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  Subjects -> ENVIRONMENTAL STUDIES (Total: 812 journals)
    - ENVIRONMENTAL STUDIES (739 journals)
    - POLLUTION (22 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (739 journals)            First | 1 2 3 4 5 6 7 8     

Julius-Kühn-Archiv     Open Access  
Kleio     Full-text available via subscription   (Followers: 2)
Knowledge Management Research & Practice     Hybrid Journal   (Followers: 17)
Koedoe : African Protected Area Conservation and Science     Open Access   (Followers: 7)
L1-Educational Studies in Language and Literature     Open Access   (Followers: 2)
Lake and Reservoir Management     Hybrid Journal   (Followers: 4)
Landscape Ecology     Hybrid Journal   (Followers: 30)
Landscapes     Hybrid Journal   (Followers: 20)
Large Marine Ecosystems     Full-text available via subscription   (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)
Letras Verdes. Revista Latinoamericana de Estudios Socioambientales     Open Access  
Leviathan : A Journal of Melville Studies     Full-text available via subscription   (Followers: 2)
Limnological Review     Open Access   (Followers: 6)
Living Reviews in Landscape Research     Open Access   (Followers: 2)
Local Environment: The International Journal of Justice and Sustainability     Hybrid Journal   (Followers: 7)
Low Carbon Economy     Open Access   (Followers: 4)
Luna Azul     Open Access  
M+A. Revista Electrónica de Medioambiente     Open Access  
Macquarie Journal of International and Comparative Environmental Law     Full-text available via subscription   (Followers: 8)
Madagascar Conservation & Development     Open Access  
Management International Review     Hybrid Journal   (Followers: 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: 12)
Modern Asian Studies     Hybrid Journal   (Followers: 7)
Modern Cartography Series     Full-text available via subscription   (Followers: 6)
Mountain Research and Development     Open Access   (Followers: 3)
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (Followers: 2)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (Followers: 7)
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 7)
Natural Areas Journal     Full-text available via subscription   (Followers: 7)
Natural Hazards     Hybrid Journal   (Followers: 101)
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: 5)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 3)
NJAS - Wageningen Journal of Life Sciences     Full-text available via subscription   (Followers: 1)
Noise Mapping     Open Access  
Noise Notes     Full-text available via subscription   (Followers: 3)
Novos Cadernos NAEA     Open Access   (Followers: 1)
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Full-text available via subscription   (Followers: 8)
Ocean Acidification     Open Access  
Ochrona Srodowiska i Zasobów Naturalnych     Open Access  
Oecologia     Hybrid Journal   (Followers: 31)
Oikos     Hybrid Journal   (Followers: 34)
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 & Security of Radioactive Material     Hybrid Journal   (Followers: 1)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 4)
Particle and Fibre Toxicology     Open Access   (Followers: 2)
Pastos y Forrajes     Open Access  
Pesquisa em Educação Ambiental     Open Access  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 5)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 1)
Philosophical Studies     Hybrid Journal   (Followers: 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: 5)
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: 15)
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)
Present Environment and Sustainable Development     Open Access  
Presidential Studies Quarterly     Hybrid Journal   (Followers: 4)

  First | 1 2 3 4 5 6 7 8     

Journal Cover   Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [12 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [2812 journals]
  • System-based identification of toxicity pathways associated with
           multi-walled carbon nanotube-induced pathological responses
    • Abstract: Publication date: 15 October 2013
      Source:Toxicology and Applied Pharmacology, Volume 272, Issue 2
      Author(s): Brandi N. Snyder-Talkington , Julian Dymacek , Dale W. Porter , Michael G. Wolfarth , Robert R. Mercer , Maricica Pacurari , James Denvir , Vincent Castranova , Yong Qian , Nancy L. Guo
      The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80μg MWCNT at 1, 7, 28, or 56days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts.

      PubDate: 2015-05-21T21:07:14Z
  • Human stem cell osteoblastogenesis mediated by novel glycogen synthase
           kinase 3 inhibitors induces bone formation and a unique bone turnover
           biomarker profile in rats
    • Abstract: Publication date: 15 October 2013
      Source:Toxicology and Applied Pharmacology, Volume 272, Issue 2
      Author(s): Peter S. Gilmour , Patrick J. O'Shea , Malbinder Fagura , James E. Pilling , Hitesh Sanganee , Hiroki Wada , Paul F. Courtney , Stefan Kavanagh , Peter A. Hall , K. Jane Escott
      Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28days exposure in rats. After 7days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH1–34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption.

      PubDate: 2015-05-21T21:07:14Z
  • Exposure to low mercury concentration in vivo impairs myocardial
           contractile function
    • Abstract: Publication date: 1 September 2011
      Source:Toxicology and Applied Pharmacology, Volume 255, Issue 2
      Author(s): Lorena Barros Furieri , Mirian Fioresi , Rogério Faustino Ribeiro Junior , María Visitación Bartolomé , Aurélia Araújo Fernandes , Victoria Cachofeiro , Vicente Lahera , Mercedes Salaices , Ivanita Stefanon , Dalton Valentim Vassallo
      Increased cardiovascular risk after mercury exposure has been described but cardiac effects resulting from controlled chronic treatment are not yet well explored. We analyzed the effects of chronic exposure to low mercury concentrations on hemodynamic and ventricular function of isolated hearts. Wistar rats were treated with HgCl2 (1st dose 4.6μg/kg, subsequent dose 0.07μg/kg/day, im, 30days) or vehicle. Mercury treatment did not affect blood pressure (BP) nor produced cardiac hypertrophy or changes of myocyte morphometry and collagen content. This treatment: 1) in vivo increased left ventricle end diastolic pressure (LVEDP) without changing left ventricular systolic pressure (LVSP) and heart rate; 2) in isolated hearts reduced LV isovolumic systolic pressure and time derivatives, and β-adrenergic response; 3) increased myosin ATPase activity; 4) reduced Na+-K+ ATPase (NKA) activity; 5) reduced protein expression of SERCA and phosphorylated phospholamban on serine 16 while phospholamban expression increased; as a consequence SERCA/phospholamban ratio reduced; 6) reduced sodium/calcium exchanger (NCX) protein expression and α-1 isoform of NKA, whereas α-2 isoform of NKA did not change. Chronic exposure for 30days to low concentrations of mercury does not change BP, heart rate or LVSP but produces small but significant increase of LVEDP. However, in isolated hearts mercury treatment promoted contractility dysfunction as a result of the decreased NKA activity, reduction of NCX and SERCA and increased PLB protein expression. These findings offer further evidence that mercury chronic exposure, even at small concentrations, is an environmental risk factor affecting heart function.

      PubDate: 2015-05-21T21:07:14Z
  • Quantitative assessment of biological impact using transcriptomic data and
           mechanistic network models
    • Abstract: Publication date: 1 November 2013
      Source:Toxicology and Applied Pharmacology, Volume 272, Issue 3
      Author(s): Ty M. Thomson , Alain Sewer , Florian Martin , Vincenzo Belcastro , Brian P. Frushour , Stephan Gebel , Jennifer Park , Walter K. Schlage , Marja Talikka , Dmitry M. Vasilyev , Jurjen W. Westra , Julia Hoeng , Manuel C. Peitsch
      Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-wide and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology.

      PubDate: 2015-05-21T21:07:14Z
  • In vitro - in vivo correlations for endocrine activity of a mixture of
           currently used pesticides
    • Abstract: Publication date: 1 November 2013
      Source:Toxicology and Applied Pharmacology, Volume 272, Issue 3
      Author(s): Camilla Taxvig , Niels Hadrup , Julie Boberg , Marta Axelstad , Rossana Bossi , Eva Cecilie Bonefeld-Jørgensen , Anne Marie Vinggaard
      Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone were seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, either of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects.

      PubDate: 2015-05-21T21:07:14Z
  • 7,12-Dimethylbenz[a]anthracene exposure induces the DNA repair response in
           neonatal rat ovaries
    • Abstract: Publication date: 1 November 2013
      Source:Toxicology and Applied Pharmacology, Volume 272, Issue 3
      Author(s): Shanthi Ganesan , Poulomi Bhattacharya , Aileen F. Keating
      7,12-Dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles at all stages of development. This study investigated DMBA-induced DNA double strand break (DSB) formation with subsequent activation of the ovarian DNA repair response in models of pre-antral or pre-ovulatory follicle loss. Postnatal day (PND) 4 Fisher 344 (F344) rat ovaries were cultured for 4days followed by single exposures of vehicle control (1% DMSO) or DMBA (12.5nM or 75nM) and maintained in culture for 4 or 8days. Alternately, PND4 F344 rat ovaries were exposed to 1μM DMBA at the start of culture for 2days. Total RNA or protein was isolated, followed by qPCR or Western blotting to quantify mRNA or protein level, respectively. γH2AX and phosphorylated ATM were localized and quantified using immunofluorescence staining. DMBA exposure increased caspase 3 and γH2AX protein. Additionally, DMBA (12.5nM and 1μM) increased levels of mRNA encoding Atm, Xrcc6, Brca1 and Rad51. In contrast, Parp1 mRNA was decreased on d4 and increased on d8 of DMBA exposure, while PARP1 protein increased after 8days of DMBA exposure. Total ATM increased in a concentration-dependent temporal pattern (75nM d4; 12.5nM d8), while pATM was localized in large primary and secondary follicles and increased after 8days of 75nM DMBA exposure compared to both control and 12.5nM DMBA. These findings support that, despite some concentration effects, DMBA induces ovarian DNA damage and that DNA repair mechanisms are induced as a potential mechanism to prevent follicle loss.

      PubDate: 2015-05-21T21:07:14Z
  • Actions of juglone on energy metabolism in the rat liver
    • Abstract: Publication date: 15 December 2011
      Source:Toxicology and Applied Pharmacology, Volume 257, Issue 3
      Author(s): Simoni Cristina Saling , Jurandir Fernando Comar , Márcio Shigueaki Mito , Rosane Marina Peralta , Adelar Bracht
      Juglone is a phenolic compound used in popular medicine as a phytotherapic to treat inflammatory and infectious diseases. However, it also acts as an uncoupler of oxidative phosphorylation in isolated liver mitochondria and, thus, may interfere with the hepatic energy metabolism. The purpose of this work was to evaluate the effect of juglone on several metabolic parameters in the isolated perfused rat liver. Juglone, in the concentration range of 5 to 50μM, stimulated glycogenolysis, glycolysis and oxygen uptake. Gluconeogenesis from both lactate and alanine was inhibited with half-maximal effects at the concentrations of 14.9 and 15.7μM, respectively. The overall alanine transformation was increased by juglone, as indicated by the stimulated release of ammonia, urea, l-glutamate, lactate and pyruvate. A great increase (9-fold) in the tissue content of α-ketoglutarate was found, without a similar change in the l-glutamate content. The tissue contents of ATP were decreased, but those of ADP and AMP were increased. Experiments with isolated mitochondria fully confirmed previous notions about the uncoupling action of juglone. It can be concluded that juglone is active on metabolism at relatively low concentrations. In this particular it resembles more closely the classical uncoupler 2,4-dinitrophenol. Ingestion of high doses of juglone, thus, presents the same risks as the ingestion of 2,4-dinitrophenol which comprise excessive compromising of ATP production, hyperthermia and even death. Low doses, i.e., moderate consumption of natural products containing juglone, however, could be beneficial to health if one considers recent reports about the consequences of chronic mild uncoupling.
      Highlights ► We investigated how juglone acts on liver metabolism. ► The actions on hepatic gluconeogenesis, glycolysis and ureogenesis. ► Juglone stimulates glycolysis and ureagenesis and inhibits gluconeogenesis. ► The cellular ATP content is diminished. ► Juglone can be consired a toxic compound for the cell economy.

      PubDate: 2015-05-21T21:07:14Z
  • Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia
           following 7 and 90days of exposure to hexavalent chromium in drinking
    • Abstract: Publication date: 15 February 2012
      Source:Toxicology and Applied Pharmacology, Volume 259, Issue 1
      Author(s): Anna K. Kopec , Suntae Kim , Agnes L. Forgacs , Timothy R. Zacharewski , Deborah M. Proctor , Mark A. Harris , Laurie C. Haws , Chad M. Thompson
      Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90days of exposure to 0, 0.3, 4, 14, 60, 170 or 520mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated dose–response modeling identified >80% of the differentially expressed genes exhibited sigmoidal dose–response curves with EC50 values ranging from 10 to 100mg/L SDD. Only 16 genes satisfying the dose-dependent differential expression criteria had EC50 values <10mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.
      Graphical abstract image Highlights ► Mouse small intestine gene expression is highly responsive to hexavalent chromium [Cr(VI)]. ► Cr(VI) elicits more differential gene expression after 7days of exposure than 90days of exposure. ► Oral exposure to Cr(VI) leads to oxidative stress, cell cycle, lipid and immune dysregulation. ► Cr(VI) elicits dose-dependent changes in gene expression with an overall median EC50 of 47mg/L SDD.

      PubDate: 2015-05-21T21:07:14Z
  • Inter-strain heterogeneity in rat hepatic transcriptomic responses to
           2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
    • Abstract: Publication date: 15 April 2012
      Source:Toxicology and Applied Pharmacology, Volume 260, Issue 2
      Author(s): Cindy Q. Yao , Stephenie D. Prokopec , John D. Watson , Renee Pang , Christine P'ng , Lauren C. Chong , Nicholas J. Harding , Raimo Pohjanvirta , Allan B. Okey , Paul C. Boutros
      The biochemical and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been the subject of intense study for decades. It is now clear that essentially all TCDD-induced toxicities are mediated by DNA–protein interactions involving the Aryl Hydrocarbon Receptor (AHR). Nevertheless, it remains unknown which AHR target genes cause TCDD toxicities. Several groups, including our own, have developed rodent model systems to probe these questions. mRNA expression profiling of these model systems has revealed significant inter-species heterogeneity in rodent hepatic responses to TCDD. It has remained unclear if this variability also exists within a species, amongst rodent strains. To resolve this question, we profiled the hepatic transcriptomic response to TCDD of diverse rat strains (L-E, H/W, F344 and Wistar rats) and two lines derived from L-E×H/W crosses, at consistent age, sex, and dosing (100μg/kg TCDD for 19h). Using this uniquely consistent dataset, we show that the majority of TCDD-induced alterations in mRNA abundance are strain/line-specific: only 11 genes were affected by TCDD across all strains, including well-known dioxin-responsive genes such as Cyp1a1 and Nqo1. Our analysis identified two novel universally dioxin-responsive genes as well as 4 genes induced by TCDD in dioxin-sensitive rats only. These 6 genes are strong candidates to explain TCDD-related toxicities, so we validated them using 152 animals in time-course (0 to 384h) and dose–response (0 to 3000μg/kg) experiments. This study reveals that different rat strains exhibit dramatic transcriptional heterogeneity in their hepatic responses to TCDD and that inter-strain comparisons can help identify candidate toxicity-related genes.

      PubDate: 2015-05-21T21:07:14Z
  • Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial
           dysfunction in 7-day lead-treated rats
    • Abstract: Publication date: 1 July 2012
      Source:Toxicology and Applied Pharmacology, Volume 262, Issue 1
      Author(s): Jonaina Fiorim , Rogério Faustino Ribeiro Júnior , Bruna Fernades Azevedo , Maylla Ronacher Simões , Alessandra Simão Padilha , Ivanita Stefanon , Maria Jesus Alonso , Mercedes Salaices , Dalton Valentim Vassallo
      Seven day exposure to a low concentration of lead acetate increases nitric oxide bioavailability suggesting a putative role of K+ channels affecting vascular reactivity. This could be an adaptive mechanism at the initial stages of toxicity from lead exposure due to oxidative stress. We evaluated whether lead alters the participation of K+ channels and Na+/K+-ATPase (NKA) on vascular function. Wistar rats were treated with lead (1st dose 4μg/100g, subsequent doses 0.05μg/100g, im, 7days) or vehicle. Lead treatment reduced the contractile response of aortic rings to phenylephrine (PHE) without changing the vasodilator response to acetylcholine (ACh) or sodium nitroprusside (SNP). Furthermore, this treatment increased basal O2 − production, and apocynin (0.3μM), superoxide dismutase (150U/mL) and catalase (1000U/mL) reduced the response to PHE only in the treated group. Lead also increased aortic functional NKA activity evaluated by K+-induced relaxation curves. Ouabain (100μM) plus L-NAME (100μM), aminoguanidine (50μM) or tetraethylammonium (TEA, 2mM) reduced the K+-induced relaxation only in lead-treated rats. When aortic rings were precontracted with KCl (60mM/L) or preincubated with TEA (2mM), 4-aminopyridine (4-AP, 5mM), iberiotoxin (IbTX, 30nM), apamin (0.5μM) or charybdotoxin (0.1μM), the ACh-induced relaxation was more reduced in the lead-treated rats. Additionally, 4-AP and IbTX reduced the relaxation elicited by SNP more in the lead-treated rats. Results suggest that lead treatment promoted NKA and K+ channels activation and these effects might contribute to the preservation of aortic endothelial function against oxidative stress.
      Highlights ► Increased free radicals production ► Increased Na+/K+ ATPase activity ► Promotes activation of the K+ channels and reduced vascular reactivity ► These effects preserve endothelial function against oxidative stress. ► Low concentrations constitute environmental cardiovascular risk factor.

      PubDate: 2015-05-21T21:07:14Z
  • Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat
           and mouse small intestinal epithelia
    • Abstract: Publication date: 15 July 2012
      Source:Toxicology and Applied Pharmacology, Volume 262, Issue 2
      Author(s): Anna K. Kopec , Chad M. Thompson , Suntae Kim , Agnes L. Forgacs , Timothy R. Zacharewski
      Continuous exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal tumors in mice but not rats. Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90days of exposure to 0.3–520mg/L (as sodium dichromate dihydrate, SDD) in drinking water. Whole-genome microarrays identified 3269 and 1815 duodenal, and 4557 and 1534 jejunal differentially expressed genes at 8 and 91days, respectively, with significant overlaps between the intestinal segments. Functional annotation identified gene expression changes associated with oxidative stress, cell cycle, cell death, and immune response that were consistent with reported changes in redox status and histopathology. Comparative analysis with B6C3F1 mouse data from a similarly designed study identified 2790 differentially expressed rat orthologs in the duodenum compared to 5013 mouse orthologs at day 8, and only 1504 rat and 3484 mouse orthologs at day 91. Automated dose–response modeling resulted in similar median EC50s in the rodent duodenal and jejunal mucosae. Comparative examination of differentially expressed genes also identified divergently regulated orthologs. Comparable numbers of differentially expressed genes were observed at equivalent Cr concentrations (μg Cr/g duodenum). However, mice accumulated higher Cr levels than rats at ≥170mg/L SDD, resulting in a ~2-fold increase in the number of differentially expressed genes. These qualitative and quantitative differences in differential gene expression, which correlate with differences in tissue dose, likely contribute to the disparate intestinal tumor outcomes.
      Highlights ► Cr(VI) elicits dose-dependent changes in gene expression in rat intestine. ► Cr(VI) elicits less differential gene expression in rats compared to mice. ► Cr(VI) gene expression can be phenotypically anchored to intestinal changes. ► Species-specific and divergent changes are consistent with species-specific tumors.

      PubDate: 2015-05-21T21:07:14Z
  • In vivo treatment with diphenyl ditelluride induces neurodegeneration in
           striatum of young rats: Implications of MAPK and Akt pathways
    • Abstract: Publication date: 15 October 2012
      Source:Toxicology and Applied Pharmacology, Volume 264, Issue 2
      Author(s): Luana Heimfarth , Samanta Oliveira Loureiro , Márcio Ferreira Dutra , Cláudia Andrade , Letícia Pettenuzzo , Fátima T. Costa Rodrigues Guma , Carlos Alberto Saraiva Gonçalves , João Batista Teixeira da Rocha , Regina Pessoa-Pureur
      In the present report 15day-old Wistar rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)2/kg body weight and parameters of neurodegeneration were analyzed in slices from striatum 6days afterwards. We found hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein—GFAP and vimentin) and from neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H, respectively) and increased MAPK (Erk, JNK and p38MAPK) as well as PKA activities. The treatment induced reactive astrogliosis in the striatum, evidenced by increased GFAP and vimentin immunocontent as well as their mRNA overexpression. Also, (PhTe)2 significantly increased the propidium iodide (PI) positive cells in NeuN positive population without altering PI incorporation into GFAP positive cells, indicating that in vivo exposure to (PhTe)2 provoked neuronal damage. Immunohistochemistry showed a dramatic increase of GFAP staining characteristic of reactive astrogliosis. Moreover, increased caspase 3 in (PhTe)2 treated striatal slices suggested apoptotic cell death. (PhTe)2 exposure decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was unaltered, suggesting that this kinase is not directly implicated in the neurotoxicity of this compound. Therefore, the present results shed light into the mechanisms of (PhTe)2-induced neurodegeneration in rat striatum, evidencing a critical role for the MAPK and Akt signaling pathways and disruption of cytoskeletal homeostasis, which could be related with apoptotic neuronal death and astrogliosis.
      Highlights ► Diphenyl ditelluride causes apoptotic neuronal death in the striatum of young rats. ► Diphenyl ditelluride causes reactive astrogliosis in the striatum of rats. ► Diphenyl ditelluride disrupts the homeostasis of the cytoskeleton of the striatum. ► The actions of diphenyl ditelluride are mediated by MAPK and Akt signaling pathways.

      PubDate: 2015-05-21T21:07:14Z
  • Curine inhibits eosinophil activation and airway hyper-responsiveness in a
           mouse model of allergic asthma
    • Abstract: Publication date: 15 November 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 1
      Author(s): Jaime Ribeiro-Filho , Andrea Surrage Calheiros , Adriana Vieira-de-Abreu , Katharinne Ingrid Moraes de Carvalho , Diego da Silva Mendes , Christianne Bandeira Melo , Marco Aurélio Martins , Celidarque da Silva Dias , Márcia Regina Piuvezam , Patrícia T. Bozza
      Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca++ influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs.
      Graphical abstract image

      PubDate: 2015-05-21T21:07:14Z
  • A rat retinal damage model predicts for potential clinical visual
           disturbances induced by Hsp90 inhibitors
    • Abstract: Publication date: 1 December 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 2
      Author(s): Dan Zhou , Yuan Liu , Josephine Ye , Weiwen Ying , Luisa Shin Ogawa , Takayo Inoue , Noriaki Tatsuta , Yumiko Wada , Keizo Koya , Qin Huang , Richard C. Bates , Andrew J. Sonderfan
      In human trials certain heat shock protein 90 (Hsp90) inhibitors, including 17-DMAG and NVP-AUY922, have caused visual disorders indicative of retinal dysfunction; others such as 17-AAG and ganetespib have not. To understand these safety profile differences we evaluated histopathological changes and exposure profiles of four Hsp90 inhibitors, with or without clinical reports of adverse ocular effects, using a rat retinal model. Retinal morphology, Hsp70 expression (a surrogate marker of Hsp90 inhibition), apoptotic induction and pharmacokinetic drug exposure analysis were examined in rats treated with the ansamycins 17-DMAG and 17-AAG, or with the second-generation compounds NVP-AUY922 and ganetespib. Both 17-DMAG and NVP-AUY922 induced strong yet restricted retinal Hsp70 up-regulation and promoted marked photoreceptor cell death 24h after the final dose. In contrast, neither 17-AAG nor ganetespib elicited photoreceptor injury. When the relationship between drug distribution and photoreceptor degeneration was examined, 17-DMAG and NVP-AUY922 showed substantial retinal accumulation, with high retina/plasma (R/P) ratios and slow elimination rates, such that 51% of 17-DMAG and 65% of NVP-AUY922 present at 30min post-injection were retained in the retina 6h post-dose. For 17-AAG and ganetespib, retinal elimination was rapid (90% and 70% of drugs eliminated from the retina at 6h, respectively) which correlated with lower R/P ratios. These findings indicate that prolonged inhibition of Hsp90 activity in the eye results in photoreceptor cell death. Moreover, the results suggest that the retina/plasma exposure ratio and retinal elimination rate profiles of Hsp90 inhibitors, irrespective of their chemical class, may predict for ocular toxicity potential.

      PubDate: 2015-05-21T21:07:14Z
  • Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of
           action of its cytotoxic component retained with improved tolerability
    • Abstract: Publication date: 1 December 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 2
      Author(s): Kirsten Achilles Poon , Kelly Flagella , Joseph Beyer , Jay Tibbitts , Surinder Kaur , Ola Saad , Joo-Hee Yi , Sandhya Girish , Noel Dybdal , Theresa Reynolds
      Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40mg/kg (~4400μgDM1/m2) and 30mg/kg (~6000μgDM1/m2) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600μgDM1/m2). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.

      PubDate: 2015-05-21T21:07:14Z
  • Suppression of human T cell proliferation by the caspase inhibitors,
           z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition
    • Abstract: Publication date: 15 November 2012
      Source:Toxicology and Applied Pharmacology, Volume 265, Issue 1
      Author(s): C.P. Lawrence , S.C. Chow
      The caspase inhibitors, benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe)-fluoromethylketone (z-VAD-FMK) and benzyloxycarbonyl (Cbz)-Ile-Glu (OMe)-Thr-Asp (OMe)-FMK (z-IETD-FMK) at non-toxic doses were found to be immunosuppressive and inhibit human T cell proliferation induced by mitogens and IL-2 in vitro. Both caspase inhibitors were shown to block NF-κB in activated primary T cells, but have little inhibitory effect on the secretion of IL-2 and IFN-γ during T cell activation. However, the expression of IL-2 receptor α-chain (CD25) in activated T cells was inhibited by both z-VAD-FMK and z-IETD-FMK, whereas the expression of the early activated T cell marker, CD69 was unaffected. During primary T cell activation via the antigen receptor, both caspase-8 and caspase-3 were activated and processed to their respective subunits, but neither caspase inhibitors had any effect on the processing of these two caspases. In sharp contrast both caspase inhibitors readily blocked apoptosis and the activation of caspases during FasL-induced apoptosis in activated primary T cells and Jurkat T cells. Collectively, the results demonstrate that both z-VAD-FMK and z-IETD-FMK are immunosuppressive in vitro and inhibit T cell proliferation without blocking the processing of caspase-8 and caspase-3.
      Highlights ► Caspase-8 and caspase-3 were activated during T cell activation and proliferation. ► T cell proliferation was blocked by caspase inhibitors. ► Caspase activation during T cell proliferation was not block by caspase inhibitors.

      PubDate: 2015-05-21T21:07:14Z
  • A polymorphism in metallothionein 1A (MT1A) is associated with
           cadmium-related excretion of urinary beta 2‐microglobulin
    • Abstract: Publication date: 15 December 2012
      Source:Toxicology and Applied Pharmacology, Volume 265, Issue 3
      Author(s): Lijian Lei , Xiuli Chang , Gerda Rentschler , Liting Tian , Guoying Zhu , Xiao Chen , Taiyi Jin , Karin Broberg
      Objectives Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. Methods In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67μg/L], moderately [U-Cd=4.23μg/L] and highly [U-Cd=9.13μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA. Results Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β=1.2, 95% CI 0.72–1.6) compared to GG carriers (β=0.30, 95% CI 0.15–0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β=0.55, 95% CI 0.27–0.84) compared to GG carriers (β=0.018, 95% CI −0.79–0.11). Conclusions MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.
      Highlights ► Cadmium is toxic to the kidney but the susceptibility differs between individuals. ► The toxic effect of cadmium is scavenged by metallothioneins. ► A common variant of metallothionein 1A was genotyped in 512 cadmium exposed humans. ► Variant carriers of this polymorphism showed more kidney damage from cadmium. ► The frequency of these variants needs to be taken into account in risk assessment.

      PubDate: 2015-05-21T21:07:14Z
  • Chemopreventive activity of compounds extracted from Casearia sylvestris
           (Salicaceae) Sw against DNA damage induced by particulate matter emitted
           by sugarcane burning near Araraquara, Brazil
    • Abstract: Publication date: 15 December 2012
      Source:Toxicology and Applied Pharmacology, Volume 265, Issue 3
      Author(s): A.M. Prieto , A.G. Santos , A.R. Csipak , C.M. Caliri , I.C. Silva , M.A. Arbex , F.S. Silva , M.R.R. Marchi , A.J. Cavalheiro , D.H.S. Silva , V.S. Bolzani , C.P. Soares
      Ethanolic extract of Casearia sylvestris is thought to be antimutagenic. In this study, we attempted to determine whether this extract and casearin X (a clerodane diterpene from C. sylvestris) are protective against the harmful effects of airborne pollutants from sugarcane burning. To that end, we used the Tradescantia micronucleus test in meiotic pollen cells of Tradescantia pallida, the micronucleus test in mouse bone marrow cells, and the comet assay in mouse blood cells. The mutagenic compound was total suspended particulate (TSP) from air. For the Tradescantia micronucleus test, T. pallida cuttings were treated with the extract at 0.13, 0.25, or 0.50mg/ml. Subsequently, TSP was added at 0.3mg/ml, and tetrads from the inflorescences were examined for micronuclei. For the micronucleus test in mouse bone marrow cells and the comet assay in mouse blood cells, Balb/c mice were treated for 15days with the extract—3.9, 7.5, or 15.0mg/kg body weight (BW)—or with casearin X—0.3, 0.25, or 1.2mg/kg BW—after which they received TSP (3.75mg/kg BW). In T. pallida and mouse bone marrow cells, the extract was antimutagenic at all concentrations tested. In mouse blood cells, the extract was antigenotoxic at all concentrations, whereas casearin X was not antimutagenic but was antigenotoxic at all concentrations. We conclude that C. sylvestris ethanolic extract and casearin X protect DNA from damage induced by airborne pollutants from sugarcane burning.
      Highlights ► We assessed DNA protection of C. sylvestris ethanolic extract. ► We assessed DNA protection of casearin X. ► We used Tradescantia pallida micronucleus test as screening. ► We used comet assay and micronucleus test in mice. ► The compounds protected DNA against sugar cane burning pollutants.

      PubDate: 2015-05-21T21:07:14Z
  • Toxicogenomic outcomes predictive of forestomach carcinogenesis following
           exposure to benzo(a)pyrene: Relevance to human cancer risk
    • Abstract: Publication date: 1 December 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 2
      Author(s): Sarah Labib , Charles H. Guo , Andrew Williams , Carole L. Yauk , Paul A. White , Sabina Halappanavar
      Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75mgBaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (±1.5 fold; false discovery rate adjusted P≤0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans.

      PubDate: 2015-05-21T21:07:14Z
  • Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A
           study to assess the drug's cardiac ion channel profile
    • Abstract: Publication date: 1 December 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 2
      Author(s): Xaver Koenig , Michael Kovar , Lena Rubi , Agnes K. Mike , Peter Lukacs , Vaibhavkumar S. Gawali , Hannes Todt , Karlheinz Hilber , Walter Sandtner
      The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥10μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias.
      Graphical abstract image

      PubDate: 2015-05-21T21:07:14Z
  • A binuclear complex constituted by diethyldithiocarbamate and copper(I)
           functions as a proteasome activity inhibitor in pancreatic cancer cultures
           and xenografts
    • Abstract: Publication date: 15 December 2013
      Source:Toxicology and Applied Pharmacology, Volume 273, Issue 3
      Author(s): Jinbin Han , Luming Liu , Xiaoqiang Yue , Jinjia Chang , Weidong Shi , Yongqiang Hua
      It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.

      PubDate: 2015-05-21T21:07:14Z
  • Bidirectional regulation of bakuchiol, an estrogenic-like compound, on
           catecholamine secretion
    • Abstract: Publication date: 1 January 2014
      Source:Toxicology and Applied Pharmacology, Volume 274, Issue 1
      Author(s): Haoping Mao , Hong Wang , Shangwei Ma , Yantong Xu , Han Zhang , Yuefei Wang , Zichang Niu , Guanwei Fan , Yan Zhu , Xiu Mei Gao
      Excess or deficiency of catecholamine (CA) secretion was related with several diseases. Recently, estrogen and phytoestrogens were reported to regulate the activity of CA system. Bakuchiol is a phytoestrogen isolated from the seeds of Psoralea corylifolia L. (Leguminosae) which has been used in Traditional Chinese medicine as a tonic or aphrodisiac. In the present study, bovine adrenal medullary cells were employed to investigate the effects and mechanisms of bakuchiol on the regulation of CA secretion. Further, its anti-depressant like and anti-stress effects were evaluated by using behavioral despair and chronic immobilization stress models. Our results indicated that bakuchiol showed bidirectional regulation on CA secretion. It stimulated basal CA secretion in a concentration dependent manner (p<0.01), while it reduced 300μM acetylcholine (ACh) (p<0.01), 100μM veratridine (Ver) (p<0.01) and 56mM K+ (p<0.05) induced CA secretion, respectively. We also found that the stimulation of basal CA secretion by bakuchiol may act through estrogen-like effect and the JNK pathway in an extra-cellular calcium independent manner. Further, bakuchiol elevated tyrosine hydroxylase Ser40 and Ser31 phosphorylation (p<0.01) through the PKA and ERK1/2 pathways, respectively. Bakuchiol inhibited ACh, Ver and 56mM K+ induced CA secretion was related with reduction of intracellular calcium rise. In vivo experiments, we found that bakuchiol significantly reduced immobilization time in behavioral despair mouse (p<0.05 or 0.01), and plasma epinephrine (E) and norepinephrine (NE) levels in chronic immobilization stress (p<0.05). Overall, these results present a bidirectional regulation of bakuchiol on CA secretion which indicated that bakuchiol may exert anti-stress and the potential anti-depressant-like effects.

      PubDate: 2015-05-21T21:07:14Z
  • Case study on the utility of hepatic global gene expression profiling in
           the risk assessment of the carcinogen furan
    • Abstract: Publication date: 1 January 2014
      Source:Toxicology and Applied Pharmacology, Volume 274, Issue 1
      Author(s): Anna Francina Jackson , Andrew Williams , Leslie Recio , Michael D. Waters , Iain B. Lambert , Carole L. Yauk
      Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2mg/kgbw) or carcinogenic (4 and 8mg/kgbw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment.

      PubDate: 2015-05-21T21:07:14Z
  • High-throughput identification of off-targets for the mechanistic study of
           severe adverse drug reactions induced by analgesics
    • Abstract: Publication date: 1 January 2014
      Source:Toxicology and Applied Pharmacology, Volume 274, Issue 1
      Author(s): Jian-Bo Pan , Nan Ji , Wen Pan , Ru Hong , Hao Wang , Zhi-Liang Ji
      Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing.

      PubDate: 2015-05-21T21:07:14Z
  • Developmental defects in zebrafish for classification of EGF pathway
    • Abstract: Publication date: 15 January 2014
      Source:Toxicology and Applied Pharmacology, Volume 274, Issue 2
      Author(s): Benoist Pruvot , Yoann Curé , Joachim Djiotsa , Audrey Voncken , Marc Muller
      One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems.

      PubDate: 2015-05-21T21:07:14Z
  • Inhibition of DNA topoisomerase I activity and induction of apoptosis by
           thiazacridine derivatives
    • Abstract: Publication date: 1 April 2013
      Source:Toxicology and Applied Pharmacology, Volume 268, Issue 1
      Author(s): Francisco W.A. Barros , Daniel P. Bezerra , Paulo M.P. Ferreira , Bruno C. Cavalcanti , Teresinha G. Silva , Marina G.R. Pitta , Maria do C.A. de Lima , Suely L. Galdino , Ivan da R. Pitta , Letícia V. Costa-Lotufo , Manoel O. Moraes , Rommel R. Burbano , Temenouga N. Guecheva , João A.P. Henriques , Cláudia Pessoa
      Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways.
      Highlights ► Thiazacridine derivatives induce mitochondrial-dependent apoptotic cell death. ► Thiazacridine derivatives inhibit DNA topoisomerase I action. ► Thiazacridine derivatives failed to cause genotoxicity on human lymphocytes.

      PubDate: 2015-05-21T21:07:14Z
  • Pulmonary instillation of low doses of titanium dioxide nanoparticles in
           mice leads to particle retention and gene expression changes in the
           absence of inflammation
    • Abstract: Publication date: 15 June 2013
      Source:Toxicology and Applied Pharmacology, Volume 269, Issue 3
      Author(s): Mainul Husain , Anne T. Saber , Charles Guo , Nicklas R. Jacobsen , Keld A. Jensen , Carole L. Yauk , Andrew Williams , Ulla Vogel , Hakan Wallin , Sabina Halappanavar
      We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2). Female C57BL/6 mice were exposed to rutile nano-TiO2 via single intratracheal instillations of 18, 54, and 162μg/mouse. Mice were sampled 1, 3, and 28days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (±1.3 fold; p <0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO2 in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities.

      PubDate: 2015-05-21T21:07:14Z
  • Evaluation of the deposition, translocation and pathological response of
           brake dust with and without added chrysotile in comparison to crocidolite
           asbestos following short-term inhalation: Interim results
    • Abstract: Publication date: 1 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 1
      Author(s): David M. Bernstein , Rick Rogers , Rosalina Sepulveda , Peter Kunzendorf , Bernd Bellmann , Heinrich Ernst , James I. Phillips
      Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6h/day for 5days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20μm) cleared quickly with T1/2 estimated as 30 and 33days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T1/2 >1000days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation.

      PubDate: 2015-05-21T21:07:14Z
  • TCDD dysregulation of 13 AHR-target genes in rat liver
    • Abstract: Publication date: 1 February 2014
      Source:Toxicology and Applied Pharmacology, Volume 274, Issue 3
      Author(s): John D. Watson , Stephenie D. Prokopec , Ashley B. Smith , Allan B. Okey , Raimo Pohjanvirta , Paul C. Boutros
      Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000μg/kg at 19h after TCDD exposure and time points ranging from 1.5 to 384h after exposure to 100μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities.
      Graphical abstract image

      PubDate: 2015-05-21T21:07:14Z
  • Applicability of rat precision-cut lung slices in evaluating nanomaterial
           cytotoxicity, apoptosis, oxidative stress, and inflammation
    • Abstract: Publication date: 1 April 2014
      Source:Toxicology and Applied Pharmacology, Volume 276, Issue 1
      Author(s): Ursula G. Sauer , Sandra Vogel , Alexandra Aumann , Annemarie Hess , Susanne N. Kolle , Lan Ma-Hock , Wendel Wohlleben , Martina Dammann , Volker Strauss , Silke Treumann , Sibylle Gröters , Karin Wiench , Bennard van Ravenzwaay , Robert Landsiedel
      The applicability of rat precision-cut lung slices (PCLuS) in detecting nanomaterial (NM) toxicity to the respiratory tract was investigated evaluating sixteen OECD reference NMs (TiO2, ZnO, CeO2, SiO2, Ag, multi-walled carbon nanotubes (MWCNTs)). Upon 24-hour test substance exposure, the PCLuS system was able to detect early events of NM toxicity: total protein, reduction in mitochondrial activity, caspase-3/-7 activation, glutathione depletion/increase, cytokine induction, and histopathological evaluation. Ion shedding NMS (ZnO and Ag) induced severe tissue destruction detected by the loss of total protein. Two anatase TiO2 NMs, CeO2 NMs, and two MWCNT caused significant (determined by trend analysis) cytotoxicity in the WST-1 assay. At non-cytotoxic concentrations, different TiO2 NMs and one MWCNT increased GSH levels, presumably a defense response to reactive oxygen species, and these substances further induced a variety of cytokines. One of the SiO2 NMs increased caspase-3/-7 activities at non-cytotoxic levels, and one rutile TiO2 only induced cytokines. Investigating these effects is, however, not sufficient to predict apical effects found in vivo. Reproducibility of test substance measurements was not fully satisfactory, especially in the GSH and cytokine assays. Effects were frequently observed in negative controls pointing to tissue slice vulnerability even though prepared and handled with utmost care. Comparisons of the effects observed in the PCLuS to in vivo effects reveal some concordances for the metal oxide NMs, but less so for the MWCNT. The highest effective dosages, however, exceeded those reported for rat short-term inhalation studies. To become applicable for NM testing, the PCLuS system requires test protocol optimization.

      PubDate: 2015-05-21T21:07:14Z
  • Mixture effects at very low doses with combinations of anti-androgenic
           pesticides, antioxidants, industrial pollutant and chemicals used in
           personal care products
    • Abstract: Publication date: 1 August 2014
      Source:Toxicology and Applied Pharmacology, Volume 278, Issue 3
      Author(s): Frances Orton , Sibylle Ermler , Subramaniam Kugathas , Erika Rosivatz , Martin Scholze , Andreas Kortenkamp
      Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations is missing. Such data can reveal whether joint effects at the receptor are induced at low levels and may support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicals were combined at three mixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists from a wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity.

      PubDate: 2015-05-21T21:07:14Z
  • Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha
           monoclonal antibody, in cynomolgus monkeys: Relevance for human safety
    • Abstract: Publication date: 1 September 2014
      Source:Toxicology and Applied Pharmacology, Volume 279, Issue 2
      Author(s): Patricia C. Ryan , Matthew A. Sleeman , Marlon Rebelatto , Bing Wang , Hong Lu , Xiaomin Chen , Chi-Yuan Wu , Mary Jane Hinrichs , Lorin Roskos , Heidi Towers , Kathleen McKeever , Rakesh Dixit
      Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥30mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress.

      PubDate: 2015-05-21T21:07:14Z
  • Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced
           neurotoxicity in rats
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Tingting Wang , Ling Zhao , Mengyu Liu , Fei Xie , Xuemei Ma , Pengxiang Zhao , Yunqi Liu , Jiala Li , Minglian Wang , Zhaona Yang , Yutong Zhang
      Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75mg/kg body weight (1/20 LD50) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity.

      PubDate: 2015-05-21T21:07:14Z
  • Analysis of the safety and pharmacodynamics of human fibrinogen
           concentrate in animals
    • Abstract: Publication date: 1 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 1
      Author(s): Andrea Beyerle , Marc W. Nolte , Cristina Solomon , Eva Herzog , Gerhard Dickneite
      Fibrinogen, a soluble 340kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent.

      PubDate: 2015-05-21T21:07:14Z
  • Development of a pluripotent stem cell derived neuronal model to identify
           chemically induced pathway perturbations in relation to neurotoxicity:
           Effects of CREB pathway inhibition
    • Abstract: Publication date: 15 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 2
      Author(s): Francesca Pistollato , Jochem Louisse , Bibiana Scelfo , Milena Mennecozzi , Benedetta Accordi , Giuseppe Basso , John Antonydas Gaspar , Dimitra Zagoura , Manuela Barilari , Taina Palosaari , Agapios Sachinidis , Susanne Bremer-Hoffmann
      According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2+ neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations.

      PubDate: 2015-05-21T21:07:14Z
  • A revised model of ex-vivo reduction of hexavalent chromium in human and
           rodent gastric juices
    • Abstract: Publication date: 15 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 2
      Author(s): Paul M. Schlosser , Alan F. Sasso
      Chronic oral exposure to hexavalent chromium (Cr-VI) in drinking water has been shown to induce tumors in the mouse gastrointestinal (GI) tract and rat oral cavity. The same is not true for trivalent chromium (Cr-III). Thus reduction of Cr-VI to Cr-III in gastric juices is considered a protective mechanism, and it has been suggested that the difference between the rate of reduction among mice, rats, and humans could explain or predict differences in sensitivity to Cr-VI. We evaluated previously published models of gastric reduction and believe that they do not fully describe the data on reduction as a function of Cr-VI concentration, time, and (in humans) pH. The previous models are parsimonious in assuming only a single reducing agent in rodents and describing pH-dependence using a simple function. We present a revised model that assumes three pools of reducing agents in rats and mice with pH-dependence based on known speciation chemistry. While the revised model uses more fitted parameters than the original model, they are adequately identifiable given the available data, and the fit of the revised model to the full range of data is shown to be significantly improved. Hence the revised model should provide better predictions of Cr-VI reduction when integrated into a corresponding PBPK model.

      PubDate: 2015-05-21T21:07:14Z
  • Use of whole genome expression analysis in the toxicity screening of
    • Abstract: Publication date: 15 October 2014
      Source:Toxicology and Applied Pharmacology, Volume 280, Issue 2
      Author(s): Eleonore Fröhlich , Claudia Meindl , Karin Wagner , Gerd Leitinger , Eva Roblegg
      The use of nanoparticles (NPs) offers exciting new options in technical and medical applications provided they do not cause adverse cellular effects. Cellular effects of NPs depend on particle parameters and exposure conditions. In this study, whole genome expression arrays were employed to identify the influence of particle size, cytotoxicity, protein coating, and surface functionalization of polystyrene particles as model particles and for short carbon nanotubes (CNTs) as particles with potential interest in medical treatment. Another aim of the study was to find out whether screening by microarray would identify other or additional targets than commonly used cell-based assays for NP action. Whole genome expression analysis and assays for cell viability, interleukin secretion, oxidative stress, and apoptosis were employed. Similar to conventional assays, microarray data identified inflammation, oxidative stress, and apoptosis as affected by NP treatment. Application of lower particle doses and presence of protein decreased the total number of regulated genes but did not markedly influence the top regulated genes. Cellular effects of CNTs were small; only carboxyl-functionalized single-walled CNTs caused appreciable regulation of genes. It can be concluded that regulated functions correlated well with results in cell-based assays. Presence of protein mitigated cytotoxicity but did not cause a different pattern of regulated processes.
      Graphical abstract image

      PubDate: 2015-05-21T21:07:14Z
  • A comprehensive evaluation of the efficacy of leading oxime therapies in
           guinea pigs exposed to organophosphorus chemical warfare agents or
    • Abstract: Publication date: 15 December 2014
      Source:Toxicology and Applied Pharmacology, Volume 281, Issue 3
      Author(s): Christina M. Wilhelm , Thomas H. Snider , Michael C. Babin , David A. Jett , Gennady E. Platoff Jr. , David T. Yeung
      The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.

      PubDate: 2015-05-21T21:07:14Z
  • Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence
           in non-obese diabetic mice by inducing differentiation of regulatory T
    • Abstract: Publication date: 15 January 2015
      Source:Toxicology and Applied Pharmacology, Volume 282, Issue 2
      Author(s): Gu-Jiun Lin , Huey-Kang Sytwu , Jyh-Cherng Yu , Yuan-Wu Chen , Yu-Liang Kuo , Chiao-Chi Yu , Hao-Ming Chang , De-Chuan Chan , Shing-Hwa Huang
      Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells.

      PubDate: 2015-05-21T21:07:14Z
  • Evaluation of the fate and pathological response in the lung and pleura of
           brake dust alone and in combination with added chrysotile compared to
           crocidolite asbestos following short-term inhalation exposure
    • Abstract: Publication date: 15 February 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 1
      Author(s): D.M. Bernstein , R.A. Rogers , R. Sepulveda , P. Kunzendorf , B. Bellmann , H. Ernst , O. Creutzenberg , J.I. Phillips
      This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake-dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6h/day for 5days to either brake-dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake-dust or crocidolite asbestos. The chrysotile fibers were relatively biosoluble whereas the crocidolite asbestos fibers persisted through the life-time of the animal. This was reflected in the lung and the pleura where no significant pathological response was observed at any time point in the brake dust or chrysotile/brake dust exposure groups through 365days post exposure. In contrast, crocidolite asbestos produced a rapid inflammatory response in the lung parenchyma and the pleura, inducing a significant increase in fibrotic response in both of these compartments. Crocidolite fibers were observed embedded in the diaphragm with activated mesothelial cells immediately after cessation of exposure. While no chrysotile fibers were found in the mediastinal lymph nodes, crocidolite fibers of up to 35μm were observed. These results provide support that brake-dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung or the pleural cavity following short term inhalation.

      PubDate: 2015-05-21T21:07:14Z
  • The effects of deoxynivalenol on gene expression in the murine thymus
    • Abstract: Publication date: 1 February 2011
      Source:Toxicology and Applied Pharmacology, Volume 250, Issue 3
      Author(s): Sandra W.M. van Kol , Peter J.M. Hendriksen , Henk van Loveren , Ad Peijnenburg
      Deoxynivalenol (DON) is a mycotoxin produced by several Fusarium species and is often detected in grains. Because of its high abundance, there has been a large interest in the effects of DON in animals and humans. DON is known to be immunosuppressive at high concentrations and immunostimulatory at low concentrations. The present study aimed to acquire insight into the modes of action of DON. For this, C57Bl6 mice were orally exposed to 5, 10, or 25mg/kg bw DON for 3, 6, or 24h and thymuses were subjected to genome-wide expression microarray analysis. Gene set enrichment analysis (GSEA) demonstrated that DON downregulated genes involved in proliferation, mitochondria, protein synthesis, and ribosomal proteins. Furthermore, GSEA showed a selective downregulation of genes highly expressed at the early precursor thymocytes stage. This indicates that early precursor thymocytes, particularly at the double-positive CD4+CD8+ stage, are more vulnerable to DON than very early or late precursor thymocytes. There was a large overlap of genes upregulated by DON with genes previously reported to be either upregulated during T cell activation or upregulated during negative selection of thymocytes that recognize “self-antigens”. This indicates that DON induces cellular events that also occur after activation of the T cell receptor, for example, release of calcium from the endoplasmatic reticulum. This T cell activation in the thymus then evokes negative selection and depletion of thymocytes, which provides a plausible explanation for the high sensitivity of the thymus for DON exposure. The expression patterns of four genes indicative for some of the processes that were affected after DON treatment were confirmed using real-time PCR. Immunocytological experiments with primary mouse thymocytes demonstrated the translocation of NFAT from the cytoplasm into the nucleus upon exposure top DON, thus providing further evidence for the involvement of T cell activation.

      PubDate: 2015-05-21T21:07:14Z
  • Modulation of methylmercury uptake by methionine: Prevention of
           mitochondrial dysfunction in rat liver slices by a mimicry mechanism
    • Abstract: Publication date: 1 April 2011
      Source:Toxicology and Applied Pharmacology, Volume 252, Issue 1
      Author(s): Daniel Henrique Roos , Robson Luiz Puntel , Marcelo Farina , Michael Aschner , Denise Bohrer , João Batista T. Rocha , Nilda B. de Vargas Barbosa
      Methylmercury (MeHg) is an ubiquitous environmental pollutant which is transported into the mammalian cells when present as the methylmercury-cysteine conjugate (MeHg–Cys). With special emphasis on hepatic cells, due to their particular propensity to accumulate an appreciable amount of Hg after exposure to MeHg, this study was performed to evaluate the effects of methionine (Met) on Hg uptake, reactive species (RS) formation, oxygen consumption and mitochondrial function/cellular viability in both liver slices and mitochondria isolated from these slices, after exposure to MeHg or the MeHg–Cys complex. The liver slices were pre-treated with Met (250μM) 15min before being exposed to MeHg (25μM) or MeHg–Cys (25μM each) for 30min at 37°C. The treatment with MeHg caused a significant increase in the Hg concentration in both liver slices and mitochondria isolated from liver slices. Moreover, the Hg uptake was higher in the group exposed to the MeHg–Cys complex. In the DCF (dichlorofluorescein) assay, the exposure to MeHg and MeHg–Cys produced a significant increase in DFC reactive species (DFC-RS) formation only in the mitochondria isolated from liver slices. As observed with Hg uptake, DFC-RS levels were significantly higher in the mitochondria treated with the MeHg–Cys complex compared to MeHg alone. MeHg exposure also caused a marked decrease in the oxygen consumption of liver slices when compared to the control group, and this effect was more pronounced in the liver slices treated with the MeHg–Cys complex. Similarly, the loss of mitochondrial activity/cell viability was greater in liver slices exposed to the MeHg–Cys complex when compared to slices treated only with MeHg. In all studied parameters, Met pre-treatment was effective in preventing the MeHg- and/or MeHg–Cys-induced toxicity in both liver slices and mitochondria. Part of the protection afforded by Met against MeHg may be related to a direct interaction with MeHg or to the competition of Met with the complex formed between MeHg and endogenous cysteine. In summary, our results show that Met pre-treatment produces pronounced protection against the toxic effects induced by MeHg and/or the MeHg–Cys complex on mitochondrial function and cell viability. Consequently, this amino acid offers considerable promise as a potential agent for treating acute MeHg exposure.

      PubDate: 2015-05-21T21:07:14Z
  • The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane:
           Ensuing energetic and oxidative stress implications
    • Abstract: Publication date: 15 June 2011
      Source:Toxicology and Applied Pharmacology, Volume 253, Issue 3
      Author(s): Gilberto L. Pardo-Andreu , Yanier Nuñez-Figueredo , Valeria G. Tudella , Osmany Cuesta-Rubio , Fernando P. Rodrigues , Cezar R. Pestana , Sérgio A. Uyemura , Andreia M. Leopoldino , Luciane C. Alberici , Carlos Curti
      Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1–25μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca2+ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds.
      Graphical abstract image Highlights Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death ► We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. ► GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. ► These actions could be implicated in the well-documented anti-cancer property of GA/structure related compounds.

      PubDate: 2015-05-21T21:07:14Z
  • Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural
           mesothelial cells
    • Abstract: Publication date: 1 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 2
      Author(s): Li-Jun Chen , Hong Ye , Qian Zhang , Feng-Zhi Li , Lin-Jie Song , Jie Yang , Qing Mu , Shan-Shan Rao , Peng-Cheng Cai , Fei Xiang , Jian-Chu Zhang , Yunchao Su , Jian-Bao Xin , Wan-Li Ma
      Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis.

      PubDate: 2015-05-21T21:07:14Z
  • Changes in cholesterol homeostasis and acute phase response link pulmonary
           exposure to multi-walled carbon nanotubes to risk of cardiovascular
    • Abstract: Publication date: 15 March 2015
      Source:Toxicology and Applied Pharmacology, Volume 283, Issue 3
      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: 2015-05-21T21:07:14Z
  • Environmental contaminants activate human and polar bear (Ursus maritimus)
           pregnane X receptors (PXR, NR1I2) differently
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      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 modeling studies suggest that amino acids that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation.

      PubDate: 2015-05-21T21:07:14Z
  • MWCNTs of different physicochemical properties cause similar inflammatory
           responses, but differences in transcriptional and histological markers of
           fibrosis in mouse lungs
    • Abstract: Publication date: 1 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 1
      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: 2015-05-21T21:07:14Z
  • Sex-related differences in murine hepatic transcriptional and proteomic
           responses to TCDD
    • Abstract: Publication date: 15 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 2
      Author(s): Stephenie D. Prokopec , John D. Watson , Jamie Lee , Raimo Pohjanvirta , Paul C. Boutros
      2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500μg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear.

      PubDate: 2015-05-21T21:07:14Z
  • Potential of extracellular microRNAs as biomarkers of acetaminophen
           toxicity in children
    • Abstract: Publication date: 15 April 2015
      Source:Toxicology and Applied Pharmacology, Volume 284, Issue 2
      Author(s): Xi Yang , William F. Salminen , Qiang Shi , James Greenhaw , Pritmohinder S. Gill , Sudeepa Bhattacharyya , Richard D. Beger , Donna L. Mendrick , William B. Mattes , Laura P. James
      Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p<0.01) followed by miR-375 (R=0.70; p=0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity.

      PubDate: 2015-05-21T21:07:14Z
  • Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor,
           administered in combination with the multireceptor-targeted somatostatin
           analog pasireotide: A 13-week study in rats
    • Abstract: Publication date: Available online 13 May 2015
      Source:Toxicology and Applied Pharmacology
      Author(s): Li Li , Kapil Vashisht , Julie Boisclair , Wenkui Li , Tsu-han Lin , Herbert A. Schmid , William Kluwe , Heidi Schoenfeld , Peter Hoffmann
      The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0–24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.

      PubDate: 2015-05-18T10:07:33Z
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