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ENVIRONMENTAL STUDIES (744 journals)            First | 1 2 3 4 5 6 7 8     

Historia Ambiental Latinoamericana y Caribeña     Open Access   (Followers: 1)
Home Health Care Management & Practice     Hybrid Journal   (Followers: 3)
Horticulture, Environment, and Biotechnology     Hybrid Journal   (Followers: 11)
Human & Experimental Toxicology     Hybrid Journal   (Followers: 6)
Human Ecology     Hybrid Journal   (Followers: 19)
Human Studies     Hybrid Journal   (Followers: 9)
Husserl Studies     Hybrid Journal  
Hydro Nepal : Journal of Water, Energy and Environment     Open Access   (Followers: 1)
Hydrology: Current Research     Open Access   (Followers: 10)
IAMURE International Journal of Ecology and Conservation     Open Access   (Followers: 3)
Ideas in Ecology and Evolution     Open Access   (Followers: 11)
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: 1)
Indoor Air     Hybrid Journal   (Followers: 2)
Information Systems Management     Hybrid Journal   (Followers: 18)
Information Technology and Management     Hybrid Journal   (Followers: 11)
Ingeniería Hidráulica 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: 4)
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: 6)
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: 2)
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: 12)
International Journal of Critical Infrastructures     Hybrid Journal   (Followers: 3)
International Journal of Disaster Risk Reduction     Hybrid Journal   (Followers: 7)
International Journal of Disaster Risk Science     Open Access   (Followers: 11)
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: 5)
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: 8)
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: 11)
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: 8)
International Journal of Renewable Energy Development     Open Access   (Followers: 6)
International Journal of Social Sciences and Management     Open Access   (Followers: 2)
International Journal of Soil, Sediment and Water     Open Access   (Followers: 8)
International Journal of Stress Management     Full-text available via subscription   (Followers: 11)
International Journal of Sustainable Construction Engineering and Technology     Open Access   (Followers: 11)
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: 2)
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: 3)
International Studies in the Philosophy of Science     Hybrid Journal   (Followers: 13)
Interventions : International Journal of Postcolonial Studies     Hybrid Journal   (Followers: 11)
IOP Conference Series: Earth and Environmental Science     Open Access   (Followers: 7)
Iranian Studies     Hybrid Journal   (Followers: 11)
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: 6)
Italian Studies     Hybrid Journal   (Followers: 6)
Jahangirnagar University Environmental Bulletin     Open Access  
Journal of Bioremediation & Biodegradation     Open Access   (Followers: 3)
Journal of Earth Science & Climatic Change     Open Access   (Followers: 7)
Journal of Petroleum & Environmental Biotechnology     Open Access   (Followers: 2)
Journal of Advances in Environmental Health Research     Open Access   (Followers: 2)
Journal of Agricultural and Environmental Ethics     Hybrid Journal   (Followers: 8)
Journal of Agricultural Biotechnology and Sustainable Development     Open Access  
Journal of Agricultural Chemistry and Environment     Open Access  

  First | 1 2 3 4 5 6 7 8     

Journal Cover   Journal of Applied Toxicology
  [SJR: 0.799]   [H-I: 53]   [10 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  [1597 journals]
  • Acute and sub‐lethal exposure to copper oxide nanoparticles causes
           oxidative stress and teratogenicity in zebrafish embryos
    • Authors: Santhanamari Ganesan; Naveenkumar Anaimalai Thirumurthi, Azhwar Raghunath, Savitha Vijayakumar, Ekambaram Perumal
      Abstract: Nano‐copper oxides are a versatile inorganic material. As a result of their versatility, the immense applications and usage end up in the environment causing a concern for the lifespan of various beings. The ambiguities surround globally on the toxic effects of copper oxide nanoparticles (CuO‐NPs). Hence, the present study endeavored to study the sub‐lethal acute exposure effects on the developing zebrafish embryos. The 48 hpf LC50 value was about 64 ppm. Therefore, we have chosen the sub‐lethal dose of 40 and 60 ppm for the study. Accumulation of CuO‐NPs was evidenced from the SEM‐EDS and AAS analyzes. The alterations in the AChE and Na+/K+‐ATPase activities disrupted the development process. An increment in the levels of oxidants with a concomitant decrease in the antioxidant enzymes confirmed the induction of oxidative stress. Oxidative stress triggered apoptosis in the exposed embryos. Developmental anomalies were observed with CuO‐NPs exposure in addition to oxidative stress in the developing embryos. Decreased heart rate and hatching delay hindered the normal developmental processes. Our work has offered valuable data on the connection between oxidative stress and teratogenicity leading to lethality caused by CuO‐NPs. A further molecular mechanism unraveling the uncharted connection between oxidative stress and teratogenicity will aid in the safe use of CuO‐NPs. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-23T07:12:50.346932-05:
      DOI: 10.1002/jat.3224
  • Influence of the surface charge of PLGA nanoparticles on their in vitro
           genotoxicity, cytotoxicity, ROS production and endocytosis
    • Authors: Anne Platel; Rodolphe Carpentier, Elodie Becart, Gwendoline Mordacq, Didier Betbeder, Fabrice Nesslany
      Abstract: With the ongoing commercialization of nanotechnology products, human exposure to nanoparticles (NPs) is set to increase dramatically and an evaluation of their potential adverse effects is essential. Surface charge, among other physico‐chemicals parameters, is a key criterion that should be considered when using a definition for nanomaterials in a regulatory context. It has recently been recognized as an important factor in determining the toxicity of NPs; however, a complete understanding of the mechanisms involved is still lacking. In this context, the aim of the present study was to investigate the influence of the surface charge modification of NPs on in vitro toxicity assays. Poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles bearing different surface charges, positive(+), neutral(n) or negative(−), were synthesized. In vitro genotoxicity assays (micronucleus and comet assays) coupled with an assessment of cytotoxicity, were performed in different cell lines (L5178Y mouse lymphoma cells, TK6 human B‐lymphoblastoid cells and 16HBE14o‐ human bronchial epithelial cells). Reactive oxygen species (ROS) production and endocytosis studies were also performed. Our results showed that PLGA(+) NPs were cytotoxic. They are endocytosed by the clathrin pathway and induced ROS in the three cell lines. They led to chromosomal aberrations without primary DNA damage in 16HBE14o‐ cells, suggesting that aneuploidy may be considered as an important biomarker when assessing the genotoxic potential of NPs. Moreover, 16HBE14o‐ cells seem to be more suitable for the in vitro screening of inhaled NPs than the regulatory L5178Y and TK6 cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-21T04:53:56.671676-05:
      DOI: 10.1002/jat.3247
  • Overproduction of reactive oxygen species and activation of MAPKs are
           involved in apoptosis induced by PM2.5 in rat cardiac H9c2 cells
    • Authors: Jing Cao; Gang Qin, Ruizan Shi, Feng Bai, Guangzhao Yang, Mingsheng Zhang, Jiyuan Lv
      Abstract: Epidemiological studies show a positive correlation between the air levels of fine particulate matter (PM2.5) and cardiovascular disorders, but how PM2.5 affects cardiomyocytes has not been studied in great deal. The aim of the present study was to obtain an insight into the links among intracellular levels of reactive oxygen species (ROS), apoptosis and mitogen‐activated protein kinases (MAPKs) in rat cardiac H9c2 cells exposed to PM2.5. H9c2 cells were incubated with PM2.5 at 100–800 µg ml–1 to evaluate the effects of PM2.5 on cell viability, cell apoptosis, intracellular levels of ROS and expression of apoptosis‐related proteins as well as activation of MAPKs. PM2.5 decreased cell viability, increased the cell apoptosis rate and intracellular ROS production in a concentration‐dependent manner. PM2.5 decreased the Bcl‐2/Bax ratio and increased cleaved caspase‐3 levels. A Western blots study showed up‐regulation of phosphorylated MAPKs including extracellular signal‐regulated protein kinases (ERKs), c‐Jun NH2‐terminal kinases (JNKs) and p38 MAPK in the PM2.5‐treated cells. The p38 MAPK inhibitor SB239063 attenuated whereas the ERKs inhibitor PD98059 augmented the effects of PM2.5 on apoptosis and the expression of related proteins. In conclusion, PM2.5 decreases cell viability and increases apoptosis by enhancing intracellular ROS production and activating the MAPKs signaling pathway in H9c2 cells. The MAPKs signaling pathway could be a new promising target for clinical therapeutic strategies against PM2.5‐induced cardiac injury. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-15T21:42:37.376182-05:
      DOI: 10.1002/jat.3249
  • Predictive performance of the Vitrigel‐eye irritancy test method
           using 118 chemicals
    • Authors: Hiroyuki Yamaguchi; Hajime Kojima, Toshiaki Takezawa
      Abstract: We recently developed a novel Vitrigel‐eye irritancy test (EIT) method. The Vitrigel‐EIT method is composed of two parts, i.e., the construction of a human corneal epithelium (HCE) model in a collagen vitrigel membrane chamber and the prediction of eye irritancy by analyzing the time‐dependent profile of transepithelial electrical resistance values for 3 min after exposing a chemical to the HCE model. In this study, we estimated the predictive performance of Vitrigel‐EIT method by testing a total of 118 chemicals. The category determined by the Vitrigel‐EIT method in comparison to the globally harmonized system classification revealed that the sensitivity, specificity and accuracy were 90.1%, 65.9% and 80.5%, respectively. Here, five of seven false‐negative chemicals were acidic chemicals inducing the irregular rising of transepithelial electrical resistance values. In case of eliminating the test chemical solutions showing pH 5 or lower, the sensitivity, specificity and accuracy were improved to 96.8%, 67.4% and 84.4%, respectively. Meanwhile, nine of 16 false‐positive chemicals were classified irritant by the US Environmental Protection Agency. In addition, the disappearance of ZO‐1, a tight junction‐associated protein and MUC1, a cell membrane‐spanning mucin was immunohistologically confirmed in the HCE models after exposing not only eye irritant chemicals but also false‐positive chemicals, suggesting that such false‐positive chemicals have an eye irritant potential. These data demonstrated that the Vitrigel‐EIT method could provide excellent predictive performance to judge the widespread eye irritancy, including very mild irritant chemicals. We hope that the Vitrigel‐EIT method contributes to the development of safe commodity chemicals. Copyright © 2015 The
      Authors . Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2015-10-15T21:30:06.711576-05:
      DOI: 10.1002/jat.3254
  • Pulmonary toxicity of indium‐tin oxide production facility particles
           in rats
    • Authors: Melissa A. Badding; Natalie R. Fix, Marlene S. Orandle, Mark W. Barger, Katherine M. Dunnick, Kristin J. Cummings, Stephen S. Leonard
      Abstract: Indium‐tin oxide (ITO) is used to make transparent conductive coatings for touch‐screen and liquid crystal display electronics. Occupational exposures to potentially toxic particles generated during ITO production have increased in recent years as the demand for consumer electronics continues to rise. Previous studies have demonstrated cytotoxicity in vitro and animal models have shown pulmonary inflammation and injury in response to various indium‐containing particles. In humans, pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which indium materials or specific processes in the workplace may be the most toxic to workers is unknown. Here we examined the pulmonary toxicity of three different particle samples that represent real‐life worker exposures, as they were collected at various production stages throughout an ITO facility. Indium oxide (In2O3), sintered ITO (SITO) and ventilation dust (VD) particles each caused pulmonary inflammation and damage in rats over a time course (1, 7 and 90 days post‐intratracheal instillation), but SITO and VD appeared to induce greater toxicity in rat lungs than In2O3 at a dose of 1 mg per rat. Downstream pathological changes such as PAP and fibrosis were observed in response to all three particles 90 days after treatment, with a trend towards greatest severity in animals exposed to VD when comparing animals that received the same dose. These findings may inform workplace exposure reduction efforts and provide a better understanding of the pathogenesis of an emerging occupational health issue. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2015-10-15T21:26:29.791328-05:
      DOI: 10.1002/jat.3253
  • Benzoquinone toxicity is not prevented by sulforaphane in CD‐1 mouse
           fetal liver cells
    • Authors: Nicola A. Philbrook; Louise M. Winn
      Abstract: Benzene is an environmental pollutant known to cause leukemia in adults, and may be associated with childhood leukemia. While the mechanisms of benzene‐mediated carcinogenicity have not been fully elucidated, increased reactive oxygen species (ROS) and DNA damage are implicated. Sulforaphane (SFN) induces nuclear factor erythroid 2‐related factor 2 (Nrf2), which contributes to SFN‐mediated protection against carcinogenesis. We exposed cultured CD‐1 mouse fetal liver cells to the benzene metabolite, benzoquinone, to determine its potential to cause DNA damage and alter DNA repair. Cells were also exposed to SFN to determine potential protective effects. Initially, cells were exposed to benzoquinone to confirm increased ROS and SFN to confirm Nrf2 induction. Subsequently, cells were treated with benzoquinone (with or without SFN) and levels of ROS, 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG; marker of oxidative DNA damage), gamma histone 2A variant X (γH2AX; marker of DNA double‐stranded breaks; DSBs) and transcript levels of genes involved in DNA repair were measured. Benzoquinone exposure led to a significant increase in ROS, which was not prevented by pretreatment with SFN or the antioxidative enzyme, catalase. DNA damage was increased after benzoquinone exposure, which was not prevented by SFN. Benzoquinone exposure significantly decreased the transcript levels of the critical base excision repair gene, 8‐oxoguanine glycosylase (Ogg1), which was not prevented by SFN. The findings of this study demonstrate for the first time that DNA damage and altered DNA repair are a consequence of benzoquinone exposure in CD‐1 mouse fetal liver cells and that SFN conferred little protection in this model. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-12T03:33:52.706615-05:
      DOI: 10.1002/jat.3251
  • Comparison of outcomes obtained in murine local lymph node assays using
           CBA/J or CBA/Ca mice
    • Authors: Yosuke Maeda; Haruka Hirosaki, Naoaki Yakata, Masahiro Takeyoshi
      Abstract: CBA/J and CBA/Ca mice are the recommended strains for local lymph node assays (LLNAs). Here, we report quantitative and qualitative comparisons between both mouse strains to provide useful information for the strain selection of sensitization testing. LLNA was conducted, in accordance with Organisation for Economic Co‐operation and Development Test Guideline No. 429, with CBA/J and CBA/Ca mice using five chemicals including typical contact sensitizers and non‐sensitizers: 2,4‐dinitrochlorobenzene (DNCB), isoeugenol, α‐hexylcinnamic aldehyde (HCA), propylene glycol (PG), and hexane; then outcomes were compared based on the raw data (disintegrations per minute, DPM), stimulation index (SI) values, EC3 values and positive/negative decisions. Although a significant difference was noted between DPM values derived from each strain of mice, SI values exhibited no considerable difference. The EC3 values for DNCB in CBA/J and CBA/Ca mice were 0.04 and 0.03, those for isoeugenol were 1.4 and 0.9, and those for HCA were 7.7 and 6.0, respectively. All EC values derived from each test system were almost equivalent and were within the range of acceptance criteria of the ICCVAM performance standard for LLNA. Positive/negative outcomes for all test chemicals were consistent. In conclusion, no considerable differences were observed in the final outcomes derived from CBA/J and CBA/Ca mice in LLNA. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-12T03:15:00.050218-05:
      DOI: 10.1002/jat.3250
  • Biodistribution and toxicity of spherical aluminum oxide nanoparticles
    • Abstract: With the rapid development of the nano‐industry, concerns about their potential adverse health effects have been raised. Thus, ranking accurately their toxicity and prioritizing for in vivo testing through in vitro toxicity test is needed. In this study, we used three types of synthesized aluminum oxide nanoparticles (AlONPs): γ‐aluminum oxide hydroxide nanoparticles (γ‐AlOHNPs), γ‐ and α‐AlONPs. All three AlONPs were spherical, and the surface area was the greatest for γ‐AlONPs, followed by the α‐AlONPs and γ‐AlOHNPs. In mice, γ‐AlOHNPs accumulated the most 24 h after a single oral dose. Additionally, the decreased number of white blood cells (WBC), the increased ratio of neutrophils and the enhanced secretion of interleukin (IL)‐8 were observed in the blood of mice dosed with γ‐AlOHNPs (10 mg kg−1). We also compared their toxicity using four different in vitro test methods using six cell lines, which were derived from their potential target organs, BEAS‐2B (lung), Chang (liver), HACAT (skin), H9C2 (heart), T98G (brain) and HEK‐293 (kidney). The results showed γ‐AlOHNPs induced the greatest toxicity. Moreover, separation of particles was observed in a transmission electron microscope (TEM) image of cells treated with γ‐AlOHNPs, but not γ‐AlONPs or α‐AlONPs. In conclusion, our results suggest that the accumulation and toxicity of AlONPs are stronger in γ‐AlOHNPs compared with γ‐AlONPs and α‐AlONPs owing their low stability within biological system, and the presence of hydroxyl group may be an important factor in determining the distribution and toxicity of spherical AlONPs. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-05T22:00:55.648455-05:
      DOI: 10.1002/jat.3233
  • Proteomic responses of human intestinal Caco‐2 cells exposed to
           silver nanoparticles and ionic silver
    • Abstract: Even although quite a number of studies have been performed so far to demonstrate nanoparticle‐specific effects of substances in living systems, clear evidence of these effects is still under debate. The present study was designed as a comparative proteomic analysis of human intestinal cells exposed to a commercial silver nanoparticle reference material and ions from AgNO3. A two‐dimensional gel electrophoresis/MALDI mass spectrometry (MS)‐based proteomic analysis was conducted after 24‐h incubation of differentiated Caco‐2 cells with non‐cytotoxic and low cytotoxic silver concentrations (2.5 and 25 µg ml−1 nanosilver, 0.5 and 5 µg ml−1 AgNO3). Out of an overall number of 316 protein spots differentially expressed at a fold change of ≥ 1.4 or ≤ −1.4 in all treatments, 169 proteins could be identified. In total, 231 spots were specifically deregulated in particle‐treated groups compared with 41 spots, which were limited to AgNO3‐treatments. Forty‐four spots (14 %) were commonly deregulated by both types of treatment. A considerable fraction of the proteins differentially expressed after treatment with nanoparticles is related to protein folding, synthesis or modification of proteins as well as cellular assembly and organization. Overlays of networks obtained for particulate and ionic treatments showed matches, indicating common mechanisms of combined particle and ionic silver exposure and exclusive ionic silver treatment. However, proteomic responses of Caco‐2 cells treated with higher concentrations of silver species also showed some differences, for example regarding proteins related to fatty acid and energy metabolism, suggesting an induction of also some different molecular mechanisms for particle exposure and ionic treatment. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-10-05T03:54:14.806293-05:
      DOI: 10.1002/jat.3231
  • Distribution and immunotoxicity by intravenous injection of iron
           nanoparticles in a murine model
    • Abstract: With the increased application of iron oxide nanoparticles (FeNPs) for biomedical imaging purposes, concerns regarding the onset of the unexpected adverse health effects following exposure have been rapidly raised. In this study, we investigated the tissue distribution and immunotoxicity of FeNPs (2 and 4 mg kg–1) over time (2, 4 and 13 weeks) after single intravenous injection. At 13 weeks after a single injection, the iron levels increased in all measured tissues compared to the control, and iron accumulation was notable in the liver, spleen and thymus. These changes were accompanied by changes in levels of redox reaction‐related elements, including copper, manganese, zinc and cobalt. In addition, as compared to the control, the number of white blood cells and percentage of neutrophils significantly increased in the treated groups, and the interleukin‐8 secretion and lactate dehydrogenase release were clearly elevated in the treated groups along with enhanced expressions of chemotaxis‐related proteins. However, expression of antigen presenting related proteins attenuated following accumulation of FeNPs. Taken together, we suggest that FeNPs may primarily induce toxicity in the liver and immune system, and immunotoxicological evaluation should be considered to predict adverse health effects following exposure to NPs. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-29T03:32:49.238425-05:
      DOI: 10.1002/jat.3232
  • Differentiation of stem cells into insulin‐producing cells under the
           influence of nanostructural polyoxometalates
    • Abstract: Two polyoxometalates (POMs) with W were synthesized by a two‐step, self‐assembling method. They were used for stimulation of mesenchymal stem cell differentiation into insulin‐producing cells. The nanocompounds (tris(vanadyl)‐substituted tungsto‐antimonate(III) anions [POM1] and tris‐butyltin‐21‐tungsto‐9‐antimonate(III) anions [POM2]) were characterized by analytical techniques, including ultraviolet‐visible, Fourier transform infrared, nuclear magnetic resonance spectroscopy, and transmission electron microscopy. We found that these polyoxotungstates, with 2–4 nm diameters, did not present toxic effects at the tested concentrations. In vitro, POM1 stimulated differentiation of a greater number of dithizone‐positive cells (also organized in clusters) than the second nanocompound (POM2). Based on our in vitro studies, we have concluded that both the POMs tested had significant biological activity acting as active stimuli for differentiation of stem cells into insulin‐producing cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-23T07:37:58.963191-05:
      DOI: 10.1002/jat.3218
  • Thyroid endocrine disruption of acetochlor on zebrafish (Danio rerio)
    • Authors: Mei Yang; Jingjin Hu, Shuying Li, Youning Ma, Wenjun Gui, Guonian Zhu
      Abstract: The herbicide acetochlor is widely used and detected in the environment and biota, and has been suspected to disrupt the thyroid endocrine system, but underlying mechanisms have not yet been clarified. In the present study, zebrafish larvae (7 days post‐fertilization) were exposed to a series concentration of acetochlor (0, 1, 3, 10, 30, 100 and 300 µg l−1) within a 14‐day window until 21 days post‐fertilization. Thyroid hormones and mRNA expression profiles of genes involved in the hypothalamic–pituitary–thyroid (HPT) axis were analyzed. Exposure to the positive control, 3,5,3′‐triiodothyronine (T3), altered the mRNA expression, suggesting that the HPT axis in the critical window of zebrafish responded to chemical exposure and could be used to evaluate the effects of chemicals on the thyroid endocrine system. The mRNA expressions of genes involved in thyroid hormone synthesis (tshβ, slc5a5 and tpo) were upregulated significantly with acetochlor treatment, which might be responsible for the increased thyroxine concentrations. The downregulation of genes related to thyroid hormone metabolism (dio1 and ugt1ab) and transport (ttr) in zebrafish larvae exposed to acetochlor might further explain the increased thyroxine levels and decreased T3 levels. The mRNA expression of the thyroid hormone receptor (trα) was also upregulated upon acetochlor exposure. Results suggested that acetochlor altered mRNA expression of the HPT axis‐related genes and changed the whole body thyroid hormone levels in zebrafish larvae. It demonstrated that acetochlor could cause endocrine disruption of the thyroid system by simulating the biological activity of T3. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-23T07:03:38.912914-05:
      DOI: 10.1002/jat.3230
  • Functional expressions of adenosine triphosphate‐binding cassette
           transporters during the development of zebrafish embryos and their effects
    • Authors: Huancai Yin; Pengli Bai, Peng Miao, Mingli Chen, Jun Hu, Xudong Deng, Jian Yin
      Abstract: Adenosine triphosphate‐binding cassette (ABC) transporters, including ABCB, ABCC and ABCG families represent general biological defenses against environmental toxicants in varieties of marine and freshwater organisms, but their physiological functions at differential developmental stages of zebrafish embryos remain undefined. In this work, functional expressions of typical ABC transporters including P‐glycoprotein (Pgp), multiresistance associated protein 1 (Mrp1) and Mrp2 were studied in zebrafish embryos at 4, 24, 48 and 72 h post‐fertilization (hpf). As a result, both the gene expressions and activities of Pgp and Mrps increased with the development of embryos. Correspondingly, 4–72 hpf embryos exhibited an increased tolerance to the toxicity caused by cadmium chloride (CdCl2) and β‐naphthoflavone (BNF) with time. Such a correlation was assumed caused by the involvement of ABC transporters in the detoxification of chemicals. In addition, the assumption was supported by the fact that model efflux inhibitors of Pgp and Mrps such as reversine 205 and MK571 significantly inhibited the efflux of toxicants and increased the toxicity of Cd and BNF in zebrafish embryos. Moreover, exposure to CdCl2 and BNF induced the gene expressions of Pgp and Mrp1 in 72 hpf embryos. Thus, functional expressions of Pgp and Mrps increased with the development of zebrafish embryos, which could cause an increasing tolerance of zebrafish embryos to CdCl2 and BNF. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-21T04:25:27.06615-05:0
      DOI: 10.1002/jat.3225
  • Oxidative stress‐related DNA damage and homologous recombination
           repairing induced by N,N‐dimethylformamide
    • Authors: Cui Wang; Jinhuan Yang, Dezhao Lu, Yongsheng Fan, Meirong Zhao, Zhuoyu Li
      Abstract: The intensified anthropogenic release of N,N‐dimethylformamide (DMF) has been proven to have hepatotoxic effects. However, the potential mechanism for DMF‐induced toxicity has rarely been investigated. Our research implicated that DMF induced a significantly dose‐dependent increase in reactive oxygen species (ROS) in HL‐7702 human liver cells. Moreover, oxidative stress‐related DNA damage, marked as 8‐hydroxy‐2′‐deoxyguanosine, was increased 1.5‐fold at 100 mmol l–1. The most severe DNA lesion (double‐strand break, DSB), measured as the formation of γH2AX foci, was increased at/above 6.4 mmol l–1, and approximately 50% of cells underwent DSB at the peak induction. Subsequently, the DNA repair system triggered by molecules of RAD50 and MRE11A induced the homologous recombination (HR) pathway by upregulation of both gene and protein levels of RAD50, RAD51, XRCC2 and XRCC3 at 16 mmol l–1 and was attenuated at 40 mmol l–1. Consequently, cellular death observed at 40 mmol l–1 was exaggerated compared with exposure at 16 mmol l–1. Although the exact mechanism relying on the DMF‐induced hepatotoxicity needs further clarification, oxidative stress and DNA damage involved in DSBs partially explain the reason for DMF‐induced liver injury. Oxidative stress‐induced DNA damage should be first considered during risk assessment on liver‐targeted chemicals. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-21T04:21:02.98119-05:0
      DOI: 10.1002/jat.3226
  • Tris(2‐chloroethyl)phosphate‐induced cell growth arrest via
           attenuation of SIRT1‐independent PI3K/Akt/mTOR pathway
    • Authors: Wenjuan Zhang; Youjian Zhang, Zhiyuan Wang, Tian Xu, Cheng Huang, Wenjun Yin, Jing Wang, Wei Xiong, Wenhong Lu, Hongyan Zheng, Jing Yuan
      Abstract: Tris(2‐chloroethyl)phosphate (TCEP) as an organophosphorus flame retardant and plasticizer has been widely used in industrial and household products. It not only was detected in residential indoor air and dust, surface and drinking water, but also in human plasma and breast milk, and tissue samples of liver, kidneys and brain from rodents. TCEP is classified as carcinogenic category 2 and toxic for reproduction category 1B. Sufficient evidence from experimental animals indicated carcinogenicity of TCEP in the liver, and kidneys as well as cell loss in the brain. However, the underlying mechanisms of TCEP‐induced hepatotoxicity are mostly unknown. We investigated the in vitro effects of TCEP as well as TCEP‐induced cell growth in the L02 and HepG2 cells through the PI3K/Akt/mTOR pathway. We found that TCEP reduced cell viability of these cell lines, induced the cell growth arrest, upregulated mRNA and protein levels of SIRT1, and attenuated the PI3K/Akt/mTOR pathway. However, growth arrest of the L02 and HepG2 cells were aggravated after inhibiting the SIRT1 expression with EX‐527. The findings above suggested that TCEP induced the cell growth arrest of L02 and HepG2 cells via attenuation of the SIRT1‐independent PI3K/Akt/mTOR pathway. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-17T07:34:11.283797-05:
      DOI: 10.1002/jat.3223
  • Zerovalent Fe, Co and Ni nanoparticle toxicity evaluated on SKOV‐3
           and U87 cell lines
    • Authors: Rosalba Gornati; Elisa Pedretti, Federica Rossi, Francesca Cappellini, Michela Zanella, Iolanda Olivato, Enrico Sabbioni, Giovanni Bernardini
      Abstract: We have considered nanoparticles (NPs) of Fe, Co and Ni, three transition metals sharing similar chemical properties. NP dissolution, conducted by radioactive tracer method and inductively coupled plasma mass spectrometry, indicated that NiNPs and FeNPs released in the medium a much smaller amount of ions than that released by Co NPs. The two considered methodological approaches, however, gave comparable but not identical results. All NPs are readily internalized by the cells, but their quantity inside the cells is less than 5%. Cytotoxicity and gene expression experiments were performed on SKOV‐3 and U87 cells. In both cell lines, CoNPs and NiNPs were definitely more toxic than FeNPs. Real‐time polymerase chain reaction experiments aimed to evaluate modifications of the expression of genes involved in the cellular stress response (HSP70, MT2A), or susceptible to metal exposure (SDHB1 and MLL), or involved in specific cellular processes (caspase3, IQSEC1 and VMP1), gave different response patterns in the two cell lines. HSP70, for example, was highly upregulated by CoNPs and NiNPs, but only in SKOV‐3 cell lines. Overall, this work underlines the difficulties in predicting NP toxicological properties based only on their chemical characteristics. We, consequently, think that, at this stage of our knowledge, biological effects induced by metal‐based NPs should be examined on a case‐by‐case basis following studies on different in vitro models. Moreover, with the only exception of U87 exposed to Ni, our results suggest that metallic NPs have caused, on gene expression, similar effects to those caused by their corresponding ions. Copyright © 2015 The
      Authors . Journal of Applied Toxicology published by John Wiley & Sons, Ltd.
      PubDate: 2015-09-17T07:31:25.199438-05:
      DOI: 10.1002/jat.3220
  • Evaluation of uptake, cytotoxicity and inflammatory effects in respiratory
           cells exposed to pristine and ‐OH and ‐COOH functionalized
           multi‐wall carbon nanotubes
    • Authors: Cinzia Lucia Ursini; Raffaele Maiello, Aureliano Ciervo, Anna Maria Fresegna, Giuliana Buresti, Fabiana Superti, Magda Marchetti, Sergio Iavicoli, Delia Cavallo
      Abstract: Toxic effects were reported for pristine‐multi‐wall carbon nanotubes (p‐MWCNTs) while the role of the functionalization on MWCNT‐induced toxicity is not yet well defined. We evaluated on human alveolar (A549) epithelial cells and normal bronchial (BEAS‐2B) cells exposed to p‐MWCNTs, MWCNTs‐OH and MWCNTs‐COOH: uptake by TEM, cell viability by different assays, membrane damage by the LDH assay and cytokine release by ELISA. The aims of the present study were to: (i) confirm MWCNT cytotoxicity mechanisms hypothesized in our previous studies; (ii) identify the most reliable viability assay to screen MWCNT toxicity; and (iii) to test our model to clarify the role of functionalization on MWCNT‐induced toxicity. In A549 cells, p‐MWCNTs and MWCNTs‐OH were localized free in the cytoplasm and inside vacuoles whereas MWCNTs‐COOH were confined inside filled cytoplasmic vesicles. WST‐1 and Trypan blue assays showed in A549 cells a similar slight viability reduction for all MWCNTs whereas in BEAS‐2B cells WST1 showed a high viability reduction at the highest concentrations, particularly for MWCNTs‐COOH. The MTT assay showed a false cytotoxicity as a result of MWCNTs‐interference. Pristine and MWCNTs‐COOH induced membrane damage, particularly in BEAS‐2B cells. MWCNTs‐COOH induced interleukin‐6 (IL‐6) and IL‐8 release in A549 cells whereas p‐MWCNTs induced IL‐8 release in BEAS‐2B cells. MWCNTs intracellular localization in A549 cells confirms the toxicity mechanisms previously hypothesized, with p‐MWCNTs disrupting the membrane and vesicle‐confined MWCNTs‐COOH inducing inflammation. WST‐1 was more reliable than MTT to test MWCNT‐toxicity. BEAS‐2B cells were more susceptible then A549 cells, particularly to MWCNT‐COOH cytotoxicity. Our results confirm the toxicity of p‐MWCNTs and demonstrate, also for the two kinds of tested functionalized MWCNTs toxic effects with a different mechanism of action. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-15T06:27:44.303623-05:
      DOI: 10.1002/jat.3228
  • Research advances on potential neurotoxicity of quantum dots
    • Authors: Tianshu Wu; Ting Zhang, Yilu Chen, Meng Tang
      Abstract: With rapid development of nanotechnology, quantum dots (QDs) as advanced nanotechnology products have been widely used in biological and biomedical studies, including neuroscience, due to their superior optical properties. In recent years, there has been intense concern regarding the toxicity of QDs with a growing number of studies. However, the knowledge of neurotoxic consequences of QDs applied in living organisms is lagging behind their development, while a potential risk of neurotoxicity arises if mass production of QDs leads to increased exposure and distribution in the nervous system. Owing to the quantum size effect of QDs, they are capable of crossing the blood–brain barrier or moving along neural pathways and entering the brain. Nevertheless, the interactions of QDs with cells and tissues in the central nervous system are not well understood. This review highlighted research advances on the neurotoxicity of QDs in the central nervous system, including oxidative stress injury, elevated cytoplasmic Ca2+ levels and autophagy to damage in vitro neural cells, and impairments of synaptic transmission and plasticity as well as brain functions in tested animals, with the hope of throwing light on future research directions of QD neurotoxicity, which is a demanding topic that requires further exploration. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-13T22:31:49.508048-05:
      DOI: 10.1002/jat.3229
  • Benzo(a)pyrene inhibits migration and invasion of extravillous trophoblast
           HTR‐8/SVneo cells via activation of the ERK and JNK pathway
    • Authors: Liyuan Liu; Yingxiong Wang, Cha Shen, Junlin He, Xueqing Liu, Yubin Ding, Rufei Gao, Xuemei Chen
      Abstract: Benzo(a)pyrene (BaP) is a persistent organic pollutant (POP) that is a serious threat to human health. Numerous studies have shown that BaP causes adverse effects in pregnancy, but the mechanism remains unclear. The moderate invasion of trophoblast cells into the endometrium is an important factor during successful embryo implantation. The aim of this study was to investigate the effect and mechanism of BaP on the invasion and migration of trophoblast cells. HTR‐8/SVneo cells were treated with different concentrations (1, 5, 10, 25, 50 and 100 μM) of BaP. The invasion and migration of HTR‐8/SVneo cells were observed after BaP treatment. The protein levels related to migration and invasion was detected by Western blot. The results confirmed that BaP inhibits the migration and invasion of extravillous trophoblast HTR‐8/SVneo cells. Further investigations indicated that the protein levels of MMP‐2, MMP‐9 and E‐cadherin in HTR‐8/SVneo cells were changed by BaP treatment. Moreover, the data demonstrated that BaP activated the MAPK signaling pathway. Pretreatment with specific inhibitors of MAPK rescued BaP‐induced change in the migration and invasion of HTR‐8/SVneo cells. Taken together, our results indicated that BaP inhibits invasion and the migration of HTR‐8/SVneo cells, which might cause a failure in early pregnancy. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-11T01:41:32.933218-05:
      DOI: 10.1002/jat.3227
  • Altered expression of histone deacetylases, inflammatory cytokines and
           contractile‐associated factors in uterine myometrium of Long Evans
           rats gestationally exposed to benzo[a]pyrene
    • Abstract: Etiology of preterm birth (PTB) is multifactorial; therefore, decreasing the incidence of PTB is a major challenge in the field of obstetrics. Epidemiological studies have reported an association between toxicants and PTB. However, there are no studies on the role of benzo[a]pyrene (BaP), an environmental toxicant, in the incidence of PTB. We first assessed the effects of BaP (150 and 300 µg kg–1 body weight) dosed via gavage from day 14 to 17 of pregnancy on gestation length in Long Evans rats. We further assessed the histopathology of the uterus, expression of inflammatory cytokines, contractile‐associated factors, histone deacetylases (HDACs) and NFқB‐p65 in myometrium collected on day 22 postpartum versus vehicle‐treated controls. In our study, rats exposed to BaP delivered prematurely (P < 0.05) compared to control. Hematoxylin and eosin staining of uterus showed squamous metaplasia, glandular and stromal hyperplasia in BaP‐exposed rats versus control. The concentrations of BaP metabolites measured by high‐pressure liquid chromatography were higher in uterine myometrium of BaP‐exposed rats while they were undetectable in controls. Quantitative real‐time polymerase chain reaction showed significant increases in mRNA expression of interleukin‐1β and ‐8, tumor necrosis factor‐α, connexin 43, cyclo‐oxygenase‐2 and prostaglandin F2α receptor as compared to controls (P < 0.05). Western blot analysis revealed that BaP exposure caused decreases in class I HDACs 1 and 3 and increases in class II HDAC 5, cyclo‐oxygenase‐2 and nuclear translocation of NFκB‐p65 relative to controls. Our results suggest that gestational exposure to BaP increases incidence of PTB through epigenetic changes that causes increases in the expression of contractile‐associated factors through the NFκB pathway. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-11T01:37:09.353576-05:
      DOI: 10.1002/jat.3216
  • Recent knowledge: Concepts of dermal absorption in relation to skin
    • Authors: Christina Phuong; Howard I. Maibach
      Abstract: Skin decontamination is an important step mitigating percutaneous absorption through the stratum corneum (SC), which is also a highly complex process. Thus, understanding diffusion mechanisms and measuring dermal absorption rates are critical to protect humans from toxic exposures. Here, highly varied literature is placed in a biological and clinical perspective in regards to decontamination. Literature from PubMed and Surge Laboratory library files were searched and reviewed for relevance. Recent data have shown multiple layers of SC structural heterogeneity, which results in unique substance partitioning characteristics across the membrane. As such, attempts to model and understand this behavior in alternative in vitro membranes prove difficult. More synthetic and natural membranes are being explored as models for in vivo behavior. In addition, commonly accepted decontamination methods are undergoing risk assessment. These recent and varied literature findings update available knowledge regarding skin decontamination and its challenges, with a focus on dermal absorption. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-09-11T01:32:42.991476-05:
      DOI: 10.1002/jat.3222
  • The impact of caffeine on connexin expression in the embryonic chick
           cardiomyocyte micromass culture system
    • Authors: Bhavesh K. Ahir; Margaret K. Pratten
      Abstract: Cardiomyocytes are electrically coupled by gap junctions, defined as clusters of low‐resistance multisubunit transmembrane channels composed of connexins (Cxs). The expression of Cx40, Cx43 and Cx45, which are present in cardiomyocytes, is known to be developmentally regulated. This study investigates the premise that alterations in gap junction proteins are one of the mechanisms by which teratogens may act. Specifically, those molecules known to be teratogenic in humans could cause their effects via disruption of cell‐to‐cell communication pathways, resulting in an inability to co‐ordinate tissue development. Caffeine significantly inhibited contractile activity at concentrations above and including 1500 μm (P < 0.05), while not affecting cell viability and total protein, in the embryonic chick cardiomyocyte micromass culture system. The effects of caffeine on key cardiac gap junction protein (Cx40, Cx43 and Cx45) expression were analysed using immunocytochemistry and in‐cell Western blotting. The results indicated that caffeine altered the expression pattern of Cx40, Cx43 and Cx45 at non‐cytotoxic concentrations (≥2000 μm), i.e., at concentrations that did not affect total cell protein and cell viability. In addition the effects of caffeine on cardiomyocyte formation and function (contractile activity score) were correlated with modulation of Cxs (Cx40, Cx43 and Cx45) expression, at above and including 2000 μm caffeine concentrations (P < 0.05). These experiments provide evidence that embryonic chick cardiomyocyte micromass culture may be a useful in vitro method for mechanistic studies of perturbation of embryonic heart development. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-24T21:05:44.799038-05:
      DOI: 10.1002/jat.3219
  • The toxic effects of indoor atmospheric fine particulate matter collected
           from allergic and non‐allergic families in Wuhan on mouse peritoneal
    • Authors: Biao Yan; Jinquan Li, Junhui Guo, Ping Ma, Zhuo Wu, ZhenHao Ling, Hai Guo, Yoshino Hiroshi, U. Yanagi, Xu Yang, Shengwei Zhu, Mingqing Chen
      Abstract: Recent studies have shown that fine particulate matter (PM2.5) is associated with multiple adverse health outcomes and PM2.5‐induced oxidative stress is now commonly known as a proposed mechanism of PM2.5‐mediated toxicity. However, the association between allergic symptoms in children and exposure to PM2.5 has not been fully elucidated, particularly the role of PM2.5 on the indoor environment involved in allergy or non‐allergy is unknown. The aim of the present study was to explore whether indoor PM2.5 from the homes of children with allergic symptoms had more increased risks of allergy than that of healthy ones and then compare the toxicity and inflammatory response of them. In this study, indoor PM2.5 was collected from the homes of schoolchildren with allergic symptoms and those of healthy ones respectively, and components of PM2.5 were analyzed. PM2.5‐mediated oxidative damage and inflammatory response were further evaluated in mouse peritoneal macrophages based on its effects on the levels of reactive oxygen species accumulation, lipid peroxidation, DNA damage or cytokine production. It seems that oxidative stress may contribute to PM2.5‐induced toxicity, and PM2.5 from the allergic indoor environment produced more serious toxic effects and an inflammatory response on mouse peritoneal macrophages than that from a non‐allergic indoor environment. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-24T21:03:21.068601-05:
      DOI: 10.1002/jat.3217
  • Human ketosteroid receptors interact with hazardous phthalate plasticizers
           and their metabolites: an in silico study
    • Authors: M. K. Sarath Josh; S. Pradeep, K. S. Vijayalekshmy Amma, R. Sudha Devi, S. Balachandran, M. N. Sreejith, Sailas Benjamin
      Abstract: Phthalic acid esters or phthalates are ubiquitous environmental pollutants known for their adverse health effects in test animals and, of late, in humans. Thus, in this molecular docking study – using Glide (Schrödinger) – the molecular interactions of 31 ligands, including 12 diphthalates, their monophthalates and phthalic acid with selected human ketosteroid receptors, i.e., androgen (hAR), progesterone (hPR) and glucocorticoid (hGR) receptors were explored and their binding affinities were compared with that of corresponding natural steroids and a known endocrine disrupting xenobiotic, bisphenol A (BPA). Mostly, diphthalates and monophthalates showed the potential for antisteroidal activity by interacting with hAR, hPR and hGR. Of them, diphenyl phthalate showed the highest G score (–7.70 kcal mol–1) with hAR, and the crucial amino acid (aa) residues in the ligand binding domain (LBD) of this receptor involved in the molecular interactions were Phe 764, Leu 704, Asn 705 and Thr 877. The mono‐iso‐decyl phthalate showed the highest G score (–8.36) with the hPR, and the crucial aa residues in the LBD interactions were Arg 766 Gln 725 and Phe 778. The mono‐iso‐decyl phthalate also showed more affinity (–8.44) towards hGR than the natural ligand, and the aa residues in the LBD interactions were Gln 570 and Met 604. In addition to these, some other phthalates established comparable interactions with certain aa residues located in the LBD of these receptors, which resulted in higher G scores. Contrastingly, BPA and some natural ligands tested in this study showed lower G scores with these receptors than certain phthalates reported herein, i.e., certain phthalates are more toxic than the proven toxic BPA. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-24T20:58:14.890977-05:
      DOI: 10.1002/jat.3221
  • Aryl hydrocarbon receptor knockout rats are insensitive to the
           pathological effects of repeated oral exposure to
    • Authors: Joshua A. Harrill; Debra Layko, Abraham Nyska, Renee R. Hukkanen, Rosa Anna Manno, Andrea Grassetti, Marie Lawson, Greg Martin, Robert A. Budinsky, J. Craig Rowlands, Russell S. Thomas
      Abstract: Sustained activation of the aryl hydrocarbon receptor (AHR) is believed to be the initial key event in AHR receptor‐mediated tumorigenesis in the rat liver. The role of AHR in mediating pathological changes in the liver prior to tumor formation was investigated in a 4‐week, repeated‐dose study using adult female wild‐type (WT) and AHR knockout (AHR‐KO) rats treated with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). Beginning at 8 weeks of age, AHR‐KO and WT rats were dosed by oral gavage with varying concentrations of TCDD (0, 3, 22, 100, 300 and 1000 ng kg−1 day−1). Lung, liver and thymus histopathology, hematology, serum chemistry and the distribution of TCDD in liver and adipose tissue were examined. Treatment‐related increases in the severity of liver and thymus pathology were observed in WT, but not AHR‐KO rats. In the liver, these included hepatocellular hypertrophy, bile duct hyperplasia, multinucleated hepatocytes and inflammatory cell foci. A loss of cellularity in the thymic cortex and thymic atrophy was observed. Treatment‐related changes in serum chemistry parameters were also observed in WT, but not AHR‐KO rats. Finally, dose‐dependent accumulation of TCDD was observed primarily in the liver of WT rats and primarily in the adipose tissue of AHR‐KO rats. The results suggest that AHR activation is the initial key event underlying the progression of histological effects leading to liver tumorigenesis following TCDD treatment. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-17T03:18:18.106857-05:
      DOI: 10.1002/jat.3211
  • Sensitive periods for 17β‐estradiol exposure during immune
           system development in sea bass head kidney
    • Abstract: An increasing body of evidence suggests that sex steroids play an important role in the development and regulation of vertebrate immune defense. Therefore, compounds with estrogenic activity may influence the immune system via receptor‐mediated pathways. The presence of estrogen receptors in immune cells and organs during the early stages of development may indicate that female steroid hormones are involved in the maturation of the fish immune system. This is of particular importance, as some marine fish are probably exposed to sources of exogenous estrogens while they reside in their estuarine nursery grounds. In this study, the influence of 17β‐estradiol (E2) on estrogen receptor and cytokine gene expression was assessed in juvenile sea bass (Dicentrarchus labrax) together with characterization of the head kidney leukocyte populations and corresponding phagocytic activity during organ regionalization from 98 to 239 dph. E2 exposure, beginning at 90 dph resulted in indirect and delayed modifications of interleukin 1β and estrogen receptor α gene expression, which may affect B‐lymphocyte proliferation in the sea bass head kidney. The E2 treatment of 120 dph fish led to an increase in estrogen receptor β2 and a decrease in transforming growth factor β1 gene expression, which coincided with decreased phagocytic activity of head kidney lymphocytes and monocytes/macrophages. Additionally, these changes were observed during developmental periods described as critical phases for B‐lymphocyte development in mammals. Consequently, exogenous estrogens have the potential to modify the innate immune response in juvenile sea bass and to exert detrimental effects on head kidney development. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-16T21:42:45.661493-05:
      DOI: 10.1002/jat.3215
  • An in vitro human skin test for assessing sensitization potential
    • Authors: S. S. Ahmed; X. N. Wang, M. Fielding, A. Kerry, I. Dickinson, R. Munuswamy, I. Kimber, A. M. Dickinson
      Abstract: Sensitization to chemicals resulting in an allergy is an important health issue. The current gold‐standard method for identification and characterization of skin‐sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in‐vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro‐haptens, respiratory sensitizers, non‐sensitizing chemicals (including skin‐irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non‐sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNγ production, respectively. Collectively, the data suggests the human in‐vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-07T07:21:20.976936-05:
      DOI: 10.1002/jat.3197
  • Perfluorinated chemicals, PFOS and PFOA, enhance the estrogenic effects of
           17β‐estradiol in T47D human breast cancer cells
    • Authors: Pacharapan Sonthithai; Tawit Suriyo, Apinya Thiantanawat, Piyajit Watcharasit, Mathuros Ruchirawat, Jutamaad Satayavivad
      Abstract: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most popular surfactants among perfluorinated compounds (PFCs), with a wide range of uses. Growing evidence suggests that PFCs have the potential to interfere with estrogen homeostasis, posing a risk of endocrine‐disrupting effects. This in vitro study aimed to investigate the estrogenic effect of these compounds on T47D hormone‐dependent breast cancer cells. PFOS and PFOA (10−12 to 10−4 M) were not able to induce estrogen response element (ERE) activation in the ERE luciferase reporter assay. The ERE activation was induced when the cells were co‐incubated with PFOS (10−10 to 10−7 M) or PFOA (10−9 to 10−7 M) and 1 nM of 17β‐estradiol (E2). PFOS and PFOA did not modulate the expression of estrogen‐responsive genes, including progesterone (PR) and trefoil factor (pS2), but these compounds enhanced the effect of E2‐induced pS2 gene expression. Neither PFOS nor PFOA affected T47D cell viability at any of the tested concentrations. In contrast, co‐exposure with PFOS or PFOA and E2 resulted in an increase of E2‐induced cell viability, but no effect was found with 10 ng ml−1 EGF co‐exposure. Both compounds also intensified E2‐dependent growth in the proliferation assay. ERK1/2 phosphorylation was increased by co‐exposure with PFOS or PFOA and E2, but not with EGF. Collectively, this study shows that PFOS and PFOA did not possess estrogenic activity, but they enhanced the effects of E2 on estrogen‐responsive gene expression, ERK1/2 activation and the growth of the hormone‐deprived T47D cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-08-03T03:06:33.538916-05:
      DOI: 10.1002/jat.3210
  • In vitro cytotoxicity of superparamagnetic iron oxide nanoparticles on
           neuronal and glial cells. Evaluation of nanoparticle interference with
           viability tests
    • Abstract: Superparamagnetic iron oxide nanoparticles (ION) have attracted great interest for use in several biomedical fields. In general, they are considered biocompatible, but little is known of their effects on the human nervous system. The main objective of this work was to evaluate the cytotoxicity of two ION (magnetite), coated with silica and oleic acid, previously determining the possible interference of the ION with the methodological procedures to assure the reliability of the results obtained. Human neuroblastoma SHSY5Y and glioblastoma A172 cells were exposed to different concentrations of ION (5–300 µg ml–1), prepared in complete and serum‐free cell culture medium for three exposure times (3, 6 and 24 h). Cytotoxicity was evaluated by means of the MTT, neutral red uptake and alamar blue assays. Characterization of the main physical–chemical properties of the ION tested was also performed. Results demonstrated that both ION could significantly alter absorbance readings. To reduce these interferences, protocols were modified by introducing additional washing steps and cell‐free systems. Significant decreases in cell viability were observed for both cell lines in specific conditions by all assays. In general, oleic acid‐coated ION were less cytotoxic than silica‐coated ION; besides, a serum‐protective effect was observed for both ION studied and cell lines. These results contribute to increase the knowledge of the potential harmful effects of ION on the human nervous system. Understanding these effects is essential to establish satisfactory regulatory policies on the safe use of magnetite nanoparticles in biomedical applications. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-26T20:27:14.367536-05:
      DOI: 10.1002/jat.3213
  • Antimicrobial agent triclosan is a proton ionophore uncoupler of
           mitochondria in living rat and human mast cells and in primary human
    • Authors: Lisa M. Weatherly; Juyoung Shim, Hina N. Hashmi, Rachel H. Kennedy, Samuel T. Hess, Julie A. Gosse
      Abstract: Triclosan (TCS) is an antimicrobial used widely in hospitals and personal care products, at ~10 mm. Human skin efficiently absorbs TCS. Mast cells are ubiquitous key players both in physiological processes and in disease, including asthma, cancer and autism. We previously showed that non‐cytotoxic levels of TCS inhibit degranulation, the release of histamine and other mediators, from rat basophilic leukemia mast cells (RBL‐2H3), and in this study, we replicate this finding in human mast cells (HMC‐1.2). Our investigation into the molecular mechanisms underlying this effect led to the discovery that TCS disrupts adenosine triphosphate (ATP) production in RBL‐2H3 cells in glucose‐free, galactose‐containing media (95% confidence interval EC50 = 7.5–9.7 µm), without causing cytotoxicity. Using these same glucose‐free conditions, 15 µm TCS dampens RBL‐2H3 degranulation by 40%. The same ATP disruption was found with human HMC‐1.2 cells (EC50 4.2–13.7 µm), NIH‐3 T3 mouse fibroblasts (EC50 4.8–7.4 µm) and primary human keratinocytes (EC50 3.0–4.1 µm) all with no cytotoxicity. TCS increases oxygen consumption rate in RBL‐2H3 cells. Known mitochondrial uncouplers (e.g., carbonyl cyanide 3‐chlorophenylhydrazone) previously were found to inhibit mast cell function. TCS‐methyl, which has a methyl group in place of the TCS ionizable proton, affects neither degranulation nor ATP production at non‐cytotoxic doses. Thus, the effects of TCS on mast cell function are due to its proton ionophore structure. In addition, 5 µm TCS inhibits thapsigargin‐stimulated degranulation of RBL‐2H3 cells: further evidence that TCS disrupts mast cell signaling. Our data indicate that TCS is a mitochondrial uncoupler, and TCS may affect numerous cell types and functions via this mechanism. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-23T21:48:50.906798-05:
      DOI: 10.1002/jat.3209
  • BDE‐209 inhibits pluripotent genes expression and induces apoptosis
           in human embryonic stem cells
    • Authors: Lili Du; Wen Sun, Huili Zhang, Dunjin Chen
      Abstract: Decabromodiphenyl ether (BDE‐209) has been detected in human serum, semen, placenta, cord blood and milk worldwide. However, little is known regarding the potential effects on the early human embryonic development of BDE‐209. In this study, human embryonic stem cell lines FY‐hES‐10 and FY‐hES‐26 were used to evaluate the potential effects and explore the toxification mechanisms using low‐level BDE‐209 exposure. Our data showed that BDE‐209 exposure (1, 10 and 100 nM) reduced the expression of pluripotent genes such as OCT4, SOX2 and NANOG and induced human embryonic stem cells (hESCs) apoptosis. The downregulation of BIRC5/BCL2 and upregulation of BAX were related to apoptosis of hESCs induced by BDE‐209 exposure. A mechanism study showed that OCT4 down‐regulation accompanied by OCT4 promoter hypermethylation and increasing miR‐145/miR‐335 levels, OCT4 inhibitors. Moreover, BDE‐209 could increase the generation of intracellular reactive oxygen species (ROS) and decrease SOD2 expression. The ROS increase and OCT4 downregulation after BDE‐209 exposure could be reversed partly by antioxidant N‐acetylcysteine supplement. These findings showed that BDE‐209 exposure could decrease pluripotent genes expression via epigenetic regulation and induce apoptosis through ROS generation in human embryonic stem cells in vitro. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-23T21:32:17.620812-05:
      DOI: 10.1002/jat.3195
  • Proposed human stratum corneum water domain in chemical absorption
    • Abstract: Compounds with varying physical and chemical properties may have different affinities to the stratum corneum (SC) and/or its intercellular lipids, keratin protein, and possible water domains. To better understand the mechanism of percutaneous absorption, we utilized 21 carbon‐14 labeled chemicals, with wide hydrophilicity (log P = −0.05 to 6.17), and quantified their absorption/adsorption properties for a short incubation time (15 min) with regards to intact SC membrane, delipidized SC membrane and SC lipid. A facile method was developed for SC/lipid absorption, providing a more equivalent procedure and comparable data. SC lipid absorption of chemical solutes positively correlated with the octanol/water partition coefficient (log P). Differences between the percent dose of chemical absorption to intact SC and the total percent dose contributed by the protein and lipid domains suggest the possibility and significance of a water domain. Absorption rate experiments showed a longer lag time for intact SC than for delipidized SC or SC lipid, suggesting that the water domain may delay chemical binding to protein and lipid domains, and may be a factor in the resistance of many chemicals to current decontamination methods. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-23T05:56:54.365679-05:
      DOI: 10.1002/jat.3208
  • Automated swimming activity monitor for examining temporal patterns of
           toxicant effects on individual Daphnia magna
    • Authors: Simon Bahrndorff; Thomas Yssing Michaelsen, Anne Jensen, Laurits Faarup Marcussen, Majken Elley Nielsen, Peter Roslev
      Abstract: Aquatic pollutants are often biologically active at low concentrations and impact on biota in combination with other abiotic stressors. Traditional toxicity tests may not detect these effects, and there is a need for sensitive high‐throughput methods for detecting sublethal effects. We have evaluated an automated infra‐red (IR) light‐based monitor for recording the swimming activity of Daphnia magna to establish temporal patterns of toxicant effects on an individual level. Activity was recorded for 48 h and the sensitivity of the monitor was evaluated by exposing D. magna to the reference chemicals K2Cr2O7 at 15, 20 and 25 °C and 2,4‐dichlorophenol at 20 °C. Significant effects (P < 0.001) of toxicant concentrations, exposure time and incubation temperatures were observed. At 15 °C, the swimming activity remained unchanged for 48 h at sublethal concentrations of K2Cr2O7 whereas activity at 20 and 25 °C was more biphasic with decreases in activity occurring after 12–18 h. A similar biphasic pattern was observed after 2,4‐dichlorophenol exposure at 20 °C. EC50 values for 2,4‐dichlorophenol and K2Cr2O7 determined from automated recording of swimming activity showed increasing toxicity with time corresponding to decreases in EC50 of 0.03–0.07 mg l–1 h–1. EC50 values determined after 48 h were comparable or lower than EC50 values based on visual inspection according to ISO 6341. The results demonstrated that the swimming activity monitor is capable of detecting sublethal behavioural effects that are toxicant and temperature dependent. The method allows EC values to be established at different time points and can serve as a high‐throughput screening tool in toxicity testing. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-21T05:31:28.545639-05:
      DOI: 10.1002/jat.3212
  • Cytotoxicity and apoptosis induced by silver nanoparticles in human liver
           HepG2 cells in different dispersion media
    • Authors: Yuying Xue; Ting Zhang, Bangyong Zhang, Fan Gong, Yanmei Huang, Meng Tang
      Abstract: Silver nanoparticles (Ag NPs) have been widely used in medical and healthcare products owing to their unique antibacterial activities. However, their safety for humans and the environment has not yet been established. This study evaluated the cellular proliferation and apoptosis of Ag NPs suspended in different solvents using human liver HepG2 cells. The ionization of Ag NPs in different dispersion media [deionized water, phosphate‐buffered saline (PBS), saline and cell culture] was measured using an Ag ion selective electrode. The MTT assay was used to examine the cell proliferation activities. The effects of Ag NPs on cell cycle, induction of apoptosis, production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed using flow cytometry. The degree of Ag NPs ionization differed with dispersion media, with the concentrations of silver ions in deionized water being the highest in all suspensions. Ag NPs could inhibit the viability of HepG2 cells in a time‐ and concentration‐dependent manner. Ag NPs (40, 80 and 160 µg ml−1) exposure could cause cell‐cycle arrest in the G2/M phase, significantly increasing the apoptosis rate and ROS generation, and decreasing the MMP in HepG2 cells more sensitive to deionized water than in cell culture. These results suggested that the cellular toxicological mechanism of Ag NPs might be related to the oxidative stress of cells by the generation of ROS, leading to mitochondria injury and induction of apoptosis. It also implies that it is important to assess the physicochemical properties of NPs in the media where the biological toxicity tests are performed. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-21T05:10:47.38802-05:0
      DOI: 10.1002/jat.3199
  • Cytochrome P450 induction response in tethered spheroids as a
           three‐dimensional human hepatocyte in vitro model
    • Authors: Lei Xia; Xin Hong, Rashidah Binte Sakban, Yinghua Qu, Nisha Hari Singh, Michael McMillian, Shannon Dallas, Jose Silva, Carlo Sensenhauser, Sylvia Zhao, Heng Keang Lim, Hanry Yu
      Abstract: Cytochrome P450 (CYP) induction is a key risk factor of clinical drug–drug interactions that has to be mitigated in the early phases of drug discovery. Three‐dimensional (3D) cultures of hepatocytes in vitro have recently emerged as a potentially better platform to recapitulate the in vivo liver structure and to maintain long‐term hepatic functions as compared with conventional two‐dimensional (2D) monolayer cultures. However, the majority of published studies on 3D hepatocyte models use rat hepatocytes and the response to CYP inducers between rodents and humans is distinct. In the present study, we constructed tethered spheroids on RGD/galactose‐conjugated membranes as an in vitro 3D model using cryopreserved human hepatocytes. CYP3A4 mRNA expression in the tethered spheroids was induced to a significantly greater extent than those in the collagen sandwich cultures, indicating the transcriptional regulation was more sensitive to the CYP inducers in the 3D model. Induction of CYP1A2, CYP2B6 and CYP3A4 activities in the tethered spheroids were comparable to, if not higher than that observed in the collagen sandwich cultures. The membrane‐based model is readily integrated into multi‐well plates for higher‐throughput drug testing applications, which might be an alternative model to screen the CYP induction potential in vitro with more physiological relevance. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-21T04:58:22.08485-05:0
      DOI: 10.1002/jat.3189
  • An improved model of predicting hepatocarcinogenic potential in rats by
           using gene expression data
    • Authors: Fumihiro Yamada; Kayo Sumida, Koichi Saito
      Abstract: Carcinogenicity studies using animals are expensive and time consuming. Therefore, the development of a highly accurate carcinogenicity prediction system to interpret short‐term test results would be beneficial. The Ames test is popular for mutagens; however, it cannot detect non‐genotoxic carcinogens. Previously, we reported a prediction system using gene expression data obtained from a short‐term (28‐day) study that screened candidate compounds for testing in long‐term carcinogenicity studies. In this study, our system was improved by adding more gene expression data. To establish our new system, we used the data of 93 test compounds (41 hepatocarcinogens and 52 non‐hepatocarcinogens). Analysis of liver gene expression data by dividing compounds into ‘for training’ and ‘for test’ categories (20 cases assigned randomly) using Support Vector Machine (SVM) identified a set of marker probe sets that could be used to predict hepatocarcinogenicity. The assigned 42 probe sets have included the cancer‐ or c‐Myc‐related genes such as Hsp90, Pink1, Hspc111, Fbx29, Hepsin, Syndecan2 and Synbindin. Compared with the older version, the improved system had a higher concordance rate with the training data and a good performance with the external test data. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-21T04:56:45.795652-05:
      DOI: 10.1002/jat.3184
  • Protein profiles of cardiomyocyte differentiation in murine embryonic stem
           cells exposed to perfluorooctane sulfonate
    • Abstract: Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant that may affect diverse systems in animals and humans, including the cardiovascular system. However, little is known about the mechanism by which it affects the biological systems. Herein, we used embryonic stem cell test procedure as a tool to assess the developmental cardiotoxicity of PFOS. The differentially expressed proteins were identified by quantitative proteomics that combines the stable isotope labeling of amino acids with high‐performance liquid chromatography‐electrospray ionization tandem mass spectrometry. Results of the embryonic stem cell test procedure suggested that PFOS was a weak embryotoxic chemical. Nevertheless, a few marker proteins related to cardiovascular development (Brachyury, GATA4, MEF2C, α‐actinin) were significantly reduced by exposure to PFOS. In total, 176 differential proteins were identified by proteomics analysis, of which 67 were upregulated and 109 were downregulated. Gene ontology annotation classified these proteins into 13 groups by molecular functions, 12 groups by cellular locations and 10 groups by biological processes. Most proteins were mainly relevant to either catalytic activity (25.6%), nucleus localization (28.9%) or to cellular component organization (19.8%). Pathway analysis revealed that 32 signaling pathways were affected, particularly these involved in metabolism. Changes in five proteins, including L‐threonine dehydrogenase, X‐ray repair cross‐complementing 5, superoxide dismutase 2, and DNA methyltransferase 3b and 3a were confirmed by Western blotting, suggesting the reliability of the technique. These results revealed potential new targets of PFOS on the developmental cardiovascular system. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-15T20:30:37.579967-05:
      DOI: 10.1002/jat.3207
  • Defensive and adverse energy‐related molecular responses precede
           tris (1, 3‐dichloro‐2‐propyl) phosphate cytotoxicity
    • Authors: Jinkang Zhang; Timothy D. Williams, James K. Chipman, Mark R. Viant
      Abstract: To understand the potentially adverse effects of human exposure to tris (1, 3‐dichloro‐2‐propyl) phosphate (TDCIPP) and explore the underlying molecular mechanisms, combined transcriptomic and metabolomic approaches were employed to investigate the molecular responses of two human cell lines exposed to different concentrations of TDCIPP. Comparative analyses of transcriptional and metabolic profiles of HepG2/C3A and A549 cells were performed after exposure to 1, 10 and 100 μM TDCIPP for 24 and 72 h. Stress responses (e.g. xenobiotic metabolism and ABC transporter pathways) were observed at the transcriptional level after 24‐h exposure to a sub‐cytotoxic concentration (10 μM). Transcription of an energy metabolism‐related pathway (oxidative phosphorylation) was down‐regulated more severely at 100 μM TDCIPP exposure, accompanied by the suppression of pathways relevant to cell proliferation (e.g. cell cycle and DNA replication), while no significant cytotoxic effects were observed. Functional metabolic changes were observed after 72 h in HepG2/C3A cells exposed to 100 μM TDCIPP that corresponded to changes detected at the transcriptional level after 24 h. Taken together, defensive responses to chemical exposure and energy‐related changes both precede the cytotoxic effects of TDCIPP in HepG2/C3A cells. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-15T19:38:25.104468-05:
      DOI: 10.1002/jat.3194
  • Effects of sulpiride and ethylene glycol monomethyl ether on endometrial
           carcinogenicity in Donryu rats
    • Authors: Yoshikazu Taketa; Kaoru Inoue, Miwa Takahashi, Yohei Sakamoto, Gen Watanabe, Kazuyoshi Taya, Midori Yoshida
      Abstract: Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten‐week‐old female Donryu rats were treated once with N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (20 mg kg−1), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride‐treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol‐17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol‐17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:39:16.58795-05:0
      DOI: 10.1002/jat.3206
  • The comparative toxicity of a reduced, crude comfrey (Symphytum
           officinale) alkaloid extract and the pure, comfrey‐derived
           pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus
           gallus domesticus)
    • Authors: Ammon W. Brown; Bryan L. Stegelmeier, Steven M. Colegate, Dale R. Gardner, Kip E. Panter, Edward L. Knoppel, Jeffery O. Hall
      Abstract: Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended comfrey be used for external use only. However, in many locations comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced comfrey alkaloid extract to purified lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol lycopsamine, intermedine or reduced comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced comfrey extract was more toxic than lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of comfrey. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
      PubDate: 2015-07-14T10:36:06.246574-05:
      DOI: 10.1002/jat.3205
  • Kupffer cell‐mediated exacerbation of methimazole‐induced
           acute liver injury in rats
    • Authors: Sho Akai; Yasuaki Uematsu, Koichi Tsuneyama, Shingo Oda, Tsuyoshi Yokoi
      Abstract: Methimazole (MTZ), an anti‐thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ‐induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine‐mediated immune responses; however, there is little evidence for immune responses associated with MTZ‐induced liver injury in rats. To investigate species differences in MTZ‐induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L‐buthionine‐S,R‐sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high‐mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune‐related genes significantly increased in BSO‐ and MTZ‐treated rats, but the change in Th2‐related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal‐regulated kinase (ERK)/c‐Jun N‐terminal kinase (JNK) proteins were accompanied by an increase in Toll‐like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1‐TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell‐mediated immune responses are crucial factors for the exacerbation of MTZ‐induced liver injury in rats, indicating apparent species differences in the immune‐mediated exacerbation of liver injury between mice and rats. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:34:08.229968-05:
      DOI: 10.1002/jat.3202
  • Effects of urban particulate matter with high glucose on human monocytes
    • Authors: Yue Zhang; Yiqun Mo, Aihua Gu, Rong Wan, Qunwei Zhang, David J. Tollerud
      Abstract: Epidemiological studies and animal experiments have shown that individuals with preexisting diseases, such as diabetes mellitus (DM), are more susceptible to particulate matter (PM)‐related cardiovascular diseases. However, the underlying mechanisms are still unclear. We hypothesized that PM and high glucose combined would cause enhanced effects on activation of monocytes and p38 mitogen‐activated protein kinase (MAPK) by inducing oxidative stress, which would further activate matrix metalloproteinases (MMPs). Human monocytes U937 were used to test the effects of urban particulate matter (U‐PM) and high glucose. The results showed that exposure of monocytes to non‐toxic doses of U‐PM alone caused generation of reactive oxygen species (ROS), increased phosphorylation of p38, and activation of monocytes which was reflected by up‐regulation of MMP‐2, MMP‐9 and proinflammatory cytokines IL‐1β and IL‐8 expression and increased activity of pro‐MMP‐2 and pro‐MMP‐9. These effects were enhanced significantly when cells were exposed to U‐PM in a high‐glucose environment. Our results also showed that pre‐treatment of cells with ROS scavengers or inhibitors abolished U‐PM and high glucose‐induced increased phosphorylation of p38. Up‐regulation of pro‐MMP‐2 and pro‐MMP‐9 activity by U‐PM in the setting of high glucose level was dramatically attenuated by treatment of cells with the p38‐specific inhibitor, SB203580. These results suggest that activation of MMPs by U‐PM with high glucose is partly through p38 phosphorylation that is induced by oxidative stress. Our findings may have important implications in understanding the potential health effects of PM on susceptible populations such as those with DM. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:33:21.403648-05:
      DOI: 10.1002/jat.3198
  • Investigating the effect of excess caffeine exposure on placental
           angiogenesis using chicken ’functional‘ placental blood vessel
    • Abstract: It is now known that over‐consumption of caffeine by pregnant mothers could have detrimental effects on normal fetal development. However, it remains obscure how caffeine's harmful effect impacts directly or indirectly on the developing embryo/fetus through damaging placenta development. In this study, we demonstrated the morphological similarities between the yolk sac and chorioallantoic membranes (CAM) of chick embryos and the villi of the mammalian placenta. Using the chick yolk sac and the CAM as a model, we found that 5–15 µmol per egg of caffeine exposure inhibited angiogenesis. Under the same condition, cell proliferation in extraembryonic mesoderm was reduced while apoptosis was enhanced. Semi‐quantitative RT‐PCR analysis revealed that caffeine treatment down‐regulated VEGF, VEGFR2, PIGF, IGF2 and NRP1 expression, but up‐regulated Ang1 and Ang2 expression. We performed in situ hybridization to show VE‐cadherin expression and as to demonstrate the blood vessels in the CAM and yolk sac membranes. This distribution of the VE‐cadherin+ blood vessels was determined to be reduced after caffeine treatment. Furthermore, MDA activity was induced after caffeine exposure, but GSH‐PX activity was inhibited after caffeine exposure; SOD activity was unchanged as compared with the control. In summary, our results suggest that caffeine exposure could negatively impact on angiogenesis in the chick yolk sac and CAM by targeting angiogenesis‐related genes. Some of these genes are also involved in regulating excess ROS generation. The results implied that the negative impact of caffeine on fetal development was partly attributed to impaired placental angiogenesis. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:22:58.690916-05:
      DOI: 10.1002/jat.3181
  • Angiogenesis is repressed by ethanol exposure during chick embryonic
    • Abstract: It is now known that excess alcohol consumption during pregnancy can cause fetal alcohol syndrome to develop. However, it is not known whether excess ethanol exposure could directly affect angiogenesis in the embryo or angiogenesis being indirectly affected because of ethanol‐induced fetal alcohol syndrome. Using the chick yolk sac membrane (YSM) model, we demonstrated that ethanol exposure dramatically inhibited angiogenesis in the YSM of 9‐day‐old chick embryos, in a dose‐dependent manner. Likewise, the anti‐angiogenesis effect of ethanol could be seen in the developing vessel plexus (at the same extra‐embryonic regions) during earlier stages of embryo development. The anti‐angiogenic effect of ethanol was found associated with excess reactive oxygen species (ROS) production; as glutathione peroxidase activity increased while superoxide dismutase 1 and 2 activities decreased in the YSMs. We further validated this observation by exposing chick embryos to 2,2′‐azobis‐amidinopropane dihydrochloride (a ROS inducer) and obtained a similar anti‐angiogenesis effect as ethanol treatment. Semiquantitative reverse transcription–polymerase chain reaction analysis of the experimental YSMs revealed that expression of angiogenesis‐related genes, vascular endothelial growth factor and its receptor, fibroblast growth factor 2 and hypoxia‐inducible factor, were all repressed following ethanol and 2,2′‐azobis‐amidinopropane dihydrochloride treatment. In summary, our results suggest that excess ethanol exposure inhibits embryonic angiogenesis through promoting superfluous ROS production during embryo development. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:22:47.184028-05:
      DOI: 10.1002/jat.3201
  • An assay to determine the sensitive window of embryos to chemical exposure
           using Xenopus tropicalis
    • Authors: Lingling Hu; Lijiao Wu, Yingang Xue, Jingmin Zhu, Huahong Shi
      Abstract: The frog embryo teratogenesis assay‐Xenopus (FETAX) is an established method to evaluate the developmental toxicity of chemicals. In FETAX, a 48 h continuous exposure is usually conducted when the X. tropicalis embryo is used as the test model. In the present study, we exposed X. tropicalis embryos to nine known teratogens for four separate 12‐h periods. The embryos showed great variations in response to nine tested compounds during different exposure periods. Based on the value of the score of malformations, the most sensitive 12 h exposure periods of embryos were significantly distinguished for all the compounds with the exception of NiCl2. The embryos were the most sensitive to retinols (e.g. all‐trans‐retinoic acid and 9‐cis‐retinoic acid) during 0–12 h and to metal compounds (e.g. triphenlytin and CdCl2) during a 24 to 36 h exposure period. In the further 3 h exposure experiment, the most sensitive period could only be determined for one of three tested compounds. Based on the present results, we proposed an assay to determine a 12 h sensitive window of embryos to chemical exposure using Xenopus tropicalis. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-14T10:22:33.386683-05:
      DOI: 10.1002/jat.3200
  • Investigation of ifosfamide and chloroacetaldehyde renal toxicity through
           integration of in vitro liver–kidney microfluidic data and
           pharmacokinetic‐system biology models
    • Authors: Eric Leclerc; Jeremy Hamon, Frederic Yves Bois
      Abstract: We have integrated in vitro and in silico data to describe the toxicity of chloroacetaldehyde (CAA) on renal cells via its production from the metabolism of ifosfamide (IFO) by hepatic cells. A pharmacokinetic (PK) model described the production of CAA by the hepatocytes and its transport to the renal cells. A system biology model was coupled to the PK model to describe the production of reactive oxygen species (ROS) induced by CAA in the renal cells. In response to the ROS production, the metabolism of glutathione (GSH) and its depletion were modeled by the action of an NFE2L2 gene‐dependent pathway. The model parameters were estimated in a Bayesian context via Markov Chain Monte Carlo (MCMC) simulations based on microfluidic experiments and literature in vitro data. Hepatic IFO and CAA in vitro intrinsic clearances were estimated to be 1.85 x 10‐9 μL s–1 cell–1 and 0.185 x 10‐9 μL s–1 cell–1,respectively (corresponding to an in vivo intrinsic IFO clearance estimate of 1.23 l h–1, to be compared to IFO published values ranging from 3 to 10 l h–1). After model calibration, simulations made at therapeutic doses of IFO showed CAA renal intracellular concentrations ranging from 11 to 131 μM. Intracellular CAA concentrations above 70 μM induced intense ROS production and GSH depletion. Those responses were time and dose dependent, showing transient and non‐linear kinetics. Those results are in agreement with literature data reporting that intracellular CAA toxic concentrations range from 35 to 320 μM, after therapeutic ifosfamide dosing. The results were also consistent with in vitro CAA renal cytotoxicity data. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-07T23:55:07.334278-05:
      DOI: 10.1002/jat.3191
  • Developing Xenopus embryos recover by compacting and expelling single wall
           carbon nanotubes
    • Authors: Brian D. Holt; Joseph H. Shawky, Kris Noel Dahl, Lance A. Davidson, Mohammad F. Islam
      Abstract: Single wall carbon nanotubes are high aspect ratio nanomaterials being developed for use in materials, technological and biological applications due to their high mechanical stiffness, optical properties and chemical inertness. Because of their prevalence, it is inevitable that biological systems will be exposed to nanotubes, yet studies of the effects of nanotubes on developing embryos have been inconclusive and are lacking for single wall carbon nanotubes exposed to the widely studied model organism Xenopus laevis (African clawed frog). Microinjection of experimental substances into the Xenopus embryo is a standard technique for toxicology studies and cellular lineage tracing. Here we report the surprising finding that superficial (12.5 ± 7.5 µm below the membrane) microinjection of nanotubes dispersed with Pluronic F127 into one‐ to two‐cell Xenopus embryos resulted in the formation and expulsion of compacted, nanotube‐filled, punctate masses, at the blastula to mid‐gastrula developmental stages, which we call “boluses.” Such expulsion of microinjected materials by Xenopus embryos has not been reported before and is dramatically different from the typical distribution of the materials throughout the progeny of the microinjected cells. Previous studies of microinjections of nanomaterials such as nanodiamonds, quantum dots or spherical nanoparticles report that nanomaterials often induce toxicity and remain localized within the embryos. In contrast, our results demonstrate an active recovery pathway for embryos after exposure to Pluronic F127‐coated nanotubes, which we speculate is due to a combined effect of the membrane activity of the dispersing agent, Pluronic F127, and the large aspect ratio of nanotubes. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-07-07T08:31:30.511702-05:
      DOI: 10.1002/jat.3203
  • 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
  • Sub‐chronic exposure to fluoride impacts the response to a
           subsequent nephrotoxic treatment with gentamicin
    • 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
    • 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
    • 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
  • Non‐clinical safety evaluation of repeated intramuscular
           administration of the AS15 immunostimulant combined with various antigens
           in rabbits and cynomolgus monkeys
    • 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
  • 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
  • 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
  • Safety concerns of herbal products and traditional Chinese herbal
           medicines: dehydropyrrolizidine alkaloids and aristolochic acid
    • Authors: Bryan L. Stegelmeier; Ammon W. Brown, Kevin D. Welch
      First page: 1433
      Abstract: In many countries, including the United States, herbal supplements, tisanes and vegetable products, including traditional Chinese medicines, are largely unregulated and their content is not registered, monitored or verified. Consequently, potent plant toxins including dehydropyrrolizidine alkaloids and other potential carcinogens can contaminate these products. As herbal and food supplement producers are left to their own means to determine the safety and purity of their products prior to marketing, disturbingly often good marketing practices currently in place are ignored and content is largely undocumented. Historical examples of poisoning and health issues relating to plant material containing dehydopyrrolizidine alkaloids and aristolochic acids were used as examples to demonstrate the risk and potential toxicity of herbal products, food supplements, or traditional medicines. More work is needed to educate consumers of the potential risk and require the industry to be more responsible to verify the content and insure the safety of their products. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2015-07-07T07:20:45.37385-05:0
      DOI: 10.1002/jat.3192
  • Distribution and biomarkers of carbon‐14‐labeled fullerene C60
           ([14C(U)]C60) in female rats and mice for up to 30 days after intravenous
    • Authors: Susan C. J. Sumner; Rodney W. Snyder, Christopher Wingard, Ninell P. Mortensen, Nathan A. Holland, Jonathan H. Shannahan, Suraj Dhungana, Wimal Pathmasiri, Li Han, Anita H. Lewin, Timothy R. Fennell
      Pages: 1452 - 1464
      Abstract: A comprehensive distribution study was conducted in female rats and mice exposed to a suspension of uniformly carbon‐14‐labeled C60 ([14C(U)]C60). Rodents were administered [14C(U)]C60 (~0.9 mg kg−1 body weight) or 5% polyvinylpyrrolidone‐saline vehicle alone via a single tail vein injection. Tissues were collected at 1 h and 1, 7, 14 and 30 days after administration. A separate group of rodents received five daily injections of suspensions of either [14C(U)]C60 or vehicle with tissue collection 14 days post exposure. Radioactivity was detected in over 20 tissues at all time points. The highest concentration of radioactivity in rodents at each time point was in liver, lungs and spleen. Elimination of [14C(U)]C60 was < 2% in urine and feces at any 24 h time points. [14C(U)]C60 and [14C(U)]C60‐retinol were detected in liver of rats and together accounted for ~99% and ~56% of the total recovered at 1 and 30 days postexposure, respectively. The blood radioactivity at 1 h after [14C(U)]C60 exposure was fourfold higher in rats than in mice; blood radioactivity was still in circulation at 30 days post [14C(U)]C60 exposure in both species (
      PubDate: 2015-02-27T06:04:19.725928-05:
      DOI: 10.1002/jat.3110
  • 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
      Pages: 1465 - 1472
      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
  • Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in
           zebrafish larvae
    • Pages: 1473 - 1480
      Abstract: Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC50 value at 60.63 and 476.84 µg ml–1, respectively, whereas the LC50 of Acid Red 26 was between 2500 and 2800 µg ml–1. Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml–1. Basic Violet 14 also caused significant up‐regulation of GCLC gene expression in a dose‐dependent manner whereas Acid Red 26 induced significant up‐regulation of NKX2.5 and down‐regulation of GATA4 at a high concentration in a dose‐dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ‐specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-27T06:35:48.327256-05:
      DOI: 10.1002/jat.3134
  • 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
      First page: 1493
      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
      First page: 1502
      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
  • Human bone morphogenetic protein‐7 does not counteract aristolochic
           acid‐induced renal toxicity
    • Pages: 1520 - 1530
      Abstract: Aristolochic acids (AA) are nephrotoxic and profibrotic agents, leading to chronic kidney disease. As some controversial studies have reported a nephroprotective effect of exogenous recombinant human bone morphogenetic protein (rhBMP)‐7 in several models of renal fibrosis, we investigated the putative effect of rhBMP‐7 to prevent progressive tubulointerstitial damage after AA intoxication in vitro and in vivo. In vitro, the toxicity of AA on renal tubular cells was demonstrated by an increase in vimentin as well as a decrease in β‐catenin expressions, reflecting a dedifferentiation process. Increased fibronectin and interleukin‐6 levels were measured in the supernatants. Enhanced α‐SMA mRNA levels associated to decreased E‐cadherin mRNA levels were also measured. Incubation with rhBMP‐7 only prevented the increase in vimentin and the decrease in β‐catenin expressions. In vivo, in a rat model of AA nephropathy, severe tubulointerstitial lesions induced by AA after 10 and 35 days (collagen IV deposition and tubular atrophy), were not prevented by the rhBMP‐7 treatment. Similarly, rhBMP‐7 did not ameliorate the significant increase in urinary concentrations of transforming growth factor‐β. In summary, our in vitro data demonstrated a poor beneficial effect of rhBMP‐7 to reverse cell toxicity while, in vivo, there was no beneficial effect of rhBMP‐7. Therefore, further investigations are needed to confirm the exact role of BMP‐7 in progressive chronic kidney disease. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-07T01:38:35.977963-05:
      DOI: 10.1002/jat.3116
  • Two‐generation reproduction and teratology studies of feeding
           aditoprim in Wistar rats
    • Authors: Xu Wang; Ziqiang Tan, Guyue Cheng, Ihsan Awais, Lingli Huang, Dongmei Chen, Yuanhu Pan, Zhenli Liu, Zonghui Yuan
      Pages: 1531 - 1538
      Abstract: Aditoprim, a new bacteriostatic agent that belongs to diaminopyrimidines, has a broad antimicrobial spectrum, good antibacterial activity and excellent pharmacokinetics. To evaluate the reproductive toxicity and teratogenic potential of aditoprim, different concentrations of aditoprim were administered to Wistar rats by feeding diets containing 0, 20, 100 and 1000 mg kg–1, respectively. Each group consisting of 18 males and 25 females (F0) was treated with different concentrations of aditoprim through a 13‐week period before mating and during mating, gestation, parturition and lactation. At weaning, 20 males and 25 females of the F1 generation weanlings per group were selected randomly as parents for the F2 generation. Selected F1 weanlings were exposed to the same diet and treatment as their parents. At 1000 mg kg–1 dose group, body weights in F0 and F1 rats, fetal body weight on day 21 (0, 4 and 21) after birth and number of viable fetuses in the F0 and F1 generation significantly decreased. Teratogenicity study was performed in combination with the F1 generation of a two‐generation reproduction study. F1 parents of the reproduction study were mated after weaning of the F2a pups. Pregnant female rats were subjected to cesarean section on gestational day 20 for teratogenic examination. At 1000 mg kg–1 group, body weights, fetal body lengths, tail lengths, litter weights and number of viable fetuses were significantly decreased. No obvious external, skeletal or visceral malformations in fetuses were noted in any groups in the teratogenic test. The no‐observed‐adverse‐effect level for reproduction/development toxicity of aditoprim was 100 mg kg–1 diet (about 7.89–9.25 mg kg–1 body weight day–1). Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-07T02:26:45.347717-05:
      DOI: 10.1002/jat.3121
  • Involvement of mitogen‐activated protein kinase and NF‐κB
           signaling pathways in perfluorooctane sulfonic acid‐induced
           inflammatory reaction in BV2 microglial cells
    • Authors: Jingying Zhu; Wenyi Qian, Yixin Wang, Rong Gao, Jun Wang, Hang Xiao
      Pages: 1539 - 1549
      Abstract: Microglial activation is closely related to the pathogenesis of neurodegenerative diseases by producing proinflammatory cytokines. Perfluorooctane sulfonic acid (PFOS), known as an emerging persistent organic pollutant, is reported to disturb human immune homeostasis; however, whether it affects cytokine production or the immune response in the central nervous system remains unclear. The present study was aimed to explore whether PFOS contributed to inflammatory action and to investigate the corresponding mechanisms in BV2 microglia. PFOS‐mediated morphologic changes, cytokine responses and signaling events were examined by light microscopy, real‐time polymerase chain reaction, enzyme‐linked immunosorbent assay and Western blot assays. Our results indicated that PFOS increased BV2 cells activation and simultaneously increased tumor necrosis factor alpha and interleukin‐6 expression. In addition, the c‐Jun N‐terminal protein kinase inhibitor (SP600125), as well as ERK1/2 blocker (PD98059), transcriptionally at least, displayed anti‐inflammatory properties on PFOS‐elicited cytokine responses. Moreover, the inflammatory transcription factor NF‐κB was specifically activated by PFOS as well. These results, taken together, suggested that PFOS exerts its functional effects on the response of microglial cell activation via, in part, the c‐Jun N‐terminal protein kinase, ERK and NF‐κB signaling pathways with its subsequent influence on proinflammatory action. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-12T07:33:11.644658-05:
      DOI: 10.1002/jat.3119
  • The effect of a methyl‐deficient diet on the global DNA methylation
           and the DNA methylation regulatory pathways
    • Authors: Shota Takumi; Kazuyuki Okamura, Hiroyuki Yanagisawa, Tomoharu Sano, Yayoi Kobayashi, Keiko Nohara
      Pages: 1550 - 1556
      Abstract: Methyl‐deficient diets are known to induce various liver disorders, in which DNA methylation changes are implicated. Recent studies have clarified the existence of the active DNA demethylation pathways that start with oxidization of 5‐methylcytosine (5meC) to 5‐hydroxymethylcytosine by ten‐eleven translocation (Tet) enzymes, followed by the action of base–excision–repair pathways. Here, we investigated the effects of a methionine–choline‐deficient (MCD) diet on the hepatic DNA methylation of mice by precisely quantifying 5meC using a liquid chromatography–electrospray ionization–mass spectrometry and by investigating the regulatory pathways, including DNA demethylation. Although feeding the MCD diet for 1 week induced hepatic steatosis and lower level of the methyl donor S‐adenosylmethionine, it did not cause a significant reduction in the 5meC content. On the other hand, the MCD diet significantly upregulated the gene expression of the Tet enzymes, Tet2 and Tet3, and the base–excision–repair enzymes, thymine DNA glycosylase and apurinic/apyrimidinic‐endonuclease 1. At the same time, the gene expression of DNA methyltransferase 1 and a, was also significantly increased by the MCD diet. These results suggest that the DNA methylation level is precisely regulated even when dietary methyl donors are restricted. Methyl‐deficient diets are well known to induce oxidative stress and the oxidative‐stress‐induced DNA damage, 8‐hydroxy‐2′‐deoxyguanosine (8OHdG), is reported to inhibit DNA methylation. In this study, we also clarified that the increase in 8OHdG number per DNA by the MCD diet is approximately 10 000 times smaller than the reduction in 5meC number, suggesting the contribution of 8OHdG formation to DNA methylation would not be significant. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-17T19:31:53.091825-05:
      DOI: 10.1002/jat.3117
  • Heterozygous p53 knockout mouse model for dehydropyrrolizidine
           alkaloid‐induced carcinogenesis
    • Authors: Ammon W. Brown; Bryan L. Stegelmeier, Steven M. Colegate, Kip E. Panter, Edward L. Knoppel, Jeffery O. Hall
      Pages: 1557 - 1563
      Abstract: Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant‐derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short‐term treatment of riddelliine 5, 15 or 45 mg kg–1 bodyweight day–1 by oral gavage for 14 days, or dosed a long‐term treatment of riddelliine 1 mg kg–1 bodyweight day–1 in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose‐responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N‐oxides. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2015-02-17T19:17:03.837317-05:
      DOI: 10.1002/jat.3120
  • Non‐clinical safety and biodistribution of AS03‐adjuvanted
           inactivated pandemic influenza vaccines
    • Pages: 1564 - 1576
      Abstract: Pandemic‐influenza vaccines containing split‐inactivated‐virus antigen have been formulated with the immunostimulatory Adjuvant System AS03 to enhance the antigen immunogenicity and reduce antigen content per dose. AS03 is an oil‐in‐water emulsion containing α‐tocopherol, squalene and polysorbate 80. To support the clinical development of AS03‐adjuvanted pandemic‐influenza vaccines, the local and systemic toxicity of test articles containing split‐influenza A(H5N1) and/or AS03 were evaluated after 3–4 intramuscular (i.m.) injections in rabbits. Treatment‐related effects were restricted to mild inflammatory responses and were induced primarily by the test articles containing AS03. The injection‐site inflammation was mild at 3 days, and minimal at 4 weeks after the last injection; and was reflected by signs of activation in the draining lymph nodes and by systemic effects in the blood including a transient increase of neutrophils. In addition, a study in mice explored the biodistribution of A(H5N1) vaccines or AS03 through radiolabelling the antigen or constituents of AS03 prior to injection. In this evaluation, 57–73% of AS03's principal constituents had cleared from the injection site 3 days after injection, and their different clearance kinetics were suggestive of AS03's dissociation. All these AS03 constituents entered into the draining lymph nodes within 30 min after injection. In conclusion, the administration of repeated doses of the H5N1/AS03 vaccine was well tolerated in the rabbit, and was primarily associated with transient mild inflammation at the injection site and draining lymph nodes. The biodistribution kinetics of AS03 constituents in the mouse were consistent with AS03 inducing this pattern of inflammation. Copyright © 2015 John Wiley & Sons, Ltd.
      PubDate: 2015-02-27T07:18:21.001473-05:
      DOI: 10.1002/jat.3130
  • Non‐clinical safety assessment of single and repeated intramuscular
           administration of a human papillomavirus‐16/18 vaccine in rabbits
           and rats
    • Pages: 1577 - 1585
      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
  • 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
    • Pages: 1586 - 1593
      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
  • Cellular localization of uranium in the renal proximal tubules during
           acute renal uranium toxicity
    • Pages: 1594 - 1600
      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
  • Transcriptional and morphological effects of tamoxifen on the early
           development of zebrafish (Danio rerio)
    • Abstract: Tamoxifen is a widely used anticancer drug with both an estrogen agonist and antagonist effect. This study focused on its endocrine disrupting effect, and overall environmental significance. Zebrafish embryos were exposed to different concentrations (0.5, 5, 50 and 500 µg l–1) of tamoxifen for 96 h. The results showed a complex effect of tamoxifen on zebrafish embryo development. For the 500 µg l–1 exposure group, the heart rate was decreased by 20% and mild defects in caudal fin and skin were observed. Expressions of a series of genes related to endocrine and morphological changes were subsequently tested through quantitative real‐time polymerase chain reaction. Bisphenol A as a known estrogen was also tested as an endocrine‐related comparison. Among the expression of endocrine‐related genes, esr1, ar, cyp19a1b, hsd3b1 and ugt1a1 were all increased by tamoxifen exposure, similar to bisphenol A. The cyp19a1b is a key gene that controls estrogen synthesis. Exposure to 0.5, 5, 50 and 500 µg l–1 of tamoxifen caused upregulation of cyp19a1b expression to 152%, 568%, 953% and 2024% compared to controls, higher than the effects from the same concentrations of bisphenol A treatment, yet vtg1 was suppressed by 24% from exposure to 500 µg l–1 tamoxifen. The expression of metabolic‐related genes such as cyp1a, cyp1c2, cyp3a65, gpx1a, gstp1, gsr and genes related to observed morphological changes such as krt17 were also found to be upregulated by high concentrations of tamoxifen. These findings indicated the potential environmental effect of tamoxifen on teleost early development. Copyright © 2015 John Wiley & Sons, Ltd.
  • Translocation and biokinetic behavior of nanoscaled europium oxide
           particles within 5 days following an acute inhalation in rats
    • Abstract: Nanoscaled europium oxide (Eu2O3) particles were inhaled by rats after acute exposure and the potential translocation of particles followed by chemical analysis and transmission electron microscopy (TEM) was investigated. An aqueous dispersion (phosphate buffer/bovine serum albumin) of a commercially available Eu2O3 particle fraction consisting partially of nanoscaled particles was aerosolized with pressurized air. After rapid evaporation, rats inhaled the dry aerosol for 6 h in a single exposure resulting in an alveolar calculated dose of approximately 39.5 μg Eu2O3. Using chemical analysis, 36.8 μg Eu2O3 was detected 1 h after lung inhalation. The amount declined slightly to 34.5 μg after 1 day and 35.0 μg after 5 days. The liver showed an increase of Eu2O3 from 32.3 ng 1 h up to 294 ng 5 days after inhalation. Additionally, lung‐associated lymph nodes, thymus, kidneys, heart and testis exhibited an increase of europium over the period investigated. In the blood, the highest amount of europium was found 1 h after treatment whereas feces, urine and mesenteric lymph nodes revealed the highest amount 1 day after treatment. Using TEM analysis, particles could be detected only in lungs, and in the liver, no particles were detectable. In conclusion, the translocation of Eu2O3 within 5 days following inhalation could be determined very precisely by chemical analysis. A translocation of Eu2O3 particulate matter to liver was not detectable by TEM analysis; thus, the overproportional level of 0.8% of the lung load observed in the liver after 5 days suggests a filtering effect of dissolved europium with accumulation. Copyright © 2015 John Wiley & Sons, Ltd.
  • Brain‐targeted distribution and high retention of silver by chronic
           intranasal instillation of silver nanoparticles and ions in
           Sprague–Dawley rats
    • Abstract: The wide applications of silver nanoparticles (AgNPs) have been concerned regarding their unintentional toxicities. Different exposure modes may cause distinct accumulation, retention and elimination profiles, which are closely related with their toxicities. Unlike silver accumulation profiles through other regular administration modes, the biodistribution, accumulation and elimination of AgNPs by intranasal instillation are not fully understood. This study conducted intranasal instillation of polyvinylpyrrolidone‐coated AgNPs in neonatal Sprague–Dawley rats at doses of 1 and 0.1 mg kg−1 day−1 for 4 and 12 weeks, respectively. The 4‐week recovery was also designed after the 12‐week exposure. Silver concentrations in the main tissues or organs were periodically monitored. Parallel exposures using silver ion were performed for the comparative studies. No physiological alterations were observed in AgNP exposures. In comparison, 1 mg kg−1 day−1 silver ions decreased body weight gain and caused mortality of 18.2%, showing ionic silver had a relatively higher toxicity than AgNPs. A relatively higher silver accumulation was observed in silver ion groups than AgNP groups. The silver ion release could not fully explain silver accumulation in AgNP exposures, showing silver distribution caused by particulate silver occurred in vivo. The highest silver concentration was in the liver at week 4, while it shifted to the brain after a 12‐week exposure. Dose‐related silver accumulation occurred for both AgNP and silver ion groups. The time course revealed a uniquely high concentration and retention of brain silver, implying chronic intranasal instillation caused brain‐targeted silver accumulation. These findings provided substantial evidence on the potential neuronal threat from the intranasal administration of AgNPs or silver colloid‐based products. Copyright © 2015 John Wiley & Sons, Ltd.
  • Effects of soap–water wash on human epidermal penetration
    • Abstract: Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the “wash‐in effect.” To understand better the effect of soap–water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C14‐labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow‐through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0–295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap–water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non‐wash groups. The observed wash‐in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash‐in effect. Further, the occurrence of a wash‐in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap–water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd.
  • An overview of the safety and biological effects of Bacillus thuringiensis
           Cry toxins in mammals
    • Abstract: Crystal proteins (Cry) produced during the growth and sporulation phases of Bacillus thuringiensis (Bt) bacterium are known as delta endotoxins. These toxins are being used worldwide as bioinsecticides to control pests in agriculture, and some Cry toxins are used against mosquitoes to control vector transmission. This review summarizes the relevant information currently available regarding the biosafety and biological effects that Bt and its insecticidal Cry proteins elicit in mammals. This work was performed because of concerns regarding the possible health impact of Cry toxins on vertebrates, particularly because Bt toxins might be associated with immune‐activating or allergic responses. The controversial data published to date are discussed in this review considering earlier toxicological studies of B. thuringiensis, spores, toxins and Bt crops. We discussed the experimental studies performed in humans, mice, rats and sheep as well as in diverse mammalian cell lines. Although the term ’toxic‘ is not appropriate for defining the effects these toxins have on mammals, they cannot be considered innocuous, as they have some physiological effects that may become pathological; thus, trials that are more comprehensive are necessary to determine their effects on mammals because knowledge in this field remains limited. Copyright © 2015 John Wiley & Sons, Ltd.
  • The role of intramolecular self‐destruction of reactive metabolic
           intermediates in determining toxicity
    • Abstract: When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N‐aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man‐made xenobiotics. Copyright © 2015 John Wiley & Sons, Ltd.
  • Development of novel in vitro photosafety assays focused on the
           Keap1–Nrf2–ARE pathway
    • Abstract: Although photoallergens require UV energy for antigen formation, the subsequent immune response is considered to be the same as in ordinary skin sensitization. Therefore, in vitro tests for skin sensitization should also be applicable for photoallergy testing. In this study, we examined whether activation of the Keap1 (Kelch‐like ECH‐associated protein 1)–Nrf2 (nuclear factor‐erythroid 2‐related factor 2)–ARE (antioxidant response element) pathway could be used to assess the photoallergenic potential of chemicals, using the reporter cell line AREc32 or KeratinoSensTM. First, we identified an appropriate UVA irradiation dose [5 J cm–2 irradiation in phosphate‐buffered saline (PBS)] by investigating the effect of UV irradiation on ARE‐dependent gene induction using untreated or 6‐methylcoumarin (6‐MC)‐treated cells. Irradiation of well‐known photoallergens under this condition increased ARE‐dependent gene expression by more than 50% compared with both vehicle and non‐irradiated controls. When the cut‐off value for detecting photoallergens was set at 50% induction, the accuracy of predicting photoallergenic/phototoxic chemicals was 70% in AREc32 cells and 67% in KeratinoSensTM cells, and the specificity was 100% in each case. We designate these assays as a photo‐ARE assay and photo‐KeratinoSensTM, respectively. Our results suggest that activation of the Keap1‐Nrf2‐ARE pathway is an effective biomarker for evaluating both photoallergenic and phototoxic potentials. Either of the above tests might be a useful component of a battery of in vitro tests/in silico methods for predicting the photoallergenicity and phototoxicity of chemicals. Copyright © 2015 John Wiley & Sons, Ltd.
  • Mitochondrial oxidative stress and dysfunction in arsenic neurotoxicity: A
    • Abstract: Arsenic is a toxic metalloid present ubiquitously on earth. Since the last decade, it has gained considerable attention due to its severe neurotoxic effects. Arsenic can cross the blood–brain barrier and accumulate in different regions of the brain suggesting its role in neurological diseases. Arsenic exposure has been associated with reactive oxygen species generation, which is supposed to be one of the mechanisms of arsenic‐induced oxidative stress. Mitochondria, being the major source of reactive oxygen species generation may present an important target of arsenic toxicity. It is speculated that the proper functioning of the brain depends largely on efficient mitochondrial functions. Multiple studies have reported evidence of brain mitochondrial impairment after arsenic exposure. In this review, we have evaluated the proposed mechanisms of arsenic‐induced mitochondrial oxidative stress and dysfunction. The understanding of molecular mechanism of mitochondrial dysfunction may be helpful to develop therapeutic strategies against arsenic‐induced neurotoxicity. The ameliorative measures undertaken in arsenic‐induced mitochondrial dysfunction have also been highlighted. Copyright © 2015 John Wiley & Sons, Ltd.
  • Distribution of single wall carbon nanotubes in the Xenopus laevis embryo
           after microinjection
    • Abstract: Single wall carbon nanotubes (SWCNTs) are advanced materials with the potential for a myriad of diverse applications, including biological technologies and large‐scale usage with the potential for environmental impacts. SWCNTs have been exposed to developing organisms to determine their effects on embryogenesis, and results have been inconsistent arising, in part, from differing material quality, dispersion status, material size, impurity from catalysts and stability. For this study, we utilized highly purified SWCNT samples with short, uniform lengths (145 ± 17 nm) well dispersed in solution. To test high exposure doses, we microinjected > 500 µg ml–1 SWCNT concentrations into the well‐established embryogenesis model, Xenopus laevis, and determined embryo compatibility and subcellular localization during development. SWCNTs localized within cellular progeny of the microinjected cells, but were heterogeneously distributed throughout the target‐injected tissue. Co‐registering unique Raman spectral intensity of SWCNTs with images of fluorescently labeled subcellular compartments demonstrated that even at regions of highest SWCNT concentration, there were no gross alterations to subcellular microstructures, including filamentous actin, endoplasmic reticulum and vesicles. Furthermore, SWCNTs did not aggregate and localized to the perinuclear subcellular region. Combined, these results suggest that purified and dispersed SWCNTs are not toxic to X. laevis animal cap ectoderm and may be suitable candidate materials for biological applications. Copyright © 2015 John Wiley & Sons, Ltd.
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