xiang Wei , Xiao-yi Wang , Du-Qiang Luo
      Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein,the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt,GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties.
      Graphical abstract image

      PubDate: 2015-03-19T15:00:59Z
       
  • The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K+ channels
           in rabbit coronary arterial smooth muscle cells
    • Abstract: Publication date: Available online 18 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Hongliang Li , Da Hye Hong , Han Sol Kim , Hye Won Kim , Won-Kyo Jung , Sung Hun Na , In Duk Jung , Yeong-Min Park , Il-Whan Choi , Won Sun Park
      We investigated the effects of the calmodulin inhibitor CGS 9343B on voltage-dependent K+ (Kv) channels using whole-cell patch clamp technique in freshly isolated rabbit coronary arterial smooth muscle cells. CGS 9343B inhibited Kv currents in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC50) value of 0.81μM. The decay rate of Kv channel inactivation was accelerated by CGS 9343B. The rate constants of association and dissociation for CGS 9343B were 2.77±0.04μM-1 s-1 and 2.55±1.50s-1, respectively. CGS 9343B did not affect the steady-state activation curve, but shifted the inactivation curve toward to a more negative potential. Train pulses (1 or 2Hz) application progressively increased the CGS 9343B-induced Kv channel inhibition. In addition, the inactivation recovery time constant was increased in the presence of CGS 9343B, suggesting that CGS 9343B-induced inhibition of Kv channel was use-dependent. Another calmodulin inhibitor, W-13, did not affect Kv currents, and did not change the inhibitory effect of CGS 9343B on Kv current. Our results demonstrated that CGS 9343B inhibited Kv currents in a state-, time-, and use-dependent manner, independent of calmodulin inhibition.


      PubDate: 2015-03-19T15:00:59Z
       
  • Editorial Board
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3




      PubDate: 2015-03-15T14:59:09Z
       
  • Cover 4-TOC
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3




      PubDate: 2015-03-15T14:59:09Z
       
  • Sex-specific patterns and deregulation of endocrine pathways in the gene
           expression profiles of Bangladeshi adults exposed to arsenic contaminated
           drinking water
    • Abstract: Publication date: Available online 7 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Alexandra Muñoz , Yana Chervona , Megan Hall , Thomas Kluz , Mary V. Gamble , Max Costa
      Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females.


      PubDate: 2015-03-12T14:58:35Z
       
  • Allometric scaling for predicting human clearance of bisphenol A
    • Abstract: Publication date: Available online 7 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Séverine H. Collet , Nicole Picard-Hagen , Marlène Z. Lacroix , Sylvie Puel , Catherine Viguie , Alain Bousquet-Melou , Pierre-Louis Toutain , Véronique Gayrard
      The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02kg (mice) to 495kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79L/min (equivalent to 25.6mL/kg.min) with a 95% prediction interval of 0.36 to 8.83L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man.


      PubDate: 2015-03-12T14:58:35Z
       
  • Inhibition of NF-κB activity in the hypothalamic paraventricular
           nucleus attenuates hypertension and cardiac hypertrophy by modulating
           cytokines and attenuating oxidative stress
    • Abstract: Publication date: Available online 7 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiao-Jing Yu , Dong-Mei Zhang , Lin-Lin Jia , Jie Qi , Xin-Ai Song , Hong Tan , Wei Cui , Wensheng Chen , Guo-Qing Zhu , Da-Nian Qin , Yu-Ming Kang
      We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy.


      PubDate: 2015-03-12T14:58:35Z
       
  • Oligofructose protects against arsenic-induced liver injury in a model of
           environment/obesity interaction
    • Abstract: Publication date: Available online 8 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Veronica L. Massey , Kendall S. Stocke , Robin H. Schmidt , Min Tan , Nadim Ajami , Rachel E. Neal , Joseph F. Petrosino , Shirish Barve , Gavin E. Arteel
      Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9ppm as sodium arsenite) for 10weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects.


      PubDate: 2015-03-12T14:58:35Z
       
  • The adverse effects of aldrin and dieldrin on both myometrial contractions
           and the secretory functions of bovine ovaries and uterus in vitro
    • Abstract: Publication date: Available online 11 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Michał H. Wrobel , Marlena Grzeszczyk , Jaroslaw Mlynarczuk , Jan Kotwica
      Aldrin and dieldrin are chloroorganic insecticides which are recognised as endocrine disruptors. The aim of the study was to investigate their effect on the secretory functions of the uterus and ovary and on myometrial contractions. Myometrial strips and uterine and ovarian cells from nonpregnant cows were incubated with the xenobiotics (0.1, 1 or 10 ng/ml) for 24 or 72 h. Next, their effect on viability of myometrial, endometrial, granulosa and luteal cells, myometrial strip contractions, the synthesis and secretion of prostaglandins (PGs: PGF2α and PGE2) from uterine cells, the secretion of oestradiol (E2), testosterone (T) and oxytocin (OT) from granulosa cells and the secretion of progesterone (P4) and OT from luteal cells were determined. Neither of the xenobiotics (10 ng/ml) affected (P>0.05) the viability of the ovarian and uterine cells, while both (0.1-10 ng/ml) decreased (P<0.05) the basal and OT-stimulated myometrial contractions. In spite of these effects, neither of the insecticides affected (P>0.05) the synthesis and the secretion of PGs from the myometrial cells. Although they also did not impair the secretion of the PGs from the endometrial cells, they abolished (P<0.05) the stimulatory effect of OT (P<0.05) on the secretion of the PGs and stimulated (P<0.05) the secretion of OT from the granulosa and luteal cells. Moreover, aldrin and dieldrin stimulated secretion of E2 and T from the granulosa cells, while only dieldrin increased (P<0.05) the secretion of P4 from luteal cells. The data show that aldrin and dieldrin stimulated the secretory function of the cultured granulosa and luteal cells and inhibited the myometrial contractions of cows in vitro, which may affect on natural parturition.


      PubDate: 2015-03-12T14:58:35Z
       
  • Gender-specific increase in susceptibility to metabolic syndrome of
           offspring rats after prenatal caffeine exposure with post-weaning high-fat
           diet
    • Abstract: Publication date: Available online 11 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Jing Li , Hanwen Luo , Yimeng Wu , Zheng He , Li Zhang , Yu Guo , Lu Ma , Jacques Magdalou , Liaobin Chen , Hui Wang
      Prenatal caffeine exposure (PCE) alters the hypothalamic-pituitary-adrenocortical (HPA) axis-associated neuroendocrine metabolic programming and induces an increased susceptibility to metabolic syndrome (MS) in intrauterine growth retardation (IUGR) offspring rats. High-fat diet (HFD) is one of the main environmental factors accounting for the incidence of MS. In this study, we aimed to clarify the gender-specific increase in susceptibility to MS in offspring rats after PCE with post-weaning HFD. Maternal Wistar rats were administered with caffeine (120mg/kg.d) from gestational day 11 until delivery. The offspring rats with normal diet or HFD were sacrificed at postnatal week 24, and blood samples were collected. Results showed that PCE not only reduced serum adrenocorticotropic hormone (ACTH) and corticosterone levels, but also enhanced serum glucose, triglyceride and total cholesterol (TCH) concentrations in the offspring rats. Moreover, several interactions among PCE, HFD and gender were observed by a three-way ANOVA analysis. In PCE offspring, HFD could aggravate the degree of increased serum triglyceride level. Meanwhile, serum corticosterone levels of females were decreased more obviously than those of males in PCE offspring. The results also revealed interactions between HFD and gender in the levels of serum ACTH, triglyceride and TCH, which were changed more evidently in female HFD offspring. These results indicate that HFD could exacerbate the dysfunction of lipid metabolism and the susceptibility to MS induced by PCE, and the female offspring are more sensitive to HFD-induced neuroendocrine metabolic dysfunction than their male counterparts.


      PubDate: 2015-03-12T14:58:35Z
       
  • Environmental exposure to lead induces oxidative stress and modulates the
           function of the antioxidant defense system and the immune system in the
           semen of males with normal semen profile
    • Abstract: Publication date: Available online 12 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Aleksandra Kasperczyk , Michał Dobrakowski , Zenon P. Czuba , Stanisław Horak , Sławomir Kasperczyk
      We investigated the associations between environmental exposure to lead and a repertoire of cytokines in seminal plasma of males with normal semen profile according to the WHO criteria. Based on the median lead concentration in seminal plasma, 65 samples were divided into two groups: low (LE) and high exposure to lead (HE). Differences in semen volume and the pH, count, motility and morphology of sperm cells were not observed between the examined groups. The total oxidant status value and the level of protein sulfhydryl groups as well as the activities of manganese superoxide dismutase and catalase were significantly higher in the HE group, whereas the total antioxidant capacity value and the activities of glutathione reductase and glutathione-S-transferase were depressed. IL-7, IL-10, IL-12, and TNF-α levels were significantly higher in the HE group compared with the LE group. Environmental exposure to lead is sufficient to induce oxidative stress in seminal plasma and to modulate antioxidant defense system.


      PubDate: 2015-03-12T14:58:35Z
       
  • The effects of in utero bisphenol A exposure on reproductive capacity in
           several generations of mice
    • Abstract: Publication date: Available online 11 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Ayelet Ziv-Gal , Wei Wang , Changqing Zhou , Jodi A. Flaws
      In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50μg/kg/day) or diethylstilbestrol (DES; 0.05μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05μg/kg/day) and BPA (50μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature.


      PubDate: 2015-03-12T14:58:35Z
       
  • Boldine enhances bile production in rats via osmotic and Farnesoid X
           receptor dependent mechanisms
    • Abstract: Publication date: Available online 12 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Jolana Cermanova , Zuzana Kadova , Marie Zagorova , Milos Hroch , Pavel Tomsik , Petr Nachtigal , Zdenka Kudlackova , Petr Pavek , Michaela Dubecka , Martina Ceckova , Frantisek Staud , Tomas Laho , Stanislav Micuda
      Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-hours after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine.


      PubDate: 2015-03-12T14:58:35Z
       
  • Antenatal Exposure to the Selective Serotonin Reuptake Inhibitor
           Fluoxetine leads to Postnatal Metabolic and Endocrine Changes Associated
           with Type 2 Diabetes in Wistar Rats
    • Abstract: Publication date: Available online 12 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Nicole E. De Long , Eric J. Barry , Christopher Pinelli , Geoffrey A. Wood , Daniel B. Hardy , Katherine M. Morrison , Valerie H. Taylor , Hertzel C. Gerstein , Alison C. Holloway
      Hypothesis 10-15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods Female nulliparous Wistar rats were given vehicle (N=15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N=15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy Conclusion These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations.


      PubDate: 2015-03-12T14:58:35Z
       
  • Developmental Bisphenol A (BPA) Exposure Leads to Sex-specific
           Modification of Hepatic Gene Expression and Epigenome at Birth that May
           Exacerbate High-fat Diet-induced Hepatic Steatosis
    • Abstract: Publication date: Available online 5 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Rita S. Strakovsky , Huan Wang , Nicki J. Engeseth , Jodi A. Flaws , William G. Helferich , Yuan-Xiang Pan , Stéphane Lezmi
      Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague–Dawley rats were dosed with vehicle (oil) or BPA (100 μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C, and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglycerides (TG) and free fatty acid (FFA) composition in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation, histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially thorough the epigenetic regulation of genes, and further alters the response to a HF diet.


      PubDate: 2015-03-07T14:56:02Z
       
  • 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
           estradiol-3-O-glucuronidation
    • 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
           simulations
    • 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
           brain
    • 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
       
  • 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
       
  • 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
       
  • Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces
           atresia, and inhibits steroid hormone production in cultured mouse antral
           follicles
    • 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
           signaling
    • 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
       
  • 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.
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      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
       
  • 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
           disease
    • 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
       
 
 
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