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  Subjects -> ENVIRONMENTAL STUDIES (Total: 796 journals)
    - ENVIRONMENTAL STUDIES (728 journals)
    - POLLUTION (21 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (39 journals)
    - WASTE MANAGEMENT (8 journals)

ENVIRONMENTAL STUDIES (728 journals)            First | 1 2 3 4 5 6 7 8     

Large Marine Ecosystems     Full-text available via subscription   (Followers: 1)
Latin American and Caribbean Ethnic Studies     Hybrid Journal   (Followers: 4)
Latin American Journal of Management for Sustainable Development     Hybrid Journal  
Legal Studies     Hybrid Journal   (Followers: 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: 6)
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: 13)
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: 319)
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)

  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  [2586 journals]
  • 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 euthanized 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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-h 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: 2015-04-14T15:42:00Z
       
  • Cover 4-TOC
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3




      PubDate: 2015-04-14T15:42:00Z
       
  • 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 10mg/kg/d; N=15) orally for 2weeks 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Nivalenol induces oxidative stress and increases Deoxynivalenol
           pro-oxidant effect in intestinal epithelial cells
    • Abstract: Publication date: Available online 14 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Marisanta Del Regno , Simona Adesso , Ada Popolo , Andrea Quaroni , Giuseppina Autore , Lorella Severino , Stefania Marzocco
      Mycotoxins are secondary fungal metabolites often found as contaminants in almost all agricultural commodities worldwide, and the consumption of food or feed contaminated by mycotoxins represents a major risk for human and animal health. Reactive oxygen species are normal products of cellular metabolism. However, disproportionate generation of reactive oxygen species poses a serious problem to bodily homeostasis and causes oxidative tissue damage. In this study we analysed the effect of two trichothecenes mycotoxins: nivalenol and deoxinivalenol, alone and in combination, on oxidative stress in the non-tumorigenic intestinal epithelial cell line IEC-6. Our results indicate the pro-oxidant nivalenol effect in IEC-6, the stronger pro-oxidant effect of nivalenol when compared to deoxynivalenol and, interestingly, that nivalenol increases deoxynivalenol pro-oxidative effects. Mechanistic studies indicate that the observed effect were mediated by NADPH oxidase, calcium homeostasis alteration, NF-kB and Nrf2 pathways activation and by iNOS and nitrotyrosine formation. The toxicological interaction by nivalenol and deoxynivalenol reported in this study in IEC-6, points out the importance of the toxic effect of these mycotoxins, mostly in combination, further highlighting the risk assessment process of these toxins that are of growing concern.


      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Editorial Board
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3




      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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 2mg) 30min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120h 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: 2015-04-14T15:42:00Z
       
  • 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 photoreceptor (PR) degeneration. With the helping of MEA (multielectrode 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 PR 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 have 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 underlying mechanism of human RP.
      Graphical abstract image

      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Chronic inorganic arsenic exposure in vitro induces a cancer cell
           phenotype in human peripheral lung epithelial cells
    • Abstract: Publication date: Available online 21 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Rachel J. Person , Ntube N. Olive Ngalame , Ngome L. Makia , Matthew W. Bell , Michael P. Waalkes , Erik J. Tokar
      Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer.


      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Proteasome activity is important for replication recovery, CHK1
           phosphorylation and prevention of G2 arrest after low-dose formaldehyde
    • Abstract: Publication date: Available online 24 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Sara Ortega-Atienza , Samantha E. Green , Anatoly Zhitkovich
      Formaldehyde (FA) is a human carcinogen with numerous sources of environmental and occupational exposures. This reactive aldehyde is also produced endogenously during metabolism of drugs and other processes. DNA–protein crosslinks (DPCs) are considered to be the main genotoxic lesions for FA. Accumulating evidence suggests that DPC repair in high eukaryotes involves proteolysis of crosslinked proteins. Here, we examined a role of the main cellular proteolytic machinery proteasomes in toxic responses of human lung cells to low FA doses. We found that transient inhibition of proteasome activity increased cytotoxicity and diminished clonogenic viability of FA-treated cells. Proteasome inactivation exacerbated suppressive effects of FA on DNA replication and increased the levels of the genotoxic stress marker γ-H2AX in normal human cells. A transient loss of proteasome activity in FA-exposed cells also caused delayed perturbations of cell cycle, which included G2 arrest and a depletion of S-phase populations at FA doses that had no effects in control cells. Proteasome activity diminished p53-Ser15 phosphorylation but was important for FA-induced CHK1 phosphorylation, which is a biochemical marker of DPC proteolysis in replicating cells. Unlike FA, proteasome inhibition had no effect on cell survival and CHK1 phosphorylation by the non-DPC replication stressor hydroxyurea. Overall, we obtained evidence for the importance of proteasomes in protection of human cells against biologically relevant doses of FA. Biochemically, our findings indicate the involvement of proteasomes in proteolytic repair of DPC, which removes replication blockage by these highly bulky lesions.


      PubDate: 2015-04-14T15:42:00Z
       
  • Neuronal changes and oxidative stress in adolescent rats after repeated
           exposure to mephedrone
    • Abstract: Publication date: Available online 24 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Raúl López-Arnau , José Martínez-Clemente , Teresa Rodrigo , David Pubill , Jorge Camarasa , Elena Escubedo
      Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3×25mg/kg, s.c. in a day, with a 2h interval between doses, for two days) at high ambient temperature (26±2°C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D2 dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone.


      PubDate: 2015-04-14T15:42:00Z
       
  • Genotoxic effect of ethacrynic acid and impact of antioxidants
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): William M. Ward , Jared D. Hoffman , George Loo
      It is known that ethacrynic acid (EA) decreases the intracellular levels of glutathione. Whether the anticipated oxidative stress affects the structural integrity of DNA is unknown. Therefore, DNA damage was assessed in EA-treated HCT116 cells, and the impact of several antioxidants was also determined. EA caused both concentration-dependent and time-dependent DNA damage that eventually resulted in cell death. Unexpectedly, the DNA damage caused by EA was intensified by either ascorbic acid or trolox. In contrast, EA-induced DNA damage was reduced by N-acetylcysteine and by the iron chelator, deferoxamine. In elucidating the DNA damage, it was determined that EA increased the production of reactive oxygen species, which was inhibited by N-acetylcysteine and deferoxamine but not by ascorbic acid and trolox. Also, EA decreased glutathione levels, which were inhibited by N-acetylcysteine. But, ascorbic acid, trolox, and deferoxamine neither inhibited nor enhanced the capacity of EA to decrease glutathione. Interestingly, the glutathione synthesis inhibitor, buthionine sulfoxime, lowered glutathione to a similar degree as EA, but no noticeable DNA damage was found. Nevertheless, buthionine sulfoxime potentiated the glutathione-lowering effect of EA and intensified the DNA damage caused by EA. Additionally, in examining redox-sensitive stress gene expression, it was found that EA increased HO-1, GADD153, and p21mRNA expression, in association with increased nuclear localization of Nrf-2 and p53 proteins. In contrast to ascorbic acid, trolox, and deferoxamine, N-acetylcysteine suppressed the EA-induced upregulation of GADD153, although not of HO-1. Overall, it is concluded that EA has genotoxic properties that can be amplified by certain antioxidants.


      PubDate: 2015-04-14T15:42:00Z
       
  • Tat-CBR1 inhibits inflammatory responses through the suppressions of
           NF-κB and MAPK activation in macrophages and TPA-induced ear edema in
           mice
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Young Nam Kim , Dae Won Kim , Hyo Sang Jo , Min Jea Shin , Eun Hee Ahn , Eun Ji Ryu , Ji In Yong , Hyun Ju Cha , Sang Jin Kim , Hyeon Ji Yeo , Jong Kyu Youn , Jae Hyeok Hwang , Ji-Heon Jeong , Duk-Soo Kim , Sung-Woo Cho , Jinseu Park , Won Sik Eum , Soo Young Choi
      Human carbonyl reductase 1 (CBR1) plays a crucial role in cell survival and protects against oxidative stress response. However, its anti-inflammatory effects are not yet clearly understood. In this study, we examined whether CBR1 protects against inflammatory responses in macrophages and mice using a Tat-CBR1 protein which is able to penetrate into cells. The results revealed that purified Tat-CBR1 protein efficiently transduced into Raw 264.7 cells and inhibited lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2), nitric oxide (NO) and prostaglandin E2 (PGE2) expression levels. In addition, Tat-CBR1 protein leads to decreased pro-inflammatory cytokine expression through suppression of nuclear transcription factor-kappaB (NF-κB) and mitogen activated protein kinase (MAPK) activation. Furthermore, Tat-CBR1 protein inhibited inflammatory responses in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation when applied topically. These findings indicate that Tat-CBR1 protein has anti-inflammatory properties in vitro and in vivo through inhibition of NF-κB and MAPK activation, suggesting that Tat-CBR1 protein may have potential as a therapeutic agent against inflammatory diseases.


      PubDate: 2015-04-14T15:42:00Z
       
  • Polychlorinated biphenyl quinone induces oxidative DNA damage and repair
           responses: The activations of NHEJ, BER and NER via ATM-p53 signaling axis
           
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Hui Dong , Qiong Shi , Xiufang Song , Juanli Fu , Lihua Hu , Demei Xu , Chuanyang Su , Xiaomin Xia , Erqun Song , Yang Song
      Our previous studies demonstrated that polychlorinated biphenyl (PCB) quinone induced oxidative DNA damage in HepG2 cells. To promote genomic integrity, DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair and apoptosis. PCB quinone-induced cell cycle arrest and apoptosis have been documented, however, whether PCB quinone insult induce DNA repair signaling is still unknown. In this study, we identified the activation of DDR and corresponding signaling events in HepG2 cells upon the exposure to a synthetic PCB quinone, PCB29-pQ. Our data illustrated that PCB29-pQ induces the phosphorylation of p53, which was mediated by ataxia telangiectasia mutated (ATM) protein kinase. The observed phosphorylated histone H2AX (γ-H2AX) foci and the elevation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) indicated that DDR was stimulated by PCB29-pQ treatment. Additionally, we found PCB29-pQ activates non-homologous end joining (NHEJ), base excision repair (BER) and nucleotide excision repair (NER) signalings. However, these repair pathways are not error-free processes and aberrant repair of DNA damage may cause the potential risk of carcinogenesis and mutagenesis.


      PubDate: 2015-04-14T15:42:00Z
       
  • Inhibitor of apoptosis signal-regulating kinase 1 protects against
           acetaminophen-induced liver injury
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Yuchao Xie , Anup Ramachandran , David G. Breckenridge , John T. Liles , Margitta Lebofsky , Anwar Farhood , Hartmut Jaeschke
      Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients.


      PubDate: 2015-04-14T15:42:00Z
       
  • A Quantitative Multiplex Nuclease Protection Assay Reveals Immunotoxicity
           Gene Expression Profiles in the Rabbit Model for Vaginal Drug Safety
           Evaluation
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Raina N. Fichorova , Kevin Mendonca , Hidemi S. Yamamoto , Ryan Murray , Neelima Chandra , Gustavo F. Doncel
      Any vaginal product that alters the mucosal environment and impairs the immune barrier increases the risk of sexually transmitted infections, especially HIV infection, which thrives on mucosal damage and inflammation. The FDA-recommended rabbit vaginal irritation (RVI) model serves as a first line selection tool for vaginal products; however, for decades it has been limited to histopathology scoring, insufficient to select safe anti-HIV microbicides. In this study we incorporate to the RVI model a novel quantitative nuclease protection assay (qNPA) to quantify mRNA levels of 25 genes representing leukocyte differentiation markers, toll-like receptors (TLR), cytokines, chemokines, epithelial repair, microbicidal and vascular markers, by designing two multiplex arrays. Tissue sections were obtained from 36 rabbits (6 per treatment arm) after 14 daily applications of a placebo gel, saline, 4% nonoxynol-9 (N-9), and three combinations of the anti-HIV microbicides tenofovir (TFV) and UC781 in escalating concentrations (highest: 10% TFV+2.5%UC781). Results showed that increased expression levels of toll-like receptor (TLR)-4, interleukin (IL)-1β, CXCL8, epithelial membrane protein (EMP)-1 (P<0.05), and decreased levels of TLR2 (P<0.05), TLR3 and bactericidal permeability increasing protein (BPI) (P<0.001) were associated with cervicovaginal mucosal alteration (histopathology). Seven markers showed a significant linear trend predicting epithelial damage (up with CD4, IL-1β, CXCL8, CCL2, CCL21, EMP1 and down with BPI). Despite the low tissue damage RVI scores, the high-dose microbicide combination gel caused activation of HIV host cells (SLC and CD4) while N-9 caused proinflammatory gene upregulation (IL-8 and TLR4) suggesting a potential for increasing risk of HIV via different mechanisms depending on the chemical nature of the test product.
      Graphical abstract image

      PubDate: 2015-04-14T15:42:00Z
       
  • Dopamine induces growth inhibition and vascular normalization through
           reprogramming M2-polarized macrophages in rat C6 glioma
    • Abstract: Publication date: Available online 25 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Tian Qin , Chenlong Wang , Xuewei Chen , Chenfan Duan , Xiaoyan Zhang , Jing Zhang , Hongyan Chai , Tian Tang , Honglei Chen , Jiang Yue , Ying Li , Jing Yang
      Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy.
      Graphical abstract image

      PubDate: 2015-04-14T15:42:00Z
       
  • Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and
           endoplasmic reticulum stress induced by carbon tetrachloride in mice
    • Abstract: Publication date: Available online 28 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Todd R. Harris , Ahmed Bettaieb , Sean Kodani , Hua Dong , Richard Myers , Nipavan Chiamvimonvat , Fawaz G. Haj , Bruce D. Hammock
      Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress.


      PubDate: 2015-04-14T15:42:00Z
       
  • Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary
           microvascular endothelial cells against hyperoxic injury: Mechanistic
           roles of antioxidant enzymes and RelB
    • Abstract: Publication date: Available online 29 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Shaojie Zhang , Ananddeep Patel , Chun Chu , Weiwu Jiang , Lihua Wang , Stephen E. Welty , Bhagavatula Moorthy , Binoy Shivanna
      Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF-κB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR-sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells.


      PubDate: 2015-04-14T15:42:00Z
       
  • Inhaled ozone (O3)-induces changes in serum metabolomic and liver
           transcriptomic profiles in rats
    • Abstract: Publication date: Available online 30 March 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Desinia B. Miller , Edward D. Karoly , Jan C. Jones , William O. Ward , Beena D. Vallanat , Debora L. Andrews , Mette C. Schladweiler , Samantha J. Snow , Virginia L. Bass , Judy E. Richards , Andrew J. Ghio , Wayne E. Cascio , Allen D. Ledbetter , Urmila P. Kodavanti
      Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.0ppm, 6h/day for two days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0ppm O3, 6h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h-post second exposure. O3 increased circulating metabolites of glycolysis, long-chain free fatty acids, branched-chain amino acids and cholesterol, while 1,5-anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, proteolysis and lipolysis. Liver gene expression increased for markers of glycolysis, TCA cycle and gluconeogenesis, and decreased for markers of steroid and fat biosynthesis. Genes involved in apoptosis and mitochondrial function were also impacted by O3. In conclusion, short-term O3 exposure induces global metabolic derangement involving glucose, lipid, and amino acid metabolism, typical of a stress–response. It remains to be examined if these alterations contribute to insulin resistance upon chronic exposure.


      PubDate: 2015-04-14T15:42:00Z
       
  • Contents
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1




      PubDate: 2015-04-14T15:42:00Z
       
  • NiO nanoparticles induce apoptosis through repressing SIRT1 in human
           bronchial epithelial cells
    • Abstract: Publication date: Available online 1 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Wei-Xia Duan , Min-Di He , Lin Mao , Feng-Hua Qian , Yu-Ming Li , Hui-Feng Pi , Chuan Liu , Chun-Hai Chen , Yong-Hui Lu , Zheng-Wang Cao , Lei Zhang , Zheng-Ping Yu , Zhou Zhou
      With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni2+ inside the cells. NiONPs at doses of 5, 10, and 20μg/cm2 inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2-associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity.


      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Editorial Board
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1




      PubDate: 2015-04-14T15:42:00Z
       
  • 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: 2015-04-14T15:42:00Z
       
  • Novel anticancer activity of phloroglucinol against breast cancer
           stem-like cells
    • Abstract: Publication date: Available online 2 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Rae-Kwon Kim , Nizam Uddin , Jin-Won Hyun , Changil Kim , Yongjoon Suh , Su-Jae Lee
      Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44+ cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and β-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse.


      PubDate: 2015-04-14T15:42:00Z
       
  • Structural and functional screening in human induced-pluripotent stem
           cell-derived cardiomyocytes accurately identifies cardiotoxicity of
           multiple drug types
    • Abstract: Publication date: Available online 2 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Kimberly R. Doherty , Dominique R. Talbert , Patricia B. Trusk , Diarmuid M. Moran , Scott A. Shell , Sarah Bacus
      Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability.


      PubDate: 2015-04-14T15:42:00Z
       
  • Increased DNA methylation of scavenger receptor class B type I contributes
           to inhibitory effects of prenatal caffeine ingestion on cholesterol uptake
           and steroidogenesis in fetal adrenals
    • Abstract: Publication date: Available online 11 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Dong-Mei Wu , Zheng He , Liang-Peng Ma , Lin-Long Wang , Jie Ping , Hui Wang
      Steroid hormones synthesized from cholesterol in the fetal adrenal are crucial for fetal development. We have observed the inhibited fetal adrenal corticosterone synthesis and increased intrauterine growth retardation (IUGR) rate in rats under prenatal caffeine ingestion. The aim of this study is to evaluate the effects of prenatal caffeine ingestion on cholesterol supply in fetal adrenal steroidogenesis in rats and explore the underlying epigenetic mechanisms. Pregnant Wistar rats were treated with 60 mg/kg·d caffeine from gestational day (GD) 7 to GD17. Histological changes of fetal adrenals and increased IUGR rates were observed in the caffeine group. There were significantly decreased steroid hormone contents and cholesterol supply in caffeine-treated fetal adrenals. Data from the gene expression array suggested that prenatal caffeine ingestion caused increased expression of genes related to DNA methylation and decreased expression of genes related to cholesterol uptake. The following conjoint analysis of DNA methylation array with these differentially expressed genes suggested that scavenger receptor class B type I (SR-BI) may play an important role in caffeine-induced cholesterol supply deficiency. Moreover, real-time RT-PCR and immunohistochemical detection certified the inhibitory effects of caffeine on both mRNA and protein expression of SR-BI in the fetal adrenal. And the increased DNA methylation frequency in the proximal promoter of SR-BI was confirmed by bisulfite-sequencing PCR. In conclusion, prenatal caffeine ingestion can induce DNA hypermethylation of the SR-BI promoter in the rat fetal adrenal. These effects may lead to decreased SR-BI expression and cholesterol uptake, which inhibits steroidogenesis in the fetal adrenal.


      PubDate: 2015-04-14T15:42:00Z
       
  • Glutathione S-transferase P protects against cyclophosphamide-induced
           cardiotoxicity in mice
    • Abstract: Publication date: Available online 10 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Daniel J. Conklin , Petra Haberzettl , Ganapathy Jagatheesan , Shahid Baba , Michael L. Merchant , Russell A. Prough , Jessica D. Williams , Sumanth D. Prabhu , Aruni Bhatnagar
      High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100-300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein-acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1-5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10-20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity.
      Graphical abstract image

      PubDate: 2015-04-14T15:42:00Z
       
  • Toxicological Significance of Renal Bcrp: Another Potential Transporter in
           the Elimination of Mercuric Ions from Proximal Tubular Cells
    • Abstract: Publication date: Available online 11 April 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Christy C. Bridges , Rudolfs K. Zalups , Lucy Joshee
      Secretion of inorganic mercury (Hg2+) from proximal tubular cells into the tubular lumen has been shown to involve the multidrug resistance-associated protein 2 (Mrp2). Considering similarities in localization and substrate specificity between Mrp2 and the breast cancer resistance protein (Bcrp), we hypothesize that Bcrp may also play a role in the proximal tubular secretion of mercuric species. In order to test this hypothesis, the uptake of Hg2+ was examined initially using inside-out membrane vesicles containing Bcrp. The results of these studies suggest that Bcrp may be capable of transporting certain conjugates of Hg2+. To further characterize the role of Bcrp in the handling of mercuric ions and in the induction of Hg2+-induced nephropathy, Sprague-Dawley and Bcrp knockout (bcrp-/- ) rats were exposed intravenously to a non-nephrotoxic (0.5 μmol • kg-1), a moderately nephrotoxic (1.5 μmol • kg-1) or a significantly nephrotoxic (2.0 μmol • kg-1) dose of HgCl2. In general, the accumulation of Hg2+ was greater in organs of bcrp-/- rats than in Sprague-Dawley rats, suggesting that Bcrp may play a role in the export of Hg2+ from target cells. Within the kidney, cellular injury and necrosis was more severe in bcrp-/- rats than in controls. The pattern of necrosis, which was localized in the inner cortex and the outer stripe of the outer medulla was significantly different from that observed in Mrp2-deficient animals. These findings suggest that Bcrp may be involved in the cellular export of select mercuric species and that its role in this export may differ from that of Mrp2.


      PubDate: 2015-04-14T15:42:00Z
       
  • 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
       
 
 
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