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  Subjects -> ENVIRONMENTAL STUDIES (Total: 755 journals)
    - ENVIRONMENTAL STUDIES (690 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (34 journals)
    - WASTE MANAGEMENT (9 journals)

ENVIRONMENTAL STUDIES (690 journals)            First | 1 2 3 4 5 6 7     

International Journal of Corrosion     Open Access   (10 followers)
International Journal of Critical Infrastructures     Hybrid Journal   (3 followers)
International Journal of Disaster Risk Reduction     Hybrid Journal   (3 followers)
International Journal of Disaster Risk Science     Open Access   (9 followers)
International Journal of Ecological Economics and Statistics     Full-text available via subscription   (1 follower)
International Journal of Ecology     Open Access   (8 followers)
International Journal of Ecology & Development     Full-text available via subscription   (1 follower)
International Journal of Energy and Environmental Engineering     Open Access   (2 followers)
International Journal of Environment     Open Access   (3 followers)
International Journal of Environment and Health     Hybrid Journal   (7 followers)
International Journal of Environment and Pollution     Hybrid Journal   (6 followers)
International Journal of Environment and Sustainable Development     Hybrid Journal   (13 followers)
International Journal of Environment and Waste Management     Hybrid Journal   (6 followers)
International Journal of Environment, Workplace and Employment     Hybrid Journal   (3 followers)
International Journal of Environmental Engineering     Hybrid Journal   (5 followers)
International Journal of Environmental Health Engineering     Open Access  
International Journal of Environmental Health Research     Hybrid Journal   (2 followers)
International Journal of Environmental Policy and Decision Making     Hybrid Journal   (10 followers)
International Journal of Environmental Protection     Open Access   (12 followers)
International Journal of Environmental Research and Public Health     Open Access   (13 followers)
International Journal of Environmental Science and Technology     Hybrid Journal   (4 followers)
International Journal of Environmental Studies     Hybrid Journal   (11 followers)
International Journal of Exergy     Hybrid Journal   (3 followers)
International Journal of Forest, Soil and Erosion     Open Access   (3 followers)
International Journal of Global Environmental Issues     Hybrid Journal   (4 followers)
International Journal of Global Warming     Hybrid Journal   (4 followers)
International Journal of Greenhouse Gas Control     Partially Free   (5 followers)
International Journal of Health Planning and Management     Hybrid Journal   (6 followers)
International Journal of Hygiene and Environmental Health     Hybrid Journal   (5 followers)
International Journal of Logistics Research and Applications: A Leading Journal of Supply Chain Management     Hybrid Journal   (9 followers)
International Journal of Philosophical Studies     Hybrid Journal   (2 followers)
International Journal of Phytoremediation     Hybrid Journal   (1 follower)
International Journal of Process Systems Engineering     Hybrid Journal   (1 follower)
International Journal of Recycling of Organic Waste in Agriculture     Open Access   (1 follower)
International Journal of Regulation and Governance     Hybrid Journal   (2 followers)
International Journal of Reliability and Safety     Hybrid Journal   (5 followers)
International Journal of Renewable Energy Development     Open Access   (4 followers)
International Journal of Soil, Sediment and Water     Open Access   (8 followers)
International Journal of Stress Management     Full-text available via subscription   (8 followers)
International Journal of Sustainable Construction Engineering and Technology     Open Access   (7 followers)
International Journal of Sustainable Engineering     Hybrid Journal   (7 followers)
International Journal of Sustainable Materials and Structural Systems     Hybrid Journal   (5 followers)
International Journal of Sustainable Society     Hybrid Journal   (7 followers)
International Journal of Testing     Hybrid Journal   (1 follower)
International Journal of the Commons     Open Access   (2 followers)
International Journal of Toxicology     Hybrid Journal   (5 followers)
International Journal of Water Resources and Environmental Engineering     Open Access  
International Review of Environmental and Resource Economics     Full-text available via subscription  
International Studies in the Philosophy of Science     Hybrid Journal   (10 followers)
Interventions : International Journal of Postcolonial Studies     Hybrid Journal   (5 followers)
Investigación ambiental Ciencia y política pública     Open Access   (1 follower)
IOP Conference Series: Earth and Environmental Science     Open Access   (7 followers)
Iranian Journal of Environmental Health Science & Engineering     Open Access   (1 follower)
Iranian Journal of Health and Environment     Open Access   (2 followers)
Iranian Studies     Hybrid Journal   (8 followers)
Irish Educational Studies     Hybrid Journal   (1 follower)
Irish Journal of Earth Sciences     Full-text available via subscription  
Irish Political Studies     Hybrid Journal   (7 followers)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (2 followers)
Isotopes in Environmental and Health Studies     Hybrid Journal   (2 followers)
Israel Studies     Full-text available via subscription   (5 followers)
ISRN Ecology     Open Access   (3 followers)
ISRN Environmental Chemistry     Open Access  
Italian Studies     Hybrid Journal   (6 followers)
Jahangirnagar University Environmental Bulletin     Open Access  
Journal of Bioremediation & Biodegradation     Open Access   (2 followers)
Journal of Earth Science & Climatic Change     Open Access   (8 followers)
Journal of Petroleum & Environmental Biotechnology     Open Access   (2 followers)
Journal of Waste Water Treatment & Analysis     Open Access   (10 followers)
Journal of Advances in Environmental Health Research     Open Access  
Journal of Agricultural and Environmental Ethics     Hybrid Journal   (7 followers)
Journal of Agricultural Biotechnology and Sustainable Development     Open Access  
Journal of Agriculture and Environment for International Development     Open Access   (5 followers)
Journal of Agrobiology     Open Access   (2 followers)
Journal of Applied Ecology     Hybrid Journal   (109 followers)
Journal of Applied Meteorology and Climatology     Full-text available via subscription   (7 followers)
Journal of Applied Psychoanalytic Studies     Hybrid Journal   (1 follower)
Journal of Applied Sciences and Environmental Management     Open Access  
Journal of Applied Sciences in Environmental Sanitation     Open Access   (4 followers)
Journal of Applied Toxicology     Hybrid Journal   (8 followers)
Journal of Applied Volcanology     Open Access   (6 followers)
Journal of Arid Environments     Hybrid Journal   (8 followers)
Journal of Asian Studies     Full-text available via subscription   (20 followers)
Journal of Biochemical and Molecular Toxicology     Hybrid Journal   (5 followers)
Journal of Black Studies     Hybrid Journal   (3 followers)
Journal of Chemical Ecology     Hybrid Journal   (1 follower)
Journal of Chemical Health and Safety     Hybrid Journal   (2 followers)
Journal of Climate     Full-text available via subscription   (20 followers)
Journal of Coastal Research     Full-text available via subscription   (9 followers)
Journal of Contaminant Hydrology     Hybrid Journal   (9 followers)
Journal of Contemporary European Studies     Hybrid Journal   (3 followers)
Journal of East African Natural History     Full-text available via subscription   (3 followers)
Journal of Ecology     Hybrid Journal   (34 followers)
Journal of Ecosystems     Open Access   (4 followers)
Journal of Empirical Legal Studies     Hybrid Journal   (5 followers)
Journal of Environment and Earth Science     Open Access   (8 followers)
Journal of Environment and Ecology     Open Access   (9 followers)
Journal of Environmental and Public Health     Open Access   (14 followers)
Journal of Environmental Assessment Policy and Management     Hybrid Journal   (4 followers)
Journal of Environmental Economics and Policy     Partially Free   (6 followers)

  First | 1 2 3 4 5 6 7     

Journal of Applied Toxicology    [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  [1594 journals]   [SJR: 0.689]   [H-I: 47]
  • Serum enhanced cytokine responses of macrophages to silica and iron oxide
           particles and nanomaterials: a comparison of serum to lung lining fluid
           and albumin dispersions
    • Abstract: The potential hazard to humans exposed to nanomaterials such as silica and iron oxide was investigated using an in vitro macrophage cell culture system. Amorphous silica and iron oxide particles and nanomaterials (NMs) were dispersed in cell culture medium supplemented with either bovine serum albumin (BSA), lung lining fluid (LLF) or serum, in order to mimic the body fluids encountered during different routes of exposure in the body. End points investigated included macrophage viability and cytokine production. Silica NMs and particles (50 and 200 nm, respectively) were unmodified (plain) or aminated (NH2). Iron oxide NMs and particles, Fe3O4 45 nm and Fe2O3 280 nm were also used in this study. Silica particles and NMs induced a dose‐dependent increase in cytotoxicity as measured by lactate dehydrogenase (LDH) release. Serum enhanced silica‐induced interleukin (IL)‐6, IL‐10, IL‐1β and MCP‐1 release, whereas albumin partially inhibited MCP‐1 release. Aminated silica, 50 nm was more potent than the 200‐nm particles at inducing monocyte chemoattractant protein‐1 (MCP‐1) production when dispersed in medium or LLF, suggesting a size specific effect for these particles and this cytokine. Iron oxide particles were relatively inert compared with the silica particles and NMs; however, serum and albumin did affect cytokine release in some treatments. In conclusion, the data suggests that serum, compared with medium, BSA and LLF is very potent at enhancing macrophage responses to silica and iron oxide particles and NMs. Size was only influential in LLF for a limited number of parameters, whereas surface chemistry was not of consequence in this in vitro macrophage system. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Evaluation of developmental toxicity using undifferentiated human
           embryonic stem cells
    • Abstract: An embryonic stem cell test (EST) has been developed to evaluate the embryotoxic potential of chemicals with an in vitro system. In the present study, novel methods to screen toxic chemicals during the developmental process were evaluated using undifferentiated human embryonic stem (hES) cells. By using surface marker antigens (SSEA‐4, TRA‐1‐60 and TRA‐1‐81), we confirmed undifferentiated conditions of the used hES cells by immunocytochemistry. We assessed the developmental toxicity of embryotoxic chemicals, 5‐fluorouracil, indomethacin and non‐embryotoxic penicillin G in different concentrations for up to 7 days. While expressions of the surface markers were not significantly affected, the embryotoxic chemicals influenced their response to pluripotent ES cell markers, such as OCT‐4, NANOG, endothelin receptor type B (EDNRB), secreted frizzled related protein 2 (SFRP2), teratocarcinoma‐derived growth factor 1 (TDGF1), and phosphatase and tensin homolog (PTEN). Most of the pluripotent ES cell markers were down‐regulated in a dose‐dependent manner after treatment with embryotoxic chemicals. After treatment with 5‐fluorouracil, indomethacin and penicillin G, we observed a remarkable convergence in the degree of up‐regulation of development, cell cycle and apoptosis‐related genes by gene expression profiles using an Affymetrix GeneChips. Taken together, these results suggest that embryotoxic chemicals have cytotoxic effects, and modulate the expression of ES cell markers as well as development‐, cell cycle‐ and apoptosis‐related genes that have pivotal roles in undifferentiated hES cells. Therefore, we suggest that hES cells may be useful for testing the toxic effects of chemicals that could impact the embryonic developmental stage. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • The in Vitro estrogenic activities of triclosan and triclocarban
    • Abstract: Triclosan (TCS) and triclocarban (TCC), as broad spectrum antibacterial agents, are distributed widely in the environment and humans. Most studies have focused on their distribution and biodegradation, but the endocrine‐disrupting effects of these chemicals, especially their estrogenic effects, are still unclear. In the present study, we investigated the estrogenic effects of TCS and TCC using a series of in vitro assays, including the ER reporter gene assay in the CV‐1 cells, E‐screen assay and evaluation of estrogen‐responsive genes in the MCF‐7 cells. The tested concentrations of TCS and TCC were both from 1 × 10–9 to 1 × 10–6 M. Results showed that TCS and TCC exerted estrogenic activities by inducing luciferase activities in an ER reporter gene assay, promoting the proliferation of the MCF‐7 cells, up‐regulating the expression of pS2 and down‐regulating ERα expression at both the mRNA and protein levels in the MCF‐7 cells. We further found that TCS and TCC could alter the expression of multiple microRNAs (mir‐22, mir‐206 and mir‐193b) in the MCF‐7 cells, which would help understand the mechanisms of their estrogenic effects on regulating the expression of ERα. In brief, our results demonstrated the potential estrogenic effects and profiled in vitro data for further risk assessment of TCS and TCC. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Usefulness of urinary kidney injury molecule‐1 (Kim‐1) as a
           biomarker for cisplatin‐induced sub‐chronic kidney injury
    • Abstract: We explored biomarkers suitable for monitoring sub‐chronic kidney injury using the three rat models of cisplatin (CDDP)‐induced kidney injury, which were designed to extend the current knowledge beyond the sub‐acute exposure period. In the pilot study, a single intravenous administration of 1.5 mg kg–1 CDDP to rats was confirmed to result in no histopathological changes. Subsequently, CDDP was intravenously administered to rats at a dose of 1.5 mg kg–1 for 4 days at 24‐h intervals (Experimental model 1) and for up to 10 weeks at weekly intervals (Experimental models 2 and 3), and the changes in blood and urine components, such as recently recommended urinary biomarkers (Kim‐1, clusterin and so on) and traditional blood biomarkers (blood urea nitrogen and serum creatinine), were examined together with the histopathological changes in renal tissues during the development of the kidney injury in each model. In these experimental models, a significant increase in urinary Kim‐1 was observed prior to the histopathological changes in renal tissues, and these changes were retained after the adverse histopathological changes. Significant changes in all of the other urinary biomarkers examined occurred along with the histopathological changes. In addition, the increase in urinary Kim‐1 after weekly treatment with CDDP for 4 weeks was reduced in a time‐dependent manner after cessation of the drug. The present findings indicate that urinary Kim‐1 is the most useful biomarker for CDDP‐induced rat sub‐chronic kidney injury among the biomarkers examined. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Impact of acute arsenic and cadmium exposure on the expression of two
           haeme oxygenase genes and other antioxidant markers in common carp
           (Cyprinus carpio)
    • Abstract: The aim was to study the effects of cadmium (Cd) and arsenic (As) on haeme oxygenases (HOs) and other oxidative stress biomarkers, and their roles in macromolecule damage in liver and kidney of common carp (Cyprinus carpio L.). HOs play a critical role in the defence system against oxidative damage, producing biliverdin and carbon monoxide with important free radical scavenging properties. However, increased HO activity in haeme degradation may also lead to a pro‐oxidant effect through the liberation of Fe‐modifying Cd and As toxicity. The response of an organism to exposure to toxic metals is in many cases brought about by changes at the level of gene expression. In this study, the genes ho‐1 and ho‐2 of the common carp were identified, and the changes in gene expressions were analysed from the aspect of Cd and As accumulation. Both ho‐1 and ho‐2 are transcriptionally induced by Cd and As, but their inductions differ in time course, dose response and tissue specificity. The expression of ho1 was mostly affected by As, primarily in the liver (45‐fold), whereas it was enhanced with higher efficacy by Cd in the kidney (25‐fold). The cellular redox status and the damage of lipid molecules were monitored via the ratio of reduced to oxidized glutathione, the levels of H2O2 and lipid peroxidation, and the activities of superoxide dismutase (SOD) and catalase (CAT). Copyright © 2014 John Wiley & Sons, Ltd.
       
  • In vitro exposure of DE‐71, a penta‐PBDE mixture, on immune
           endpoints in bottlenose dolphins (Tursiops truncatus) and B6C3F1 mice
    • Abstract: Polybrominated diphenyl ethers (PBDEs) are an emerging contaminant of concern with low level exposures demonstrating toxicity in laboratory animals and wildlife, although immunotoxicity studies have been limited. Bottlenose dolphin peripheral blood leukocytes (PBLs) and mouse splenocytes were exposed to environmentally relevant DE‐71 (a penta‐PBDE mixture) concentrations (0–50 µg ml−1) in vitro. Natural killer (NK) cell activity and lymphocyte (B and T cell) proliferation were evaluated using the parallelogram approach for risk assessment. This study aimed to substantiate results from field studies with dolphins, assess the sensitivities between the mouse model and dolphins, and to evaluate risk using the parallelogram approach. In mouse cells, NK cell activity increased at in vitro doses 0.05, 0.5 and 25 µg DE‐71 ml−1, whereas proliferation was not modulated. In dolphin cells, NK cell activity and lymphocyte proliferation was not altered after in vitro exposure. In vitro exposure of dolphin PBLs to DE‐71 showed similar results to correlative field studies; NK cell activity in mice was more sensitive to in vitro exposure than dolphins, and the parallelogram approach showed correlation with all three endpoints to predict risk in bottlenose dolphins. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Verification of responses of Japanese medaka (Oryzias latipes) to
           anti‐androgens, vinclozolin and flutamide, in short‐term
           assays
    • Abstract: Various testing methods for the detection of the endocrine disruptive activities of chemicals have been developed in freshwater fish species. However, a few relatively easier specific methods for detecting anti‐androgenic activities are available for fish. The aim of this study was to verify the papillary process in Japanese medaka (Oryzias latipes) as an indicator of the anti‐androgenic activity of chemicals. Japanese medaka were exposed to two types of anti‐androgenic compounds, vinclozolin and flutamide, using two short‐term assays; one was conformed to the existing short‐term reproduction assay using adult fish (adult test) and the other was a test based on the same methods but using juvenile fish at the beginning of exposure (juvenile test). Significant decreases in male papillary processes were observed in the juvenile test treated with the highest concentration of both antiandrogens (640 µg l–1 vinclozolin and 1000 µg l–1 flutamide); however, no significant effects were observed in the adult test. Consequently, our results indicate that papillary processes in Japanese medaka can be used as the end‐point for screening the anti‐androgenic activity of chemicals using juvenile fish for a specific period based on the existing short‐term reproduction assay. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Protective role of edaravone against neomycin‐induced ototoxicity in
           zebrafish
    • Abstract: Aminoglycosides such as neomycin are one of the most commonly prescribed types of antibiotics worldwide. However, these drugs appear to generate free radicals within the inner ear, which can result in permanent hearing loss. We evaluated the effects of edaravone, a neuroprotective agent, on neomycin‐induced ototoxicity in transgenic zebrafish. The 5‐day post fertilization (dpf) zebrafish larvae were exposed to 125 μM neomycin and various concentrations of edaravone for 1 h. Hair cell survival was calculated as average numbers of the hair cells in the control group, which was not exposed to neomycin. Ultrastructural changes were evaluated using a scanning electron microscope (SEM) and transmission electron microscope (TEM). Edaravone protected against neomycin‐induced hair cell loss in the neuromasts (1000 μM: 11.6 ± 1.1 cells, neomycin only: 5.5 ± 0.5 cells; n = 10, P 
       
  • Toxic effects of colloidal nanosilver in zebrafish embryos
    • Abstract: A variety of consumer products containing silver nanoparticles (Ag NPs) are currently marketed. However, their safety for humans and for the environment has not yet been established and no standard method to assess their toxicity is currently available. The objective of this work was to develop an effective method to test Ag NP toxicity and to evaluate the effects of ion release and Ag NP size on a vertebrate model. To this aim, the zebrafish animal model was exposed to a solution of commercial nanosilver. While the exposure of embryos still surrounded by the chorion did not allow a definite estimation of the toxic effects exerted by the compound, the exposure for 48 h of 3‐day‐old zebrafish hatched embryos afforded a reliable evaluation of the effects of Ag NPs. The effects of the exposure were detected especially at molecular level; in fact, some selected genes expressed differentially after the exposure. The Ag NP toxic performance was due to the combined effect of Ag+ ion release and Ag NP size. However, the effect of NP size was particularly detectable at the lowest concentration of nanosilver tested (0.01 mg l–1) and depended on the solubilization media. The results obtained indicate that in vivo toxicity studies of nanosilver should be performed with ad hoc methods (in this case using hatched embryos) that might be different depending on the type of nanosilver. Moreover, the addition of this compound to commercial products should take into consideration the Ag NP solubilization media. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Molecular impact of juvenile hormone agonists on neonatal Daphnia magna
    • Abstract: Daphnia magna has been used extensively to evaluate organism‐ and population‐level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical‐specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH‐responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH‐responsive genes. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • A chronic oral reference dose for hexavalent chromium‐induced
           intestinal cancer
    • Abstract: High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)‐induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1). © 2013 The
      Authors . Journal of Applied Toxicology published by John Wiley & Sons, Ltd.
       
  • Direct exposure at the air–liquid interface: evaluation of an in
           vitro approach for simulating inhalation of airborne substances
    • Abstract: In toxicology, the strategies for testing the hazardous potential of substances are changing as a result of the ongoing progress in the development of in vitro methods and the demand of the authorities to reduce animal testing. Even in the complex field of inhalation toxicology with its high requirements on the technical implementation and cell culture models, the preconditions for using such methods are fulfilled. We here introduce a sophisticated technique that enables the stable and reproducible exposure of cultivated cells to airborne substances at the air–liquid interface by means of the CULTEX® Radial Flow System (RFS) module. The feasibility and suitability of the experimental setup is demonstrated by dose‐response investigations of mainstream cigarette smoke and particulate matter of four substances in different lung epithelial cell lines. A dose‐dependent cytotoxcity of the test substances was verified by applying different exposure times. The high reproducibility of the results indicate the reliability of the presented method and recommend the integration of such in vitro approaches in the field of inhalation toxicology by advancing their regulatory validation. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Evaluation of adverse human lung function effects in controlled ozone
           exposure studies
    • Abstract: The US EPA is evaluating controlled human ozone exposure studies to determine the adequacy of the current ozone National Ambient Air Quality Standard of 75 ppb. These studies have shown that ozone exposures of 80 ppb and greater are associated with lung function decrements. Here, we critically review studies with exposures below 80 ppb to determine the lowest ozone concentration at which decrements are causally associated with ozone exposure and could be considered adverse using the Adverse Effects/Causation Framework. Regarding causation, the framework includes consideration of whether exposure‐related effects are primary or secondary, statistically significant, isolated or independent, or due to study limitations. Regarding adversity, the framework indicates one should consider whether effects are adaptive, compensatory, precursors to an apical effect, severe, transient and/or reversible. We found that, at exposures below 72 ppb ozone, lung function effects are primary effects, but are isolated, independent and not statistically different compared to effects observed during filtered air exposure, indicating a lack of causation. Up to 72 ppb, lung function effects may be precursors to an apical effect, but are not likely adverse because they are transient, reversible, of low severity, do not interfere with normal activity and do not result in permanent respiratory injury or progressive respiratory dysfunction. Overall, these studies do not demonstrate a causal association between ozone concentrations in the range of the current National Ambient Air Quality Standard and adverse effects on lung function. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Usefulness of optical coherence tomography to detect central serous
           chorioretinopathy in monkeys
    • Abstract: Many systemic drugs can induce ocular toxicity and several ocular side‐effects have been identified in clinical studies. However, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. Optical coherence tomography (OCT) is useful because it can provide real‐time images throughout a study period, whereas histopathology only provides images of sacrificed animals. Using OCT alongside histopathology, attempts were made to find effective approaches for screening of drug‐induced ocular toxicity in monkeys. Such approaches could be used in preclinical studies prior to human trials. Six male cynomolgus monkeys (Macaca fascicularis Raffles) were orally administered one of six candidate MAPK/ERK kinase (MEK) inhibitors. Central serous chorioretinopathy, a known side‐effect of such inhibitors, was identified in four monkeys by OCT. Artifacts generated during tissue processing meant that histopathology could not detect edematous changes. Thus, OCT is a useful tool to detect ocular toxicity which cannot be detected by histopathology in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Characterization of the allergenic potential of proteins: an assessment of
           the kiwifruit allergen actinidin
    • Abstract: Assessment of the potential allergenicity (IgE‐inducing properties) of novel proteins is an important challenge in the overall safety assessment of foods. Resistance to digestion with pepsin is commonly measured to characterize allergenicity, although the association is not absolute. We have previously shown that specific IgE antibody production induced by systemic [intraperitoneal (i.p.)] exposure of BALB/c strain mice to a range of proteins correlates with allergenic potential for known allergens. The purpose of the present study was to explore further the utility of these approaches using the food allergen, actinidin. Recently, kiwifruit has become an important allergenic foodstuff, coincident with its increased consumption, particularly as a weaning food. The ability of the kiwifruit allergen actinidin to stimulate antibody responses has been compared with the reference allergen ovalbumin, and with the non‐allergen bovine haemoglobin. Haemoglobin was rapidly digested by pepsin whereas actinidin was resistant unless subjected to prior chemical reduction (reflecting intracellular digestion conditions). Haemoglobin stimulated detectable IgG antibody production at relatively high doses (10%), but failed to provoke detectable IgE. In contrast, actinidin was both immunogenic and allergenic at relatively low doses (0.25% to 1%). Vigorous IgG and IgG1 antibody and high titre IgE antibody responses were recorded, similar to those provoked by ovalbumin. Thus, actinidin displays a marked ability to provoke IgE, consistent with allergenic potential. These data provide further encouragement that in tandem with analysis of pepsin stability, the induction of IgE after systemic exposure of BALB/c strain mice provides a useful approach for the prospective identification of protein allergens. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Monomethylated trivalent arsenic species disrupt steroid receptor
           interactions with their DNA response elements at non‐cytotoxic
           cellular concentrations
    • Abstract: Arsenic (As) is considered a top environmental chemical of human health because it has been linked to adverse health effects including cancer, diabetes, cardiovascular disease, and reproductive and developmental problems. In several cell culture and animal models, As acts as an endocrine disruptor, which may underlie many of its health effects. Previous work showed that steroid receptor (SR)‐driven gene expression is disrupted in cells treated with inorganic As (arsenite, iAs+3). In those studies, low iAs+3 concentrations (0.1–0.7 μM) stimulated hormone‐inducible transcription, whereas somewhat higher but still non‐cytotoxic levels (1–3 μM) inhibited transcription. This investigation focuses on the mechanisms underlying these inhibitory effects and evaluates the role of methylated trivalent As metabolites on SR function. Recent evidence suggests that, compared with iAs, methylated forms may have distinct biochemical effects. Here, fluorescence polarization (FP) experiments utilizing purified, hormone‐bound human glucocorticoid (GR) and progesterone receptor (PR) have demonstrated that neither inorganic (iAs+3) nor dimethylated (DMA+3) species of trivalent As affect receptor interactions with glucocorticoid DNA response elements (GREs). However, monomethylated forms (monomethylarsenite, MMA+3 and monomethylarsonic diglutathione, MADG) strongly inhibit GR‐GRE and PR‐GRE binding. Additionally, speciation studies of iAs+3‐treated H4IIE rat hepatoma cells show that, under treatment conditions that cause inhibition of hormone‐inducible gene transcription, the intracellular concentration of MADG is sufficient to inhibit GR‐GRE and PR‐GRE interactions in vivo. These results indicate that arsenic's inhibitory endocrine disruption effects are probably caused in part by methylated metabolites' disruption of SR ability to bind DNA response elements that are crucial to hormone‐driven gene transcription. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Ketamine attenuates cytochrome p450 aromatase gene expression and
           estradiol‐17β levels in zebrafish early life stages
    • Abstract: Ketamine, a dissociative anesthetic, is a noncompetitive antagonist of N‐methyl‐D‐aspartate‐type glutamate receptors. In rodents and non‐human primates as well as in zebrafish embryos, ketamine has been shown to be neurotoxic. In cyclic female rats, ketamine has been shown to decrease serum estradiol‐17β (E2) levels. E2 plays critical roles in neurodevelopment and neuroprotection. Cytochrome p450 (CYP) aromatase catalyzes E2 synthesis from androgens. Although ketamine down‐regulates a number of CYP enzymes in rodents, its effect on the CYP aromatase (CYP19) is not known. Zebrafish have been used as a model system for examining mechanisms underlying drug effects. Here, using wild‐type (WT) zebrafish (Danio rerio) embryos, we demonstrate that ketamine significantly reduced E2 levels compared with the control. However, the testosterone level was elevated in ketamine‐treated embryos. These results are concordant with data from mammalian studies. Ketamine also attenuated the expression of the ovary form of CYP aromatase (cyp19a1a) at the transcriptional level but not the brain form of aromatase, cyp19a1b. Exogenous E2 potently induced the expression of cyp19a1b and vtg 1, both validated biomarkers of estrogenicity and endocrine disruption, but not cyp19a1a expression. Attenuation of activated ERK/MAPK levels, reportedly responsible for reduced human cyp19 transcription, was also observed in ketamine‐treated embryos. These results suggest that reduced E2 levels in ketamine‐treated embryos may have resulted from the suppression of cyp19a1a transcription. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
       
  • Microcystins in potable surface waters: toxic effects and removal
           strategies
    • Abstract: In freshwater, harmful cyanobacterial blooms threaten to increase with global climate change and eutrophication of surface waters. In addition to the burden and necessity of removal of algal material during water treatment processes, bloom‐forming cyanobacteria can produce a class of remarkably stable toxins, microcystins, difficult to remove from drinking water sources. A number of animal intoxications over the past 20 years have served as sentinels for widespread risk presented by microcystins. Cyanobacterial blooms have the potential to threaten severely both public health and the regional economy of affected communities, particularly those with limited infrastructure or resources. Our main objectives were to assess whether existing water treatment infrastructure provides sufficient protection against microcystin exposure, identify available options feasible to implement in resource‐limited communities in bloom scenarios and to identify strategies for improved solutions. Finally, interventions at the watershed level aimed at bloom prevention and risk reduction for entry into potable water sources were outlined. We evaluated primary studies, reviews and reports for treatment options for microcystins in surface waters, potable water sources and treatment plants. Because of the difficulty of removal of microcystins, prevention is ideal; once in the public water supply, the coarse removal of cyanobacterial cells combined with secondary carbon filtration of dissolved toxins currently provides the greatest potential for protection of public health. Options for point of use filtration must be optimized to provide affordable and adequate protection for affected communities. Copyright © 2013 John Wiley & Sons, Ltd.
       
  • Exposure to parabens at the concentration of maximal proliferative
           response increases migratory and invasive activity of human breast cancer
           cells in vitro
    • Abstract: Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen‐responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. As proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen‐responsive human breast cancer cell lines (MCF‐7, T‐47‐D, ZR‐75‐1). Cells were maintained short‐term (1 week) or long‐term (20 ± 2 weeks) in phenol‐red‐free medium containing 5% charcoal‐stripped serum with no addition, 10–8 M 17β‐oestradiol, 1–5 × 10–4 M methylparaben, 10‐5 M n‐propylparaben or 10–5 M n‐butylparaben. Long‐term exposure (20 ± 2 weeks) of MCF‐7 cells to methylparaben, n‐propylparaben or n‐butylparaben increased migration as measured using a scratch assay, time‐lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E‐cadherin and β‐catenin in the long‐term paraben‐exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long‐term paraben‐exposed T‐47‐D and ZR‐75‐1 cells using a scratch assay and time‐lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Involvement of immune‐ and inflammatory‐related factors in
           flucloxacillin‐induced liver injury in mice
    • Abstract: Drug‐induced liver injury (DILI) is a serious problem in pre‐clinical stages of drug development and clinical pharmacotherapy, but the pathogenesis of DILI has not been elucidated. Flucloxacillin (FLX), which is a β‐lactam antibiotic of the penicillin class that is used widely in Europe and Australia, rarely causes DILI. Clinical features suggest that FLX‐induced liver injury is caused by immune‐ and inflammatory‐related factors, but the mechanism of FLX‐induced liver injury is unknown. The purpose of this study was to elucidate the mechanisms of FLX‐induced liver injury in vivo. Plasma alanine aminotransferase, aspartate aminotransferase and total‐bilirubin levels were significantly elevated in FLX‐administered mice [1000 mg kg–1, intraperitoneally (i.p.)]. Toll‐like receptor 4 (TLR4) ligands, such as high‐mobility group box 1 (HMGB1) and S100A8/A9, were significantly increased in FLX‐administered mice, and inflammatory factors, such as interleukin (IL)‐1β, tumor necrosis factor‐alpha (TNF‐α), macrophage inflammatory protein (MIP)‐2, CXC chemokine‐ligand‐1 (CXCL1) and monocyte chemoattractant protein (MCP)‐1, were also significantly elevated. IL‐17‐related transcriptional factors and cytokines were increased, and the administration of recombinant IL‐17 (2 mg per body weight, i.p.) resulted in an exacerbation of the FLX‐induced liver injury. TLR4‐associated‐signal transduction may be involved in FLX‐induced liver injury, and IL‐17 is an exacerbating factor. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Impact of glyphosate and glyphosate‐based herbicides on the
           freshwater environment
    • Abstract: Glyphosate [N‐(phosphonomethyl) glycine] is a broad spectrum, post emergent herbicide and is among the most widely used agricultural chemicals globally. Initially developed to control the growth of weed species in agriculture, this herbicide also plays an important role in both modern silviculture and domestic weed control. The creation of glyphosate tolerant crop species has significantly increased the demand and use of this herbicide and has also increased the risk of exposure to non‐target species. Commercially available glyphosate‐based herbicides are comprised of multiple, often proprietary, constituents, each with a unique level of toxicity. Surfactants used to increase herbicide efficacy have been identified in some studies as the chemicals responsible for toxicity of glyphosate‐based herbicides to non‐target species, yet they are often difficult to chemically identify. Most glyphosate‐based herbicides are not approved for use in the aquatic environment; however, measurable quantities of the active ingredient and surfactants are detected in surface waters, giving them the potential to alter the physiology of aquatic organisms. Acute toxicity is highly species dependant across all taxa, with toxicity depending on the timing, magnitude, and route of exposure. The toxicity of glyphosate to amphibians has been a major focus of recent research, which has suggested increased sensitivity compared with other vertebrates due to their life history traits and reliance on both the aquatic and terrestrial environments. This review is designed to update previous reviews of glyphosate‐based herbicide toxicity, with a focus on recent studies of the aquatic toxicity of this class of chemicals. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Interaction of citrate‐coated silver nanoparticles with earthworm
           coelomic fluid and related cytotoxicity in Eisenia andrei
    • Abstract: Understanding the interaction of nanoparticles with biological fluid is important for predicting the behavior and toxicity of nanoparticles in living systems. The earthworm Eisenia andrei was exposed to citrate‐coated silver nanoparticles (cAgNPs), and the interaction of cAgNPs with earthworm coelomic fluid (ECF), the cytotoxicity of cAgNPs in earthworm coelomocytes was assessed. The neutral red retention assay showed a reduction in lysosomal stability after exposure. The toxicity of silver ions dissolved from cAgNPs in the soil medium was not significant. The aggregation and dissolution of cAgNPs increased in ECF, which contains various electrolytes that alter the properties of nanoparticles, and their subsequent toxicity. Microscopic and dissolution studies demonstrated that the aggregation of cAgNPs rapidly increased, and readily dissolved in ECF. The bioavailability of cAgNPs to earthworms induced lysosomal cytotoxicity. This is the first report to test the interaction and lysosomal cytotoxicity of nanoparticles in earthworm biofluids. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Nitroaromatic compounds: Environmental toxicity, carcinogenicity,
           mutagenicity, therapy and mechanism
    • Abstract: Vehicle pollution is an increasing problem in the industrial world. Aromatic nitro compounds comprise a significant portion of the threat. In this review, the class includes nitro derivatives of benzene, biphenyls, naphthalenes, benzanthrone and polycyclic aromatic hydrocarbons, plus nitroheteroaromatic compounds. The numerous toxic manifestations are discussed. An appreciable number of drugs incorporate the nitroaromatic structure. The mechanistic aspects of both toxicity and therapy are addressed in the context of a unifying mechanism involving electron transfer, reactive oxygen species, oxidative stress and antioxidants. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Preliminary safety evaluation of a taurocholate‐conjugated
           low‐molecular‐weight heparin derivative (LHT7): a potent
           angiogenesis inhibitor
    • Abstract: In our previous studies, taurocholic acid (TA)‐conjugated low‐molecular‐weight heparin derivative (LHT7) has been proven to be a potent anti‐angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism‐related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg–1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg–1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism‐related studies showed that blood pressure at 50 mg kg–1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg–1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Molecular biomarkers of phospholipidosis in rat blood and heart after
           amiodarone treatment
    • Abstract: Phospholipidosis (PLD) is characterized by an intracellular accumulation of phospholipids in lysosomes and concurrent development of concentric lamellar bodies. It is induced in humans and in animals by drugs with a cationic amphiphilic structure. The purpose of the present study was to identify a set of molecular biomarkers of PLD in rat blood and heart, hypothetically applicable in preclinical screens within the drug development process. A toxicological study was set up in rats orally treated up to 11 days with 300 mg kg–1 per day–1 amiodarone (AMD). Light and transmission electron microscopy investigations were performed to confirm the presence of lamellar bodies indicative of phospholipid accumulation. The effects of AMD upon the transcriptome of these tissues were estimated using DNA microarray technology. Microarray data analysis showed that a total of 545 and 8218 genes were modulated by AMD treatment in heart and blood, respectively. Some genes implicated in the phospholipid accumulation in cells, such as phospholipase A2, showed similar alterations of gene expression. After transcriptome criteria of analysis and target selection, including also the involvement in the onset of PLD, 7 genes (Pla2g2a, Pla2g7, Gal, Il1b, Cebpb, Fcgr2b, Acer 2) were selected as candidate biomarkers of PLD in heart and blood tissues, and their potential usefulness as a sensitive screening test was screened and confirmed by quantitative Real‐Time PCR analysis. Collectively, these data underscore the importance of transcriptional profiling in drug discovery and development, and suggest blood as a surrogate tissue for possible phospholipid accumulation in cardiomyocytes. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Mode of action human relevance (species concordance) framework: Evolution
           of the Bradford Hill considerations and comparative analysis of weight of
           evidence
    • Abstract: The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of “how much information is enough” to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose–response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The
      Authors . Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
       
  • Growth evaluation method by live imaging of Daphnia magna and its
           application to the estimation of an insect growth regulator
    • Abstract: The zooplankton Daphnia magna has been widely used as a test organism to assess the toxicity of chemical substances because of its important position in aquatic ecology and its ease of handling. Among the various endpoints for toxicity evaluation, growth rate is one of the most critical and many studies have been conducted. However, measurement of growth rate was time‐consuming and not an ideal endpoint in terms of screening. In this study, we demonstrated a live imaging method to monitor the growth of daphnids by area measurement. In this method, daphnid images were directly obtained from a swimming chamber and these images were processed for the evaluation of growth. The reliability of this method was confirmed by comparison with the conventional dry weight method of the same animals. The body area of daphnids using this method showed a strong correlation with the dry weight method, with R2 = 0.930. In addition, we quantified the effect of a toxicant, fenoxycarb, on the growth of the animal. Fenoxycarb concentrations of 0, 0.027, 0.27 and 2.7 µg l–1 were tested and their effects on growth were estimated by the live imaging method. In the toxicity test, the area of daphnids decreased significantly with increasing fenoxycarb concentration. These results indicate that the present live imaging method is a reliable approach for daphnid toxicity testing. This method is promising for high‐throughput Daphnia toxicity tests and real‐time individual observations. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Fish multigeneration test with preliminary short‐term reproduction
           assay for estrone using Japanese medaka (Oryzias latipes)
    • Abstract: The most potent chemicals potentially causing adverse effects on fish species are estrogens in human waste. Sewage is a source of these estrogens and it is difficult to reduce. In particular, although the bioactivity of estrone is estimated to be about half of that of estradiol, multiple studies report that more than 100 ng l–1 of estrone can be detected in urban rivers, including discharges from sewage treatment works; approximately two times as high as estradiol. Few studies have been conducted to investigate the long‐term effects of estrone on wildlife; therefore, we conducted fish multigeneration test using Japanese medaka (Oryzias latipes). Medaka were exposed to estrone for 27 weeks across three generations in environmentally relevant concentrations, being 5.74, 11.4, 24.0, 47.1 and 91.4 ng l–1. No effects on reproduction were observed in the first generation; however, a decline in egg production and fertility was observed in the second generation exposed to 91.4 ng l–1 estrone, which is lower than some known environmental concentrations in urban environments. Furthermore, histopathological abnormalities were observed in the third generation exposed to both 47.1 and 91.4 ng l–1, suggesting that estrone possibly exerts severe effects on the third or later generations. However, appearances of testis–ova were observed in the second and third generation they were not consistent with actual effects on reproduction, notwithstanding the testis‐ova is regarded as the key evidence for endocrine disruption. Accordingly, we consider that qualitative measurement of abnormalities using histopathological observations is required for appropriate evaluation of endocrine disruption. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Development and utilization of an ex vivo bromodeoxyuridine local lymph
           node assay protocol for assessing potential chemical sensitizers
    • Abstract: The murine local lymph node assay (LLNA) is widely used to identify chemicals that may cause allergic contact dermatitis. Exposure to a dermal sensitizer results in proliferation of local lymph node T cells, which has traditionally been measured by in vivo incorporation of [3H]methyl thymidine. A more recent non‐isotopic variation of the assay utilizes bromodeoxyuridine (BrdU) incorporation in vivo. To further improve the utility of this assay, we developed an ex vivo BrdU labeling procedure eliminating the need for in vivo injections. The results of this assay correctly identified a strong sensitizer (i.e., trimellitic anhydride) as well as weak/moderate sensitizers (i.e., eugenol, cinnamaldehyde and hexylcinnaminic aldehyde). As anticipated, neither non‐sensitizers isopropanol and lactic acid nor the false negative chemical nickel II sulfate hexahydrate induced a positive threshold response in the assay. The results of this assay are in close agreement with those of the in vivo LLNA:BrdU‐enzyme‐linked immunosorbent assay labeling procedure. We also used the ex vivo BrdU LLNA procedure to evaluate ammonium hexachloroplatinate, ammonium tetrachloroplatinate and cis‐diamminedichloroplatinum(II) and the assay correctly identified them as sensitizers based on the calculation of EC2 values. We conclude that this ex vivo BrdU labeling method offers predictive capacity comparable to previously established LLNA protocols while eliminating animal injections and the use of radioisotope. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
       
  • Comparative cytotoxicity of nanosilver in human liver HepG2 and colon
           Caco2 cells in culture
    • Abstract: The use of silver nanoparticles in food, food contact materials, dietary supplements and cosmetics has increased significantly owing to their antibacterial and antifungal properties. As a consequence, the need for validated rapid screening methods to assess their toxicity is necessary to ensure consumer safety. This study evaluated two widely used in vitro cell culture models, human liver HepG2 cells and human colon Caco2 cells, as tools for assessing the potential cytotoxicity of food‐ and cosmetic‐related nanoparticles. The two cell culture models were utilized to compare the potential cytotoxicity of 20‐nm silver. The average size of the silver nanoparticle determined by our transmission electron microscopy (TEM) analysis was 20.4 nm. The dynamic light scattering (DLS) analysis showed no large agglomeration of the silver nanoparticles. The concentration of the 20‐nm silver solution determined by our inductively coupled plasma–mass spectrometry (ICP‐MS) analysis was 0.962 mg ml–1. Our ICP‐MS and TEM analysis demonstrated the uptake of 20‐nm silver by both HepG2 and Caco2 cells. Cytotoxicity, determined by the Alamar Blue reduction assay, was evaluated in the nanosilver concentration range of 0.1 to 20 µg ml–1. Significant concentration‐dependent cytotoxicity of the nanosilver in HepG2 cells was observed in the concentration range of 1 to 20 µg ml–1 and at a higher concentration range of 10 to 20 µg ml–1 in Caco2 cells compared with the vehicle control. A concentration‐dependent decrease in dsDNA content was observed in both cell types exposed to nanosilver but not controls, suggesting an increase in DNA damage. The DNA damage was observed in the concentration range of 1 to 20 µg ml–1. Nanosilver‐exposed HepG2 and Caco2 cells showed no cellular oxidative stress, determined by the dichlorofluorescein assay, compared with the vehicle control in the concentration range used in this study. A concentration‐dependent decrease in mitochondria membrane potential in both nanosilver exposed cell types suggested increased mitochondria injury compared with the vehicle control. The mitochondrial injury in HepG2 cells was significant in the concentration range of 1 to 20 µg ml–1, but in Caco2 cells it was significant at a higher concentration range of 10 to 20 µg ml–1. These results indicated that HepG2 cells were more sensitive to nanosilver exposure than Caco2 cells. It is generally believed that cellular oxidative stress induces cytotoxicity of nanoparticles. However, in this study we did not detect any nanosilver‐induced oxidative stress in either cell type at the concentration range used in this study. Our results suggest that cellular oxidative stress did not play a major role in the observed cytotoxicity of nanosilver in HepG2 and Caco2 cells and that a different mechanism of nanosilver‐induced mitochondrial injury leads to the cytotoxicity. The HepG2 and Caco2 cells used this study appear to be targets for silver nanoparticles. The results of this study suggest that the differences in the mechanisms of toxicity induced by nanosilver may be largely as a consequence of the type of cells used. This differential rather than universal response of different cell types exposed to nanoparticles may play an important role in the mechanism of their toxicity. In summary, the results of this study indicate that the widely used in vitro models, HepG2 and Caco2 cells in culture, are excellent systems for screening cytotoxicity of silver nanoparticles. These long established cell culture models and simple assays used in this study can provide useful toxicity and mechanistic information that can help to better inform safety assessments of food‐ and cosmetic‐related silver nanoparticles. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
       
  • Role of the modulation of CYP1A1 expression and activity in
           chemoprevention
    • Abstract: As one of the main extra‐hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo‐a‐pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP). This review takes an in‐depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors. Copyright © 2014 John Wiley & Sons, Ltd.
       
  • Carbon‐based nanomaterials accelerate arteriolar thrombus formation
           in the murine microcirculation independently of their shape
    • Abstract: Although carbon‐based nanomaterials (CBNs) have been shown to exert prothrombotic effects in microvessels, it is poorly understood whether CBNs also have the potential to interfere with the process of leukocyte‐endothelial cell interactions and whether the shape of CBNs plays a role in these processes. Thus, the aim of this study was to compare the acute effects of two differently shaped CBNs, fiber‐shaped single‐walled carbon nanotubes (SWCNT) and spherical ultrafine carbon black (CB), on thrombus formation as well as on leukocyte‐endothelial cell interactions and leukocyte transmigration in the murine microcirculation upon systemic administration in vivo. Systemic administration of both SWCNT and CB accelerated arteriolar thrombus formation at a dose of 1 mg kg–1 body weight, whereas SWCNT exerted a prothrombotic effect also at a lower dose (0.1 mg kg–1 body weight). In vitro, both CBNs induced P‐selectin expression on human platelets and formation of platelet‐granulocyte complexes. In contrast, injection of fiber‐shaped SWCNT or of spherical CB did not induce leukocyte–endothelial cell interactions or leukocyte transmigration. In vitro, both CBNs slightly increased the expression of activation markers on human monocytes and granulocytes. These findings suggest that systemic administration of CBNs accelerates arteriolar thrombus formation independently of the CBNs' shape, but does not induce leukocyte–endothelial cell interactions or leukocyte transmigration. Copyright © 2014 John Wiley & Sons, Ltd.
       
 
 
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