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    - ENVIRONMENTAL STUDIES (690 journals)
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ENVIRONMENTAL STUDIES (690 journals)            First | 1 2 3 4     

Showing 601 - 378 of 378 Journals sorted alphabetically
Rivista di Studi sulla Sostenibilità     Full-text available via subscription  
Russian Journal of Ecology     Hybrid Journal   (Followers: 1)
S.A.P.I.EN.S     Open Access   (Followers: 2)
Safety Science     Hybrid Journal   (Followers: 28)
San Francisco Estuary and Watershed Science     Open Access   (Followers: 1)
SAR and QSAR in Environmental Research     Hybrid Journal   (Followers: 1)
Saúde e Meio Ambiente : Revista Interdisciplinar     Open Access  
Scandinavian Journal of Work, Environment & Health     Partially Free   (Followers: 12)
Science of The Total Environment     Hybrid Journal   (Followers: 22)
Sciences Eaux & Territoires : la Revue du Cemagref     Open Access  
Scientific Journal of Environmental Sciences     Open Access   (Followers: 1)
Sepsis     Hybrid Journal  
Smart Grid and Renewable Energy     Open Access   (Followers: 9)
Social and Environmental Accountability Journal     Hybrid Journal   (Followers: 2)
Soil and Sediment Contamination: An International Journal     Hybrid Journal   (Followers: 2)
Soil and Tillage Research     Hybrid Journal   (Followers: 6)
SourceOCDE Environnement et developpement durable     Full-text available via subscription   (Followers: 1)
SourceOECD Environment & Sustainable Development     Full-text available via subscription  
South Pacific Journal of Natural and Applied Sciences     Hybrid Journal  
Southern Forests : a Journal of Forest Science     Hybrid Journal   (Followers: 6)
Sriwijaya Journal of Environment     Open Access  
Stochastic Environmental Research and Risk Assessment     Hybrid Journal   (Followers: 4)
Strategic Behavior and the Environment     Full-text available via subscription   (Followers: 2)
Strategic Planning for Energy and the Environment     Hybrid Journal   (Followers: 4)
Studies in Conservation     Hybrid Journal   (Followers: 11)
Studies in Environmental Science     Full-text available via subscription   (Followers: 6)
Sustainability     Open Access   (Followers: 18)
Sustainability in Environment     Open Access   (Followers: 1)
Sustainability of Water Quality and Ecology     Hybrid Journal   (Followers: 2)
Sustainable Cities and Society     Hybrid Journal   (Followers: 24)
Sustainable Development     Hybrid Journal   (Followers: 16)
Sustainable Development Law & Policy     Open Access   (Followers: 6)
Sustainable Development Strategy and Practise     Open Access  
Sustainable Environment Research     Open Access  
Sustainable Technologies, Systems & Policies     Open Access   (Followers: 8)
TECHNE - Journal of Technology for Architecture and Environment     Open Access   (Followers: 7)
Tecnogestión     Open Access  
Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica     Open Access  
The Historic Environment : Policy & Practice     Hybrid Journal   (Followers: 5)
The International Journal on Media Management     Hybrid Journal   (Followers: 5)
Theoretical Ecology     Hybrid Journal   (Followers: 8)
Theoretical Ecology Series     Full-text available via subscription   (Followers: 1)
Toxicologic Pathology     Hybrid Journal   (Followers: 16)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 4)
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 16)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 17)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 7)
Toxicology in Vitro     Hybrid Journal   (Followers: 12)
Toxicology Letters     Hybrid Journal   (Followers: 12)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 10)
Toxicon     Hybrid Journal   (Followers: 4)
Toxin Reviews     Hybrid Journal   (Followers: 1)
Trace Metals and other Contaminants in the Environment     Full-text available via subscription   (Followers: 2)
Trace Metals in the Environment     Full-text available via subscription   (Followers: 2)
Transportation Research Part D: Transport and Environment     Hybrid Journal   (Followers: 26)
Transylvanian Review of Systematical and Ecological Research     Open Access  
Trends in Ecology & Evolution     Full-text available via subscription   (Followers: 194)
Trends in Environmental Analytical Chemistry     Hybrid Journal   (Followers: 2)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 26)
Tropicultura     Open Access  
UCLA Journal of Environmental Law and Policy     Open Access   (Followers: 5)
UD y la Geomática     Open Access  
Universidad y Ciencia     Open Access   (Followers: 1)
Urban Studies     Hybrid Journal   (Followers: 53)
Veredas do Direito : Direito Ambiental e Desenvolvimento Sustentável     Open Access  
VertigO - la revue électronique en sciences de l’environnement     Open Access   (Followers: 3)
Villanova Environmental Law Journal     Open Access  
Waste Management & Research     Hybrid Journal   (Followers: 8)
Water Environment Research     Full-text available via subscription   (Followers: 40)
Water International     Hybrid Journal   (Followers: 13)
Water, Air, & Soil Pollution     Hybrid Journal   (Followers: 22)
Water, Air, & Soil Pollution : Focus     Hybrid Journal   (Followers: 9)
Waterlines     Full-text available via subscription   (Followers: 2)
Weather and Forecasting     Full-text available via subscription   (Followers: 15)
Weather, Climate, and Society     Full-text available via subscription   (Followers: 11)
Web Ecology     Open Access   (Followers: 6)
Wetlands     Hybrid Journal   (Followers: 25)
Wilderness & Environmental Medicine     Hybrid Journal   (Followers: 3)
Wildlife Australia     Full-text available via subscription   (Followers: 2)
Wiley Interdisciplinary Reviews - Climate Change     Hybrid Journal   (Followers: 18)
Wiley Interdisciplinary Reviews : Energy and Environment     Hybrid Journal   (Followers: 5)
William & Mary Environmental Law and Policy Review     Open Access   (Followers: 2)
World Environment     Open Access   (Followers: 1)
World Journal of Entrepreneurship, Management and Sustainable Development     Hybrid Journal   (Followers: 5)
World Journal of Environmental Engineering     Open Access   (Followers: 2)
World Journal of Environmental Research     Open Access   (Followers: 1)
Worldviews: Global Religions, Culture, and Ecology     Hybrid Journal   (Followers: 8)
Zoology and Ecology     Hybrid Journal   (Followers: 5)
气候与环境研究     Full-text available via subscription   (Followers: 1)

  First | 1 2 3 4     

Journal Cover Journal of Applied Toxicology
  [SJR: 0.996]   [H-I: 61]   [15 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  [1616 journals]
  • The percutaneous toxicokinetics of Sulphur mustard in a damaged skin
           porcine model and the evaluation of WoundStat™ as a topical
    • Authors: Charlotte A. Hall; Helen L. Lydon, Christopher H. Dalton, J. Kevin Chipman, John S. Graham, Robert P. Chilcott
      Abstract: This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for decontamination of superficial (non-haemorrhaging), sulphur mustard-contaminated wounds. The dorsal skin of 12 female pigs was subjected to controlled physical damage and exposed to 10 μL 14C–radiolabelled sulphur mustard (14C–SM). Animals were randomly assigned to either a control or a treatment group. In the latter, WoundStat™ was applied 30 s post exposure and left in situ for 1 h. Skin lesion progression and decontaminant efficacy were quantified over 6 h using a range of biophysical measurements. Skin, blood and organ samples were taken post mortem for histopathological assessment, 14C–SM distribution and toxicokinetic analyses. Application of SM to damaged skin without decontamination was rapidly followed by advanced signs of toxicity, including ulceration and decreased blood flow at the exposure site in all animals. WoundStat™ prevented ulceration and improved blood flow at the exposure site in all decontaminated animals (n = 6). Furthermore, significantly smaller quantities of 14C–SM were detected in the blood (45% reduction), and recovered from skin (70% reduction) and skin surface swabs (99% reduction) at 6 h post-challenge. Overall, the distribution of 14C–SM in the internal organs was similar for both groups, with the greatest concentration in the kidneys, followed by the liver and small intestine. WoundStat™ significantly reduced the amount of 14C–SM recovered from the liver, a key organ for SM metabolism and detoxification. This study demonstrates that WoundStat™ is a suitable product for reducing the ingress and toxicity of a chemical warfare agent. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-17T06:05:49.176195-05:
      DOI: 10.1002/jat.3453
  • Toxicity of inhaled particulate matter on the central nervous system:
           neuroinflammation, neuropsychological effects and neurodegenerative
    • Authors: Yan Wang; Lilin Xiong, Meng Tang
      Abstract: Particulate matter (PM) combined with meteorological factors cause the haze, which brings inconvenience to people's daily life and deeply endanger people's health. Accumulating literature, to date, reported that PM are closely related to cardiopulmonary disease. Outpatient visits and admissions as a result of asthma and heart attacks gradually increase with an elevated concentration of PM. Owing to its special physicochemical property, the brain could be a potential target beyond the cardiopulmonary system. Possible routes of PM to the brain via a direct route or stimulation of pro-inflammatory cytokines have been reported in several documents concerning toxicity of engineered nanoparticles in rodents. Recent studies have demonstrated that PM have implications in oxidative stress, inflammation, dysfunction of cellular organelles, as well as the disturbance of protein homeostasis, promoting neuron loss and exaggerating the burden of central nervous system (CNS). Moreover, the smallest particles (nano-sized particles), which were involved in inflammation, reactive oxygen species (ROS), microglial activation and neuron loss, may accelerate the process of the neurodevelopmental disorder and neurodegenerative disease. Potential or other undiscovered mechanisms are not mutually exclusive but complementary aspects of each other. Epidemiology studies have shown that exposure to PM could bring about neurotoxicity and play a significant role in the etiology of CNS disease, which has been gradually corroborated by in vivo and in vitro studies. This review highlights research advances on the health effects of PM with an emphasis on neurotoxicity. With the hope of enhancing awareness in the public and calling for prevention and protective measures, it is a critical topic that requires proceeding exploration. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-16T04:01:42.075744-05:
      DOI: 10.1002/jat.3451
  • Altered expression of the Olr59, Ethe1, and Slc10a2 genes in the liver of
           F344 rats by neonatal thyroid hormone disruption
    • Authors: Kana Matsubara; Naoki Nakamura, Seigo Sanoh, Shigeru Ohta, Shigeyuki Kitamura, Naoto Uramaru, Shinichi Miyagawa, Taisen Iguchi, Nariaki Fujimoto
      Abstract: Many concerns have been expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals in the environment. The disruption of thyroid hormones in the neonatal period may lead to permanent effects on thyroid hormone homeostasis as well as related developmental disorders, as thyroid hormones are essential for regulating the growth and differentiation of many tissues. To understand the long-term alteration in gene expressions by neonatal administration of thyroid hormone-like chemicals in general, we identified genes whose expression was altered in the liver, an important component of the thyroid hormone axis, by neonatal exposure to triiodothyronine (T3). T3 was administered to male F344 rats on postnatal days 1, 3, and 5 (week 0). At 8 weeks of age, cDNA microarray analysis was used to identify hepatic genes whose expression was altered by neonatal exposure to T3. Among the up-regulated genes that were identified, the expression of Olr59, Ethe1, and Slc10a2 increased specifically in rats neonatally exposed to T3. Interestingly, altered hepatic expression of these genes indeed increased when a hydroxylated polybrominated diphenyl ether (PBDE), OH-BDE42, which is capable of binding to the TR, was given neonatally. Our data demonstrated that neonatal exposure to thyroid hormones could affect the long-term expression of the genes, which could be useful markers for neonatal effects by thyroid hormone-disrupting chemicals. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-16T03:47:31.872555-05:
      DOI: 10.1002/jat.3452
  • Hydroxyapatite nanoparticle-induced mitochondrial energy metabolism
           impairment in liver cells: in vitro and in vivo studies
    • Authors: Yang Xue; Qingqing Chen, Jiao Sun
      Abstract: Hydroxyapatite nanoparticles (HAP-NPs) have been extensively developed as drug carriers, bone implants, coating materials, etc. in the human body. However, research focusing on the potential side effects of HAP-NPs on the mitochondria-associated energy metabolism in liver cells is lacking. In this study, HAP-NPs with a long diameter of 80 nm and a short diameter of 20 nm were evaluated for their ability to induce mitochondrial energy metabolism dysfunction in vitro and in vivo. In the in vitro system, the buffalo rat hepatocyte (BRL) cell line was directly exposed to the HAP-NPs. The results of these experiments showed that the HAP-NPs induced inhibition of mitochondrial dehydrogenase activity, which was accompanied by a decrease in the mitochondrial membrane potential (MMP). In addition, HAP-NPs elevated the hepatic levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased the levels of GSH and SOD. These data indicated that HAP-NPs induced a lowered rate of electron transfer in the mitochondrial respiratory chain, accompanied by a decrease in the activity of the mitochondrial respiratory chain complexes I, II and III. Furthermore, HAP-NPs induced a decline in the enzymatic expression in the Krebs cycle. We also investigated the role of Kupffer cells (KCs, rat-derived) in the effects induced by the HAP-NPs. The supernatant from the HAP-NP-treated KCs was used to stimulate the BRL cells. We observed that the HAP-NPs had the ability to induce KC activation. The activation of KCs then led to the release of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and reactive oxygen species (ROS), and induced the inhibition of mitochondrial respiratory chain complexes I, II and III in the BRL cells. In the in vivo study, the TEM examination revealed mitochondrial swelling and vacuolar degeneration in the HAP-NP-treated hepatocytes. In addition, the amount of succinate (Suc), an intermediate in the mitochondrial Krebs cycle, also declined in the 1H NMR spectroscopic measurements. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:55:52.531921-05:
      DOI: 10.1002/jat.3450
  • Comparative luciferase assay for establishing reliable in vitro screening
           system of juvenile hormone agonists
    • Authors: Hitoshi Miyakawa; Taisen Iguchi
      Abstract: The cultured cell-based in vitro assay using the stringency of ligand-receptor interactions is typically useful for screening certain hormone agonists from among a very large number of molecules. However, ligands are frequently altered or modified through evolution; indeed, even in the same receptor orthologs, different ligand sensitivity profiles are considered to arise among species and/or taxa. Such ligand transition has been observed in juvenile hormone (JH), one of the most important endocrine factors in arthropods. To understand the molecular basis of ligand selectivity alteration in hormone receptors, we compared the amino acid sequences and ligand selectivity of the JH receptor, Methoprene-tolerant (Met), among three insects (Drosophila melanogaster, Aedes aegypti and Tribolium castaneum) and one crustacean (Daphnia pulex). Compared with D. pulex, we found that the receptors of the three insects showed a higher sensitivity to JH III, which is the major innate JH ligand in insects. Furthermore, point mutation analysis in Met sequences revealed a candidate amino acid residue that is important for increasing JH sensitivity in insects. Amino acid mutations in Met may have affected changes in ligand selectivity intermittently over the course of the evolution of the JH-signaling pathway. These findings are useful to improve the existing (developing) cultured cell-based assay system and may shed light on the relationship between functional diversification in hormonal signaling and the molecular evolution of hormone receptors. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:55:34.721642-05:
      DOI: 10.1002/jat.3459
  • Effects of aging on cadmium concentrations and renal dysfunction in
           inhabitants in cadmium-polluted regions in Japan
    • Authors: Hoang Duc Phuc; Teruhiko Kido, Nguyen Thi Phuong Oanh, Ho Dung Manh, Le Thai Anh, Yuko Oyama, Rie Okamoto, Akie Ichimori, Kazuhiro Nogawa, Yasushi Suwazono, Hideaki Nakagawa
      Abstract: The absorption of cadmium (Cd) may lead to Cd-related diseases such as renal tubular dysfunction and bone disease, and it is known to take around 10–30 years to reduce Cd concentrations to half their original levels. Urinary β2-microglobulin (β2-MG), N-acetyl-β-D-glucosaminidase (NAG), protein, glucose and albumin were used as indicators of renal dysfunction caused by Cd exposure. Our previous study found that urinary Cd concentrations had increased recently and that age was more strongly associated with urinary β2-MG concentration than recent Cd body burden. Therefore, the purpose of the present study was to investigate the effect of aging on Cd concentrations and renal dysfunction. The Cd, β2-MG, NAG, protein, glucose and albumin concentrations in the urine of 40 Japanese subjects (20 females and 20 males) environmentally exposed to Cd were collected. They lived in the Kakehashi River basin and were divided into three age categories: 50–69, 70–79 and 80–99 years. Significant differences in urinary Cd and β2-MG concentrations were found among age groups, with urinary Cd levels tending to increase with age in both sexes. No significant correlations were found between urinary Cd and any indicators of renal dysfunction. The correlation between age, Cd and indicators of renal dysfunction was observed more clearly in females than in males. Age is more strongly correlated with indicators of renal dysfunction than Cd body burden. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:40:26.271581-05:
      DOI: 10.1002/jat.3455
  • Structural and functional alterations in Malpighian tubules as biomarkers
           of environmental pollution: synopsis and prospective
    • Authors: Anita Giglio; Pietro Brandmayr
      Abstract: Although a number of biomarkers of pollutant exposure have been identified in invertebrate species, little is known about the effect on Malpighian tubules playing an essential role in excretion and osmoregulation. Analyses of structural and functional alterations on this organ can be useful to predict the effects at the organism and population level in monitoring studies of environmental pollution. The aim of the present review is to provide a synthesis of existing knowledge on cellular damages induced by xenobiotics in Malpighian tubules both under laboratory and field conditions. We compared studies of exposure to pesticides and heavy metals as mainly environmental contaminants from anthropogenic activities. This report provided evidence that the exposure to xenobiotics has an effect on this organ and reinforces the need for further research integrating molecular biomarkers with analysis on Malpighian tubules. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:35:31.017191-05:
      DOI: 10.1002/jat.3454
  • A quantitative in silico model for predicting skin sensitization using a
           nearest neighbours approach within expert-derived structure–activity
           alert spaces
    • Authors: Steven J. Canipa; Martyn L. Chilton, Rachel Hemingway, Donna S. Macmillan, Alun Myden, Jeffrey P. Plante, Rachael E. Tennant, Jonathan D. Vessey, Thomas Steger-Hartmann, Janet Gould, Jedd Hillegass, Sylvain Etter, Benjamin P. C. Smith, Angela White, Paul Sterchele, Ann De Smedt, Devin O'Brien, Rahul Parakhia
      Abstract: Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-28T03:21:38.064119-05:
      DOI: 10.1002/jat.3448
  • Development of haemostatic decontaminants for treatment of wounds
           contaminated with chemical warfare agents. 3: Evaluation of in vitro
           topical decontamination efficacy using damaged skin
    • Authors: Helen L. Lydon; Charlotte A. Hall, Christopher H. Dalton, J. Kevin Chipman, John S. Graham, Robert P. Chilcott
      Abstract: Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-20T08:00:31.265147-05:
      DOI: 10.1002/jat.3446
  • Toxaphene-induced mouse liver tumorigenesis is mediated by the
           constitutive androstane receptor
    • Authors: Zemin Wang; Xilin Li, Qiangen Wu, James C. Lamb, James E. Klaunig
      Abstract: Toxaphene was shown to increase liver tumor incidence in B6C3F1 mice following chronic dietary exposure. Preliminary evidence supported a role for the constitutive androstane receptor (CAR) in the mode of action of toxaphene-induced mouse liver tumors. However, these results could not rule out a role for the pregnane X receptor (PXR) in liver tumor formation. To define further the nuclear receptors involved in this study, we utilized CAR, PXR and PXR/CAR knockout mice (CAR−/−, PXR−/− and PXR−/−/CAR−/−) along with the wild-type C57BL/6. In this study CAR-responsive genes Cyp3a11 and Cyp2b10 were induced in the liver of C57BL/6 (wild-type) mice by toxaphene (30–570-fold) (at the carcinogenic dose 320 ppm) and phenobarbital (positive control) (16–420-fold) following 14 days' dietary treatment. In contrast, in CAR−/− mice, no induction of these genes was seen following treatment with either chemical. Cyp3a11 and Cyp2b10 were also induced in PXR−/− mice with toxaphene and phenobarbital but were not changed in treated PXR−/−/CAR−/− mice. Similarly, induction of liver pentoxyresorufin-O-deethylase (CAR activation) activity by toxaphene and phenobarbital was absent in CAR−/− and PXR−/−/CAR−/− mice treated with phenobarbital or toxaphene. Ethoxyresorufin-O-deethylase (EROD, represents aryl hydrocarbon receptor activation) activity in CAR−/− mice treated with toxaphene or phenobarbital was increased compared with untreated control, but lower overall in activity in comparison to the wild-type mouse. Liver EROD activity was also induced by both phenobarbital and toxaphene in the PXR−/− mice but not in the PXR−/−/CAR−/− mice. Toxaphene treatment increased 7-benzyloxyquinoline activity (a marker for PXR activation) in a similar pattern to that seen with pentoxyresorufin-O-deethylase. These observations indicate that EROD and PXR activation are evidence, as expected, of secondary overlap to primary CAR receptor activation. Together, these results definitively show that activation of the CAR nuclear receptor is the mode of action of toxaphene-induced mouse liver tumors. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-20T07:20:33.00805-05:0
      DOI: 10.1002/jat.3445
  • Automated image analysis of intra-tumoral and peripheral endocrine organ
           vascular bed regression using ‘Fibrelength’ as a novel structural
    • Authors: Adam Hargreaves; Alison Bigley, Shirley Price, Jane Kendrew, Simon T. Barry
      Abstract: The study of vascular modulation has received a great deal of attention in recent years as knowledge has increased around the role of angiogenesis within disease contexts such as cancer. Despite rapidly expanding insights into the molecular processes involved and the concomitant generation of a number of anticancer vascular modulating chemotherapeutics, techniques used in the measurement of structural vascular change have advanced more modestly, particularly with regard to the preclinical quantification of off-target vascular regression within systemic, notably endocrine, blood vessels. Such changes translate into a number of major clinical side effects and there remains a need for improved preclinical screening and analysis. Here we present the generation of a novel structural biomarker, which can be incorporated into a number of contemporary image analysis platforms and used to compare tumour versus systemic host tissue vascularity. By contrasting the measurements obtained, the preclinical efficacy of vascular modulating chemotherapies can be evaluated in light of the predicted therapeutic window. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-10T08:21:00.150677-05:
      DOI: 10.1002/jat.3438
  • Threshold limit values of the cadmium concentration in rice in the
           development of itai-itai disease using benchmark dose analysis
    • Authors: Kazuhiro Nogawa; Masaru Sakurai, Masao Ishizaki, Teruhiko Kido, Hideaki Nakagawa, Yasushi Suwazono
      Abstract: The aim of this study was to estimate the benchmark dose (BMD) as the threshold limit level of the cadmium (Cd) concentration in rice for itai-itai disease and/or suspected disease; it was based on the data that previously evaluated the association for such diseases with the Cd concentration in rice by using a logistic regression model. From 1971 to 1976, a total of 2446 rice samples were analyzed across the 88 hamlets in the Jinzu river basin. The mean Cd concentration in rice in each hamlet was used as the index of external Cd exposure of the entire population of the hamlet. We employed the incidence of itai-itai disease and/or suspected disease obtained from the available 55 hamlets. As the threshold, the lower limit of the BMD (BMDL) of the Cd concentration in rice for itai-itai disease and/or suspected disease was estimated using a logistic model, setting the benchmark response at 1% or 2%. The estimated BMDLs of the Cd concentration in rice for itai-itai disease and/or suspected disease were 0.62–0.76 and 0.27–0.56 mg kg−1 in men and women, respectively. The lowest BMDL was 0.27 mg kg−1 in women. In the present study, the threshold limit level of the Cd concentration in rice for itai-itai disease, which is the most severe form of chronic Cd poisoning, was estimated for the first time. This result provides important information about the worldwide standard for the Cd concentration in rice. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-10T07:35:34.350451-05:
      DOI: 10.1002/jat.3444
  • Effects of neonatal 17α-ethinyloestradiol exposure on female-paced
           mating behaviour in the rat
    • Authors: Chiaki Komine; Shingo Nakajima, Yasuhiko Kondo, Yasuyuki Horii, Midori Yoshida, Maiko Kawaguchi
      Abstract: Correct perinatal oestrogen levels are critical for sexual differentiation. For example, perinatal exposure to oestrogen causes masculinization and defeminization of the brain in female rats and also induces delayed effects after maturation characterized by early onset of abnormal oestrus cycling. However, the mechanisms underlying the above effects of oestrogen remain to be fully determined. 17α-ethinyloestradiol (EE), a common synthetic oestrogen widely used in oral contraceptives, binds specifically to oestrogen receptors. In this study, we demonstrated the effects of a single neonatal injection of high- or low-dose EE on reproductive behaviours. Female rats within 24 h after birth were subcutaneously injected with sesame oil, EE (0.02, 2 mg kg−1) and 17β-oestradiol (E2) (20 mg kg−1). Between 11 and 15 weeks of age, sexual behaviour was tested twice in a paced mating situation. Latency to enter, lordosis and soliciting behaviour were recorded. Both high-dose EE- and E2-treated females showed a significantly lower lordosis quotient, decreased soliciting behaviours, increased rejection and fighting numbers. Accessibility to males was also delayed by neonatal E2 exposure, although it was shortened by high-dose EE exposure. In contrast, low-dose EE-treated females did not exhibit impaired sexual behaviour. These results suggest that single neonatal exposure to a high dose of EE or E2 disturbs the normal development of the female brain, resulting in impaired sexual behaviours in a female-paced mating situation. Besides, the differences noted between high-dose EE- and E2-treated females might be caused by different affinities of the oestrogen receptors, metabolic rates or mechanisms of action. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-08T04:45:39.271089-05:
      DOI: 10.1002/jat.3449
  • Role of connexin 43 in cadmium-induced proliferation of human prostate
           epithelial cells
    • Authors: Qingping Liu; Xiaoli Ji, Zehe Ge, Haipeng Diao, Xiuli Chang, Lihua Wang, Qing Wu
      Abstract: Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca2+ and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27Kip1 (p27) and p21Waf1/Cip1 (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-08T04:40:36.656654-05:
      DOI: 10.1002/jat.3441
  • Pancreatic impairment and Igf2 hypermethylation induced by developmental
           exposure to bisphenol A can be counteracted by maternal folate
    • Authors: Zhenxing Mao; Wei Xia, Wenqian Huo, Tongzhang Zheng, Bryan A. Bassig, Huailong Chang, Tian Chen, Feie Li, Yunxin Pan, Yang Peng, Yuanyuan Li, Shunqing Xu
      Abstract: Increasing evidence indicates that bisphenol A (BPA), a widely manufactured environmental pollutant, can induce changes in DNA methylation paatterns, which is a potential mechanism linking this environmental exposure to disease development. We investigated the influence of developmental exposure to BPA on pancreatic DNA methylation patterns and whether maternal folate supplementation can modify the epigenetic status and pancreatic impairment induced by BPA. Our results showed that maternal dietary folate supplementation in rats exposed to BPA counteracted the observed BPA-induced pancreatic impairments in the offspring, which included disrupted insulin secretion and glucose intolerance, and impaired morphology and ultrastructure of β cells. Moreover, these pancreatic dysfunctions were shown to be associated with low expression and DNA hypermethylation of insulin-like growth factor-2 (Igf2) in islets induced by exposure to BPA during the developmental period. Importantly, maternal dietary folate supplementation was demonstrated to negate this Igf2 DNA hypermethylation in the offspring, which was consistent with the upregulation of Igf2 expression. Overall, our results suggest that early developmental exposure to BPA alters the DNA methylation of Igf2, that these altered methylation patterns are associated with impaired β-cell function in the offspring and that these effects can be counteracted by maternal folate supplementation. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:15:35.443618-05:
      DOI: 10.1002/jat.3430
  • Carboxylated nanodiamonds can be used as negative reference in in vitro
           nanogenotoxicity studies
    • Authors: H. Moche; V. Paget, D. Chevalier, E. Lorge, N. Claude, H. A. Girard, J. C. Arnault, S. Chevillard, F. Nesslany
      Abstract: Nanodiamonds (NDs) are promising nanomaterials for biomedical applications. However, a few studies highlighted an in vitro genotoxic activity for detonation NDs, which was not evidenced in one of our previous work quantifying γ-H2Ax after 20 and 100 nm high-pressure high-temperature ND exposures of several cell lines. To confirm these results, in the present work, we investigated the genotoxicity of the same 20 and 100 nm NDs and added intermediate-sized NDs of 50 nm. Conventional in vitro genotoxicity tests were used, i.e., the in vitro micronucleus and comet assays that are recommended by the French National Agency for Medicines and Health Products Safety for the toxicological evaluation of nanomedicines. In vitro micronucleus and in vitro comet assays (standard and hOGG1-modified) were therefore performed in two human cell lines, the bronchial epithelial 16HBE14o– cells and the colon carcinoma T84 cells. Our results did not show any genotoxic activity, whatever the test, the cell line or the size of carboxylated NDs. Even though these in vitro results should be confirmed in vivo, they reinforce the potential interest of carboxylated NDs for biomedical applications or even as a negative reference nanoparticle in nanotoxicology. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:15:29.055648-05:
      DOI: 10.1002/jat.3443
  • Horseradish extract promotes urinary bladder carcinogenesis when
           administered to F344 rats in drinking water
    • Authors: Young-Man Cho; Mai Hasumura, Toshio Imai, Shigeaki Takami, Akiyoshi Nishikawa, Kumiko Ogawa
      Abstract: Horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate and other isothiocyanates, has been used as a food additive. To evaluate the potential hazards of HRE, a 104-week chronic study, a 2-week analysis of cell proliferation in the urinary bladder and a medium-term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. In the 104-week chronic study with 32 male rats per group, no treatment-related increases in the incidences of neoplastic lesions in any organ, including urinary bladder, were observed, except for simple hyperplasia in the urinary bladder in rats treated with HRE at concentrations of more than 0.01% (5.0 mg kg−1 body weight day−1). In the promotion study, HRE treatment after N-butyl-N-(4-hydroxybutyl)nitrosamine initiation caused a clear increase in papillary or nodular hyperplasia, papilloma, and urothelial carcinoma of the urinary bladder in the groups given HRE for 13 weeks at doses higher than 0.005%, 0.01%, and 0.04% (2.7, 5.4 and 20.5 mg kg−1 body weight day−1), respectively. In the 2-week cell proliferation analysis, treatment with HRE at concentrations greater than 0.005% (3.9 mg kg−1 body weight day−1) caused transient increases in 5-bromo-2′-deoxyuridine labeling indices in the urothelium. Although clear tumor induction was not observed, administration of relatively low-dose HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis. Further studies are needed to elucidate the mode of action of HRE in the rat urinary bladder to facilitate data extrapolation from the present study and provide insights into risk assessment. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:00:24.141191-05:
      DOI: 10.1002/jat.3434
  • Preclinical safety assessments of nano-sized constructs on cardiovascular
           system toxicity: A case for telemetry
    • Authors: Hoay Yan Cheah; Lik Voon Kiew, Hong Boon Lee, Nina Japundžić-Žigon, Marίa J. Vicent, See Ziau Hoe, Lip Yong Chung
      Abstract: While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T06:55:35.428124-05:
      DOI: 10.1002/jat.3437
  • Arachidonic acid-containing phosphatidylcholine characterized by
           consolidated plasma and liver lipidomics as an early onset marker for
           tamoxifen-induced hepatic phospholipidosis
    • Authors: Kosuke Saito; Keisuke Goda, Akio Kobayashi, Naohito Yamada, Kyoko Maekawa, Yoshiro Saito, Shoichiro Sugai
      Abstract: Lipid profiling has emerged as an effective approach to not only screen disease and drug toxicity biomarkers but also understand their underlying mechanisms of action. Tamoxifen, a widely used antiestrogenic agent for adjuvant therapy against estrogen-positive breast cancer, possesses side effects such as hepatic steatosis and phospholipidosis (PLD). In the present study, we administered tamoxifen to Sprague–Dawley rats and used lipidomics to reveal tamoxifen-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. Treatment with tamoxifen for 28 days caused hepatic PLD in rats. We compared the plasma and liver lipid profiles in treated vs. untreated rats using a multivariate analysis to determine differences between the two groups. In total, 25 plasma and 45 liver lipids were identified and altered in the tamoxifen-treated group. Of these lipids, arachidonic acid (AA)-containing phosphatidylcholines (PCs), such as PC (17:0/20:4) and PC (18:1/20:4), were commonly reduced in both plasma and liver. Conversely, tamoxifen increased other phosphoglycerolipids in the liver, such as phosphatidylethanolamine (18:1/18:1) and phosphatidylinositol (18:0/18:2). We also examined alteration of AA-containing PCs and some phosphoglycerolipids in the pre-PLD stage and found that these lipid alterations were initiated before pathological alteration in the liver. In addition, changes in plasma and liver levels of AA-containing PCs were linearly associated. Moreover, levels of free AA and mRNA levels of AA-synthesizing enzymes, such as fatty acid desaturase 1 and 2, were decreased by tamoxifen treatment. Therefore, our study demonstrated that AA-containing PCs might have potential utility as novel and predictive biomarkers for tamoxifen-induced PLD. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:25:51.161293-05:
      DOI: 10.1002/jat.3442
  • Evaluation of divided attention psychophysical task performance and
           effects on pupil sizes following smoked, vaporized and oral cannabis
    • Authors: Matthew N. Newmeyer; Madeleine J. Swortwood, Megan E. Taylor, Osama A. Abulseoud, Thomas H. Woodward, Marilyn A. Huestis
      Abstract: Establishing science-based driving per se blood Δ9-tetrahydrocannabinol (THC) limits is challenging, in part because of prolonged THC detection in chronic, frequent users. Therefore, documenting observable signs of impairment is important for driving under the influence of drugs. We evaluated frequent and occasional cannabis smokers' performance on the modified Romberg balance, one leg stand (OLS), and walk and turn (WAT) tasks, and pupil size effects following controlled placebo (0.001% THC), smoked, vaporized and oral (6.9% [~50.4 mg] THC) cannabis administration. Significant effects following inhaled doses were not observed due to delayed tasks administration 1.5 and 3.5 h post-dose, but significant impairment was observed after oral dosing (blood THC concentrations peaked 1.5–3.5 h post-dose). Occasional smokers' odds of exhibiting ≥2 clues on the OLS or WAT following oral dosing were 6.4 (95% CI 2.3–18.4) times higher than after placebo, with THC and 11-hydroxy-THC blood concentrations individually producing odds ratios of 1.3 (1.1–1.5) and 1.5 (1.3–1.8) for impairment in these tasks, respectively. Pupil sizes after oral dosing under the direct lighting condition were significantly larger than after placebo by mean (SE, 95% CI) 0.4 (0.1, 0.2–0.6) mm at 1.5 h and 0.5 (0.2, 0.2–0.8) mm at 3.5 h among all participants. Oral cannabis administration impaired occasional cannabis users' performance on the OLS and WAT tasks compared to placebo, supporting other reports showing these tasks are sensitive to cannabis-related impairment. Occasional smokers' impairment was related to blood THC and 11-hydroxy-THC concentrations. These are important public health policy findings as consumption of edible cannabis products increases. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2017-01-31T03:20:47.354758-05:
      DOI: 10.1002/jat.3440
  • Megakaryocyte expansion and macrophage infiltration in bone marrow of rats
           subchronically treated with MNX, N-nitroso environmental degradation
           product of munitions compound RDX
    • Authors: Sindhura Ramasahayam; Sridhar Jaligama, Sahar M. Atwa, Joshua T. Salley, Marissa Thongdy, Benny L. Blaylock, Sharon A. Meyer
      Abstract: Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague–Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg−1 day−1 MNX (¼ LD50) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1+-macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:15:53.528673-05:
      DOI: 10.1002/jat.3439
  • Glaucarubulone glucoside from Castela macrophylla suppresses MCF-7 breast
           cancer cell growth and attenuates benzo[a]pyrene-mediated CYP1A gene
    • Authors: Simone A. M. Badal; Malyn M. Asuncion Valenzuela, Dain Zylstra, George Huang, Pallavi Vendantam, Sheena Francis, Ashley Quitugua, Louisa H. Amis, Willie Davis, Tzuen-Rong J. Tzeng, Helen Jacobs, David J. Gangemi, Greg Raner, Leah Rowland, Jonathan Wooten, Petreena Campbell, Eileen Brantley, Rupika Delgoda
      Abstract: Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside (Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF-7 breast adenocarcinoma cells (IC50 = 121 nm) to a greater extent than standard of care anticancer agents 5-fluorouracil, tamoxifen (IC50>10 μm) and the tamoxifen metabolite 4-hydroxytamoxifen (IC50 = 2.6 μm), yet was not cytotoxic to non-tumorigenic MCF-10A breast epithelial cells. Additionally, Gg induced MCF-7 breast cancer cell death. Gg blocked increases in reactive oxygen species in MCF-10A cells mediated by the polyaromatic hydrocarbon benzo[a]pyrene (B[a]P) metabolite B[a]P 1,6-quinone, yet downregulated the expression of genes that promote antioxidant activity in MCF-7 cells. This implies that Gg exhibits antioxidant and cytoprotective actions in non-tumorigenic breast epithelial cells and pro-oxidant, cytotoxic actions in breast cancer cells. Furthermore, Gg inhibited the activities of human CYP1A according to non-competitive kinetics and attenuated the ability of B[a]P to induce CYP1A gene expression in MCF-7 cells. These data indicate that Gg selectively suppresses MCF-7 breast cancer cell growth without impacting non-tumorigenic breast epithelial cells and blocks B[a]P-mediated CYP1A induction. Taken together, our data provide a rationale for further investigations of Gg and similar plant isolates as potential agents to treat and prevent breast cancer. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:05:41.74938-05:0
      DOI: 10.1002/jat.3436
  • Prediction of drug-induced liver injury using keratinocytes
    • Authors: Rika Hirashima; Tomoo Itoh, Robert H. Tukey, Ryoichi Fujiwara
      Abstract: Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression. They also showed a higher inducibility of IL-1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI-associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI-associated genes might be involved in the onset and progression of drug-induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T02:10:44.058808-05:
      DOI: 10.1002/jat.3435
  • Current and prospective sights in mechanism of deoxynivalenol-induced
           emesis for future scientific study and clinical treatment
    • Authors: Liangkai Chen; Zhao Peng, Andreas K. Nüssler, Liegang Liu, Wei Yang
      Abstract: Deoxynivalenol (DON), one of trichothecene mycotoxins produced by the fungus Fusarium, is commonly detected in cereal foods and in secondary food production across the world. Lower concentrations of DON induce a dose-related feed refusal (anorexia), whereas it acts as a potent emetic agent at higher levels. DON-induced emesis in humans and livestock can be observed and recorded in both undeveloped and developed regions such as Lixian, Guide and Huangzhong in China and Illinois in the USA. Some studies with different animal models (pigs and minks) suggested that DON could change expressions of 5-hydroxytryptamine, peptide YY, neuropeptide Y2 receptor and nucleobindin-2/nesfatin-1 in plasma and different areas of the brain. Some selective antagonist of 5-hydroxytryptamine 3 receptors can inhibit DON-induced emetic response. Otherwise, the Ca2+ homeostasis and MAPK pathway could be potential directions in future studies. Dolasetron, dantrolene and JNJ-31020028 can be used in clinical treatment but they have potential toxic effects. (−)Epicatechin, ginger phytochemicals and isoflavone can be tested in in vitro and in vivo for their usage as food additives for reducing the emesis. The present review summarizes and discusses some information from previous and recent prominent publications with the aim to provide some comprehensive and helpful data for understanding the mechanism of DON-induced emesis. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T01:35:59.169765-05:
      DOI: 10.1002/jat.3433
  • Oxidative stress-mediated developmental toxicity induced by isoniazide in
           zebrafish embryos and larvae
    • Authors: Yu Zou; Yun Zhang, Liwen Han, Qiuxia He, Hairong Hou, Jian Han, Ximin Wang, Chengyun Li, Juan Cen, Kechun Liu
      Abstract: Isoniazide (INH) is an important first-line drug that is used to treat tuberculosis. However, the effect of INH on fetal growth has not yet been elucidated, and the mechanism of INH-induced developmental toxicity is still unknown. In the present study, we employed zebrafish embryos and larvae to investigate the developmental toxicity of INH. The survival rates of the embryos and larvae as well as the hatching rates of embryos were significantly reduced. Morphological abnormalities, including spinal curvature, yolk retention, swimming bladder absence, tail bending and shorter body lengths were induced by INH. Histopathological analysis showed loose cell-to-cell contacts and large vacuoles in the larval hepatocytes. Thin intestinal walls, frayed gut villi and widespread cell lysis were observed in the intestines of the larvae in the higher concentration (8, 16 mm) exposure groups. In addition, exposure to high doses (≥ 6 mm) of INH significantly reduced the locomotor capacity of the zebrafish larvae. INH significantly increased the levels of reactive oxygen species and malondialdehyde and decreased the superoxide dismutase activity in zebrafish larvae, which suggested that oxidative stress was induced and that the antioxidant capacity was inhibited. Superoxide dismutase 1 and liver fatty acid-binding protein mRNA levels were significantly downregulated, while the GSTP2 and cytochrome P450 3A mRNA levels were significantly upregulated in the INH-exposed zebrafish larvae. The overall results indicated that INH caused a dose- and time-dependent increase in developmental toxicity and that oxidative stress played an important role in the developmental toxicity induced by INH in zebrafish larvae. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T00:55:41.043004-05:
      DOI: 10.1002/jat.3432
  • Lethal and sublethal effects of aniline and chlorinated anilines on
           zebrafish embryos and larvae
    • Authors: Yoshifumi Horie; Takahiro Yamagishi, Masaaki Koshio, Taisen Iguchi, Norihisa Tatarazako
      Abstract: Environmental risk assessments show increased attention to the sublethal effects of chemicals on aquatic organisms. The Organization for Economic Cooperation and Development (OECD) established the “Fish, Short-term Toxicity Test on Embryo and Sac-fry Stages” (OECD test 212) to predict lethal effects. It is still unclear, however, whether this test can predict sublethal effects. Although their sublethal effects are still unknown, chlorinated anilines are widely used in various fields. The purpose of this study, therefore, is to investigate sublethal effects of chlorinated anilines using OECD test 212 with zebrafish, and to examine the correlation of several sublethal effects between embryo and larval stages. Embryos were exposed to aniline and nine chlorinated anilines until 8 days post-fertilization. A delayed lethal effect was observed from three of the 10 anilines tested. In the control group, the swim bladder inflated after hatching, but there was no swim-bladder inflation after exposure to the chlorinated anilines. Fertilized eggs exposed to lower concentrations of test chemicals showed effects during embryogenesis that did not affect mortality rates, such as changes in body curvature and edema. Our results show that chlorinated anilines induce not only lethal effects but also a variety of sublethal effects. Moreover, a detailed estimate of these effects requires study during both embryonic and larval stages. OECD test 212 may therefore prove useful as a method for screening chemicals for lethal and sublethal effects. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T00:41:40.559454-05:
      DOI: 10.1002/jat.3431
  • Comparison of protocols measuring diffusion and partition coefficients in
           the stratum corneum
    • Authors: H. Rothe; C. Obringer, J. Manwaring, C. Avci, W. Wargniez, J. Eilstein, N. Hewitt, R. Cubberley, H. Duplan, D. Lange, C. Jacques-Jamin, M. Klaric, A. Schepky, S. Grégoire
      Abstract: Partition (K) and diffusion (D) coefficients are important to measure for the modelling of skin penetration of chemicals through the stratum corneum (SC). We compared the feasibility of three protocols for the testing of 50 chemicals in our main studies, using three cosmetics-relevant model chemicals with a wide range of logP values. Protocol 1: SC concentration-depth profile using tape-stripping (measures KSC/v and DSC/HSC2, where HSC is the SC thickness); Protocol 2A: incubation of isolated SC with chemical (direct measurement of KSC/v only) and Protocol 2B: diffusion through isolated SC mounted on a Franz cell (measures KSC/v and DSC/HSC2, and is based on Fick's laws). KSC/v values for caffeine and resorcinol using Protocol 1 and 2B were within 30% of each other, values using Protocol 2A were ~two-fold higher, and all values were within 10-fold of each other. Only indirect determination of KSC/v by Protocol 2B was different from the direct measurement of KSC/v by Protocol 2A and Protocol 1 for 7-EC. The variability of KSC/v for all three chemicals using Protocol 2B was higher compared to Protocol 1 and 2A. DSC/HSC2 values for the three chemicals were of the same order of magnitude using all three protocols. Additionally, using Protocol 1, there was very little difference between parameters measured in pig and human SC. In conclusion, KSC/v, and DSC values were comparable using different methods. Pig skin might be a good surrogate for human skin for the three chemicals tested. Copyright © 2017 The
      Authors Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2017-01-31T00:30:48.636916-05:
      DOI: 10.1002/jat.3427
  • The dental resin monomers HEMA and TEGDMA have inhibitory effects on
           osteoclast differentiation with low cytotoxicity
    • Authors: Hiroyuki Inamitsu; Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Hiroshi Murata, Takayuki Tsukuba
      Abstract: The dental resin monomers 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are released from the resin matrix due to unpolymerized monomers; once released, they influence various biological functions and the viability of cells in the oral environment. Although HEMA and TEGDMA have various effects on cells, including inflammation, inhibition of cell proliferation or differentiation, and apoptosis, the effects of these monomers on osteoclasts remain unknown. In this study, we investigated the effects of HEMA and TEGDMA on osteoclast differentiation of bone marrow-derived macrophages or murine monocytic cell line RAW-D. Both HEMA and TEGDMA inhibited osteoclast formation and their bone-resorbing activity at non-cytotoxic concentrations. Moreover, HEMA and TEGDMA decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of osteoclast differentiation, and of osteoclast markers that are transcriptionally regulated by NFATc1, including Src and cathepsin K. Regarding their effects on signaling pathways involved in osteoclast differentiation, HEMA impaired the phosphorylation of extracellular signal-regulated kinase and Jun N-terminal kinase, whereas TEGDMA attenuated the phosphorylation of Akt and Jun N-terminal kinase. Thus, HEMA and TEGDMA inhibit osteoclast differentiation through different signaling pathways. This is the first report on the effects of the monomers HEMA and TEGDMA on osteoclasts. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-26T02:50:36.657216-05:
      DOI: 10.1002/jat.3429
  • Prediction of skin sensitization potency using machine learning approaches
    • Authors: Qingda Zang; Michael Paris, David M. Lehmann, Shannon Bell, Nicole Kleinstreuer, David Allen, Joanna Matheson, Abigail Jacobs, Warren Casey, Judy Strickland
      Abstract: The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-10T20:00:36.440976-05:
      DOI: 10.1002/jat.3424
  • Issue Information - TOC
    • Pages: 391 - 394
      Abstract: No abstract is available for this article.
      PubDate: 2017-02-20T20:02:39.181219-05:
      DOI: 10.1002/jat.3401
  • Assessment of temperature-induced hERG channel blockade variation by drugs
    • Authors: Rahul R. Kauthale; Shruta S. Dadarkar, Raghib Husain, Vikas V. Karande, Madhumanjiri M. Gatne
      Pages: 513 - 513
      PubDate: 2017-02-20T20:02:39.279482-05:
      DOI: 10.1002/jat.3447
  • Current sights for mechanisms of deoxynivalenol-induced hepatotoxicity and
           prospective views for future scientific research: A mini review
    • Authors: Zhao Peng; Liangkai Chen, Andreas K. Nüssler, Liegang Liu, Wei Yang
      Abstract: Deoxynivalenol (DON) belongs to the group B trichothecenes, which are the most common mycotoxins in cereal commodities. It is very stable within the temperature range 170–350 °C, showing no reduction in its concentration after 30 min at 170 °C. This chemical property is a very dangerous factor for human and animal health. Liver is also responsible for the detoxification and formation of DON-glucuronide in both human and animals. Some studies already demonstrated that DON could induce liver damage remarkably through DON altering expressions of p53, caspase-3, caspase-7, caspase-8 and Bax in different cell lines. At the same time, other publications illustrated some opposite results. At present, a full and systematic discussion of the hepatic toxicity of DON is still lacking. Therefore, the aim of the present review is to summarize and update the prominent evidence, regarding DON effects on liver tissues and cell lines. Moreover, based on the current studies we outline some of the identified molecule targets or pathways involved in DON-induced hepatotoxicity, and put forward our opinions and suggest an hypothesis for future research. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T05:00:35.441691-05:
      DOI: 10.1002/jat.3428
  • Glucose-rich diet aggravates monocrotophos-induced dopaminergic neuronal
           dysfunction in Caenorhabditis elegans
    • Authors: Chinnu Salim; P. S. Rajini
      Abstract: The present study aimed to obtain insights into the mechanism(s) by which glucose-rich diet aggravates monocrotophos (MCP)-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans. In this study, we exposed three different strains of worms (wild-type N2, CB1112 (cat-2(e1112)II, tyrosine hydroxylase-deficient mutant, catecholamine absent) and the transgenic BZ555 (egls1-dat-1p::green fluorescent protein [GFP]) (in which bright GFP is tagged to the dopamine neuronal soma and processes) grown and maintained in normal nematode growth medium or 2% glucose enriched-nematode growth medium to MCP (0.75 mm) for 48 h. After the exposure, dopamine-mediated behaviors such as repulsion to nonanone, chemotaxis index and basal slowing response were determined in worms. Dopamine, 3,4-dihydroxy phenyl acetic acid and homovanillic acid content were quantified in N2 worms. The extent of neurodegeneration was visualized and quantified in dat-1::GFP worms. Basal slowing response study clearly indicated that cat-2 worms exposed to MCP and glucose were less affected compared to N2 of the same treatment. Learning and memory were affected by MCP and glucose. While MCP-treated worms showed lesser repulsion to nonanone compared to control worms, MCP-treated, glucose-fed worms showed a greater reduction in repulsion to nonanone. Further, MCP-treated, glucose-fed worms exhibited a marked reduction in dopamine content and an increase in 3,4-dihydroxy phenyl acetic acid and homovanillic acid levels compared to that in control. Dat-1::GFP showed a significant degeneration of dopaminergic neurons when exposed to glucose and MCP. Thus, our results clearly demonstrate that glucose-rich diet aggravates the dopaminergic neuronal dysfunction induced by MCP in C. elegans. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T03:10:56.48517-05:0
      DOI: 10.1002/jat.3426
  • Genotoxic risk of ethyl-paraben could be related to telomere shortening
    • Authors: F. Finot; A. Kaddour, L. Morat, I. Mouche, N. Zaguia, C. Cuceu, D. Souverville, S. Négrault, O. Cariou, A. Essahli, N. Prigent, J. Saul, F. Paillard, L. Heidingsfelder, P. Lafouge, M. Al Jawhari, W. M. Hempel, M. El May, B. Colicchio, A. Dieterlen, E. Jeandidier, L. Sabatier, J. Clements, R. M'Kacher
      Abstract: The ability of parabens to promote the appearance of multiple cancer hallmarks in breast epithelium cells provides grounds for regulatory review of the implication of the presence of parabens in human breast tissue. It is well documented that telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer. In the present study, we evaluated the genotoxic effect of ethyl 4-hydroxybenzoate (ethyl-paraben), with and without metabolic activation (S9), in studies following OECD guidelines. We observed a significant increase in genotoxic damage using the Mouse Lymphoma Assay and in vitro micronucleus (MN) tests in the L5178Y cell line in the presence of S9 only after a short exposure. A high frequency of MN was observed in the TK6 cells after a short exposure (3 h) in the presence of S9 and a long exposure (26 h) without S9. We found significant increases in the MN frequency and induced chromosomal aberrations in the lymphocytes of only one donor after ethyl-paraben exposure in the presence of S9 after a short exposure. Cytogenetic characterization of the paraben-treated cells demonstrated telomere shortening associated with telomere loss and telomere deletions in L5178Y and TK6 cells and lymphocytes of the paraben sensitive-donor. In a control cohort of 68 human lymphocytes, telomere length and telomere aberrations were age-dependent and showed high inter-individual variation. This study is the first to link telomere shortening and the genotoxic effect of ethyl paraben in the presence of S9 and raises the possibility that telomere shortening may be a proxy for underlying inter-individual sensitivity to ethyl-paraben. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T01:20:39.560916-05:
      DOI: 10.1002/jat.3425
  • In vitro detection of diesel exhaust particles induced human lung
           carcinoma epithelial cells damage and the effect of resveratrol
    • Authors: Qifei Li; Mingjie Tang, Anhong Zhou
      Abstract: People are taking up antioxidants in their daily diet and being exposed to a potential diesel exhaust particles (DEP)-containing environment. Thus it is important to study in vitro cellular responses when cells are exposed to DEP with or without antioxidant treatment. The investigation of DEP and resveratrol (RES) on cellular biophysical and biochemical changes is needed to better understand the mechanisms of DEP and RES in mammalian cells. A combination of two non-invasive techniques (atomic force microscopy, AFM, and Raman spectroscopy, RM) and multimodal tools were applied to evaluate the biophysical, biochemical alterations and cytokine, membrane potential and cell cycle of cells with or without RES pretreatment to different times of DEP exposure. AFM results indicated that RES protected cells from DEP-induced damage to cytoskeleton and cell architectures, and noted that RES treatments also attenuated DEP-induced alterations in cell elasticity and surface adhesion force over DEP incubation time. RM monitored the changes in characteristic Raman peak intensities of DNA and protein over the DEP exposure time for both RES and non-RES treated groups. The cytokine and chemokine changes quantified by Multiplex ELISA revealed that the inflammatory responses were enhanced with the increase in DEP exposure time and that RES enhanced the expression levels of cytokine and chemokine. This work demonstrated that significant biophysical and biochemical changes in cells might be relevant to early pathological changes induced by DEP damage. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-09T02:10:33.832997-05:
      DOI: 10.1002/jat.3423
  • Responses of A549 human lung epithelial cells to cristobalite and
           α-quartz exposures assessed by toxicoproteomics and gene expression
    • Authors: Ngoc Q. Vuong; Patrick Goegan, Francesco De Rose, Dalibor Breznan, Errol M. Thomson, Julie S. O'Brien, Subramanian Karthikeyan, Andrew Williams, Renaud Vincent, Premkumari Kumarathasan
      Abstract: In this study, we used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite (CR) and α-quartz (Min-U-Sil 5, MI). Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2′-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. While cytotoxicity assays revealed little difference between CR and MI exposures, proteomic and gene expression analyses unveiled both similar and unique molecular changes in A549 cells. For instance, two-dimensional gel electrophoresis data indicated that the expression of proteins in the cell death (e.g., ALDH1A1, HTRA2 and PRDX6) and cell proliferation (e.g., FSCN1, HNRNPAB and PGK1) pathways were significantly different between the two silica particles. Reverse transcription–polymerase chain reaction data provided additional evidence supporting the proteomic findings. Preliminary assessment of the physical differences between CR and MI suggested that the extent of surface interaction between particles and cells could explain some of the observed biological effects. However, the differential dose–response curves for some other genes and proteins suggest that other physical attributes of particulate matter can also contribute to particulate matter-related cellular toxicity. Our results demonstrated that toxicoproteomic and gene expression analyses are sensitive in distinguishing subtle toxicity differences associated with silica particles of varying physical properties compared to traditional cytotoxicity endpoints. Copyright © 2016 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:27:31.453633-05:
      DOI: 10.1002/jat.3420
  • Relationship between increasing concentrations of two carcinogens and
           statistical image descriptors of foci morphology in the cell
           transformation assay
    • Authors: Giulia Callegaro; Raffaella Corvi, Susan Salovaara, Chiara Urani, Federico M. Stefanini
      Abstract: Cell Transformation Assays (CTAs) have long been proposed for the identification of chemical carcinogenicity potential. The endpoint of these in vitro assays is represented by the phenotypic alterations in cultured cells, which are characterized by the change from the non-transformed to the transformed phenotype. Despite the wide fields of application and the numerous advantages of CTAs, their use in regulatory toxicology has been limited in part due to concerns about the subjective nature of visual scoring, i.e. the step in which transformed colonies or foci are evaluated through morphological features. An objective evaluation of morphological features has been previously obtained through automated digital processing of foci images to extract the value of three statistical image descriptors. In this study a further potential of the CTA using BALB/c 3T3 cells is addressed by analysing the effect of increasing concentrations of two known carcinogens, benzo[a]pyrene and NiCl2, with different modes of action on foci morphology. The main result of our quantitative evaluation shows that the concentration of the considered carcinogens has an effect on foci morphology that is statistically significant for the mean of two among the three selected descriptors. Statistical significance also corresponds to visual relevance. The statistical analysis of variations in foci morphology due to concentration allowed to quantify morphological changes that can be visually appreciated but not precisely determined. Therefore, it has the potential of providing new quantitative parameters in CTAs, and of exploiting all the information encoded in foci. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:22:41.031246-05:
      DOI: 10.1002/jat.3419
  • Activation of interleukin-6 and -8 expressions by methylmercury in human
           U937 macrophages involves RelA and p50
    • Authors: Megumi Yamamoto; Noureen Khan, Muflihatul Muniroh, Eriko Motomura, Rie Yanagisawa, Takami Matsuyama, Christoph F. A. Vogel
      Abstract: The accumulation of macrophages has been observed around lesions of the brain in patients with Minamata disease. In this condition, mercury has been detected histochemically in macrophages throughout the brain. However, the role of macrophages in the neurotoxicity of methylmercury (MeHg) and the molecular mechanisms of their response to MeHg exposure remain to be elucidated. Here, we investigated how MeHg affects the expression of proinflammatory cytokines such as interleukin (IL)-6 and IL-8 in cultured human U937 macrophages. Compared with controls, IL-6 and IL-8 mRNA expression was maximally induced in U937 macrophages after treatment with 10 μM MeHg for 6 h. The protein secretion of IL-6 and IL-8 was significantly stimulated by MeHg in U937 macrophages. Results from luciferase reporter assay indicated functional activation of nuclear factor kappa B and the involvement of subunit RelA and p50 in MeHg-induced IL-6 and IL-8 activation, which was confirmed by siRNA knockdown experiments. MeHg exposure at 4 μM also significantly induced IL-8 expression in U-87 MG cells at mRNA and protein level, indicating that IL-8 induction might be a general mode of action of MeHg treatment among different cell types. These results indicate a possible involvement of an early inflammatory response, including IL-6 and IL-8 expression in the pathogenesis of MeHg. N-acetyl-l-cysteine suppressed MeHg-induced activation of IL-6 and IL-8 mRNA expression in U937 macrophages, indicating the effectiveness of N-acetyl-l-cysteine as a therapeutic drug in MeHg-induced inflammation. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:11:59.571068-05:
      DOI: 10.1002/jat.3411
  • Comparative in vitro toxicity assessment of perfluorinated carboxylic
    • Authors: Cecon T. Mahapatra; Nur P. Damayanti, Samuel C. Guffey, Jennifer S. Serafin, Joseph Irudayaraj, Maria S. Sepúlveda
      Abstract: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetic fluorinated compounds that are highly bioaccumulative and persistent organic pollutants. Perfluorooctanoic acid (PFOA), an eight-carbon chain perfluorinated carboxylic acid, was used heavily for the production of fluoropolymers, but concerns have led to its replacement by shorter carbon chain homologues such as perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA). However, limited toxicity data exist for these substitutes. We evaluated the toxicity of PFOA, PFHxA and PFBA on a zebrafish liver cell line and investigated the effects of exposure on cell metabolism. Gross toxicity after 96 h of exposure was highest for PFOA and PFO–, while PFHxA and PFBA exhibited lower toxicity. Although the structural similarity of these compounds to fatty acids suggests the possibility of interference with the transport and metabolism of lipids, we could not detect any differential expression of peroxisome proliferator-activated receptor (ppar-α, -β and -γ), fabp3 and crot genes after 96 h exposure to up to 10 ppm of the test compounds. However, we observed localized lipid droplet accumulation only in PFBA-exposed cells. To study the effects of these compounds on cell metabolism, we conducted fluorescence lifetime imaging microscopy using naturally fluorescent biomarkers, NADH and FAD. The fluorescence lifetimes of NADH and FAD and the bound/free ratio of each of these coenzymes decreased in a dose- and carbon length-dependent manner, suggesting disruption of cell metabolism. In sum, our study revealed that PFASs with shorter carbon chains are less toxic than PFOA, and that exposure to sublethal dosage of PFOA, PFHxA or PFBA affects cell metabolism. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:07:47.368594-05:
      DOI: 10.1002/jat.3418
  • Evidence for direct effects of glyphosate on ovarian function: glyphosate
           influences steroidogenesis and proliferation of bovine granulosa but not
           theca cells in vitro
    • Authors: Maria Chiara Perego; Luis F. Schutz, Francesca Caloni, Cristina Cortinovis, Marco Albonico, Leon J. Spicer
      Abstract: Glyphosate (GLY) is a common herbicide used worldwide but its effect on ovarian function in mammals is unknown. The aim of this study was to determine the potential endocrine disruptor effects of GLY on ovarian function evaluating cell proliferation, steroidogenesis and gene expression using bovine granulosa cells (GC) and theca cells as in vitro models. GC proliferation was impaired (P 
      PubDate: 2016-12-05T01:02:57.281996-05:
      DOI: 10.1002/jat.3417
  • Zebrafish larva as a reliable model for in vivo assessment of membrane
           remodeling involvement in the hepatotoxicity of chemical agents
    • Authors: Normand Podechard; Martine Chevanne, Morgane Fernier, Arnaud Tête, Aurore Collin, Doris Cassio, Olivier Kah, Dominique Lagadic-Gossmann, Odile Sergent
      Abstract: The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-28T20:20:40.71505-05:0
      DOI: 10.1002/jat.3421
  • Lack of in vivo mutagenicity of 1,2-dichloropropane and dichloromethane in
           the livers of gpt delta rats administered singly or in combination
    • Authors: Tadashi Hirata; Young-Man Cho, Takeshi Toyoda, Jun-ichi Akagi, Isamu Suzuki, Akiyoshi Nishikawa, Kumiko Ogawa
      Abstract: 1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) are possible causative agents associated with the development of cholangiocarcinoma in employees working in printing plant in Osaka, Japan. However, few reports have demonstrated an association between these agents and cholangiocarcinoma in rodent carcinogenicity studies. Moreover, the combined effects of these compounds have not been fully elucidated. In the present study, we evaluated the in vivo mutagenicity of 1,2-DCP and DCM, alone or combined, in the livers of gpt delta rats. Six-week-old male F344 gpt delta rats were treated with 1,2-DCP, DCM or 1,2-DCP + DCM by oral administration for 4 weeks at the dose (200 mg kg−1 body weight 1,2-DCP and 500 mg kg−1 body weight DCM) used in the carcinogenesis study performed by the National Toxicology Program. In vivo mutagenicity was analyzed by gpt mutation/Spi− assays in the livers of rats. In addition, gene and protein expression of CYP2E1 and GSTT1, the major enzymes responsible for the genotoxic effects of 1,2-DCP and DCM, were analyzed by quantitative polymerase chain reaction and western blotting. Gpt and Spi− mutation frequencies were not increased by 1,2-DCP and/or DCM in any group. Additionally, there were no significant changes in the gene and protein expression of CYP2E1 and GSTT1 in any group. These results indicated that 1,2-DCP, DCM and 1,2-DCP + DCM had no significant impact on mutagenicity in the livers of gpt delta rats under our experimental conditions. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-28T20:10:28.936621-05:
      DOI: 10.1002/jat.3416
  • Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether
           and tertiary-butyl alcohol in rats: Contribution of binding to
           α2u–globulin in male rats and high-exposure nonlinear kinetics to
           toxicity and cancer outcomes
    • Authors: Susan J. Borghoff; Caroline Ring, Marcy I. Banton, Teresa L. Leavens
      Abstract: In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The
      Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd
      PubDate: 2016-11-24T21:20:34.980706-05:
      DOI: 10.1002/jat.3412
  • Immunotoxic effects of in vitro exposure of dolphin lymphocytes to
           Louisiana sweet crude oil and Corexit™
    • Authors: Natasha D. White; Celine Godard-Codding, Sarah J. Webb, Gregory D. Bossart, Patricia A. Fair
      Abstract: The Deepwater Horizon oil spill was one of the worst environmental disasters on record in the United States. Response efforts to reduce the magnitude of the oil slick included the use of thousands of gallons of the chemical dispersant Corexit™ in surface and deep-water environments. The immunotoxicity of Louisiana sweet crude oil and the chemical dispersant Corexit was examined using lymphocyte proliferation (LP) and natural killer cell (NK) assays as measures of impact on the adaptive (LP) and innate (NK) immune response in bottlenose dolphins. Study results show that both high-energy media-accommodated fractions (MAF) and chemically enhanced MAF (CEMAF) mixtures modulate immune function. Following exposure to Louisiana sweet crude, both B- and T-cell proliferation of white blood cells was increased for all exposure concentrations, compared to control; however, this increase was only significant for the 50% and 100% treatments. In contrast, exposure of white blood cells to the CEMAF mixture significantly decreased both T- and B-cell proliferation in the 25%, 50% and 100% treatments. NK cell activity was enhanced significantly by CEMAF mixtures for the 50% and 100% treatments. The immunosuppression of LP at environmentally relevant concentrations of oil and dispersant suggests that marine mammals may be unable to mount an adequate defense against xenobiotic threats following exposure to oil and dispersant, leaving them more susceptible to disease. In contrast, NK cell activity was significantly enhanced, which may increase an organism's tumor or viral surveillance ability by mounting an enhanced immune response. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-20T19:30:20.742455-05:
      DOI: 10.1002/jat.3414
  • Effects of oral exposure to the phthalate substitute acetyl tributyl
           citrate on female reproduction in mice
    • Authors: Lindsay M. Rasmussen; Nivedita Sen, Xiaosong Liu, Zelieann R. Craig
      Abstract: Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food and medical plastics, cosmetics and toys. Although systemically safe up to 1000 mg kg−1 day−1, its ability to cause reproductive toxicity in females at levels below 50 mg kg−1 day−1 has not been examined. This study evaluated the effects of lower ATBC exposures on female reproduction using mice. Adult CD-1 females (n = 7–8 per treatment) were dosed orally with tocopherol-stripped corn oil (vehicle), 5 or 10 mg kg−1 day−1 ATBC daily for 15 days, and then bred with a proven breeder male. ATBC exposure did not alter body weights, estrous cyclicity, and gestational and litter parameters. Relative spleen weight was slightly increased in the 5 mg kg−1 day−1 group. ATBC at 10 mg kg−1 day−1 targeted ovarian follicles and decreased the number of primordial, primary and secondary follicles present in the ovary. These findings suggest that low levels of ATBC may be detrimental to ovarian function, thus, more information is needed to understand better the impact of ATBC on female reproduction. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-20T19:05:26.696815-05:
      DOI: 10.1002/jat.3413
  • Cytotoxicity, oxidative stress and inflammation induced by ZnO
           nanoparticles in endothelial cells: interaction with palmitate or
    • Authors: Yu Gong; Yuejia Ji, Fang Liu, Juan Li, Yi Cao
      Abstract: Recent studies showed that ZnO nanoparticles (NPs) might induce the toxicity to human endothelial cells. However, little is known about the interaction between ZnO NPs and circulatory components, which is likely to occur when NPs enter the blood. In this study, we evaluated ZnO NP-induced cytotoxicity, oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs), with the emphasis on the interaction with palmitate (PA) or lipopolysaccharide (LPS), because PA and LPS are normal components in human blood that increase in metabolic diseases. Overall, ZnO NPs induced cytotoxicity and intracellular reactive oxygen species (ROS) at a concentration of 32 μg ml−1, but did not significantly affect the release of inflammatory cytokines or adhesion of THP-1 monocytes to HUVECs. In addition, exposure to ZnO NPs dose-dependently promoted intracellular Zn ions in HUVECs. PA and LPS have different effects. Two hundred μm PA significantly induced cytotoxicity and THP-1 monocyte adhesion, but did not affect ROS or release of inflammatory cytokines. In contrast, 1 μg ml−1 LPS significantly induced ROS, release of inflammatory cytokines and THP-1 monocyte adhesion, but not cytotoxicity. The presence of ZnO NPs did not significantly affect the toxicity induced by PA or LPS. In addition, the accumulation of Zn ions after ZnO NP exposure was not significantly affected by the presence of PA or LPS. We concluded that there was no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-15T03:15:48.464872-05:
      DOI: 10.1002/jat.3415
  • Developmental toxicity of auranofin in zebrafish embryos
    • Authors: Xiao-Yan Gao; Kang Li, Ling-Ling Jiang, Ming-Fang He, Cun-Hai Pu, Dongzhou Kang, Jingjing Xie
      Abstract: Auranofin (AF) is used in clinic for the treatment of rheumatoid arthritis, repurposing of AF as an anticancer drug has just finished a phase I/II clinical trial, but the developmental toxicity of AF remains obscure. This study focused on its developmental toxicity by using zebrafish embryos. Zebrafish embryos were exposed to different concentrations (1, 2.5, 5, 10 μm) of AF from 2 h post-fertilization (hpf) to 72 hpf. At 72 hpf, two major developmental defects caused by AF were found, namely severe pericardial edema and hypopigmentation, when embryos were exposed to concentrations higher than 2.5 μm. Biochemical detection of oxidative stress enzyme combined with expressions of a series of genes related to oxidative stress, cardiac, metal stress and pigment formation were subsequently tested. The superoxide dismutase activity was decreased while malondialdehyde content was accumulated by AF treatment. The expression of oxidative stress-related genes (sod1, gpx1a, gst), pigment-related genes (mitfb, trp-1a) and one metal stress-related gene ctr1 were all decreased by AF exposure. The expressions of cardiac-related genes (amhc, vmhc) and one metal-related gene hsp70 were found to be significantly upregulated by AF exposure. These findings indicated the potential developmental toxicity of AF on zebrafish early development. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-04T05:26:39.395219-05:
      DOI: 10.1002/jat.3410
  • Antagonistic effect of N-ethylmaleimide on arsenic-mediated oxidative
           stress-induced poly(ADP-ribosyl)ation and cytotoxicity
    • Authors: Alexander Sheng-Shin Wang; Yu-Ting Chou, Yeong-Shiau Pu
      Abstract: Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As2O3) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2O2)-induced PARylation was suppressed by As2O3 exposure in different human cancer cells. Moreover, As2O3 treatment promoted H2O2-induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As2O3-mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l-buthionine-sulfoximine blocked the antagonistic effect of NEM on As2O3, thereby continuing As2O3-mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As2O3-mediated DNA damage in a glutathione-dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-04T03:25:50.223404-05:
      DOI: 10.1002/jat.3394
  • Toxicokinetics and toxicodynamics of chlorpyrifos is altered in embryos of
           Japanese medaka exposed to oil sands process-affected water: evidence for
           inhibition of P-glycoprotein
    • Authors: Hattan A. Alharbi; Jane Alcorn, Ahmed Al-Mousa, John P. Giesy, Steve B. Wiseman
      Abstract: Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface mining oil sands industry in Alberta, Canada. Studies were performed in vitro by use of Caco-2 cells, and in vivo with larvae of Japanese medaka (Oryzias latipes) to determine if organic compounds from the aqueous phase of OSPW inhibit ATP binding cassette protein ABCB1 (permeability-glycoprotein, P-gp). Neutral and basic fractions of OSPW inhibited activity of P-gp in Caco-2 cells by 1.9- and 2.0-fold, respectively, while the acidic fraction had the least effect. The organophosphate pesticides chlorpyrifos (a substrate of P-gp) and malathion (not a substrate of P-gp), were used as model chemicals to investigate inhibition of P-gp in larvae. Co-exposure to chlorpyrifos and an extract of OSPW containing basic and neutral compounds reduced survival of larvae to 26.5% compared to survival of larvae exposed only to chlorpyrifos, which was 93.7%. However, co-exposure to malathion and the extract of OSPW did not cause acute lethality compared to exposure only to malathion. Accumulation and bioconcentration of chlorpyrifos, but not malathion, was greater in larvae co-exposed with the extract of OSPW. The terminal elimination half-life of chlorpyrifos in larvae exposed to chlorpyrifos in freshwater was 5 days compared with 11.3 days in larvae exposed to chlorpyrifos in OSPW. Results suggest that in non-acute exposures, basic and neutral organic compounds in the water-soluble fraction of OSPW inhibit activity of P-gp, which suggests that OSPW has the potential to cause adverse effects by chemosensitization. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-24T01:40:32.491926-05:
      DOI: 10.1002/jat.3397
  • Biological factor related to Asian sand dust particles contributes to the
           exacerbation of asthma
    • Authors: Akiko Honda; Takahiro Sawahara, Tomohiro Hayashi, Kenshi Tsuji, Wataru Fukushima, Mizuki Oishi, Gaku Kitamura, Hitomi Kudo, Sho Ito, Seiichi Yoshida, Takamichi Ichinose, Kayo Ueda, Hirohisa Takano
      Abstract: Epidemiologic studies have revealed that Asian sand dust particles (ASDs) can affect respiratory and immune health represented by asthma. Factors responsible for the exacerbation of asthma remain unclear. The fungus Bjerkandera adusta ( and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) have been identified in ASDs collected from the atmosphere when an ASD event occurred. We investigated the effects of and BaP related to ASDs on respiratory and immune systems. Bone marrow-derived antigen-presenting cells (APCs) and splenocytes from atopic prone NC/Nga mice and human airway epithelial cells were exposed to the or to BaP in the presence and absence of heated-ASDs (H-ASDs). and BaP in both the presence and absence of H-ASDs increased the expression of cell surface molecules on APCs. H-ASDs alone slightly activated APCs. The expressions induced by were higher than those induced by BaP in the presence and absence of H-ASDs. There were no remarkable effects on the activation of splenocytes or the proinflammatory responses in airway epithelial cells. These results suggest that rather than BaP contributes to the exacerbation of asthma regardless of the presence or absence of sand particles, particularly by the activation of the immune system via APCs. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-07T00:26:24.356663-05:
      DOI: 10.1002/jat.3395
  • Immunomodulatory effects of metal salts at sub-toxic concentrations
    • Authors: Carmen Steinborn; Christoph Diegel, Manuel Garcia-Käufer, Carsten Gründemann, Roman Huber
      Abstract: Because different metals are used in complementary medicine for the treatment of diseases related to a dysfunction of the immune system, this study aimed at determining the immunomodulatory potential of Pb(NO3)2, AuCl3, Cu(NO3)2, HgCl2, AgNO3, SnCl2, AsCl3 and SbCl3 at sub-toxic concentrations and at assessing possible toxic side effects of low-concentrated metal preparations. The influence of the metal salts on primary human mononuclear cells was analyzed by measuring cell viability using the water-soluble tetrazolium salt assay, apoptosis and necrosis induction by annexin V/propidium iodide staining and proliferation by carboxyfluorescein diacetate succinimidyl ester staining and flow cytometry. Effects on T-cell activation were assessed with CD69 and CD25 expression using flow cytometry whereas CD83, CD86 and CD14 expression was measured to evaluate the influence on dendritic cell maturation. Alterations of interleukin-2 and interferon-γ secretion were detected by enzyme-linked immunosorbent assay and genotoxic effects were analyzed using the comet assay. At sub-toxic concentrations retardation of T-cell proliferation was caused by Pb(NO3)2, AuCl3 and Cu(NO3)2 and inhibitory effects on interleukin-2 secretion were measured after incubation with Pb(NO3)2, AuCl3, Cu(NO3)2, HgCl2 and AsCl3. Cu(NO3)2 had immunosuppressive activity at dosages within the serum reference range for copper. All other metal salts showed effects at dosages above upper serum limits of normal. Therefore, only low-concentrated copper preparations are promising to have immunomodulatory potential. Toxic side effects of metal preparations used in complementary medicine are improbable because upper limits of metals set in the drinking water ordinance are either not exceeded or the duration of their application is limited. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-07T00:16:03.207197-05:
      DOI: 10.1002/jat.3390
  • Disposition of intravenously or orally administered silver nanoparticles
           in pregnant rats and the effect on the biochemical profile in urine
    • Authors: Timothy R. Fennell; Ninell P. Mortensen, Sherry R. Black, Rodney W. Snyder, Keith E. Levine, Eric Poitras, James M. Harrington, Christopher J. Wingard, Nathan A. Holland, Wimal Pathmasiri, Susan C. J. Sumner
      Abstract: Few investigations have been conducted on the disposition and fate of silver nanoparticles (AgNP) in pregnancy. The distribution of a single dose of polyvinylpyrrolidone (PVP)-stabilized AgNP was investigated in pregnant rats. Two sizes of AgNP, 20 and 110 nm, and silver acetate (AgAc) were used to investigate the role of AgNP diameter and particle dissolution in tissue distribution, internal dose and persistence. Dams were administered AgNP or AgAc intravenously (i.v.) (1 mg kg−1) or by gavage (p.o.) (10 mg kg−1), or vehicle alone, on gestation day 18 and euthanized at 24 or 48 h post-exposure. The silver concentration in tissues was measured using inductively-coupled plasma mass spectrometry. The distribution of silver in dams was influenced by route of administration and AgNP size. The highest concentration of silver (μg Ag g−1 tissue) at 48 h was found in the spleen for i.v. administered AgNP, and in the lungs for AgAc. At 48 h after p.o. administration of AgNP, the highest concentration was measured in the cecum and large intestine, and for AgAc in the placenta. Silver was detected in placenta and fetuses for all groups. Markers of cardiovascular injury, oxidative stress marker, cytokines and chemokines were not significantly elevated in exposed dams compared to vehicle-dosed control. NMR metabolomics analysis of urine indicated that AgNP and AgAc exposure impact the carbohydrate, and amino acid metabolism. This study demonstrates that silver crosses the placenta and is transferred to the fetus regardless of the form of silver. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-03T03:58:13.817031-05:
      DOI: 10.1002/jat.3387
  • Association between perfluorooctanoic acid exposure and degranulation of
           mast cells in allergic inflammation
    • Authors: Jun-Kyoung Lee; Soyoung Lee, Moon-Chang Baek, Byung-Heon Lee, Hyun-Shik Lee, Taeg Kyu Kwon, Pil-Hoon Park, Tae-Yong Shin, Dongwoo Khang, Sang-Hyun Kim
      Abstract: Perfluorooctanoic acid (PFOA) has wide applications, including as a raw material for converted paper and packaging products. With the widespread use of PFOA, concerns regarding its potential environmental and health impacts have increased. In spite of the known hepatotoxicity and genotoxicity of PFOA, correlation with PFOA and allergic inflammation is not well known. In this study, the effect of PFOA on the degranulation of mast cells and mast cell-mediated allergic inflammation in the presence of FcεRI cross-linking was evaluated. In immunoglobulin (Ig) E-stimulated mast cells, PFOA increased the release of histamine and β-hexosaminidase by the up-regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 by the activation of nuclear factor (NF)-κB in IgE-stimulated mast cells. Also, PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF-α, IgE and IgG1 in the ovalbumin-induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI-mediated mast cell degranulation and allergic symptoms. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-29T03:47:18.076078-05:
      DOI: 10.1002/jat.3389
  • Toxicological role of an acyl glucuronide metabolite in diclofenac-induced
           acute liver injury in mice
    • Authors: Shingo Oda; Yuji Shirai, Sho Akai, Akira Nakajima, Koichi Tsuneyama, Tsuyoshi Yokoi
      Abstract: The acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs are potentially chemically reactive and are suggested to be implicated in toxicity, including hepatotoxicity, nephrotoxicity and drug hypersensitivity reactions. However, it remains unknown whether AG formation is related to toxicity in vivo. In this study, we sought to determine whether AG is involved in the pathogenesis of liver injury using a mouse model of diclofenac (DIC)-induced liver injury. Mice that were administered DIC alone exhibited significantly increased plasma alanine aminotransferase levels, whereas mice that were pretreated with the UDP-glucuronosyltransferase inhibitor (−)-borneol (BOR) exhibited suppressed alanine aminotransferase levels at 3 and 6 h after DIC administration although not significant at 12 h. The plasma DIC-AG concentrations were significantly lower in BOR- and DIC-treated mice than in mice treated with DIC alone. The mRNA expression levels of chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2 and the neutrophil marker CD11b were reduced in the livers of mice that had been pretreated with BOR compared to those that had been administered DIC alone, whereas mRNA expression of the macrophage marker F4/80 was not altered. An immunohistochemical analysis at 12 h samples revealed that the numbers of myeloperoxidase- and lymphocyte antigen 6 complex-positive cells that infiltrated the liver were significantly reduced in BOR- and DIC-treated mice compared to mice that were treated with DIC alone. These results indicate that DIC-AG is partly involved in the pathogenesis of DIC-induced acute liver injury in mice by activating innate immunity and neutrophils. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-27T03:52:22.435402-05:
      DOI: 10.1002/jat.3388
  • Aflatoxin biomarkers in hair may facilitate long-term exposure studies
    • Authors: Innocent Mupunga; Christo D. Izaaks, Leshweni J. Shai, David R. Katerere
      Pages: 395 - 399
      Abstract: Aflatoxins are highly toxic fungal metabolites produced by some members of the Aspergillus species. They are low molecular weight lipophilic compounds that are easily absorbed from the gastrointestinal tract. They contaminate most staple foods, including maize, peanuts, peanut butter and sorghum mainly in the tropics where hot and humid conditions promote fungal growth. Absorbed aflatoxins are metabolized by the cytochrome P450 enzyme system in the liver into toxic metabolites. Aflatoxin B (AFB)1 is the most toxic, carcinogenic and mutagenic naturally occurring toxin. Aflatoxin exposure assessment has been traditionally achieved through food use frequency questionnaires and laboratory analysis of food samples. However, estimation of individual exposure to aflatoxins based on these methods may not be accurate. The use of aflatoxin biomarkers in urine and blood for use in exposure studies has emerged in more recent times. However, the current biomarkers (e.g., AFB-N7-guanine and AFB1-albumin adduct) in use have a short half-life and are only practically useful to indicate levels over 24 h–3 months post-exposure. There is therefore an immediate need to study and evaluate alternative biomarkers in non-conventional matrices such as hair and nails. Hair analysis revealed considerable interest in forensic analysis particularly in the detection of drugs of abuse where it has emerged as a sensitive and specific technique complementary to blood and urinalysis. This article provides an overview of aflatoxins, current aflatoxin biomarkers and proposes the use of hair as a potential matrix for biomarkers of long-term aflatoxin exposure. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-09T02:06:48.350395-05:
      DOI: 10.1002/jat.3422
  • Sex-specific characterization and evaluation of the Alzheimer's disease
           genetic risk factor sorl1 in zebrafish during aging and in the adult brain
           following a 100 ppb embryonic lead exposure
    • Authors: Jinyoung Lee; Samuel M. Peterson, Jennifer L. Freeman
      Pages: 400 - 407
      Abstract: Developmental lead (Pb) exposure is suggested in laboratory studies to be a trigger for neurodegenerative diseases such as Alzheimer's disease (AD). Sortilin-related receptor, L (DLR class) A repeats-containing (SORL1) is a recently identified AD genetic risk factor. SORL1 has limited characterization in vertebrate models in comparison to other AD genetic risk factors. To characterize SORL1 further, protein sequence homology between humans, mice and zebrafish was analyzed and showed conservation of functional repeats and domain orientation. Next, spatial expression of sorl1 in zebrafish larvae was completed and diffuse expression in neural tissue that was not restricted to the brain was observed. Influences of sex and age on quantitative expression of sorl1 in the brain of adult zebrafish were then assessed. Sex-specific alteration of sorl1 expression transpired during the aging process in females. The zebrafish was then utilized to investigate the impacts of a 100 ppb embryonic Pb exposure on sorl1 expression and other known AD genetic risk factors. Sex-specific quantitative gene expression analysis was completed with adult zebrafish brain to compare those developmentally exposed to Pb or a control treatment, but no significant difference in sorl1 expression or other AD genetic risk factors was observed. Overall, this study provided characterization of sorl1 with changes in brain expression during aging being female-specific. This finding is in agreement with females being more prone to the onset of AD, but analysis of additional AD genetic risk factors is needed to facilitate our understanding of the impact of a 100 ppb embryonic Pb exposure. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-18T04:45:32.56419-05:0
      DOI: 10.1002/jat.3372
  • Salinity-dependent toxicity of water-dispersible, single-walled carbon
           nanotubes to Japanese medaka embryos
    • Authors: Chisato Kataoka; Kousuke Nakahara, Kaori Shimizu, Shinsuke Kowase, Seiji Nagasaka, Shinsuke Ifuku, Shosaku Kashiwada
      Pages: 408 - 416
      Abstract: To investigate the effects of salinity on the behavior and toxicity of functionalized single-walled carbon nanotubes (SWCNTs), which are chemical modified nanotube to increase dispersibility, medaka embryos were exposed to non-functionalized single-walled carbon nanotubes (N-SWCNTs), water-dispersible, cationic, plastic-polymer-coated, single-walled carbon nanotubes (W-SWCNTs), or hydrophobic polyethylene glycol-functionalized, single-walled carbon nanotubes (PEG-SWCNTs) at different salinities, from freshwater to seawater. As reference nanomaterials, we tested dispersible chitin nanofiber (CNF), chitosan-chitin nanofiber (CCNF) and chitin nanocrystal (CNC, i.e. shortened CNF). Under freshwater conditions, with exposure to 10 mg l−1 W-SWCNTs, the yolk sacks of 57.8% of embryos shrank, and the remaining embryos had a reduced heart rate, eye diameter and hatching rate. Larvae had severe defects of the spinal cord, membranous fin and tail formation. These toxic effects increased with increasing salinity. Survival rates declined with increasing salinity and reached 0.0% in seawater. In scanning electron microscope images, W-SWCNTs, CNF, CCNF and CNC were adsorbed densely over the egg chorion surface; however, because of chitin's biologically harmless properties, only W-SWCNTs had toxic effects on the medaka eggs. No toxicity was observed from N-SWCNT and PEG-SWCNT exposure. We demonstrated that water dispersibility, surface chemistry, biomedical properties and salinity were important factors in assessing the aquatic toxicity of nanomaterials. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-18T04:50:32.43129-05:0
      DOI: 10.1002/jat.3373
  • Methylparaben stimulates tumor initiating cells in ER+ breast cancer
    • Authors: M. Angeles Lillo; Cydney Nichols, Chanel Perry, Stephanie Runke, Raisa Krutilina, Tiffany N. Seagroves, Gustavo A. Miranda-Carboni, Susan A. Krum
      Pages: 417 - 425
      Abstract: A body of epidemiological evidence implicates exposure to endocrine disrupting chemicals (EDCs) with increased susceptibility to breast cancer. To evaluate the physiological effects of a suspected EDC in vivo, we exposed MCF-7 breast cancer cells and a patient-derived xenograft (PDX, estrogen receptor positive) to physiological levels of methylparaben (mePB), which is commonly used in personal care products as a preservative. mePB pellets (4.4 μg per day) led to increased tumor size of MCF-7 xenografts and ER+ PDX tumors. mePB has been thought to be a xenoestrogen; however, in vitro exposure of 10 nM mePB failed to increase MCF-7 cell proliferation or induction of canonical estrogen-responsive genes (pS2 and progesterone receptor), in contrast to 17β-estradiol (E2) treatment. MCF-7 and PDX-derived mammospheres exhibited increased size and up-regulation of canonical stem cell markers ALDH1, NANOG, OCT4 and SOX2 when exposed to mePB; these effects were not observed for MDA-MB-231 (ER−) mammospheres. As tumor-initiating cells (TICs) are also believed to be responsible for chemoresistance, mammospheres were treated with either tamoxifen or the pure anti-estrogen fulvestrant in the presence of mePB. Blocking the estrogenic response was not sufficient to block NANOG expression in mammospheres, pointing to a non-classic estrogen response or an ER-independent mechanism of mePB promotion of mammosphere activity. Overall, these results suggest that mePB increases breast cancer tumor proliferation through enhanced TIC activity, in part via regulation of NANOG, and that mePB may play a direct role in chemoresistance by modulating stem cell activity. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-01T02:21:04.824239-05:
      DOI: 10.1002/jat.3374
  • Differences in the mechanisms of action of BDE-47 and its metabolites on
           OVCAR-3 and MCF-7 cell apoptosis
    • Authors: Anna Karpeta; Ewa Łucja Gregoraszczuk
      Pages: 426 - 435
      Abstract: Data concerning possible carcinogenic action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent tissues are limited. Our earlier studies showed that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) stimulated OVCAR-3 and MCF-7 cell proliferation, while its hydroxylated metabolites (5-OH-BDE-47 and 6-OH-BDE-47) increased estrogen receptors protein expression and extracellular signal-regulated kinase 1/2 and protein kinase Cα phosphorylation in these cell lines. In addition to cell proliferative disorder, a failure in the regulation of apoptosis can also lead to the formation and development of tumors. Therefore, in the present study, we investigated the effect of BDE-47 and its metabolites (2.5–50 ng ml–1) on the expression of apoptosis regulatory genes and proteins, caspase-8 and -9 activity and DNA fragmentation induced by extracellular signal-regulated kinase inhibitor (PD098059) and protein kinase Cα inhibitor (Gӧ 6976) in ovarian (OVCAR-3) and breast (MCF-7) cancer cells. In OVCAR-3 cells, BDE-47 upregulated expression of most of the investigated genes and increased protein expression of tumor necrosis factor (TNF)-α, TNF receptor 1, caspase-6, Bcl-xl and caspase-8 activity. Whereas in MCF-7 cells, BDE-47 resulted in the downregulation of most of the investigated genes, and decreased caspase-8 and -9 activity. In both OVCAR-3 and MCF-7 cells, the expression of most of the investigated genes were downregulated by metabolites. Exposure of OVCAR-3 cells to 5-OH-BDE-47 corresponded with a decrease in the protein expression of caspase-6, caspase-9 and Bcl-xl and treatment with 6-OH-BDE-47 decreased Bcl-xl and TNF receptor 1 expression in OVCAR-3 cells and caspase-9 expression in MCF-7 cells. Hydroxylated metabolites of BDE-47 have strong inhibitory effects on apoptosis in ovarian and breast tumor cells and thus should be considered potential carcinogens in hormone-dependent cancers. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-02T10:05:24.975284-05:
      DOI: 10.1002/jat.3375
  • RNA-sequencing analysis reveals the hepatotoxic mechanism of
           perfluoroalkyl alternatives, HFPO2 and HFPO4, following exposure in mice
    • Authors: Jianshe Wang; Xiaoyang Wang, Nan Sheng, Xiujuan Zhou, Ruina Cui, Hongxia Zhang, Jiayin Dai
      Pages: 436 - 444
      Abstract: The toxicological impact of traditional perfluoroalkyl chemicals has led to the elimination and restriction of these substances. However, many novel perfluoroalkyl alternatives remain unregulated and little is known about their potential effects on environmental and human health. Daily administration of two alternative perfluoroalkyl substances, HFPO2 and HFPO4 (1 mg kg−1 body weight), for 28 days resulted in hepatomegaly and hepatic histopathological injury in mice, particularly in the HFPO4 group. We generated and compared high-throughput RNA-sequencing data from hepatic tissues in control and treatment group mice to clarify the mechanism of HFPO2 and HFPO4 hepatotoxicity. We identified 146 (101 upregulated, 45 downregulated) and 1295 (716 upregulated, 579 downregulated) hepatic transcripts that exhibited statistically significant changes (fold change ≥2 or ≤0.5, false discovery rate 
      PubDate: 2016-08-24T01:25:56.405956-05:
      DOI: 10.1002/jat.3376
  • Observations on conducting whole-cell patch clamping of the hERG cardiac
           K+ channel in pure human serum
    • Authors: Jiesheng Kang; Yongyi Luo, Michelle Searles, David Rampe
      Pages: 445 - 453
      Abstract: Inhibition of the human ether-a-go-go-related gene (hERG) K+ channel by drugs leads to QT prolongation on the electrocardiogram and can result in serious cardiac arrhythmia. For this reason, screening of drugs on hERG is mandatory during the drug development process. Patch clamp electrophysiology in a defined physiological saline solution (PSS) represents the standard method for assaying drug effects on the channel. To make the assay more translatable to clinical studies, we have conducted whole-cell patch clamping of hERG using pure human serum as the extracellular medium. Pure human serum had little effect on the hERG channel waveform or the current–voltage relationship when compared to PSS. hERG current recordings were highly stable in serum at room temperature, but prolonged recordings at the physiological temperature required prior heat inactivation of the serum. Compared to PSS, the IC50 values, conducted at room temperature, of the classic hERG blocking drugs cisapride, moxifloxacin, and terfenadine were shifted to the right by an extent predicted by their known plasma protein binding, but we did not detect any differences in IC50s between male and female serum. Total plasma levels of these drugs associated with clinical QT prolongation corresponded to small (
      PubDate: 2016-08-24T01:35:38.572982-05:
      DOI: 10.1002/jat.3377
  • Exposure to cyclic volatile methylsiloxanes (cVMS) causes
           anchorage-independent growth and reduction of BRCA1 in non-transformed
           human breast epithelial cells
    • Authors: Abdullah Farasani; Philippa D. Darbre
      Pages: 454 - 461
      Abstract: Dermal absorption of components of personal care products (PCPs) may contribute to breast cancer development. Cyclic volatile methylsiloxanes (cVMS) are used widely in the formulation of PCPs, and their presence has been recently detected in human blood. The objectives of this study were to investigate any genotoxic effects after short- (1 week) or longer-term (30 weeks) exposure to hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4) or decamethylcyclopentasiloxane (D5) in MCF-10 A and MCF-10F immortalized non-transformed human breast epithelial cells. Genotoxic effects were assessed by an ability of cells to grow in suspension culture, from DNA damage measured by comet assays, and from a reduction in levels of DNA repair proteins measured by RT-PCR and western immunoblotting. Dose-dependent anchorage-independent growth in methocel culture was observed after exposure to D3 (10−13 M–10−5 M) and D4/D5 (10−9 M–10−5 M). DNA damage was measured by the comet assay after 1-h exposure to D3 (10−6 M–10−5 M) and D4 (10−5 M). BRCA1 mRNA and BRCA1 protein levels were reduced after 30-week exposure to 10−5 M D4 and D5 in both cell lines. Reduced levels of mRNAs for other DNA repair proteins (BRCA2, ATM, ATR, CHK1 and CHK2) were also observed after exposure to 10−5 M D5 in both cell lines, and some reductions after exposure to D3 and D4. If cVMS can not only enable anchorage-independent growth of non-transformed breast epithelial cells and damage DNA, but also compromise DNA repair systems, then there is the potential for them to impact on breast carcinogenesis. Further risk assessment now requires information concerning the extent to which cVMS may be present in human breast tissues. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-07T06:30:25.910126-05:
      DOI: 10.1002/jat.3378
  • The role of surface chemistry in the cytotoxicity profile of graphene
    • Authors: Waqar Majeed; Shawn Bourdo, Dayton M. Petibone, Viney Saini, Kieng Bao Vang, Zeid A. Nima, Karrer M. Alghazali, Emilie Darrigues, Anindya Ghosh, Fumiya Watanabe, Daniel Casciano, Syed F. Ali, Alexandru S. Biris
      Pages: 462 - 470
      Abstract: Graphene and its derivative, because of their unique physical, electrical and chemical properties, are an important class of nanomaterials being proposed as foundational materials in nanomedicine as well as for a variety of industrial applications. A major limitation for graphene, when used in biomedical applications, is its poor solubility due to its rather hydrophobic nature. Therefore, chemical functionalities are commonly introduced to alter both its surface chemistry and biochemical activity. Here, we show that surface chemistry plays a major role in the toxicological profile of the graphene structures. To demonstrate this, we chemically increased the oxidation level of the pristine graphene and compared the corresponding toxicological effects along with those for the graphene oxide. X-ray photoelectron spectroscopy revealed that pristine graphene had the lowest amount of surface oxygen, while graphene oxide had the highest at 2.5% and 31%, respectively. Low and high oxygen functionalized graphene samples were found to have 6.6% and 24% surface oxygen, respectively. Our results showed a dose-dependent trend in the cytotoxicity profile, where pristine graphene was the most cytotoxic, with decreasing toxicity observed with increasing oxygen content. Increased surface oxygen also played a role in nanomaterial dispersion in water or cell culture medium over longer periods. It is likely that higher dispersity might result in graphene entering into cells as individual flakes ~1 nm thick rather than as more cytotoxic aggregates. In conclusion, changes in graphene's surface chemistry resulted in altered solubility and toxicity, suggesting that a generalized toxicity profile would be rather misleading. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-04T22:00:26.495518-05:
      DOI: 10.1002/jat.3379
  • Oxidative stress and cytotoxic effects of silver ion in mouse lung
           macrophages J774.1 cells
    • Authors: Ilseob Shim; Kyunghee Choi, Seishiro Hirano
      Pages: 471 - 478
      Abstract: Silver is commonly used as a disinfectant, and chronic exposure to silver may cause argyria, resulting in a gray–blue discoloration of human skin. However, the mechanism for cellular toxicity of silver has not been well explained. We studied the mode of cell death, the ratio of glutathione disulfide/glutathione, induction of metallothionein and activation of mitogen-activated protein kinases in J774.1 cells together with activation of antioxidant responsive element and nuclear factor-κB in CHO cells following exposure to silver ion (Ag+) to investigate the mechanism by which Ag+ causes lethal effects. Ag+ increased phosphorylation levels of extracellular signal-regulated, c-Jun N-terminal and p38 mitogen-activated protein kinases and remarkably increased the ratio of glutathione disulfide/glutathione in both a time- and concentration-dependent manner. Luciferase reporter gene assays revealed that antioxidant responsive element and nuclear factor-κB were activated following exposure to Ag+. In addition, exposure to Ag+ increased the mRNA and protein levels of metallothionein. We investigated whether or not Ag+ killed J774.1 cells by inducing apoptosis. Ag+ increased the activity of caspase-3/7 which was abrogated by caspase 3 and pan-caspase inhibitors. However, these inhibitors did not ameliorate the cytotoxic effects of Ag+, suggesting that Ag+ causes oxidative stress, which leads to necrotic rather than apoptotic cell death in J774.1 cells by decreasing functional sulfhydryl groups including glutathione in the cells. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-14T04:55:49.311991-05:
      DOI: 10.1002/jat.3382
  • Correlation between antibodies to bisphenol A, its target enzyme protein
           disulfide isomerase and antibodies to neuron-specific antigens
    • Authors: Datis Kharrazian; Aristo Vojdani
      Pages: 479 - 484
      Abstract: Evidence continues to increase linking autoimmunity and other complex diseases to the chemicals commonly found in our environment. Bisphenol A (BPA) is a synthetic monomer used widely in many forms, from food containers to toys, medical products and many others. The potential for BPA to participate as a triggering agent for autoimmune diseases is likely due to its known immunological influences. The goal of this research was to determine if immune reactivity to BPA has any correlation with neurological antibodies. BPA binds to a target enzyme called protein disulfide isomerase (PDI). Myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) are neuronal antigens that are target sites for neuroinflammation and neuroautoimmunity. We determined the co-occurrence of anti-MBP and anti-MOG antibodies with antibodies made against BPA bound to human serum albumin in 100 healthy human subjects. Correlation between BPA to PDI, BPA to MOG, BPA to MBP, PDI to MBP and PDI to MOG were all highly statistically significant (P 
      PubDate: 2016-09-09T11:17:13.249387-05:
      DOI: 10.1002/jat.3383
  • Toxic effects of 4-methylthio-3-butenyl isothiocyanate (Raphasatin) in the
           rat urinary bladder without genotoxicity
    • Authors: Isamu Suzuki; Young-Man Cho, Tadashi Hirata, Takeshi Toyoda, Jun-ichi Akagi, Yasushi Nakamura, Azusa Sasaki, Takako Nakamura, Shigehisa Okamoto, Koji Shirota, Noboru Suetome, Akiyoshi Nishikawa, Kumiko Ogawa
      Pages: 485 - 494
      Abstract: We recently reported that 4-methylthio-3-butenyl isothiocyanate (MTBITC) exerts chemopreventive effects on the rat esophageal carcinogenesis model at a low dose of 80 ppm in a diet. In contrast, some isothiocyanates (ITCs) have been reported to cause toxic effects, promotion activity, and/or carcinogenic potential in the urinary bladder of rats. In the present study, we investigated whether MTBITC had toxic effects in the urinary bladder similar to other ITCs, such as phenethyl ITC (PEITC). First, to examine the early toxicity of MTBITC, rats were fed a diet supplemented with 100, 300 or 1000 ppm MTBITC for 14 days. Treatment with 1000 ppm MTBITC caused increased organ weights and histopathological changes in the urinary bladder, producing lesions similar to those of 1000 ppm PEITC. In contrast, rats treated with 100 or 300 ppm MTBITC showed no signs of toxicity. Additionally, we performed in vivo genotoxicity studies to clarify whether MTBITC may exhibit a carcinogenic potential through a genotoxic mechanism in rats. Rats were treated with MTBITC for 3 days at doses of 10, 30 or 90 mg kg−1 body weight by gavage, and comet assays in the urinary bladder and micronucleus assays in the bone marrow were performed. No genotoxic changes were observed after treatment with MTBITC at all doses. Overall, these results suggested that the effects of MTBITC in the rat urinary bladder are less than those of PEITC, but that MTBITC could have toxic effects through a nongenotoxic mechanism in the urinary bladder of rats at high doses. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-15T23:31:54.945759-05:
      DOI: 10.1002/jat.3384
  • Comparative genotoxicity of silver nanoparticles in human liver HepG2 and
           lung epithelial A549 cells
    • Authors: J. Wang; B. Che, L. W. Zhang, G. Dong, Q. Luo, L. Xin
      Pages: 495 - 501
      Abstract: With the rapid expanding of human exposure to silver nanoparticles (AgNPs), genotoxicity screening of nanosilver is necessary to ensure consumer safety. Here, we assessed one key DNA damage responsive pathway activated by GADD45a gene after 24 h of AgNPs exposure in stable luciferase reporter cell systems based on two widely used in vitro cell models, human liver HepG2 and lung epithelial A549 cells. The comet assay and micronucleus test were also conducted to confirm the genetic damage induced by AgNPs. Our results showed that AgNPs produced a strong dose-dependent increase in transcriptional activation of GADD45a promoter indicated by luciferase activity accompanying by the significant decreases in cell viability. Surprisingly, in HepG2-luciferase cells, the relative luciferase activity was greater than 4.5× the control level after being treated with 200 μg ml–1 AgNPs. These results were generally in line with the positive and dose-dependent responses in cytotoxicity, DNA strand breaks indicated by Olive tail moment, tail DNA (%) and tail length, and chromosome damage indicated by induction of micronuclei, nucleoplasmic bridges, and nuclear buds. Additionally, compared with the A549-luciferase cells, the HepG2-luciferase cells seemed to be more susceptible to AgNPs as higher levels of genotoxicity were induced. We concluded that our GADD45a promoter-driven luciferase reporter gene cell system, together with the comet assay and micronucleus test, can be used as valuable tools for rapid screening of genotoxic potential of nanosilver. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-07T06:45:50.883692-05:
      DOI: 10.1002/jat.3385
  • Comparison of the local pulmonary distribution of nanoparticles
           administered intratracheally to rats via gavage needle or microsprayer
           delivery devices
    • Authors: Guihua Zhang; Naohide Shinohara, Yutaka Oshima, Toshio Kobayashi, Nobuya Imatanaka, Kenji Kawaguchi, Masashi Gamo
      Pages: 502 - 507
      Abstract: Intratracheal administration methods are used to conduct toxicological assessments of inhaled nanoparticles (NPs), and gavage needles or microsprayers are common intratracheal delivery devices. The NP suspension is delivered in a liquid state via gavage needle and as a liquid aerosol via microsprayer. The differences in local pulmonary NP distribution (called the microdistribution) arising from the different states of the NP suspension cause differential pulmonary responses; however, this has yet to be investigated. Herein, using microbeam X-ray fluorescence microscopy, we quantitatively evaluated the TiO2 pulmonary microdistribution (per mesh: 100 μm × 100 μm) in lung sections from rats administered an intratracheal dose of TiO2 NPs (6 mg kg−1) via gavage needle or microsprayer. The results revealed that: (i) using a microsprayer appears to reduce the variations in TiO2 content (ng mesh−1) among rats (e.g., coefficients of variation, n = 3, microsprayer vs gavage needle: 13% vs 30%, for the entire lungs); (ii) TiO2 appears to be deposited less in the right middle lobes than in the rest of the lung lobes, irrespective of the chosen intratracheal delivery device; and (iii) similar TiO2 contents (ng mesh−1) and frequencies are deposited in the lung lobes of rats administered TiO2 NPs via gavage needle or microsprayer. This suggests that the physical state of the administered NP suspension does not markedly alter TiO2 pulmonary microdistribution. The results of this investigation are important for the standardization of intratracheal administration methods. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-06T23:04:58.348776-05:
      DOI: 10.1002/jat.3386
  • Pharmacokinetics of 14C-ortho-phenylphenol following intravenous
           administration in pigs
    • Authors: Emma Nixon; James D. Brooks, Patricia A. Routh, Jason T. Chittenden, Ronald E. Baynes
      Pages: 508 - 512
      Abstract: Workers in the USA are exposed to industrial formulations, which may be toxic. These formulations often contain preservatives or biocides such as ortho-phenylphenol (OPP). There are limited data describing OPP following intravenous administration to assess truly the clearance of this chemical in humans and other species. In vivo experiments were conducted in pigs to determine related pharmacokinetic parameters. 14C-OPP was administered as an intravenous bolus dose. Blood, feces, urine and tissue samples were collected for analysis by liquid scintillation. Data were analyzed using non-compartmental and compartmental pharmacokinetic model approaches. These data fitted a three-compartment model and showed that the half-life of 14C-OPP following the intravenous bolus in pigs was 46.26 ± 10.01 h. The kidneys play a crucial role in clearance of 14C-OPP with a large percentage of the dose being found in the urine (70.3 ± 6.9% dose). Comparisons with other species suggest that 14C-OPP clearance in pigs (2.48 ml h–1 kg–1) is less than that in humans (18.87 ml h–1 kg–1) and rats (35.51 ml h–1 kg–1). Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-04T22:00:09.282996-05:
      DOI: 10.1002/jat.3380
  • Reproductive disorders in female rats after prenatal exposure to
    • Abstract: Betamethasone is the drug of choice for antenatal treatment, promoting fetal lung maturation and decreasing mortality. Previous studies in rats reported male programming and alteration in sperm parameters and sexual behavior following intrauterine betamethasone exposure. The impact on the female reproductive development is not known. In this study, rat female offspring was assessed for sexual development, morphophysiology of the reproductive tract and fertility after maternal exposure to 0.1 mg kg−1 of betamethasone or vehicle on gestational days 12, 13, 18 and 19. The treatment promoted reduction of litter weight on postnatal day 1, morphological masculinization in females, delay in the age of puberty onset, reduction in estrus number, increase in estrous cycle length and increase in luteinizing hormone serum levels and uterus weight. The females from the betamethasone group showed an increase of myometrial uterine area and decrease in endometrial uterine area. These animals also performed less lordosis during the sexual behavior test and showed impaired reproductive performance. The uterus showed higher contraction in the treated group as shown by a pharmacological assay. In conclusion, prenatal betamethasone exposure in rats promoted female masculinization, altered sexual development and reproductive parameters. Copyright © 2017 John Wiley & Sons, Ltd.
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