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  Subjects -> ENVIRONMENTAL STUDIES (Total: 804 journals)
    - ENVIRONMENTAL STUDIES (733 journals)
    - POLLUTION (21 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (733 journals)            First | 1 2 3 4 5 6 7 8     

IEEE Transactions on Network and Service Management     Hybrid Journal   (Followers: 10)
IMA Journal of Management Mathematics     Hybrid Journal   (Followers: 1)
Indiana Journal of Global Legal Studies     Full-text available via subscription   (Followers: 2)
Indoor Air     Hybrid Journal   (Followers: 1)
Information Systems Management     Hybrid Journal   (Followers: 17)
Information Technology and Management     Hybrid Journal   (Followers: 9)
IngenierĂ­a HidrĂ¡ulica y Ambiental     Open Access  
Inhalation Toxicology     Hybrid Journal   (Followers: 7)
Integrated Environmental Assessment and Management     Hybrid Journal   (Followers: 5)
Interdisciplinary Environmental Review     Hybrid Journal   (Followers: 4)
Interfaces     Full-text available via subscription   (Followers: 6)
International Aquatic Research     Open Access   (Followers: 3)
International Archives of Occupational and Environmental Health     Hybrid Journal   (Followers: 4)
International Environmental Agreements: Politics, Law and Economics     Hybrid Journal   (Followers: 11)
International Gambling Studies     Hybrid Journal   (Followers: 5)
International Innovation - climate     Open Access  
International innovation. Environment     Open Access  
International Journal of Acarology     Hybrid Journal   (Followers: 1)
International Journal of Advancement in Earth and Enviromental Sciences     Open Access   (Followers: 1)
International Journal of African Renaissance Studies - Multi-, Inter- and Transdisciplinarity     Hybrid Journal   (Followers: 2)
International Journal of Agricultural and Environmental Information Systems     Full-text available via subscription   (Followers: 1)
International Journal of Alternative Propulsion     Hybrid Journal   (Followers: 1)
International Journal of Applied Psychoanalytic Studies     Hybrid Journal   (Followers: 2)
International Journal of Chinese Culture and Management     Hybrid Journal   (Followers: 2)
International Journal of Corrosion     Open Access   (Followers: 11)
International Journal of Critical Infrastructures     Hybrid Journal   (Followers: 3)
International Journal of Disaster Risk Reduction     Hybrid Journal   (Followers: 6)
International Journal of Disaster Risk Science     Open Access   (Followers: 9)
International Journal of Ecological Economics and Statistics     Full-text available via subscription  
International Journal of Ecology     Open Access   (Followers: 8)
International Journal of Ecology & Development     Full-text available via subscription   (Followers: 2)
International Journal of Energy and Environmental Engineering     Open Access   (Followers: 2)
International Journal of Environment     Open Access   (Followers: 3)
International Journal of Environment and Health     Hybrid Journal   (Followers: 7)
International Journal of Environment and Pollution     Hybrid Journal   (Followers: 5)
International Journal of Environment and Sustainable Development     Hybrid Journal   (Followers: 16)
International Journal of Environment and Waste Management     Hybrid Journal   (Followers: 6)
International Journal of Environment, Workplace and Employment     Hybrid Journal   (Followers: 3)
International Journal of Environmental Engineering     Hybrid Journal   (Followers: 5)
International Journal of Environmental Health Research     Hybrid Journal   (Followers: 2)
International Journal of Environmental Policy and Decision Making     Hybrid Journal   (Followers: 11)
International Journal of Environmental Protection     Open Access   (Followers: 13)
International Journal of Environmental Research and Public Health     Open Access   (Followers: 17)
International Journal of Environmental Science and Technology     Hybrid Journal   (Followers: 5)
International Journal of Environmental Studies     Hybrid Journal   (Followers: 10)
International Journal of Exergy     Hybrid Journal   (Followers: 4)
International Journal of Forest, Soil and Erosion     Open Access   (Followers: 4)
International Journal of Global Environmental Issues     Hybrid Journal   (Followers: 4)
International Journal of Global Warming     Hybrid Journal   (Followers: 5)
International Journal of Greenhouse Gas Control     Partially Free   (Followers: 6)
International Journal of Health Planning and Management     Hybrid Journal   (Followers: 6)
International Journal of Hygiene and Environmental Health     Hybrid Journal   (Followers: 6)
International Journal of Logistics Research and Applications : A Leading Journal of Supply Chain Management     Hybrid Journal   (Followers: 10)
International Journal of Philosophical Studies     Hybrid Journal   (Followers: 2)
International Journal of Phytoremediation     Hybrid Journal   (Followers: 2)
International Journal of Process Systems Engineering     Hybrid Journal   (Followers: 1)
International Journal of Recycling of Organic Waste in Agriculture     Open Access   (Followers: 2)
International Journal of Reliability and Safety     Hybrid Journal   (Followers: 7)
International Journal of Renewable Energy Development     Open Access   (Followers: 5)
International Journal of Social Sciences and Management     Open Access   (Followers: 1)
International Journal of Soil, Sediment and Water     Open Access   (Followers: 8)
International Journal of Stress Management     Full-text available via subscription   (Followers: 10)
International Journal of Sustainable Construction Engineering and Technology     Open Access   (Followers: 10)
International Journal of Sustainable Engineering     Hybrid Journal   (Followers: 7)
International Journal of Sustainable Materials and Structural Systems     Hybrid Journal   (Followers: 5)
International Journal of Sustainable Society     Hybrid Journal   (Followers: 7)
International Journal of Testing     Hybrid Journal   (Followers: 1)
International Journal of the Commons     Open Access   (Followers: 3)
International Journal of Toxicology     Hybrid Journal   (Followers: 6)
International Journal of Water Resources and Environmental Engineering     Open Access   (Followers: 1)
International Studies in the Philosophy of Science     Hybrid Journal   (Followers: 11)
Interventions : International Journal of Postcolonial Studies     Hybrid Journal   (Followers: 10)
IOP Conference Series: Earth and Environmental Science     Open Access   (Followers: 7)
Iranian Studies     Hybrid Journal   (Followers: 10)
Irish Educational Studies     Hybrid Journal   (Followers: 2)
Irish Journal of Earth Sciences     Full-text available via subscription  
Irish Political Studies     Hybrid Journal   (Followers: 9)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1)
Isotopes in Environmental and Health Studies     Hybrid Journal   (Followers: 1)
Israel Studies     Full-text available via subscription   (Followers: 5)
Italian Studies     Hybrid Journal   (Followers: 6)
Jahangirnagar University Environmental Bulletin     Open Access  
Journal of Bioremediation & Biodegradation     Open Access   (Followers: 2)
Journal of Earth Science & Climatic Change     Open Access   (Followers: 7)
Journal of Petroleum & Environmental Biotechnology     Open Access   (Followers: 2)
Journal of Advanced Research in Civil and Environmental Engineering     Open Access   (Followers: 1)
Journal of Advances in Environmental Health Research     Open Access   (Followers: 2)
Journal of Agricultural and Environmental Ethics     Hybrid Journal   (Followers: 9)
Journal of Agricultural Biotechnology and Sustainable Development     Open Access  
Journal of Agricultural Chemistry and Environment     Open Access  
Journal of Agriculture and Environment     Open Access   (Followers: 1)
Journal of Agriculture and Environment for International Development     Open Access   (Followers: 6)
Journal of Agrobiology     Open Access   (Followers: 2)
Journal of Applied Ecology     Hybrid Journal   (Followers: 122)
Journal of Applied Meteorology and Climatology     Full-text available via subscription   (Followers: 8)
Journal of Applied Psychoanalytic Studies     Hybrid Journal   (Followers: 1)
Journal of Applied Sciences and Environmental Management     Open Access   (Followers: 1)
Journal of Applied Sciences in Environmental Sanitation     Open Access   (Followers: 6)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 9)
Journal of Applied Volcanology     Open Access   (Followers: 8)

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Journal Cover   Journal of Applied Toxicology
  [SJR: 0.799]   [H-I: 53]   [9 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0260-437X - ISSN (Online) 1099-1263
   Published by John Wiley and Sons Homepage  [1610 journals]
  • Accumulation and toxicity of intravenously‐injected functionalized
           graphene oxide in mice
    • Authors: Kai‐Ping Wen; Ying‐Chieh Chen, Chia‐Hui Chuang, Hwan‐You Chang, Chi‐Young Lee, Nyan‐Hwa Tai
      Abstract: Graphene and its functionalized derivatives have recently emerged as interesting nanomaterials with promising applications in biomedicine. In this study, the long‐term in vivo biodistribution of intravenously injected nanographene oxide (NGO) functionalized with poly sodium 4‐styrenesulfonate (PSS) was systematically examined and the potential toxicity over 6 months of NGO‐PSS nanoparticles was investigated. Our results showed that the nanoparticles mainly accumulate in the lung, liver and spleen, where they persist for at least 6 months. These nanoparticles result in acute liver injury and chronic inflammation of the lung, liver and spleen, as evidenced by blood biochemistry results and histological examinations. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-23T04:54:20.261061-05:
      DOI: 10.1002/jat.3187
  • Zebrafish as a model for studying the developmental neurotoxicity of
    • Authors: Peipei Guo; Zhibin Huang, Tao Tao, Xiaohui Chen, Wenqing Zhang, Yiyue Zhang, Chunshui Lin
      Abstract: Anesthetics can cause widespread apoptotic neurodegeneration and adverse effects on synaptogenesis during early postnatal life. Synaptogenesis correlates with several proteins, including myelin basic protein (MBP). However, little is known about the adverse effects of exposure to propofol on MBP, particularly during embryonic development. Our goal was to use zebrafish to explore the effect of propofol on embryonic development, apoptosis and MBP expression. Zebrafish embryos were exposed to propofol at defined doses and stages from 6 to 48 h postfertilization by immersion. The survival rate, hatchability, aberration rate, cell apoptosis and gene expression were analyzed at defined stages. Analysis revealed that doses of 1, 2 and 3 µg ml–1 propofol were reasonable anesthetic concentrations for zebrafish embryos. These doses of propofol caused a significant decrease in hatchability and an increase in aberration rate. Moreover, 6 days postfertilization (dpf) larvae are anesthetized by immersion into water containing 1, 2 or 3 µg ml–1 of propofol. The number of apoptotic cells in the head of propofol‐treated 36 h postfertilization embryos were significantly increased, and the expression of caspases‐3, ‐8 and ‐9 were upregulated. Apoptosis was also induced in the brain of 3 dpf larvae exposed to propofol. However, propofol caused a decrease in mbp gene and protein (dose‐dependent) expression levels in the central nervous system of 3 dpf zebrafish. These data show that embryonic exposure to propofol is neurotoxic, causing increased apoptosis and decreased MBP expression. We believe zebrafish can be used as a novel model to explore the mechanisms of propofol neurotoxicity. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-23T04:30:04.96548-05:0
      DOI: 10.1002/jat.3183
  • Biological effect of food additive titanium dioxide nanoparticles on
           intestine: an in vitro study
    • Authors: Zheng‐Mei Song; Ni Chen, Jia‐Hui Liu, Huan Tang, Xiaoyong Deng, Wen‐Song Xi, Kai Han, Aoneng Cao, Yuanfang Liu, Haifang Wang
      Abstract: Titanium dioxide nanoparticles (TiO2 NPs) are widely found in food‐related consumer products. Understanding the effect of TiO2 NPs on the intestinal barrier and absorption is essential and vital for the safety assessment of orally administrated TiO2 NPs. In this study, the cytotoxicity and translocation of two native TiO2 NPs, and these two TiO2 NPs pretreated with the digestion simulation fluid or bovine serum albumin were investigated in undifferentiated Caco‐2 cells, differentiated Caco‐2 cells and Caco‐2 monolayer. TiO2 NPs with a concentration less than 200 µg ml–1 did not induce any toxicity in differentiated cells and Caco‐2 monolayer after 24 h exposure. However, TiO2 NPs pretreated with digestion simulation fluids at 200 µg ml–1 inhibited the growth of undifferentiated Caco‐2 cells. Undifferentiated Caco‐2 cells swallowed native TiO2 NPs easily, but not pretreated NPs, implying the protein coating on NPs impeded the cellular uptake. Compared with undifferentiated cells, differentiated ones possessed much lower uptake ability of these TiO2 NPs. Similarly, the traverse of TiO2 NPs through the Caco‐2 monolayer was also negligible. Therefore, we infer the possibility of TiO2 NPs traversing through the intestine of animal or human after oral intake is quite low. This study provides valuable information for the risk assessment of TiO2 NPs in food. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-23T04:06:17.670193-05:
      DOI: 10.1002/jat.3171
  • The toxic effects of Bisphenol A on the mouse spermatocyte GC‐2 cell
           line: the role of the
           Ca2+‐calmodulin‐Ca2+/calmodulin‐dependent protein kinase
           II axis
    • Authors: Wenyi Qian; Yixin Wang, Jingying Zhu, Changfei Mao, Qiang Wang, Fei Huan, Jie Cheng, Yanqing Liu, Jun Wang, Hang Xiao
      Abstract: Bisphenol A (BPA), an endocrine‐disrupting chemical (EDC), is known to induce male reproductive toxicity in rodents. However, its toxic effects on the germ cells are still poorly understood. It has been proposed that Ca2+ homeostasis and Ca2+ sensors, including calmodulin (CaM) and calmodulin‐dependent protein kinase II (CaMKII), play critical roles in spermatogenesis. Therefore, in the present study, we aimed to investigate whether a perturbation in Ca2+‐CaM‐CaMKII signaling was involved in the BPA‐induced injury to mouse spermatocyte GC‐2spd (ts) (GC‐2) cells. Our results showed that BPA (range from 0.2 to 20 μM) induced obvious GC‐2 cell injury, including decreased cell viability, the release of mitochondrial cytochrome c and the activation of caspase‐3. However, these processes could be partially abrogated by pretreatment with a Ca2+ chelator (BAPTA/AM), a CaM antagonist (W7) or a CaMKII inhibitor (KN93). These results, taken together, indicate that BPA exposure contributes to male germ cell injury, which may be partially mediated through a perturbation in Ca2+/CaM/CaMKII signaling and the mitochondrial apoptotic process. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-18T07:08:22.642556-05:
      DOI: 10.1002/jat.3188
  • Chromium oxide nanoparticle‐induced genotoxicity and
           p53‐dependent apoptosis in human lung alveolar cells
    • Authors: Violet Aileen Senapati; Abhishek Kumar Jain, Govind Sharan Gupta, Alok Kumar Pandey, Alok Dhawan
      Abstract: Chromium oxide (Cr2O3) nanoparticles (NPs) are being increasingly used as a catalyst for aromatic compound manufacture, abrading agents and as pigments (e.g., Viridian). Owing to increased applications, it is important to study the biological effects of Cr2O3 NPs on human health. The lung is one of the main exposure routes to nanomaterials; therefore, the present study was designed to determine the genotoxic and apoptotic effect of Cr2O3 NPs in human lung epithelial cells (A549). The study also elucidated the molecular mechanism of its toxicity. Cr2O3 NPs led to DNA damage, which was deduced by comet assay and cytokinesis block micronucleus assay. The damage could be mediated by the increased levels of reactive oxygen species. Further, the oxygen species led to a decrease in mitochondrial membrane potential and an increase in the ratio of BAX/Bcl‐2 leading to mitochondria‐mediated apoptosis induced by Cr2O3 NPs, which ultimately leads to cell death. Hence, there is a need of regulations to be imposed in NP usage. The study provided insight into the caspase‐dependent mechanistic pathway of apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-18T06:49:15.366062-05:
      DOI: 10.1002/jat.3174
  • Analysis of cytotoxic effects of silver nanoclusters on human peripheral
           blood mononuclear cells ‘in vitro’
    • Authors: Sandra Teresa Orta‐García; Germán Plascencia‐Villa, Angeles Catalina Ochoa‐Martínez, Tania Ruiz‐Vera, Francisco Javier Pérez‐Vázquez, J Jesús Velázquez‐Salazar, Miguel José Yacamán, Hugo Ricardo Navarro‐Contreras, Iván N. Pérez‐Maldonado
      Abstract: The antimicrobial properties of silver nanoparticles (AgNPs) have made these particles one of the most used nanomaterials in consumer products. Therefore, an understanding of the interactions (unwanted toxicity) between nanoparticles and human cells is of significant interest. The aim of this study was to assess the in vitro cytotoxicity effects of silver nanoclusters (AgNC, < 2 nm diameter) on peripheral blood mononuclear cells (PBMC). Using flow cytometry and comet assay methods, we demonstrate that exposure of PBMC to AgNC induced intracellular reactive oxygen species (ROS) generation, DNA damage and apoptosis at 3, 6 and 12 h, with a dose‐dependent response (0.1, 1, 3, 5 and 30 µg ml–1). Advanced electron microscopy imaging of complete and ultrathin‐sections of PBMC confirmed the cytotoxic effects and cell damage caused by AgNC. The present study showed that AgNC produced without coating agents induced significant cytotoxic effects on PBMC owing to their high aspect ratio and active surface area, even at much lower concentrations (
      PubDate: 2015-06-17T06:02:30.505112-05:
      DOI: 10.1002/jat.3190
  • Sub‐chronic exposure to fluoride impacts the response to a
           subsequent nephrotoxic treatment with gentamicin
    • Authors: Mariana Cárdenas‐González; Tania Jacobo Estrada, Rafael Rodríguez‐Muñoz, Jonatan Barrera‐Chimal, Norma A. Bobadilla, Olivier C. Barbier, Luz M. Del Razo
      Abstract: Fluoride is an important groundwater contaminant, and more than 200 million people are exposed to high fluoride levels in drinking water, the major source of fluoride exposure. Exposure above 2 ppm of fluoride is associated with renal impairment in humans. In rats, moderate levels of fluoride induce kidney injury at early stages in which the glomerular filtration rate (GFR) is not altered. In the present study, we investigated if sub‐nephrotoxic stimulus induced by fluoride might impact the response to a subsequent nephrotoxic treatment with gentamicin. Male Wistar rats (~21 days) were exposed to 0, 15 or 50 ppm of fluoride through drinking water during 40 days. Afer that, rats were co‐exposed to gentamicin (40 mg kg–1 day–1, 7 days). Gentamicin induced a marked decrease in the GFR and an increase in urinary levels as well as the protein and mRNA expression of biomarkers of early kidney injury, such as Kim‐1. Interestingly, gentamicin nephrotoxicity was less pronounced in groups previously exposed to fluoride than in the group only treated with gentamicin. Fluoride induced Hsp72, a cytoprotective molecule, which might have improved the response against gentamicin. Moreover, fluoride decreased the expression of megalin, a molecule necessary for internalization of gentamicin into the proximal tubule, potentially reducing gentamicin accumulation. The present results suggest that fluoride reduced gentamicin‐induced nephrotoxicity by inducing a compensatory response carried out by Hsp72 and by decreasing gentamicin accumulation. These findings should not be interpreted to suggest that fluoride is a protective agent as megalin deficiency could lead to serious adverse effects on the kidney physiology. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-17T05:36:53.142301-05:
      DOI: 10.1002/jat.3186
  • Distribution and biomarker of carbon‐14 labeled fullerene C60
           ([14C(U)]C60) in pregnant and lactating rats and their offspring after
           maternal intravenous exposure
    • Authors: Rodney W. Snyder; Timothy R. Fennell, Christopher J. Wingard, Ninell P. Mortensen, Nathan A. Holland, Jonathan H. Shannahan, Wimal Pathmasiri, Anita H. Lewin, Susan C. J. Sumner
      Abstract: A comprehensive distribution study was conducted in pregnant and lactating rats exposed to a suspension of uniformly carbon‐14 labeled C60 ([14C(U)]C60). Rats were administered [14C(U)]C60 (~0.2 mg [14C(U)]C60 kg–1 body weight) or 5% polyvinylpyrrolidone (PVP)‐saline vehicle via a single tail vein injection. Pregnant rats were injected on gestation day (GD) 11 (terminated with fetuses after either 24 h or 8 days), GD15 (terminated after 24 h or 4 days), or GD18 (terminated after 24 h). Lactating rats were injected on postnatal day 8 and terminated after 24 h, 3 or 11 days. The distribution of radioactivity in pregnant dams was influenced by both the state of pregnancy and time of termination after exposure. The percentage of recovered radioactivity in pregnant and lactating rats was highest in the liver and lungs. Radioactivity was quantitated in over 20 tissues. Radioactivity was found in the placenta and in fetuses of pregnant dams, and in the milk of lactating rats and in pups. Elimination of radioactivity was < 2% in urine and feces at each time point. Radioactivity remained in blood circulation up to 11 days after [14C(U)]C60 exposure. Biomarkers of inflammation, cardiovascular injury and oxidative stress were measured to study the biological impacts of [14C(U)]C60 exposure. Oxidative stress was elevated in female pups of exposed dams. Metabolomics analysis of urine showed that [14C(U)]C60 exposure to pregnant rats impacted the pathways of vitamin B, regulation of lipid and sugar metabolism and aminoacyl‐tRNA biosynthesis. This study demonstrated that [14C(U)]C60 crosses the placenta at all stages of pregnancy examined, and is transferred to pups via milk. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-17T04:13:53.329712-05:
      DOI: 10.1002/jat.3177
  • Complement C5a–C5aR interaction enhances MAPK signaling pathway
           activities to mediate renal injury in trichloroethylene sensitized BALB/c
    • Authors: Jia‐xiang Zhang; Wan‐sheng Zha, Liang‐ping Ye, Feng Wang, Hui Wang, Tong Shen, Chang‐hao Wu, Qi‐xing Zhu
      Abstract: We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi‐organ damage including the kidneys. In particular, excessive deposition of C5 and C5b‐9‐the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE‐sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up‐regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE‐induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro‐inflammatory cytokines IL‐2, TNF‐α and IFN‐γ in the kidney tissue (P 
      PubDate: 2015-06-10T05:53:11.117764-05:
      DOI: 10.1002/jat.3179
  • Hepatotoxicity mechanisms of isoniazid: A mini‐review
    • Authors: Hozeifa M. Hassan; Hong‐li Guo, Bashir A. Yousef, Zhang Luyong, Jiang Zhenzhou
      Abstract: Isoniazid (INH) is an antituberculosis drug associated with idiosyncratic liver injury in susceptible patients. INH‐induced hepatotoxicity remains a significant clinical problem, but the underlying mechanisms are still unclear, despite the growing evidence that INH and/or its major metabolite, hydrazine, play an important role in hepatotoxicity. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-10T05:47:41.354338-05:
      DOI: 10.1002/jat.3175
  • Bik subcellular localization in response to oxidative stress induced by
           chemotherapy, in Two different breast cancer cell lines and a
           Non‐tumorigenic epithelial cell line
    • Authors: Aglaé Trejo‐Vargas; Elisa Hernández‐Mercado, Rosa María Ordóñez‐Razo, Roberto Lazzarini, Diego Julio Arenas‐Aranda, María Concepción Gutiérrez‐Ruiz, Mina Königsberg, Armando Luna‐López
      Abstract: Cancer chemotherapy remains one of the preferred therapeutic modalities against malignancies despite its damaging side effects. An expected outcome while utilizing chemotherapy is apoptosis induction. This is mainly regulated by a group of proteins known as the Bcl‐2 family, usually found within the endoplasmic reticulum or the mitochondria. Recently, these proteins have been located in other sites and non‐canonic functions have been unraveled. Bik is a pro‐apoptotic protein, which becomes deregulated in cancer, and as apoptosis is associated with oxidative stress generation, our objective was to determine the subcellular localization of Bik either after a direct oxidative insult due to H2O2, or indirectly by cisplatin, an antineoplastic agent. Experiments were performed in two human transformed mammary gland cell lines MDA‐MB‐231 and MCF‐7, and one non‐tumorigenic epithelial cell line MCF‐10A. Our results showed that in MCF‐7, Bik is localized within the cytosol and that after oxidative stress treatment it translocates into the nucleus. However, in MDA‐MB‐231, Bik localizes in the nucleus and translocates to the cytosol. In MCF10A Bik did not change its cellular site after either treatment. Interestingly, MCF10A were more resistant to cisplatin than transformed cell lines. This is the first report showing that Bik is located in different cellular compartments depending on the cancer stage, and it has the ability to change its subcellular localization in response to oxidative stress. This is associated with increased sensitivity when exposed to toxic agents, thus rendering novel opportunities to study new therapeutic targets allowing the development of more active and less harmful agents. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-09T06:56:58.217996-05:
      DOI: 10.1002/jat.3173
  • Bisphenol A affects placental layers morphology and angiogenesis during
           early pregnancy phase in mice
    • Authors: Sabrina Tait; Roberta Tassinari, Francesca Maranghi, Alberto Mantovani
      Abstract: Bisphenol A (BPA) is a widespread endocrine disrupter mainly used in food contact plastics. Much evidence supports the adverse effects of BPA, particularly on susceptible groups such as pregnant women. The present study considered placental development – relevant for pregnancy outcomes and fetal nutrition/programming – as a potential target of BPA. Pregnant CD‐1 mice were administered per os with vehicle, 0.5 (BPA05) or 50 mg kg−1 (BPA50) body weight day−1 of BPA, from gestational day (GD) 1 to GD11. At GD12, BPA50 induced significant degeneration and necrosis of giant cells, increased vacuolization in the junctional zone in the absence of glycogen accumulation and reduction of the spongiotrophoblast layer. In addition, BPA05 induced glycogen depletion as well as significant nuclear accumulation of β‐catenin in trophoblasts of labyrinthine and spongiotrophoblast layers, supporting the activation of the Wnt/β‐catenin pathway. Transcriptomic analysis indicated that BPA05 promoted and BPA50 inhibited blood vessel development and branching; morphologically, maternal vessels were narrower in BPA05 placentas, whereas embryonic and maternal vessels were irregularly dilated in the labyrinth of BPA50 placentas. Quantitative polymerase chain reaction evidenced an estrogen receptor β induction by BPA50, which did not correspond to downstream genes activation; indeed, the transcription factor binding sites analysis supported the AhR/Arnt complex as regulator of BPA50‐modulated genes. Conversely, Creb appeared as the main transcription factor regulating BPA05‐modulated genes. Embryonic structures (head, forelimb) showed divergent perturbations upon BPA05 or BPA50 exposure, potentially related to unbalanced embryonic nutrition and/or to modulation of genes involved in embryo development. Our findings support placenta as an important target of BPA, even at environmentally relevant dose levels. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-09T05:54:55.40227-05:0
      DOI: 10.1002/jat.3176
  • Probabilistic hazard assessment for skin sensitization potency by
           dose–response modeling using feature elimination instead of
           quantitative structure–activity relationships
    • Authors: Thomas Luechtefeld; Alexandra Maertens, James M. McKim, Thomas Hartung, Andre Kleensang, Vanessa Sá‐Rocha
      Abstract: Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose–response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high‐quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals' potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter‐relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose‐informed random forest/hidden Markov model was superior to the dose‐naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose‐informed hidden Markov model strongly reduced " false‐negatives" (i.e. extreme sensitizers as non‐sensitizer) on all data sets. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-05T07:10:27.019247-05:
      DOI: 10.1002/jat.3172
  • Integrating mitochondriomics in children's environmental health
    • Authors: Kelly J. Brunst; Andrea A. Baccarelli, Rosalind J. Wright
      Abstract: The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally‐induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-05T07:09:06.97524-05:0
      DOI: 10.1002/jat.3182
  • Letter to the Editor
    • Authors: Vagner Oliveira‐Carvalho; Ludmila Rodrigues Pinto Ferreira, Edimar Alcides Bocchi
      PubDate: 2015-06-05T07:06:01.144074-05:
      DOI: 10.1002/jat.3185
  • Difficulties in establishing regulations for engineered nanomaterials and
           considerations for policy makers: avoiding an unbalance between benefits
           and risks
    • Authors: Luis Guillermo Garduño‐Balderas; Ismael Manuel Urrutia‐Ortega, Estefany Ingrid Medina‐Reyes, Yolanda Irasema Chirino
      Abstract: Current evidence of engineered nanomaterials’ (ENM) toxicity has led to a latent concern about hazards for both humans and the environment. For this reason, some efforts have been made to suggest frameworks or other guidance to regulate ENM handling; however, the real exposure risk to humans has not been well established. The aims of this work were to analyze the difficulties in establishing regulations for ENM and to discuss some considerations that may be helpful for policy makers involved in the regulation of ENM. Difficulties in establishing regulations are based on the novel properties of ENM associated with cytotoxic effects, the insufficiency of standardized methods to test those effects and the lack of epidemiological evidence of ENM toxicity, especially in occupational settings. Nevertheless, we offer some suggestions for establishing regulations, which include frameworks oriented towards protecting personnel exposed to ENM without decreasing production. In addition, we propose an ENM data sheet to offer available information of ENM. Finally, ethical aspects should also be considered in developing ENM regulations because every person who is working around or consuming ENM has the right to be informed about the potential risk. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-06-05T07:04:23.407074-05:
      DOI: 10.1002/jat.3180
  • Non‐clinical safety evaluation of repeated intramuscular
           administration of the AS15 immunostimulant combined with various antigens
           in rabbits and cynomolgus monkeys
    • Authors: N. Garçon; J. Silvano, C. F. Kuper, N. Baudson, C. Gérard, R. Forster, L. Segal
      Abstract: Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post‐mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen‐specific antibody titers were determined by enzyme‐linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment‐related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment‐free period. Transient but significant differences in biochemistry parameters were observed post‐injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15‐containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines. Copyright © 2015 The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
      PubDate: 2015-06-01T20:18:59.225297-05:
      DOI: 10.1002/jat.3167
  • Toxicogenomic responses of human liver HepG2 cells to silver nanoparticles
    • Authors: Saura C. Sahu; Jiwen Zheng, Jeffrey J. Yourick, Robert L. Sprando, Xiugong Gao
      Abstract: The increased use of silver nanoparticles (AgNPs) in foods and cosmetics has raised public safety concerns. However, only limited knowledge exists on the effect of AgNPs on the cellular transcriptome. This study evaluated global gene expression profiles of human liver HepG2 cells exposed to 20 and 50 nm AgNPs for 4 and 24 h at 2.5 µg ml–1. Exposure to 20 nm AgNPs resulted in 811 altered genes after 4 h, but much less after 24 h. Exposure to 50 nm AgNPs showed minimal altered genes at both exposure times. The HepG2 cells responded to the toxic insult of AgNPs by transiently upregulating stress response genes such as metallothioneins and heat shock proteins. Functional analysis of the altered genes showed more than 20 major biological processes were affected, of which metabolism, development, cell differentiation and cell death were the most dominant categories. Several cellular pathways were also impacted by AgNP exposure, including the p53 signaling pathway and the NRF2‐mediated oxidative stress response pathway, which may lead to increased oxidative stress and DNA damage in the cell and potentially result in genotoxicity and carcinogenicity. Together, these results indicate that HepG2 cells underwent a multitude of cellular processes in response to the toxic insult of AgNP exposure, and suggest that toxicogenomic characterization of human HepG2 cells could serve as an alternative model for assessing toxicities of NPs. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2015-05-26T00:18:17.224014-05:
      DOI: 10.1002/jat.3170
  • Short‐term, low‐dose cadmium exposure induces
           hyperpermeability in human renal glomerular endothelial cells
    • Authors: Liqun Li; Fengyun Dong, Dongmei Xu, Linna Du, Suhua Yan, Hesheng Hu, Corrinne G. Lobe, Fan Yi, Carolyn M. Kapron, Ju Liu
      Abstract: The kidney is the principal organ targeted by exposure to cadmium (Cd), a well‐known toxic metal. Even at a low level, Cd damages glomerular filtration. However, little is known about the effects of Cd on the glomerular endothelium, which performs the filtration function and directly interacts with Cd in blood plasma. In this study, we cultured human renal glomerular endothelial cells (HRGECs) in the presence of serum with treatment of a short term (1 h) and low concentration (1 μm) of Cd, which mimics the pattern of glomerular endothelium exposure to Cd in vivo. We found that this short‐term, low‐dose Cd exposure does not induce cytotoxicity, but increases permeability in HRGECs monolayers and redistributes adherens junction proteins vascular endothelial‐cadherin and β‐catenin. Though short‐term, low‐dose Cd exposure activates all three major mitogen activated protein kinases, only the inhibitor of p38 mitogen activated protein kinase partially prevents Cd‐induced hyperpermeability in HRGECs. Our data indicate that the presence of Cd in blood circulation might directly disrupt the glomerular endothelial cell barrier and contribute to the development of clinical symptoms of glomerular diseases. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-25T21:57:08.646349-05:
      DOI: 10.1002/jat.3168
  • Onset of hepatocarcinogen‐specific cell proliferation and cell cycle
           aberration during the early stage of repeated hepatocarcinogen
           administration in rats
    • Authors: Masayuki Kimura; Hajime Abe, Sayaka Mizukami, Takeshi Tanaka, Megu Itahashi, Nobuhiko Onda, Toshinori Yoshida, Makoto Shibutani
      Abstract: We have previously reported that a 28‐day treatment of carcinogens evoking target cell proliferation activates G1/S checkpoint function and apoptosis, as well as induction of aberrant ubiquitin D (Ubd) expression, suggesting disruptive spindle checkpoint function, in rats. The present study aimed to determine the onset time of rat liver cells to undergo carcinogen‐specific cell cycle aberration and proliferation. Animals were treated orally with a hepatocarcinogenic dose of methyleugenol or thioacetamide for 3, 7 or 28 days. For comparison, some animals were subjected to partial hepatectomy or treated with noncarcinogenic hepatotoxicants (acetaminophen, α‐naphthyl isothiocyanate or promethazine). Carcinogen‐specific liver cell kinetics appeared at day 28 as evident by increases of cell proliferation, p21Cip1+ cells, phosphorylated‐Mdm2+ cells and cleaved caspase 3+ cells, and upregulation of DNA damage‐related genes. Hepatocarcinogens also downregulated Rbl2 and upregulated Cdkn1a and Mdm2, and decreased Ubd+ cells co‐expressing phosphorylated‐histone H3 (p‐Histone H3) and p‐Histone H3+ cell ratio within the Ki‐67+ proliferating population. These results suggest that it takes 28 days to induce hepatocarcinogen‐specific early withdrawal of proliferating cells from M phase due to disruptive spindle checkpoint function as evidenced by reduction of Ubd+ cells staying at M phase. Disruption of G1/S checkpoint function reflected by downregulation of Rbl2 as well as upregulation of Mdm2 suggestive of sequestration of retinoblastoma protein is responsible for the facilitation of carcinogen‐induced cell proliferation at day 28. Accumulation of DNA damage probably in association with facilitation of p53 degradation by activation of Mdm2 may be a prerequisite for aberrant p21Cip1 activation, which is responsible for apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-22T07:41:41.042646-05:
      DOI: 10.1002/jat.3163
  • RNA sequencing provides insights into the toxicogenomic response of ZF4
           cells to methyl methanesulfonate
    • Authors: Zhouquan Li; Yong Long, Liqiao Zhong, Guili Song, Xiaohua Zhang, Li Yuan, Zongbin Cui, Heping Dai
      Abstract: Whole genome transcriptomic studies are powerful for characterizing the molecular mechanisms underlying the physiological effects of chemicals, and are informative for environmental health risk assessment. Alkylating agents are an abundant class of chemicals that can damage DNA in the environment, and are used for anticancer treatments. Currently, little is known regarding the molecular mechanisms of toxic alkylating agents in zebrafish cell lines. In this study, RNA‐sequencing was used to investigate the transcriptomic responses of zebrafish ZF4 cells following exposure to the model genotoxicant methyl methanesulfonate (MMS). The half‐maximal inhibitory concentration (IC50) of MMS was 639.16 ± 61.8 µm, and apoptosis was induced within 24 h of exposure. RNA sequencing identified 3601 differentially expressed genes (DEGs) that were upregulated and 3037 that were downregulated. Gene ontology enrichment analysis revealed that most DEGs belonged to synthesis and metabolism categories. RNA‐associated processes were the most upregulated, while cell cycle and adhesion were the most repressed processes, and neuron‐related processes were the most downregulated developmental process. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified DNA damage repair, cell cycle, apoptosis and spliceosome as overrepresented terms. Six types of alternative splicing were detected. In total, 1156 alternative splicing DEGs were specifically expressed following MMS treatment, many of which belonged to metabolism and catabolic process categories. Cluster analysis of orthologs was able to extrapolate toxicotranscriptomic data between zebrafish and yeast. These results provide insight into the genome‐wide response of ZF4 cells following exposure to MMS, and this knowledge will inform future toxicogenomic data analysis and environmental health risk assessment. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-22T07:22:45.239857-05:
      DOI: 10.1002/jat.3147
  • A method for estimating the glomerular filtration rate in conscious
    • Authors: Hiroshi Satoh; Nana Nomiya, Daiki Imai, Shigeru Sato, Ken Sakurai, Kiyoshi Takasuna, Kazuhisa Furuhama
      Abstract: To establish a method for estimating the glomerular filtration rate (GFR) in conscious monkeys, the radiographic contrast medium iodixanol and the standard agent inulin were coadministered as tracers to male cynomolgus monkeys (Macaca fascicularis) as a bolus injection; blood was collected after 60, 90 and 120 min. An equation based on a single‐blood‐sample method derived from Jacobsson's formula was prepared using the data from healthy and saline‐ and gentamicin‐treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisample method with inulin or iodixanol. When the GFR decreased to more than 60% of the basal reference level, serum creatinine concentrations tended to increase, whereas serum blood urea nitrogen concentrations fluctuated. The results suggest that the single‐sample‐blood method with iodixanol is a practical tool for estimating the monkey GFR in a toxicological research setting therefore minimizing animal sufferings. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-21T00:40:24.316596-05:
      DOI: 10.1002/jat.3178
  • Developmental toxicity and endocrine disruption of naphthenic acids on the
           early life stage of zebrafish (Danio rerio)
    • Authors: Jie Wang; Xiaofeng Cao, Yi Huang, Xiaoyan Tang
      Abstract: Oil sands process‐affected water (OSPW) has been reported to exhibit adverse effects on the environment and wildlife. Although the compounds responsible are unknown, naphthenic acids (NAs) have been considered to be implicated. The current study was designed to investigate whether NAs might cause developmental toxicity and endocrine disruption on the early life stage of zebrafish (Danio rerio). The success of embryo hatch was inhibited by 2.5 mg l–1 oil sands NAs (OS‐NAs) exposure, and both OSPW NAs and commercial NAs (C‐NAs) exposure resulted in a variety of developmental lesions in the fish larvae, such as yolk sac edema, pericardial edema and spinal malformation. The transcription of genes involved cytochrome P450 aromatase (CYP19a and CYP19b), estrogen receptors (ERα, ERβ1 and ERβ2), and vitellogenin (VTG) was analyzed to evaluate the endocrine disrupting effects of NAs. Significant up‐regulated gene expressions of CYP19b, ERα and VTG were observed in both OS‐NAs and C‐NAs groups, which indicated the deleteriously estrogenic potential of NAs. These results confirmed that NAs derived from crude petroleum could negatively impact the development and endocrine function of zebrafish, and be primarily responsible for the toxicity of OSPW. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-21T00:36:44.988264-05:
      DOI: 10.1002/jat.3166
  • Directional and color preference in adult zebrafish: Implications in
           behavioral and learning assays in neurotoxicology studies
    • Authors: Zachary A. Bault; Samuel M. Peterson, Jennifer L. Freeman
      Abstract: The zebrafish (Danio rerio) is a useful vertebrate model organism for neurological studies. While a number of behavior and learning assays are recently reported in the literature for zebrafish, many of these assays are still being refined. The initial purpose of this study was to apply a published T‐maze assay for adult zebrafish that measures how quickly an organism can discriminate between different color stimuli after receiving reinforcement to measure learning in a study investigating the later life impacts of developmental Pb exposure. The original results were inconclusive as the control group showed a directional and color preference. To assess directional preference further, a three‐chambered testing apparatus was constructed and rotated in several directions. The directional preference observed in males was alleviated by rotating the arms pointing west and east. In addition, color preference was investigated using all combinations of five different colors (orange, yellow, green, blue and purple). With directional preference alleviated results showed that both male and female zebrafish preferred colors of shorter wavelengths. An additional experiment tested changes in color preference due to developmental exposure to Pb in adult male zebrafish. Results revealed that Pb‐exposed males gained and lost certain color preferences compared to control males and the preference for short wavelengths was decreased. Overall, these results show that consideration and pretesting should be completed before applying behavioral and learning assays involving adult zebrafish to avoid innate preferences and confounding changes in neurotoxicology studies and that developmental Pb exposure alters color preferences in adult male zebrafish. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-20T21:12:27.765722-05:
      DOI: 10.1002/jat.3169
  • Effect‐directed identification of endocrine disruptors in plastic
           baby teethers
    • Authors: Elisabeth Berger; Theodoros Potouridis, Astrid Haeger, Wilhelm Püttmann, Martin Wagner
      Abstract: Concerns have been raised regarding the human health effects of endocrine disrupting chemicals (EDCs), many of which are associated with and leaching from plastics. As infants are particularly vulnerable to EDCs, we have investigated whether plastic teethers for babies represent a relevant source of exposure. Applying effect‐directed analysis, we use bioassays to screen teethers, toys used to soothe a baby's teething ache, for endocrine activity and chemical analysis to identify the causative compounds. We detected significant endocrine activity in two of 10 plastic teethers. Those samples leached estrogenic and/or antiandrogenic activity as detected in the Yeast Estrogen Screen and Yeast Antiandrogen Screen. After sample fractionation, gas chromatography–mass spectrometry non‐target screening revealed that methyl‐, ethyl‐ and propylparaben were responsible for the observed estrogenic and antiandrogenic activity in one product. The second product is likely to contain at least six different antiandrogenic compounds that remain so far unidentified. This study demonstrates that plastic teethers can be a source of infant exposure to well‐established and unknown EDCs. Because of their limited value to the product, but potential toxicity, manufacturers should critically revisit the use of parabens in plastic teethers and further toys. Moreover, plastic teethers might leach EDCs that escape routine analysis and, thus, toxicological evaluation. The resulting uncertainty in product safety poses a problem to consumers, producers and regulators that remain to be resolved. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-18T07:27:48.753651-05:
      DOI: 10.1002/jat.3159
  • Acute and subchronic toxicity of 20  kHz and
           60  kHz magnetic fields in rats
    • Authors: Izumi Nishimura; Atsushi Oshima, Kazumoto Shibuya, Takashi Mitani, Tadashi Negishi
      Abstract: Despite increasing use of intermediate frequency (IF) magnetic fields (MFs) in occupational and domestic settings, scientific evidence necessary for health risk assessments of IF MF is insufficient. Male and female Crl:CD(SD) rats (12 per sex per group) were exposed to 20 kHz, 0.20 mT(root mean square, rms) or 60 kHz, 0.10 mT(rms) sinusoidal MFs for 22 h day−1 for 14 days (acute) or 13 weeks (subchronic). Experiments were duplicated for each frequency to ensure outcome reproducibility, and examinations were blinded for quality assurance. All rats survived without significant clinical signs until the end of experiments. Some changes in body weight between the MF‐exposed and control groups were observed over the course of exposure, although the directions of the changes were inconsistent and not statistically significant after subchronic exposure. There were significant differences between MF‐exposed and control groups in some organ weights and parameters in hematology and clinical chemistry, but these were minor in magnitude and not repeated in duplicate experiments. Histopathological findings reflecting toxicity were sporadic. Frequencies of other findings were similar to historic data in this rat strain, and findings had no specific relationship to changes in organ weight or parameters of hematology and clinical chemistry in each animal. The changes observed throughout this study were considered biologically isolated and were attributable to chance associations rather than to MF exposure. The results, in particular the histopathological evidence, indicate an absence of toxicity in IF MF‐exposed rats and do not support the hypothesis that IF MF exposure produces significant toxicity. Copyright © 2015. The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
      PubDate: 2015-05-17T23:57:37.168612-05:
      DOI: 10.1002/jat.3161
  • Silver nanoparticles affect the neural development of zebrafish embryos
    • Authors: Qi Xin; Jeanette M. Rotchell, Jinping Cheng, Jun Yi, Qiang Zhang
      Abstract: Silver nanoparticles (AgNPs) have been widely used in commercial products. This study aims to understand the impact of AgNPs on the early developmental stages in zebrafish (Danio rerio) embryos. Embryos were exposed to two sizes of AgNPs at three dose levels, as well to free Ag+ ions, for a range of 4–96 h post‐fertilization (hpf). The acute exposure study showed that exposure to AgNPs affected the neurological development, and the exposed embryos exhibited anomalies such as small head with hypoplastic hindbrain, small eye and cardiac defects. At the molecular level, AgNPs altered the expression profiles of neural development‐related genes (gfap, huC and ngn1), metal‐sensitive metallothioneins and ABCC genes in exposed embryos. The expression of AhR2 and Cyp1A, which are usually considered to mediate polycyclic aromatic hydrocarbon toxicity, were also significantly changed. A size‐dependent uptake of AgNPs was observed, whereby 4 nm AgNPs were more efficiently taken up compared with the 10 nm‐sized particles. Importantly, the head area accumulated AgNPs more efficiently than the trunk area of exposed zebrafish embryos. No free Ag+ ions, which can be potentially released from the AgNP solutions, were detected. This study suggests that AgNPs could affect the neural development of zebrafish embryos, and the toxicity of AgNPs may be partially attributed to the comparatively higher uptake in the head area. These results indicate the potential neurotoxicity of AgNPs and could be extended to other aquatic organisms. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-15T00:29:17.852587-05:
      DOI: 10.1002/jat.3164
  • Intracellular calcium levels as screening tool for nanoparticle toxicity
    • Authors: Claudia Meindl; Tatjana Kueznik, Martina Bösch, Eva Roblegg, Eleonore Fröhlich
      Abstract: The use of engineered nano‐sized materials led to revolutionary developments in many industrial applications and in the medical field. These materials, however, also may cause cytotoxicity. In addition to size, surface properties and shape were identified as relevant parameters for cell damage. Cell damage may occur as disruption of membrane integrity, induction of apoptosis and by organelle damage. Generation of oxidative stress may serve as an indicator for cytotoxicity. Effects occurring upon short contact of particles with cells, for instance in the systemic blood circulation, could be identified according to increases of intracellular [Ca2+] levels, which are caused by variety of toxic stimuli. Negatively charged, neutral and positively charged polystyrene particles of different sizes were used to study the role of size and surface properties on viability, membrane disruption, apoptosis, lysosome function, intracellular [Ca2+] levels and generation of oxidative stress. Silica particles served to test this hypothesis. Twenty nm polystyrene particles as well as 12 nm and 40 nm silica particles caused membrane damage and apoptosis with no preference of the surface charge. Only 20 nm plain and amine functionalized polystyrene particles cause oxidative stress and only the plain particles lysosomal damage. A potential role of surface charge was identified for 200 nm polystyrene particles, where only the amidine particles caused lysosomal damage. Increases in intracellular [Ca2+] levels and cytotoxicity after 24 h was often linked but determination of intracellular [Ca2+] levels could serve to characterize further the type of membrane damage. © 2015 The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
      PubDate: 2015-05-14T21:12:31.32087-05:0
      DOI: 10.1002/jat.3160
  • Toxicological effects of pet food ingredients on canine bone
           marrow‐derived mesenchymal stem cells and enterocyte‐like
    • Authors: M. T. Ortega; B. Jeffery, J. E. Riviere, N. A. Monteiro‐Riviere
      Abstract: We developed an in vitro method to assess pet food ingredients safety. Canine bone marrow‐derived mesenchymal stem cells (BMSC) were differentiated into enterocyte‐like cells (ELC) to assess toxicity in cells representing similar patterns of exposure in vivo. The toxicological profile of clove leave oil, eugenol, guanosine monophosphate (GMP), GMP + inosine monophosphate, sorbose, ginger root extract, cinnamon bark oil, cinnamaldehyde, thyme oil, thymol and citric acid was assessed in BMSC and ELC. The LC50 for GMP + inosine monophosphate was 59.42 ± 0.90 and 56.7 ± 3.5 mg ml–1 for BMSC and ELC; 56.84 ± 0.95 and 53.66 ± 1.36 mg ml–1 for GMP; 0.02 ± 0.001 and 1.25 ± 0.47 mg ml–1 for citric acid; 0.077 ± 0.002 and 0.037 ± 0.01 mg ml–1 for cinnamaldehyde; 0.002 ± 0.0001 and 0.002 ± 0.0008 mg ml–1 for thymol; 0.080 ± 0.003 and 0.059 ± 0.001 mg ml–1 for thyme oil; 0.111 ± 0.002 and 0.054 ± 0.01 mg ml–1 for cinnamon bark oil; 0.119 ± 0.0004 and 0.099 ± 0.011 mg ml–1 for clove leave oil; 0.04 ± 0.001 and 0.028 ± 0.002 mg ml–1 for eugenol; 2.80 ± 0.11 and 1.75 ± 0.51 mg ml–1 for ginger root extract; > 200 and 116.78 ± 7.35 mg ml–1 for sorbose. Lemon grass oil was evaluated at 0.003–0.9 in BMSC and .03‐0.9 mg ml–1 in ELC and its mechanistic effect was investigated. The gene toxicology studies showed regulation of 61% genes in CYP450 pathway, 37% in cholestasis and 33% in immunotoxicity pathways for BMSC. For ELC, 80% for heat shock response, 69% for beta‐oxidation and 65% for mitochondrial energy metabolism. In conclusion, these studies provide a baseline against which differential toxicity of dietary feed ingredients can be assessed in vitro for direct effects on canine cells and demonstrate differential toxicity in differentiated cells that represent gastrointestinal epithelial cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-14T18:22:26.588619-05:
      DOI: 10.1002/jat.3158
  • Safety data on 19 vehicles for use in 1 month oral rodent
           pre‐clinical studies: administration of
           hydroxypropyl‐ß‐cyclodextrin causes renal toxicity
    • Authors: Guy Healing; Tabassum Sulemann, Peter Cotton, Jayne Harris, Adam Hargreaves, Rowena Finney, Sarah Kirk, Carolin Schramm, Clare Garner, Perrine Pivette, Lisa Burdett
      Abstract: Potential new drugs are assessed in pre‐clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl‐ß‐cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-10T20:18:00.800754-05:
      DOI: 10.1002/jat.3155
  • Maternal exposure to hexachlorophene targets intermediate‐stage
           progenitor cells in the hippocampal neurogenesis involving myelin
           vacuolation of cholinergic and glutamatergic inputs in mice
    • Authors: Mizuho Kato; Hajime Abe, Megu Itahashi, Yoh Kikuchihara, Masayuki Kimura, Sayaka Mizukami, Toshinori Yoshida, Makoto Shibutani
      Abstract: Hexachlorophene (HCP) has been shown to induce myelin vacuolation due to intramyelinic edema of the nerve fibers in animal neural tissue. We investigated the maternal exposure effect of HCP on hippocampal neurogenesis in the offspring of pregnant mice supplemented with 0 (control), 33 or 100 ppm HCP in diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, offspring as examined in males exhibited decreased granule cell lineage populations expressing paired box 6, sex‐determining region Y‐box 2 and eomesodermin in the hippocampal subgranular zone (SGZ) accompanied by myelin vacuolation involving white matter tracts of the hippocampal fimbria at ≥ 33 ppm. However, SGZ cellular populations expressing brain lipid binding protein and doublecortin were unchanged at any dose. Transcript expression of cholinergic receptor genes, Chrna4 and Chrnb2, and glutamate receptor genes, Grm1 and Grin2d, examined at 100 ppm, decreased in the dentate gyrus. HCP exposure did not alter the number of proliferating or apoptotic cells in the SGZ, or reelin‐ or calcium‐binding protein‐expressing γ‐aminobutyric acid (GABA)ergic interneurons in the dentate hilus, on PND 21 and PND 77. All neurogenesis‐related changes observed in HCP‐exposed offspring on PND 21 disappeared on PND 77, suggesting that maternal HCP exposure at ≥ 33 ppm reversibly decreased type 2 intermediate‐stage progenitor cells in the hippocampal neurogenesis. Myelin vacuolation might be responsible for changes in neurogenesis possibly by reducing nerve conduction velocity of cholinergic inputs from the septal–hippocampal pathway to granule cell lineages and/or GABAergic interneurons, and of glutamatergic inputs to granule cell lineages. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-05-05T09:13:26.853194-05:
      DOI: 10.1002/jat.3162
  • Adverse Outcome Pathways can drive non‐animal approaches for safety
    • Authors: Natalie Burden; Fiona Sewell, Melvin E. Andersen, Alan Boobis, J. Kevin Chipman, Mark T. D. Cronin, Thomas H. Hutchinson, Ian Kimber, Maurice Whelan
      Abstract: Adverse Outcome Pathways (AOPs) provide an opportunity to develop new and more accurate safety assessment processes for drugs and other chemicals, and may ultimately play an important role in regulatory decision making. Not only can the development and application of AOPs pave the way for the development of improved evidence‐based approaches for hazard and risk assessment, there is also the promise of a significant impact on animal welfare, with a reduced reliance on animal‐based methods. The establishment of a useable and coherent knowledge framework under which AOPs will be developed and applied has been a first critical step towards realizing this opportunity. This article explores how the development of AOPs under this framework, and their application in practice, could benefit the science and practice of safety assessment, while in parallel stimulating a move away from traditional methods towards an increased acceptance of non‐animal approaches. We discuss here the key areas where current, and future initiatives should be focused to enable the translation of AOPs into routine chemical safety assessment, and lasting 3Rs benefits. © 2015 The
      Authors . Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2015-05-05T08:56:05.682065-05:
      DOI: 10.1002/jat.3165
  • mRNAs and miRNAs in whole blood associated with lung hyperplasia,
           fibrosis, and bronchiolo‐alveolar adenoma and adenocarcinoma after
           multi‐walled carbon nanotube inhalation exposure in mice
    • Authors: Brandi N. Snyder‐Talkington; Chunlin Dong, Linda M. Sargent, Dale W. Porter, Lauren M. Staska, Ann F. Hubbs, Rebecca Raese, Walter McKinney, Bean T. Chen, Lori Battelli, David T. Lowry, Steven H. Reynolds, Vincent Castranova, Yong Qian, Nancy L. Guo
      Abstract: Inhalation exposure to multi‐walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo‐alveolar adenoma and adenocarcinoma. Six‐week‐old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA‐damaging agent methylcholanthrene (MCA, 10 µg g−1 body weight) or vehicle (corn oil). One week after injections, mice were exposed by inhalation to MWCNT (5 mg m−3, 5 hours per day, 5 days per week) or filtered air (control) for a total of 15 days. At 17 months post‐exposure, mice were euthanized and examined for the development of pathological changes in the lung, and whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. Numerous mRNAs and miRNAs in the blood were significantly up‐ or down‐regulated in animals developing pathological changes in the lung after MCA/corn oil administration followed by MWCNT/air inhalation, including fcrl5 and miR‐122‐5p in the presence of hyperplasia, mthfd2 and miR‐206‐3p in the presence of fibrosis, fam178a and miR‐130a‐3p in the presence of bronchiolo‐alveolar adenoma, and il7r and miR‐210‐3p in the presence of bronchiolo‐alveolar adenocarcinoma, among others. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT‐induced lung pathological changes. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-29T23:36:08.828959-05:
      DOI: 10.1002/jat.3157
  • In vitro neurotoxicity evaluation of piperazine designer drugs in
           differentiated human neuroblastoma SH‐SY5Y cells
    • Authors: M. D. Arbo; R. Silva, D. J. Barbosa, D. Dias Silva, S. P. Silva, J. P. Teixeira, M. L. Bastos, H. Carmo
      Abstract: Abuse of synthetic drugs is widespread worldwide. Studies indicate that piperazine designer drugs act as substrates at dopaminergic and serotonergic receptors and/or transporters in the brain. This work aimed to investigate the cytotoxicity of N‐benzylpiperazine, 1‐(3‐trifluoromethylphenyl)piperazine, 1‐(4‐methoxyphenyl)piperazine and 1‐(3,4‐methylenedioxybenzyl)piperazine in the differentiated human neuroblastoma SH‐SY5Y cell line. Cytotoxicity was evaluated after 24 h incubations through the MTT reduction and neutral red uptake assays. Oxidative stress (reactive oxygen and nitrogen species production and glutathione content) and energetic (ATP content) parameters, as well as intracellular Ca2+, mitochondrial membrane potential, DNA damage (comet assay) and cell death mode were also evaluated. Complete cytotoxicity curves were obtained after 24 h incubations with each drug. A significant decrease in intracellular total glutathione content was noted for all the tested drugs. All drugs caused a significant increase of intracellular free Ca2+ levels, accompanied by mitochondrial hyperpolarization. However, ATP levels remained unchanged. The investigation of cell death mode revealed a predominance of early apoptotic cells. No genotoxicity was found in the comet assay. Among the tested drugs, 1‐(3‐trifluoromethylphenyl)piperazine was the most cytotoxic. Overall, piperazine designer drugs are potentially neurotoxic, supporting concerns on risks associated with the abuse of these drugs. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-20T20:48:22.46823-05:0
      DOI: 10.1002/jat.3153
  • In vitro study of biocompatibility of a graphene composite with gold
           nanoparticles and hydroxyapatite on human osteoblasts
    • Authors: Liana Crisan; Bogdan Crisan, Olga Soritau, Mihaela Baciut, Alexandru Radu Biris, Grigore Baciut, Ondine Lucaciu
      Abstract: The purpose of this study was to evaluate the biocompatibility of some composites consisting of different proportions of graphene in combination with gold nanoparticles (AuNPs) and nanostructured hydroxyapatite (HA) on osteoblast viability, proliferation and differentiation. Au/HA@graphene composites synthesized by the catalytic chemical vapor deposition induction heating method with acetylene as the carbon source and over an Au/HA catalyst, were characterized by transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy and showed that the few‐layer graphene was grown over the Au/HA catalyst. The cytocompatibility study was performed using the fluorescein diacetate assay for assessment of the viability and proliferation of osteoblasts cultivated in the presence of HA, Au/HA and Au/HA@graphene composites as colloidal suspensions or as substrates. The most favorable composites for cell adhesion and proliferation were HA, Au/HA and Au/HA composites with 1.6% and 3.15% concentration of graphenes. Immunocytochemical staining performed after 19 days of osteoblasts cultivation on substrates showed that the graphene composites induced low expression of alkaline phosphatase compared to the control group and HA and Au/HA substrates. The presence of graphene in the substrate composition also induced an increased level of intracellular osteopontin and cytoskeleton reorganization (actin‐F) depending on graphene concentration, suggesting cell activation, increased cellular adhesion and acquisition of a mechanosensorial osteocyte phenotype. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-20T20:15:45.376371-05:
      DOI: 10.1002/jat.3152
  • Preclinical safety evaluation of low molecular weight
           heparin–deoxycholate conjugates as an oral anticoagulant
    • Authors: Ji‐young Kim; Ok‐Cheol Jeon, Hyun Tae Moon, Seung Rim Hwang, Youngro Byun
      Abstract: The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin–deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg−1 of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4‐week oral toxicity study with a 4‐week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg−1 day−1 did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg−1 day−1 and one female dog treated with 1000 mg kg−1 day−1 could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4‐week oral toxicity study with a 4‐week recovery in beagle dogs. Thus, while the no‐observed‐adverse‐effect level value from the 4‐week study in both male and female rats was 1000 mg kg−1 day−1, those from the 4‐week study in male and female beagle dogs were 300 and 1000 mg kg−1 day−1, respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-20T19:26:21.800263-05:
      DOI: 10.1002/jat.3146
  • Establishment of a mouse model for amiodarone‐induced liver injury
           and analyses of its hepatotoxic mechanism
    • Authors: Shohei Takai; Shingo Oda, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima, Tsuyoshi Yokoi
      Abstract: Drug‐induced liver injury (DILI) is the most frequent cause of post‐marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD‐induced liver injury, mice were administered AMD [1000 mg kg–1, per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg–1, intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX‐pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD‐administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD‐administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl3), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD‐induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD‐induced liver injury using an in vivo mouse model. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-20T19:19:47.146916-05:
      DOI: 10.1002/jat.3141
  • Bisphenol A inhibits duodenal movement ex vivo of rat through nitric
           oxide‐mediated soluble guanylyl cyclase and α‐adrenergic
           signaling pathways
    • Authors: Kaushik Sarkar; Panchali Tarafder, Goutam Paul
      Abstract: The gastrointestinal tract is directly exposed to bisphenol A (BPA)‐tainted foods and beverages stored in polycarbonate plastic containers. The effect of BPA on the movement of small intestine has not been reported until now. We report here the effect of BPA on the movement of the duodenum ex vivo in a rat model. We found significant inhibition of duodenal movement by BPA (10–320 µ M). We suggest that BPA‐induced inhibition of duodenal movement might be due to the suppression of stimulatory and/or activation of inhibitory motor neurons in enteric plexuses innervating the longitudinal and circular visceral smooth muscle cells in the duodenal wall. We observed a significant reversal of BPA‐induced depression of duodenal movement by methylene blue, a soluble guanylyl cyclase blocker and N‐ω‐nitro‐ L‐arginine methyl ester, a nitric oxide (NO) synthase inhibitor; but significant potentiation of the movement by sodium nitroprusside, a NO donor. From the results, we may suggest that BPA‐induced inhibition of the movement might be partially due to activation of inhibitory motor neurons that secrete NO, a relaxant, on to smooth muscle cells. Furthermore, we found significant reversal of BPA‐induced depression of the movement in phentolamine, an α‐adrenergic receptor blocker, pretreated preparation. This result proves that norepinephrine secreting motor neurons may also be involved in BPA‐induced inhibition of the movement. From the results, we conclude that BPA inhibits the movement of the duodenum through NO‐mediated soluble guanylyl cyclase and α‐adrenergic signaling pathways in visceral smooth muscle cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-16T05:40:57.910581-05:
      DOI: 10.1002/jat.3154
  • The surfactant dipalmitoylphophatidylcholine modifies acute responses in
           alveolar carcinoma cells in response to low‐dose silver nanoparticle
    • Authors: A. Murphy; K. Sheehy, A. Casey, G. Chambers
      Abstract: Nanotechnology is a rapidly growing field with silver nanoparticles (AgNP) in particular utilized in a wide variety of consumer products. This has presented a number of concerns relating to exposure and the associated toxicity to humans and the environment. As inhalation is the most common exposure route, this study investigates the potential toxicity of AgNP to A549 alveolar epithelial carcinoma cells and the influence of a major component of lung surfactant dipalmitoylphosphatidylcholine (DPPC) on toxicity. It was illustrated that exposure to AgNP generated low levels of oxidative stress and a reduction in cell viability. While DPPC produced no significant effect on viability studies its presence resulted in increased reactive oxygen species formation. DPPC also significantly modified the inflammatory response generated by AgNP exposure. These findings suggest a possible interaction between AgNP and DPPC causing particles to become more reactive, thus increasing oxidative insult and inflammatory response within A549 cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-16T05:34:06.971437-05:
      DOI: 10.1002/jat.3148
  • Microminipigs as a new experimental animal model for toxicological
           studies: comparative pharmacokinetics of perfluoroalkyl acids
    • Authors: Keerthi S. Guruge; Michiko Noguchi, Koji Yoshioka, Eriko Yamazaki, Sachi Taniyasu, Miyako Yoshioka, Noriko Yamanaka, Mitsutaka Ikezawa, Nobuhiko Tanimura, Masumi Sato, Nobuyoshi Yamashita, Hiroaki Kawaguchi
      Abstract: In this study, we evaluated the efficacy of a novel minipig strain, the Microminipig (MMPig), as an animal model for studying the pharmacokinetics of a mixture of 10 perfluoroalkyl acids (PFAAs). After a single oral dose was given, we found that the blood depuration of PFAAs (blood t1/2), which we calculated using first‐order elimination curves, ranged from 1.6 to 86.6 days. Among the five body compartments analyzed, the liver was the greatest site of accumulation of perfluorooctanesulfonate and longer chain perfluorinated carboxylates such as perfluorodecanoic acid, perfluoroundecanoic acid and perfluorododecanoic acid. We observed an increasing accumulation trend of perfluorinated carboxylates in the organs associated with the fluorinated carbon chain length. The perfluorononanoic acid burden was the highest among the treated compounds 21 days after a single exposure, as 29% of the given perfluorononanoic acid dose was accumulated in the tissues. The persistence of PFAAs in edible pig tissues even after 21 days post‐exposure raises concerns about the safety of swine products. This was the first study to use MMPigs to elucidate the pharmacokinetics of a group of environmental pollutants. We found that MMPigs could be excellent experimental animals for toxicological studies due to their easy handling, cost efficacy for target compounds and ease of waste treatment. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-15T08:17:20.50335-05:0
      DOI: 10.1002/jat.3145
  • Acrylamide induces locomotor defects and degeneration of dopamine neurons
           in Caenorhabditis elegans
    • Authors: Jia Li; Dan Li, Yongsheng Yang, Tiantian Xu, Ping Li, Defu He
      Abstract: Acrylamide can form in foods during the cooking process and cause multiple adverse effects. However, the neurotoxicity and mechanisms of acrylamide have not been fully elucidated. In Caenorhabditis elegans, we showed that 48 h exposure to 10–625 mg l−1 acrylamide resulted in a significant decline in locomotor frequency of body bending, head thrashing and pharynx pumping. In addition, acrylamide exposure reduced crawling speeds and changed angles of body bending. It indicates that acrylamide induces locomotor defects, along with parkinsonian‐like movement impairment, including bradykinesia and hypokinesia. Acrylamide also affected chemotaxis plasticity and reduced learning ability. Using transgenic nematodes, we found that acrylamide induced downexpression of Pdat‐1 and led to the degeneration of dopaminergic neurons. Moreover, the enhanced expression of unc‐54, encoding a subunit of α‐synuclein was found. It illustrates that acrylamide is efficient in inducing crucial parkinsonian pathology, including dopaminergic damage and α‐synuclein aggregation. These findings suggest the acrylamide‐induced locomotor defects and neurotoxicity are associated with Parkinson's disease. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-15T07:51:39.378714-05:
      DOI: 10.1002/jat.3144
  • PM2.5‐induced oxidative stress increases adhesion molecules
           expression in human endothelial cells through the
           ERK/AKT/NF‐κB‐dependent pathway
    • Authors: Wei Rui; Longfei Guan, Fang Zhang, Wei Zhang, Wenjun Ding
      Abstract: The aim of this study was to explore the intracellular mechanisms underlying the cardiovascular toxicity of air particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM2.5) in a human umbilical vein cell line, EA.hy926. We found that PM2.5 exposure triggered reactive oxygen species (ROS) generation, resulting in a significant decrease in cell viability. Data from Western blots showed that PM2.5 induced phosphorylation of Jun N‐terminal kinase (JNK), extracellular signal regulatory kinase (ERK), p38 mitogen‐activated protein kinase (MAPK) and protein kinase B (AKT), and activation of nuclear factor kappa B (NF‐κB). We further observed a significant increase in expressions of intercellular adhesion molecule‐1 (ICAM‐1) and vascular adhesion molecule‐1 (VCAM‐1) in a time‐ and dose‐dependent manner. Moreover, the adhesion of monocytic THP‐1 cells to EA.hy926 cells was greatly enhanced in the presence of PM2.5. However, N‐acetylcysteine (NAC), a scavenger of ROS, prevented the increase of ROS generation, attenuated the phosphorylation of the above kinases, and decreased the NF‐κB activation as well as the expression of ICAM‐1 and VCAM‐1. Furthermore, ERK inhibitor (U0126), AKT inhibitor (LY294002) and NF‐κB inhibitor (BAY11‐7082) significantly down‐regulated PM2.5‐induced ICAM‐1 and VCAM‐1 expression as well as adhesion of THP‐1 cells, but not JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580), indicating that ERK/AKT/NF‐κB is involved in the signaling pathway that leads to PM2.5‐induced ICAM‐1 and VCAM‐1 expression. These findings suggest PM2.5‐induced ROS may function as signaling molecules triggering ICAM‐1 and VCAM‐1 expressions through activating the ERK/AKT/NF‐κB‐dependent pathway, and further promoting monocyte adhesion to endothelial cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-15T07:37:09.723701-05:
      DOI: 10.1002/jat.3143
  • Aluminium oxide nanoparticles induced morphological changes, cytotoxicity
           and oxidative stress in Chinook salmon (CHSE‐214) cells
    • Authors: Koigoora Srikanth; Amit Mahajan, Eduarda Pereira, Armando Costa Duarte, Janapala Venkateswara Rao
      Abstract: Aluminium oxide nanoparticles (Al2O3 NPs) are increasingly used in diverse applications that has raised concern about their safety. Recent studies suggested that Al2O3 NPs induced oxidative stress may be the cause of toxicity in algae, Ceriodaphnia dubia, Caenorhabditis elegans and Danio rerio. However, there is paucity on the toxicity of Al2O3 NPs on fish cell lines. The current study was aimed to investigate Al2O3 NPs induced cytotoxicity, oxidative stress and morphological abnormality of Chinnok salmon cells (CHSE‐214). A dose‐dependent decline in cell viability was observed in CHSE‐214 cells exposed to Al2O3 NPs. Oxidative stress induced by Al2O3 NPs in CHSE‐214 cells has resulted in the significant reduction of superoxide dismutase, catalase and glutathione in a dose‐dependent manner. However, a significant increase in glutathione sulfo‐transferase and lipid peroxidation was observed in CHSE‐214 cells exposed to Al2O3 NPs in a dose‐dependent manner. Significant morphological changes in CHSE‐214 cells were observed when exposed to Al2O3 NPs at 6, 12 and 24 h. The cells started to detach and appear spherical at 6 h followed by loss of cellular contents resulting in the shrinking of the cells. At 24 h, the cells started to disintegrate and resulted in cell death. Our data demonstrate that Al2O3 NPs induce cytotoxicity and oxidative stress in a dose‐dependent manner in CHSE‐214 cells. Thus, our current work may serve as a base‐line study for future evaluation of toxicity studies using CHSE‐214 cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-15T07:06:31.862304-05:
      DOI: 10.1002/jat.3142
  • Particulate matter phagocytosis induces tissue factor in differentiating
    • Authors: M. Milano; P. Dongiovanni, A. Artoni, S. Gatti, L. Rosso, F. Colombo, V. Bollati, M. Maggioni, P. M. Mannucci, P. A. Bertazzi, S. Fargion, L. Valenti
      Abstract: Airborne exposure to particulate matter with diameter
      PubDate: 2015-04-08T22:41:25.814999-05:
      DOI: 10.1002/jat.3156
  • Impaired aquaporins expression in the gastrointestinal tract of rat after
           mercury exposure
    • Authors: Cinzia Bottino; Marta Vázquez, Vicenta Devesa, Umberto Laforenza
      Abstract: The main route of exposure to mercury in humans is through the diet. Consequently, the gastrointestinal mucosa is exposed to the mercurial forms, where they cause intestinal fluid accumulation, mucosal injuries and diarrhea. The relationship between inorganic mercury (HgCl2) and methylmercury (CH3HgCl) exposure and water movement in the gastrointestinal tract is still unexplored. The leading role of aquaporins (AQPs) in the rapid bidirectional movement of fluid in the gastrointestinal tract of mammals is well established. The present study evaluates the effect of HgCl2 and CH3HgCl exposure on AQP expression in different portions of the gastrointestinal tract of rats treated by gavage (5 mg kg–1 of mercury species, single dose, 4 days). The results show that mercury species reduce mRNA and protein levels of AQPs in different parts of the gastrointestinal tract. In the stomach, treated rats show a significant reduction of expression of AQP3 (80–90% for mRNA and 50% for protein) and AQP4 (95–99% for mRNA and 20–40% for protein). In the small and large intestine, treated rats experience a significant reduction of AQP3 and AQP7 expression. Protein contents of both AQPs are reduced in similar proportions in jejunum (AQP3: 40–50%; AQP7: 45–50%) and colon (AQP3: 35–40%; AQP7: 45–60%), regardless of the treatment. Our results indicate that some AQPs are downregulated in the rat gastrointestinal tract by mercury exposure, suggesting a possible role of AQPs in the development of mercury gastrointestinal symptoms. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-08T20:55:50.964966-05:
      DOI: 10.1002/jat.3151
  • Co‐treatment with the non‐steroidal anti‐androgen drug,
           flutamide and the natural estrogen, 17β‐estradiol does not lead
           to additive reproductive impairment in juvenile Murray rainbowfish
           (Melanotaenia fluviatilis)
    • Authors: Harpreet Bhatia; Anupama Kumar, Jun Du, John C. Chapman, Mike J. McLaughlin
      Abstract: The aim of this study was to investigate if the anti‐androgen, flutamide, and the estrogen, 17β‐estradiol work together to feminize juvenile Murray rainbowfish (Melanotaenia fluviatilis). Fish (60 days post‐hatch) were exposed to 25 ng/L 17β‐estradiol (E2), 25 µg/L flutamide (Flu low), 250 µg/L flutamide (Flu high), E2 + Flu low and E2 + Flu high. After 35 days of exposure, concentrations of sex steroid hormones, 17β‐estradiol and 11‐keto testosterone (11‐KT), were determined in the head; and vitellogenin (VTG) concentration was measured in the tail. The abdomens were used for histological investigation of the gonads. Treatment with E2 + Flu high resulted in reduction in body weights and lengths in males and condition factor in females. Intersex was noted in Flu high and E2 + Flu high treatments. Exposures to E2 and/or Flu (low and high) resulted in precocious oocyte development but inhibited sperm development. The 17β‐estradiol levels decreased significantly in the heads of both sexes after exposures to E2 and/or Flu (high and low). Flu high and E2 alone increased the 11‐KT levels in both sexes. However, E2 + Flu low decreased 11‐KT levels in males and increased them in females. Flutamide (low and high) induced VTG protein in the tails of both sexes. In males, VTG was not induced in the tail after exposure to E2. No significant effect of flutamide on E2‐induced VTG concentration was noted. We conclude that co‐treatment with flutamide and 17β‐estradiol does not lead to additive reproductive impairment in juvenile Murray rainbowfish. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-04-08T07:40:51.66153-05:0
      DOI: 10.1002/jat.3135
  • Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen
           species‐induced insulin resistance in mice
    • Authors: Hailong Hu; Qian Guo, Changlin Wang, Xiao Ma, Hongjuan He, Yuri Oh, Yujie Feng, Qiong Wu, Ning Gu
      Abstract: There have been few reports about the possible toxic effects of titanium dioxide (TiO2) nanoparticles on the endocrine system. We explored the endocrine effects of oral administration to mice of anatase TiO2 nanoparticles (0, 64 and 320 mg kg–1 body weight per day to control, low‐dose and high‐dose groups, respectively, 7 days per week for 14 weeks). TiO2 nanoparticles were characterized by scanning and transmission electron microscopy (TEM) and dynamic light scattering (DLS), and their physiological distribution was investigated by inductively coupled plasma. Biochemical analyzes included plasma glucose, insulin, heart blood triglycerides (TG), free fatty acid (FFA), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), total cholesterol (TC), tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐6 and reactive oxygen species (ROS)‐related markers (total SOD, GSH and MDA). Phosphorylation of IRS1, Akt, JNK1, and p38 MAPK were analyzed by western blotting. Increased titanium levels were found in the liver, spleen, small intestine, kidney and pancreas. Biochemical analyzes showed that plasma glucose significantly increased whereas there was no difference in plasma insulin secretion. Increased ROS levels were found in serum and the liver, as evidenced by reduced total SOD activity and GSH level and increased MDA content. Western blotting showed that oral administration of TiO2 nanoparticles induced insulin resistance (IR) in mouse liver, shown by increased phosphorylation of IRS1 (Ser307) and reduced phosphorylation of Akt (Ser473). The pathway by which TiO2 nanoparticles increase ROS‐induced IR were included in the inflammatory response and phosphokinase, as shown by increased serum levels of TNF‐α and IL‐6 and increased phosphorylation of JNK1 and p38 MAPK in liver. These results show that oral administration of TiO2 nanoparticles increases ROS, resulting in IR and increasing plasma glucose in mice. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-31T05:59:02.869333-05:
      DOI: 10.1002/jat.3150
  • Augmenting effects of gestational arsenite exposure of C3H mice on the
           hepatic tumors of the F2 male offspring via the F1 male offspring
    • Authors: Keiko Nohara; Kazuyuki Okamura, Takehiro Suzuki, Hikari Murai, Takaaki Ito, Keiko Shinjo, Shota Takumi, Takehiro Michikawa, Yutaka Kondo, Kenichiro Hata
      Abstract: Gestational exposure can affect the F2 generation through exposure of F1 germline cells. Previous studies reported that arsenite exposure of only F0 females during their pregnancy increases hepatic tumors in the F1 males in C3H mice, whose males are predisposed spontaneously to develop hepatic tumors later in life. The present study addressed the effects of gestational arsenite exposure on tumorigenesis of the F2 males in C3H mice. Expression analysis of several genes in the normal livers at 53 and 80 weeks of age clearly showed significant changes in the F2 males obtained by crossing gestational arsenite‐exposed F1 (arsenite‐F1) males and females compared to the control F2 males. Some of the changes were shown to occur in a late‐onset manner. Then the tumor incidence was assessed at 75–82 weeks of age in the F2 males obtained by reciprocal crossing between the control and arsenite‐F1 males and females. The results demonstrated that the F2 males born to arsenite‐F1 males developed tumors at a significantly higher rate than the F2 males born to the control F1 males, irrespective of exposure of F1 females. Gene expressions of hepatocellular carcinoma markers β‐catenin (CTNNB1) and interleukin‐1 receptor antagonist in the tumors were significantly upregulated in the F2 males born to arsenite‐F1 males compared to those born to the control F1 males. These results show that arsenite exposure of only F0 pregnant mice causes late‐onset changes and augments tumors in the livers of the F2 males by affecting the F1 male offspring. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-30T22:47:14.094101-05:
      DOI: 10.1002/jat.3149
  • Gene expression profiling of the hippocampal dentate gyrus in an adult
           toxicity study captures a variety of neurodevelopmental dysfunctions in
           rat models of hypothyroidism
    • Authors: Ayako Shiraki; Fumiyo Saito, Hirotoshi Akane, Yumi Akahori, Nobuya Imatanaka, Megu Itahashi, Toshinori Yoshida, Makoto Shibutani
      Abstract: We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region‐specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6‐propyl‐2‐thiouracil at a doses of 0, 0.1 and 10 mg kg−1 body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real‐time reverse‐transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28‐day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-30T20:50:06.345358-05:
      DOI: 10.1002/jat.3140
  • Development of toxicity values and exposure estimates for
           tetrabromobisphenol A: application in a margin of exposure assessment
    • Authors: Daniele Wikoff; Chad Thompson, Camarie Perry, Matthew White, Susan Borghoff, Lauren Fitzgerald, Laurie C. Haws
      Abstract: Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2‐year bioassay for TBBPA. The objective of the present study was to develop a cancer‐based and a non‐cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2‐year and 13‐week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg−1 day−1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg−1 day−1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E−7 to 3.9 E−6 mg kg−1 day−1 based on age‐adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E −7 to 8.4 E−5 mg kg−1 day−1. Resulting margin of exposure (MOE) values were > 800 000 for non‐cancer endpoints and > 32 000 000 for cancer‐based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. © 2015. The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
      PubDate: 2015-03-30T20:10:22.288627-05:
      DOI: 10.1002/jat.3132
  • Evaluation of combinations of in vitro sensitization test descriptors for
           the artificial neural network‐based risk assessment model of skin
    • Authors: Morihiko Hirota; Shiho Fukui, Kenji Okamoto, Satoru Kurotani, Noriyasu Imai, Miyuki Fujishiro, Daiki Kyotani, Yoshinao Kato, Toshihiko Kasahara, Masaharu Fujita, Akemi Toyoda, Daisuke Sekiya, Shinichi Watanabe, Hirokazu Seto, Osamu Takenouchi, Takao Ashikaga, Masaaki Miyazawa
      Abstract: The skin sensitization potential of chemicals has been determined with the use of the murine local lymph node assay (LLNA). However, in recent years public concern about animal welfare has led to a requirement for non‐animal risk assessment systems for the prediction of skin sensitization potential, to replace LLNA. Selection of an appropriate in vitro test or in silico model descriptors is critical to obtain good predictive performance. Here, we investigated the utility of artificial neural network (ANN) prediction models using various combinations of descriptors from several in vitro sensitization tests. The dataset, collected from published data and from experiments carried out in collaboration with the Japan Cosmetic Industry Association (JCIA), consisted of values from the human cell line activation test (h‐CLAT), direct peptide reactivity assay (DPRA), SH test and antioxidant response element (ARE) assay for chemicals whose LLNA thresholds have been reported. After confirming the relationship between individual in vitro test descriptors and the LLNA threshold (e.g. EC3 value), we used the subsets of chemicals for which the requisite test values were available to evaluate the predictive performance of ANN models using combinations of h‐CLAT/DPRA (N = 139 chemicals), the DPRA/ARE assay (N = 69), the SH test/ARE assay (N = 73), the h‐CLAT/DPRA/ARE assay (N = 69) and the h‐CLAT/SH test/ARE assay (N = 73). The h‐CLAT/DPRA, h‐CLAT/DPRA/ARE assay and h‐CLAT/SH test/ARE assay combinations showed a better predictive performance than the DPRA/ARE assay and the SH test/ARE assay. Our data indicates that the descriptors evaluated in this study were all useful for predicting human skin sensitization potential, although combinations containing h‐CLAT (reflecting dendritic cell‐activating ability) were most effective for ANN‐based prediction. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-30T19:40:57.244347-05:
      DOI: 10.1002/jat.3105
  • Test battery with the human cell line activation test, direct peptide
           reactivity assay and DEREK based on a 139 chemical data set for predicting
           skin sensitizing potential and potency of chemicals
    • Authors: Osamu Takenouchi; Shiho Fukui, Kenji Okamoto, Satoru Kurotani, Noriyasu Imai, Miyuki Fujishiro, Daiki Kyotani, Yoshinao Kato, Toshihiko Kasahara, Masaharu Fujita, Akemi Toyoda, Daisuke Sekiya, Shinichi Watanabe, Hirokazu Seto, Morihiko Hirota, Takao Ashikaga, Masaaki Miyazawa
      Abstract: To develop a testing strategy incorporating the human cell line activation test (h‐CLAT), direct peptide reactivity assay (DPRA) and DEREK, we created an expanded data set of 139 chemicals (102 sensitizers and 37 non‐sensitizers) by combining the existing data set of 101 chemicals through the collaborative projects of Japan Cosmetic Industry Association. Of the additional 38 chemicals, 15 chemicals with relatively low water solubility (log Kow > 3.5) were selected to clarify the limitation of testing strategies regarding the lipophilic chemicals. Predictivities of the h‐CLAT, DPRA and DEREK, and the combinations thereof were evaluated by comparison to results of the local lymph node assay. When evaluating 139 chemicals using combinations of three methods based on integrated testing strategy (ITS) concept (ITS‐based test battery) and a sequential testing strategy (STS) weighing the predictive performance of the h‐CLAT and DPRA, overall similar predictivities were found as before on the 101 chemical data set. An analysis of false negative chemicals suggested a major limitation of our strategies was the testing of low water‐soluble chemicals. When excluded the negative results for chemicals with log Kow > 3.5, the sensitivity and accuracy of ITS improved to 97% (91 of 94 chemicals) and 89% (114 of 128). Likewise, the sensitivity and accuracy of STS to 98% (92 of 94) and 85% (111 of 129). Moreover, the ITS and STS also showed good correlation with local lymph node assay on three potency classifications, yielding accuracies of 74% (ITS) and 73% (STS). Thus, the inclusion of log Kow in analysis could give both strategies a higher predictive performance. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-29T21:26:10.794897-05:
      DOI: 10.1002/jat.3127
  • A novel in chemico method to detect skin sensitizers in highly diluted
           reaction conditions
    • Authors: Yusuke Yamamoto; Haruna Tahara, Ryota Usami, Toshihiko Kasahara, Yoshihiro Jimbo, Takanori Hioki, Masaharu Fujita
      Abstract: The direct peptide reactivity assay (DPRA) is a simple and versatile alternative method for the evaluation of skin sensitization that involves the reaction of test chemicals with two peptides. However, this method requires concentrated solutions of test chemicals, and hydrophobic substances may not dissolve at the concentrations required. Furthermore, hydrophobic test chemicals may precipitate when added to the reaction solution. We previously established a high‐sensitivity method, the amino acid derivative reactivity assay (ADRA). This method uses novel cysteine (NAC) and novel lysine derivatives (NAL), which were synthesized by introducing a naphthalene ring to the amine group of cysteine and lysine residues. In this study, we modified the ADRA method by reducing the concentration of the test chemicals 100‐fold. We investigated the accuracy of skin sensitization predictions made using the modified method, which was designated the ADRA‐dilutional method (ADRA‐DM). The predictive accuracy of the ADRA‐DM for skin sensitization was 90% for 82 test chemicals which were also evaluated via the ADRA, and the predictive accuracy in the ADRA‐DM was higher than that in the ADRA and DPRA. Furthermore, no precipitation of test compounds was observed at the initiation of the ADRA‐DM reaction. These results show that the ADRA‐DM allowed the use of test chemicals at concentrations two orders of magnitude lower than that possible with the ADRA. In addition, ADRA‐DM does not have the restrictions on test compound solubility that were a major problem with the DPRA. Therefore, the ADRA‐DM is a versatile and useful method. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-25T00:19:24.155741-05:
      DOI: 10.1002/jat.3139
  • Particle uptake efficiency is significantly affected by type of capping
           agent and cell line
    • Authors: Fan Zhang; Phillip Durham, Christie M. Sayes, Boris L. T. Lau, Erica D. Bruce
      Abstract: Surface‐functionalized silver nanoparticles (AgNPs) are the most deployed engineered nanomaterials in consumer products because of their optical, antibacterial and electrical properties. Almost all engineered nanoparticles are coated with application‐specific capping agents (i.e. organic/inorganic ligands on particle surface) to enhance their stability in suspension or increase their biocompatibility for biomedicine. The aim of this study was to investigate the contribution of the selected capping agents to their observed health impacts using realistic dose ranges. AgNPs capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma (A549) and human colon adenocarcinoma (Caco‐2) cell lines and compared against exposures to Ag ions. Cellular uptake and cytotoxicity were evaluated up to 24 h. Tannic acid capped AgNPs induced higher cellular uptake and rate in both cell lines. Citrate‐capped and PVP‐capped AgNPs behaved similarly over 24 h. All three of the capped AgNPs penetrated more into the A549 cells than Caco‐2 cells. In contrast, the uptake rate of Ag ions in Caco‐2 cells (0.11 ± 0.0001 µg h–1) was higher than A549 cells (0.025 ± 0.00004 µg h–1). The exposure concentration of 3 mg l–1 is below the EC50 value for all of the AgNPs; therefore, little cytotoxicity was observed in any experiment conducted herein. Exposure of Ag ions, however, interrupted cell membrane integrity and cell proliferation (up to 70% lysed after 24 h). These findings indicate cellular uptake is dependent on capping agent, and when controlled to realistic exposure concentrations, cellular function is not significantly affected by AgNP exposure. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-24T23:21:44.462642-05:
      DOI: 10.1002/jat.3138
  • Comparative effects of sulfhydryl compounds on target organellae, nuclei
           and mitochondria, of hydroxylated fullerene‐induced cytotoxicity in
           isolated rat hepatocytes
    • Authors: Yoshio Nakagawa; Akiko Inomata, Akio Ogata, Dai Nakae
      Abstract: DNA damage and cytotoxicity induced by a hydroxylated fullerene [C60(OH)24], which is a spherical nanomaterial and/or a water‐soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60(OH)24 at a concentration of 50 μM caused time (0 to 3 h)‐dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single‐cell agarose‐gel electrophoresis. C60(OH)24‐induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N‐acetyl‐L‐cysteine (NAC), L‐cysteine and L‐methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C60(OH)24. In addition, DNA fragmentation caused by C60(OH)24 was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C60(OH)24‐induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C60(OH)24 elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox‐state imbalance caused by C60(OH)24. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-23T04:41:18.036497-05:
      DOI: 10.1002/jat.3137
  • Meloxicam inhibits fipronil‐induced apoptosis via modulation of the
           oxidative stress and inflammatory response in SH‐SY5Y cells
    • Authors: Jae Hyeon Park; Youn Sun Park, Je‐Bong Lee, Kyung‐Hun Park, Min‐kyoung Paik, Mihye Jeong, Hyun Chul Koh
      Abstract: Oxidative stress and inflammatory responses have been identified as key elements of neuronal cell apoptosis. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in human neuroblastoma SH‐SY5Y cells treated with fipronil (FPN). Based on the cytotoxic mechanism of FPN, we examined the neuroprotective effects of meloxicam against FPN‐induced neuronal cell death. Treatment of SH‐SY5Y cells with FPN induced apoptosis via activation of caspase‐9 and ‐3, leading to nuclear condensation. In addition, FPN induced oxidative stress and increased expression of cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) via inflammatory stimulation. Pretreatment of cells with meloxicam enhanced the viability of FPN‐exposed cells through attenuation of oxidative stress and inflammatory response. FPN activated mitogen activated protein kinase (MAPK) and inhibitors of MAPK abolished FPN‐induced COX‐2 expression. Meloxicam also attenuated FPN‐induced cell death by reducing MAPK‐mediated pro‐inflammatory factors. Furthermore, we observed both nuclear accumulation of p53 and enhanced levels of cytosolic p53 in a concentration‐dependent manner after FPN treatment. Pretreatment of cells with meloxicam blocked the translocation of p53 from the cytosol to the nucleus. Together, these data suggest that meloxicam may exert anti‐apoptotic effects against FPN‐induced cytotoxicity by both attenuating oxidative stress and inhibiting the inflammatory cascade via inactivation of MAPK and p53 signaling. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-13T12:18:27.333032-05:
      DOI: 10.1002/jat.3136
  • Investigation on cobalt‐oxide nanoparticles cyto‐genotoxicity
           and inflammatory response in two types of respiratory cells
    • Authors: Delia Cavallo; Aureliano Ciervo, Anna Maria Fresegna, Raffaele Maiello, Paola Tassone, Giuliana Buresti, Stefano Casciardi, Sergio Iavicoli, Cinzia Lucia Ursini
      Abstract: The increasing use of cobalt oxide (Co3O4) nanoparticles (NPs) in several applications and the suggested genotoxic potential of Co‐oxide highlight the importance of evaluating Co3O4 NPs toxicity. Cyto‐genotoxic and inflammatory effects induced by Co3O4 NPs were investigated in human alveolar (A549), and bronchial (BEAS‐2B) cells exposed to 1–40 µg ml–1. The physicochemical properties of tested NPs were analysed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cytotoxicity was studied to analyze cell viability (WST1 test) and membrane damage (LDH assay), direct/oxidative DNA damage was assessed by the Formamido‐pyrimidine glycosylase (Fpg)‐modified comet assay and inflammation by interleukin (IL)‐6, IL‐8 and tumor necrosis factor‐alpha (TNF‐α) release (ELISA). In A549 cells, no cytotoxicity was found, whereas BEAS‐2B cells showed a viability reduction at 40 µg ml–1 and early membrane damage at 1, 5 and 40 µg ml–1. In A549 cells, direct and oxidative DNA damage at 20 and 40 µg ml–1 were detected without any effects on cytokine release. In BEAS‐2B cells, significant direct DNA damage at 40 µg ml–1 and significant oxidative DNA damage with a peak at 5 µg ml–1, that was associated with increased TNF‐α release at 1 µg ml–1 after 2 h and increased IL‐8 release at 20 µg ml–1 after 24 h, were detected. The findings show in the transformed alveolar cells no cytotoxicity and genotoxic/oxidative effects at 20 and 40 µg ml–1. In normal bronchial cells, moderate cytotoxicity, direct DNA damage only at the highest concentration and significant oxidative‐inflammatory effects at lower concentrations were detected. The findings confirm the genotoxic‐oxidative potential of Co3O4 NPs and show greater sensitivity of BEAS‐2B cells to cytotoxic and oxidative‐inflammatory effects suggesting the use of different cell lines and multiple end‐points to elucidate Co3O4 NPs toxicity. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-13T12:08:33.285112-05:
      DOI: 10.1002/jat.3133
  • Cellular localization of uranium in the renal proximal tubules during
           acute renal uranium toxicity
    • Authors: Shino Homma‐Takeda; Keisuke Kitahara, Kyoko Suzuki, Benjamin J. Blyth, Noriyoshi Suya, Teruaki Konishi, Yasuko Terada, Yoshiya Shimada
      Abstract: Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high‐resolution quantitative in situ measurements by high‐energy synchrotron radiation X‐ray fluorescence analysis in renal sections from a rat model of uranium‐induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg–1 body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g–1, sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g–1). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50‐fold above mean renal concentration) in micro‐regions was found near the nuclei. These uranium levels were maintained up to 8 days post‐administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100‐fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site‐specific accumulation of uranium in micro‐regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-13T11:52:31.309239-05:
      DOI: 10.1002/jat.3126
  • Time profiles and toxicokinetic parameters of key biomarkers of exposure
           to cypermethrin in orally exposed volunteers compared with previously
           available kinetic data following permethrin exposure
    • Authors: Mylène Ratelle; Jonathan Coté, Michèle Bouchard
      Abstract: Biomonitoring of pyrethroid exposure is largely conducted but human toxicokinetics has not been fully documented. This is essential for a proper interpretation of biomonitoring data. Time profiles and toxicokinetic parameters of key biomarkers of exposure to cypermethrin in orally exposed volunteers have been documented and compared with previously available kinetic data following permethrin dosing. Six volunteers ingested 0.1 mg kg–1 bodyweight of cypermethrin acutely. The same volunteers were exposed to permethrin earlier. Blood samples were taken over 72 h after treatment and complete timed urine voids were collected over 84 h postdosing. Cis‐ and trans‐3‐(2,2‐dichlorovinyl)‐2,2‐dimethylcyclopropane‐1‐carboxylic acids (trans‐ and cis‐DCCA) and 3‐phenoxybenzoic acid (3‐PBA) metabolites, common to both cypermethrin and permethrin, were quantified. Blood and urinary time courses of all three metabolites were similar following cypermethrin and permethrin exposure. Plasma levels of metabolites reached peak values on average ≈ 5–7 h post‐dosing; the elimination phase showed mean apparent half‐lives (t½) for trans‐DCCA, cis‐DCCA and 3‐PBA of 5.1, 6.9 and 9.2 h, respectively, following cypermethrin treatment as compared to 7.1, 6.2 and 6.5 h after permethrin dosing. Corresponding mean values obtained from urinary rate time courses were peak values at ≈ 9 h post‐dosing and apparent elimination t½ of 6.3, 6.4 and 6.4 h for trans‐DCCA, cis‐DCCA and 3‐PBA, respectively, following cypermethrin treatment as compared to 5.4, 4.5 and 5.7 h after permethrin dosing. These data confirm that the kinetics of cypermethrin is similar to that of permethrin in humans and that their common biomarkers of exposure may be used for an overall assessment of exposure. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-13T11:33:30.932661-05:
      DOI: 10.1002/jat.3124
  • Non‐clinical safety assessment of single and repeated intramuscular
           administration of a human papillomavirus‐16/18 vaccine in rabbits
           and rats
    • Authors: Lawrence Segal; Danielle Morelle, Kari Kaaber, Eric Destexhe, Nathalie Garçon
      Abstract: The human papillomavirus (HPV)‐16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus‐like particles assembled from the L1 major capsid proteins of the cervical cancer‐causing viral types HPV‐16 and HPV‐18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV‐16/18 vaccine or AS04 alone, three repeated‐dose studies were performed in rabbits and rats. One rabbit study also included a single‐dose evaluation. In rabbits (~2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (~250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment‐related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment‐related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV‐16/18 vaccine. Additional treatment‐related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle‐fibre regeneration and focal points of macrophage infiltration. Therefore, in these non‐clinical models, the single and repeated dose administrations of the HPV‐16/18 vaccine or AS04 alone were safe and well tolerated. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-03-06T09:02:51.11051-05:0
      DOI: 10.1002/jat.3131
  • Sertoli cell as a model in male reproductive toxicology: Advantages and
    • Authors: Mariana M. S. Reis; Ana C. Moreira, Mário Sousa, Premendu P. Mathur, Pedro F. Oliveira, Marco G. Alves
      Pages: 870 - 883
      Abstract: Pressure towards population aging in the demographic pyramid is not only due to sociological/personal choices but also due to subfertility or infertility. There are several chemicals and mixtures that impair male fertility. While experimental animal models are crucial to identify compounds that affect male fertility, it is essential to use reliable in vitro models to determine cellular targets and intracellular pathways that mediate chemical toxicity in the male reproductive system. In this review, we focused on the somatic Sertoli cell (SC) that, within the testis, is a major target for hormonal signaling and provides physical and nutritional support to developing germ cells. The different outcomes possible in each type of study: in vivo versus in vitro (either in primary or immortalized cell cultures) are analyzed. Herein, we intend to clarify the unique features that render SCs as excellent candidates for a robust in vitro model to study the deleterious effects of chemicals on male reproductive health. The sensitivity of SCs to toxicants/pharmaceuticals is discussed and, based on the literature reviewed we propose the in vitro study of SC physiology as a model to disclose deleterious effects of substances to male fertility. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-18T22:01:36.896633-05:
      DOI: 10.1002/jat.3122
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