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  Subjects -> ENVIRONMENTAL STUDIES (Total: 754 journals)
    - ENVIRONMENTAL STUDIES (681 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (41 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (681 journals)            First | 1 2 3 4     

Showing 601 - 378 of 378 Journals sorted alphabetically
Scandinavian Journal of Work, Environment & Health     Partially Free   (Followers: 12)
Science of The Total Environment     Hybrid Journal   (Followers: 18)
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: 8)
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)
Stochastic Environmental Research and Risk Assessment     Hybrid Journal   (Followers: 4)
Strategic Behavior and the Environment     Full-text available via subscription  
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: 17)
Sustainability in Environment     Open Access  
Sustainability of Water Quality and Ecology     Hybrid Journal   (Followers: 2)
Sustainable Cities and Society     Hybrid Journal   (Followers: 25)
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: 9)
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: 4)
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: 5)
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 17)
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: 178)
Trends in Environmental Analytical Chemistry     Hybrid Journal   (Followers: 2)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 25)
Turkish Journal of Engineering and Environmental Sciences     Open Access   (Followers: 1)
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: 50)
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: 37)
Water International     Hybrid Journal   (Followers: 12)
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: 10)
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: 4)
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  [1612 journals]
  • 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 (B.ad) 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 B.ad 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 B.ad or to BaP in the presence and absence of heated-ASDs (H-ASDs). B.ad 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 B.ad 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 B.ad 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
       
  • 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
      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
       
  • 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
       
  • Can CuO nanoparticles lead to epigenetic regulation of antioxidant enzyme
           system?
    • Authors: Sandesh Chibber; Rishi Shanker
      Abstract: Copper has been used from ancient time in various applications. Scientists have exploited its means of exposure and consequences to living organisms. The peculiar property of nanomaterials that is a high surface to volume ratio has increased the range of application in products. Copper oxide nanoparticles (CuO NPs) are widely used in industrial applications such as semiconductor devices, gas sensor, batteries, solar energy converter, microelectronics, heat transfer fluids and consumer products. In contrast, acute toxicity of CuO NPs has also been reported. Subsequently, human and environmental health may be at a high risk. Their frequent use can also contaminate ecosystems. Therefore, the toxicity of CuO NPs needs to be thoroughly understood. In this review, we have tried to discuss the recent facts and mechanism that have been explored for CuO NPs-induced toxicity at a cellular, in vivo and ecotoxicological level. Accordingly, the main cause for induction of toxicity by CuO NPs is the generation of reactive oxygen species (ROS) followed by the mitochondrial destruction that leads to apoptosis via the intrinsic pathway or under the condition such as hypoxia cell on exposure to CuO NPs may commit to necrosis. Moreover, CuO NPs also result in activation of MAPK pathways, ERKs and JNK/SAPK thus play an important role in the activation of AP-1. Furthermore, CuO NPs also leads to up-regulation of p53 and caspase three genes. Therefore, careful measures are required to explore omic technology to understand the molecular mechanism of the deleterious effects caused by CuO NPs. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-30T03:00:29.591128-05:
      DOI: 10.1002/jat.3392
       
  • Autophagy function and its relationship to pathology, clinical
           applications, drug metabolism and toxicity
    • Authors: Dayton M. Petibone; Waqar Majeed, Daniel A. Casciano
      Abstract: Autophagy is a cellular process that facilitates nutrient turnover and removal of expended macromolecules and organelles to maintain homeostasis. The recycling of cytosolic macromolecules and damaged organelles by autophagosomes occurs through the lysosomal degradation pathway. Autophagy can also be upregulated as a prosurvival pathway in response to stress stimuli such as starvation, hypoxia or cell damage. Over the last two decades, there has been a surge in research revealing the basic molecular mechanisms of autophagy in mammalian cells. A corollary of an advanced understanding of autophagy has been a concurrent expansion of research into understanding autophagic function and dysfunction in pathology. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets in treating disease and cancer. In this review, advances in understanding the molecular basis of mammalian autophagy, methods used to induce and evaluate autophagy, and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis are discussed. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-29T03:52:13.343122-05:
      DOI: 10.1002/jat.3393
       
  • 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
       
  • Natural remedies for non‐steroidal anti‐inflammatory
           drug‐induced toxicity
    • Authors: Jerine Peter Simon; Sabina Evan Prince
      Abstract: The liver is an important organ of the body, which has a vital role in metabolic functions. The non‐steroidal anti‐inflammatory drug (NSAID), diclofenac causes hepato‐renal toxicity and gastric ulcers. NSAIDs are noted to be an agent for the toxicity of body organs. This review has elaborated various scientific perspectives of the toxicity caused by diclofenac and its mechanistic action in affecting the vital organ. This review suggests natural products are better remedies than current clinical drugs against the toxicity caused by NSAIDs. Natural products are known for their minimal side effects, low cost and availability. On the other hand, synthetic drugs pose the danger of adverse effects if used frequently or over a long period. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-22T02:20:46.590665-05:
      DOI: 10.1002/jat.3391
       
  • 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
      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
       
  • Oxidative stress and cytotoxic effects of silver ion in mouse lung
           macrophages J774.1 cells
    • Authors: Ilseob Shim; Kyunghee Choi, Seishiro Hirano
      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
      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
       
  • 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
      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
       
  • 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
      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
      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
       
  • Effects of methyl mercury exposure on pancreatic beta cell development and
           function
    • Authors: Lauren Schumacher; Louise C. Abbott
      Abstract: Methyl mercury is an environmental contaminant of worldwide concern. Since the discovery of methyl mercury exposure due to eating contaminated fish as the underlying cause of the Minamata disaster, the scientific community has known about the sensitivity of the developing central nervous system to mercury toxicity. Warnings are given to pregnant women and young children to limit consumption of foods containing methyl mercury to protect the embryonic, fetal and postnatally developing central nervous system. However, evidence also suggests that exposure to methyl mercury or various forms of inorganic mercury may also affect development and function of other organs. Numerous reports indicate a worldwide increase in diabetes, particularly type 2 diabetes. Quite recently, methyl mercury has been shown to have adverse effects on pancreatic beta (β) cell development and function, resulting in insulin resistance and hyperglycemia and may even lead to the development of diabetes. This review discusses possible mechanisms by which methyl mercury exposure may adversely affect pancreatic β cell development and function, and the role that methyl mercury exposure may have in the reported worldwide increase in diabetes, particularly type 2 diabetes. While additional information is needed regarding associations between mercury exposure and specific mechanisms of the pathogenesis of diabetes in the human population, methyl mercury's adverse effects on the body's natural sources of antioxidants suggest that one possible therapeutic strategy could involve supplementation with antioxidants. Thus, it is important that additional investigation be undertaken into the role of methyl mercury exposure and reduced pancreatic β cell function. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-04T22:00:17.284753-05:
      DOI: 10.1002/jat.3381
       
  • 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
      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
       
  • 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
      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
       
  • Methylparaben stimulates tumor initiating cells in ER+ breast cancer
           models
    • Authors: M. Angeles Lillo; Cydney Nichols, Chanel Perry, Stephanie Runke, Raisa Krutilina, Tiffany N. Seagroves, Gustavo A. Miranda‐Carboni, Susan A. Krum
      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
       
  • 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
      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
       
  • 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
      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
       
  • Comparative ovarian microarray analysis of juvenile hormone‐responsive
           genes in water flea Daphnia magna: potential targets for toxicity
    • Authors: Kenji Toyota; Timothy D. Williams, Tomomi Sato, Norihisa Tatarazako, Taisen Iguchi
      Abstract: The freshwater zooplankton Daphnia magna has been extensively employed in chemical toxicity tests such as OECD Test Guidelines 202 and 211. Previously, it has been demonstrated that the treatment of juvenile hormones (JHs) or their analogues to female daphnids can induce male offspring production. Based on this finding, a rapid screening method for detection of chemicals with JH‐activity was recently developed using adult D. magna. This screening system determines whether a chemical has JH‐activity by investigating the male offspring inducibility. Although this is an efficient high‐throughput short‐term screening system, much remains to be discovered about JH‐responsive pathways in the ovary, and whether different JH‐activators act via the same mechanism. JH‐responsive genes in the ovary including developing oocytes are still largely undescribed. Here, we conducted comparative microarray analyses using ovaries from Daphnia magna treated with fenoxycarb (Fx; artificial JH agonist) or methyl farnesoate (MF; a putative innate JH in daphnids) to elucidate responses to JH agonists in the ovary, including developing oocytes, at a JH‐sensitive period for male sex determination. We demonstrate that induction of hemoglobin genes is a well‐conserved response to JH even in the ovary, and a potential adverse effect of JH agonist is suppression of vitellogenin gene expression, that might cause reduction of offspring number. This is the first report demonstrating different transcriptomics profiles from MF and an artificial JH agonist in D. magna ovary, improving understanding the tissue‐specific mode‐of‐action of JH. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-24T01:25:51.702113-05:
      DOI: 10.1002/jat.3368
       
  • 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
      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
       
  • 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
      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
       
  • Combining web‐based tools for transparent evaluation of data for risk
           assessment: developmental effects of bisphenol A on the mammary gland as a
           case study
    • Authors: Linda Molander; Annika Hanberg, Christina Rudén, Marlene Ågerstrand, Anna Beronius
      Abstract: Different tools have been developed that facilitate systematic and transparent evaluation and handling of toxicity data in the risk assessment process. The present paper sets out to explore the combined use of two web‐based tools for study evaluation and identification of reliable data relevant to health risk assessment. For this purpose, a case study was performed using in vivo toxicity studies investigating low‐dose effects of bisphenol A on mammary gland development. The reliability of the mammary gland studies was evaluated using the Science in Risk Assessment and Policy (SciRAP) criteria for toxicity studies. The Health Assessment Workspace Collaborative (HAWC) was used for characterizing and visualizing the mammary gland data in terms of type of effects investigated and reported, and the distribution of these effects within the dose interval. It was then investigated whether there was any relationship between study reliability and the type of effects reported and/or their distribution in the dose interval. The combination of the SciRAP and HAWC tools allowed for transparent evaluation and visualization of the studies investigating developmental effects of BPA on the mammary gland. The use of these tools showed that there were no apparent differences in the type of effects and their distribution in the dose interval between the five studies assessed as most reliable and the whole data set. Combining the SciRAP and HAWC tools was found to be a useful approach for evaluating in vivo toxicity studies and identifying reliable and sensitive information relevant to regulatory risk assessment of chemicals. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-04T02:55:33.536584-05:
      DOI: 10.1002/jat.3363
       
  • A modified multiparametric assay using HepaRG cells for predicting the
           degree of drug‐induced liver injury risk
    • Authors: Takafumi Tomida; Hayao Okamura, Tsuyoshi Yokoi, Yoshihiro Konno
      Abstract: The approach for predicting the degree of drug‐induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty‐eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100‐fold the therapeutic maximum plasma concentration (Cmax). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut‐off values of each parameter, the TC50 (toxic concentration that decreased the response by 50%) and EC200 (effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut‐off: score ≥ 1; area under a receiver operating characteristic curve (ROC‐AUC): 0.88], and for WDN and BW categories (cut‐off: score ≥ 3; ROC‐AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-02T06:16:51.114998-05:
      DOI: 10.1002/jat.3371
       
  • Cytotoxicity and proliferative capacity impairment induced on human brain
           cell cultures after short‐ and long‐term exposure to magnetite
           nanoparticles
    • Authors: Teresa Coccini; Francesca Caloni, Lenin Javier Ramírez Cando, Uliana De Simone
      Abstract: Since magnetic iron oxide nanoparticles (IONP) as magnetite (Fe3O4NPs) have potential applications in life sciences, industrial fields and biomedical care, the risks for occupational, general population and patients rises correspondingly. Excessive IONP accumulation in central nervous system (CNS) cells can lead to a disruption of normal iron metabolism/homeostasis, which is a characteristic hallmark resembling that of several neurodegenerative disorders. Fe3O4NPs‐ versus Fe3O4 bulk‐induced toxic effects have been assessed in two human CNS cells namely astrocytes (D384) and neurons (SH‐SY5Y) after short‐term exposure (4–24‐48 h) to 1–100 μg ml−1, and long‐term exposure to lower concentrations. Short‐term Fe3O4NPs induced significant concentration‐ and time‐dependent alterations of mitochondrial function in D384 (25–75% cell viability decrease): effects started at 25 μg ml−1 after 4 h, and 1 μg ml−1 after 48 h. SH‐SY5Y were less susceptible: cytotoxicity occurred after 48  h only with 35–45% mortality (10–100 μg ml−1). Accordingly, a more marked intracellular iron accumulation was observed in astrocytes than neurons. Membrane integrity was unaltered in both CNS cell types. Lowering Fe3O4NP concentrations (0.05–10 μg ml−1) and prolonging the exposure time (up to 10 days), D384 toxicity was again observed (colony number decrease at ≥0.05 μg ml−1, morphology alterations and colony size reduction at ≥0.5 μg ml−1). Effects on SH‐SY5Y appeared at the highest concentration only. Fe3O4 bulk was always remarkably toxic toward both cells. In summary, human cultured astrocytes were susceptible to both Fe3O4NP and bulk forms following short‐term and extended exposure to low concentrations, while neurons were more resistant to NPs. Cellular iron overload may trigger adverse responses by releasing iron ions (particularly in astrocytes) thus compromising the normal functions of CNS. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-02T06:06:33.450912-05:
      DOI: 10.1002/jat.3367
       
  • Multivariate models for prediction of human skin sensitization hazard
    • Authors: Judy Strickland; Qingda Zang, Michael Paris, David M. Lehmann, David Allen, Neepa Choksi, Joanna Matheson, Abigail Jacobs, Warren Casey, Nicole Kleinstreuer
      Abstract: One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non‐animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays – the direct peptide reactivity assay (DPRA), human cell line activation test (h‐CLAT) and KeratinoSens™ assay – six physicochemical properties and an in silico read‐across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h‐CLAT and read‐across; (2) DPRA, h‐CLAT, read‐across and KeratinoSens; or (3) DPRA, h‐CLAT, read‐across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63–79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
      PubDate: 2016-08-02T06:03:58.640092-05:
      DOI: 10.1002/jat.3366
       
  • Development of an in vivo anti‐androgenic activity detection assay using
           fenitrothion in Japanese medaka (Oryzias latipes)
    • Authors: Yoshifumi Horie; Haruna Watanabe, Hitomi Takanobu, Ayano Yagi, Takahiro Yamagishi, Taisen Iguchi, Norihisa Tatarazako
      Abstract: The effects of endocrine disruptors, including anti‐androgenic chemicals, on aquatic environments have received increased attention in recent years. Currently, the method used to screen chemicals for anti‐androgenic activity is called the androgenized female stickleback screen, and it was established by the Organization of Economic Cooperation and Development in 2011 using the three‐spined stickleback. However, screening chemicals for anti‐androgenic activity has yet to be established using Japanese medaka. Thus, the purpose of this study was to establish a screening method for anti‐androgenic activity utilizing the number of papillary processes in Japanese medaka (Oryzias latipes) as an indicator of the chemical's anti‐androgenic activity. Thus, at 35 days post‐fertilization, medaka were exposed to fenitrothion, an anti‐androgenic compound, for 28 days. In the control group, the formation of papillary processes was observed in XY medaka, but not in XX medaka. However, after fenitrothion exposure, the number of papillary processes was significantly decreased in a dose‐dependent manner in XY medaka; in the 300 μg l−1 concentration group, four of 11 XY medaka showed no papillary processes even if there were no significant effects on total length and wet body weight compared with the control group. Our results indicate that the number of papillary processes in Japanese medaka can be used as an indicator of anti‐androgenic activity and that this model may prove useful as a chemical screening method. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-27T07:20:27.803937-05:
      DOI: 10.1002/jat.3365
       
  • Effect of 4‐week inhalation exposure to 1‐bromopropane on
           blood pressure in rats
    • Authors: Fen Huang; Sahoko Ichihara, Yuki Yamada, Shameema Banu, Gaku Ichihara
      Abstract: The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Several recent studies have documented the reproductive and neurological toxicities of 1‐bromopropane (1‐BP). Given that 1‐BP increased reactive oxygen species in the brain of rats, we hypothesized that 1‐BP also has cardiovascular toxicity through increased oxidative stress. To test this hypothesis, male F344 and Wistar Nagoya rats (n = 7–8 per group per test) were exposed to 0 or 1000 ppm of 1‐BP via inhalation for 4 weeks (8 h per day, 7 days per week). The exposure to 1‐BP increased systolic blood pressure. This effect was associated with a significant decrease in the reduced/oxidized glutathione ratio. A significant increase in nitrotyrosine levels, activation of the NADPH oxidase pathway, which was evidenced by upregulation of gp91phox, a NADPH oxidase subunit, and significant decreases in the expressions of antioxidant molecules such as Cu/Zn‐ and Mn‐superoxide dismutase catalase, and nuclear factor erythroid 2‐related factor 2, were observed in the aortas of Wistar Nagoya rats exposed to 1‐BP. Our results indicate that subacute (4‐week) inhalation exposure to 1‐BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway. Further study is needed to assess whether NADPH oxidase activation causes the increase in blood pressure in the rats exposed to 1‐BP. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-25T00:30:39.872069-05:
      DOI: 10.1002/jat.3364
       
  • Pulmonary persistence of graphene nanoplatelets may disturb physiological
           and immunological homeostasis
    • Authors: Eun‐Jung Park; Sang Jin Lee, Kyuhong Lee, Young Chul Choi, Byoung‐Seok Lee, Gwang‐Hee Lee, Dong‐Wan Kim
      Abstract: Accumulated evidence suggests that chronic pulmonary accumulation of harmful particles cause adverse pulmonary and systemic health effects. In our previous study, most of the graphene nanoplatelet (GNP) remained in the lung until 28 days after a single instillation. In this study, we sought to evaluate the local and systemic health effect after a long pulmonary persistence of GNP. As expected, GNP remained in the lung on day 90 after a single intratracheal instillation (1.25, 2.5 and 5 mg kg−1). In the lung exposed at the highest dose, the total number of cells and the percentage of lymphocytes significantly increased in the BAL fluid with an increase in both the number of GNP‐engulfed macrophages and the percentage of apoptotic cells. A Th1‐shifted immune response, the elevated chemokine secretion and the enhanced expression of cytoskeletal‐related genes were observed. Additionally, the expression of natriuretic‐related genes was noteworthy altered in the lungs. Moreover, the number of white blood cells (WBC) and the percentage of macrophages and neutrophils clearly increased in the blood of mice exposed to a 5‐mg kg−1 dose, whereas total protein, BUN and potassium levels significantly decreased. In conclusion, we suggest that the long persistence of GNP in the lung may cause adverse health effects by disturbing immunological‐ and physiological‐homeostasis of our body. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-21T05:50:40.280098-05:
      DOI: 10.1002/jat.3361
       
  • Hepatocytes cocultured with Sertoli cells in bioreactor favors Sertoli
           barrier tightness in rat
    • Authors: P. Zeller; A. Legendre, S. Jacques, M. J. Fleury, F. Gilard, G. Tcherkez, E. Leclerc
      Abstract: The lack of a reliable in vitro system to assess reprotoxicity is an emerging problem in the context of European law for Registration, Evaluation, Authorization and Restriction of Chemicals (REACH, 2007), as it requires a reduction in animal utilization for testing. Furthermore, in vitro reprotoxicological tests would be more relevant and greatly improved by integrating both hepatic metabolism and the blood–testis barrier. Here, we took advantage of an integrated insert in a dynamic microfluidic platform (IIDMP) to co‐cultivate hepatocytes in biochip and Sertoli cells in the bicameral chamber. This microfluidic tool has been previously demonstrated to be helpful in cell function and/or quality improvement. We demonstrate that permeability of the Sertoli barrier is reduced by dynamic coculture in our system. Exometabolomics analysis reveals that interactions between hepatocytes and Sertoli cells may have been mediated by the polyamines increase and/or mid‐chain fatty acid decrease in the circulating medium. These metabolic changes may be involved in permeability reduction by contributing to modifying junction protein quantity and localization. The present study gives an example of IIDMP as an in vitro partitioning/transport model for cell culture and toxicological testing. Further, based on both our previous results using an intestinal–hepatic cell coculture and the present study, IIDMP seems to be well‐suited for (i) assessing the dose–response effect of chemicals within the rodent or human male reproductive tract, and (ii) improving the quality of reprotoxicological assays by including hepatic metabolism. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-21T05:45:34.727774-05:
      DOI: 10.1002/jat.3360
       
  • In vitro toxicology studies of extracellular vesicles
    • Authors: Sayantan Maji; Irene K. Yan, Mansi Parasramka, Swathi Mohankumar, Akiko Matsuda, Tushar Patel
      Abstract: Extracellular vesicles (EVs) are membrane‐bound vesicles released from cells into the extracellular environment. There is emerging interest in the use of EVs as potential therapeutic interventions. We sought to evaluate the safety of EVs that may be therapeutically used by performing in vitro toxicological assessments. EVs were obtained from mesenchymal stem cells (MSC‐EV) or from bovine milk (BM‐EV) by differential ultracentrifugation, and quantitated using nanoparticle tracking analysis. Genotoxic effects, hematological effects, immunological effects and endotoxin production were evaluated at two dose levels. Neither MSC‐EVs nor BM‐EVs elicited detectable genotoxic effects using either the alkaline comet assay or micronucleus assay. Hemolysis was observed with BM‐EVs but not with MSC‐EVs. MSC‐EVs did not have any significant effect on either spontaneous or collagen‐induced platelet aggregation. In contrast, BM‐EVs were noted to increase collagen‐induced platelet aggregation, even though no spontaneous increase in platelet aggregation was noted. Both types of EVs induced leukocyte proliferation, which was greater with BM‐EV. Neither MSC‐EVs nor BM‐EVs induced HL‐60 phagocytosis, although BM‐EVs decreased zymosan‐induced phagocytosis. Furthermore, neither MSC‐EVs nor BM‐EVs induced nitric oxide production. Unlike MSC‐EVs, BM‐EVs tested positive for endotoxin and induced complement activation. There are significant differences in toxicological profiles between MSC‐EVs and BM‐EVs that may reflect variations in techniques for EV isolation, EV content or cross‐species differences. The safety of MSC‐EV supports their use for disease therapeutics, whereas detailed safety and toxicological assessment will be necessary before the use of BM‐EVs. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-20T05:20:51.296356-05:
      DOI: 10.1002/jat.3362
       
  • Molecular docking reveals the potential of phthalate esters to inhibit the
           enzymes of the glucocorticoid biosynthesis pathway
    • Authors: Shahzad Ahmad; Mohemmed Faraz Khan, Suhel Parvez, Mohammad Akhtar, Sheikh Raisuddin
      Abstract: Glucocorticoids (GCs) are well known to exert broad‐based effects on metabolism, behavior and immunity. Their impaired synthesis and production lead to adverse health effects. Some environmental toxicants, including phthalate esters (PAEs), are associated with endocrine disruption. These endocrine‐disrupting chemicals (EDCs) also cause adrenal toxicity and alteration of GC biosynthesis and their functions. Using in silico tools of Schrodinger Maestro 9.4, we performed a molecular docking study of 32 ligands including PAEs of a known endocrine‐disrupting potential with the selected enzymes of the GC biosynthesis pathway (GBP) such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β‐HSD. Binding affinities of the PAEs were compared with known inhibitors of these enzymes. Amongst PAEs, diphenyl benzene‐1, 2 – dicarboxylate (DPhP) showed the lowest docking score of −8.95616 kcal mol−1 against CYP21A1. Besides, benzyl butyl benzene‐1,2‐dicarboxylate (BBzP), bis(7‐methylnonyl) benzene‐1,2 dicarboxylate (DIDP) and bis(2‐ethylhexyl) benzene‐1,2‐dicarboxylate (DEHP) also showed comparable molecular interaction with enzymes of GBP. DPhP showed a significant molecular interaction with different enzymes of GBP such as CYP21A1, CYP11A1 and CYP11B2. These interactions mainly included H‐bonding, hydrophobic, polar and van dar Waals' interactions. Interestingly, this in silico study revealed that certain PAEs have more inhibitory potential against enzymes of GBP than their respective known inhibitors. Such studies become more relevant in the risk assessment of exposure to mixtures of phthalate eaters. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-18T01:01:17.086181-05:
      DOI: 10.1002/jat.3355
       
  • Identification of microRNA biomarker candidates in urine and plasma from
           rats with kidney or liver damage
    • Authors: Francis S. Wolenski; Pooja Shah, Tomoya Sano, Tadahiro Shinozawa, Hugues Bernard, Matt J. Gallacher, Shylah D. Wyllie, Georgianna Varrone, Lisa A. Cicia, Mary E. Carsillo, Craig D. Fisher, Sean E. Ottinger, Erik Koenig, Patrick J. Kirby
      Abstract: MicroRNAs (miRNA) are short single‐stranded RNA sequences that have a role in the post‐transcriptional regulation of genes. The identification of tissue specific or enriched miRNAs has great potential as novel safety biomarkers. One longstanding goal is to associate the increase of miRNA in biofluids (e.g., plasma and urine) with tissue‐specific damage. Next‐generation sequencing (miR‐seq) was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen [APAP] or carbon tetrachloride [CCL4]). Analyses with traditional serum chemistry and histopathology confirmed that toxicant‐induced organ damage was specific. In animals treated with cisplatin, levels of five miRNAs were significantly altered in the kidney, 14 in plasma and six in urine. In APAP‐treated animals, five miRNAs were altered in the liver, 74 in plasma and six in urine; for CCL4 the changes were five, 20 and 6, respectively. Cisplatin treatment caused an elevation of miR‐378a in the urine, confirming the findings of other similar studies. There were 17 in common miRNAs elevated in the plasma after treatment with either APAP or CCL4. Four of these (miR‐122, −802, −31a and −365) are known to be enriched in the livers of rats. Interestingly, the increase of serum miR‐802 in both hepatotoxicant treatments was comparable to that of the well‐known liver damage marker miR‐122. Taken together, comparative analysis of urine and plasma miRNAs demonstrated their utility as biomarkers of organ injury. Copyright © 2016 The
      Authors . Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2016-07-11T03:20:51.930644-05:
      DOI: 10.1002/jat.3358
       
  • Toxicity of single‐wall carbon nanotubes functionalized with
           polyethylene glycol in zebrafish (Danio rerio) embryos
    • Authors: Felipe A. Girardi; Gisele E. Bruch, Carolina S. Peixoto, Lidiane Dal Bosco, Sangram K. Sahoo, Carla O. F. Gonçalves, Adelina P. Santos, Clascídia A. Furtado, Cristiano Fantini, Daniela M. Barros
      Abstract: Single‐wall carbon nanotubes functionalized with polyethylene glycol (SWCNT‐PEG) are promising materials for biomedical applications such as diagnostic devices and controlled drug‐release systems. However, several questions about their toxicological profile remain unanswered. Thus, the aim of this study was to investigate the action of SWCNT‐PEG in Danio rerio zebrafish embryos at the molecular, physiological and morphological levels. The SWCNT used in this study were synthesized by the high‐pressure carbon monoxide process, purified and then functionalized with distearoyl phosphatidylethanolamine block copolymer‐PEG (molecular weight 2 kDa). The characterization process was carried out with low‐resolution transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy. Individual zebrafish embryos were exposed to the SWCNT‐PEG. Toxic effects occurred only at the highest concentration tested (1 ppm) and included high mortality rates, delayed hatching and decreased total larval length. For all the concentrations tested, the alkaline comet assay revealed no genotoxicity, and Raman spectroscopy measurements on the histological slices revealed no intracellular nanotubes. The results shown here demonstrate that SWCNT‐PEG has low toxicity in zebrafish embryos, but more studies are needed to understand what mechanisms are involved. However, the presence of residual metals is possibly among the primary mechanisms responsible for the toxic effects observed, because the purification process was not able to remove all metal contamination, as demonstrated by the thermogravimetric analysis. More attention must be given to the toxicity of these nanomaterials before they are used in biomedical applications. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-06-20T03:40:51.371492-05:
      DOI: 10.1002/jat.3346
       
  • Cytotoxic effects of psychotropic benzofuran derivatives,
           N‐methyl‐5‐(2‐aminopropyl)benzofuran and its N‐demethylated
           derivative, on isolated rat hepatocytes
    • Authors: Yoshio Nakagawa; Toshinari Suzuki, Yukie Tada, Akiko Inomata
      Abstract: The novel psychoactive compounds derived from amphetamine have been illegally abused as recreational drugs, some of which are known to be hepatotoxic in humans and experimental animals. The cytotoxic effects and mechanisms of 5‐(2‐aminopropyl)benzofuran (5‐APB) and N‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB), both of which are benzofuran analogues of amphetamine, and 3,4‐methylenedioxy‐N‐methamphetamine (MDMA) were studied in freshly isolated rat hepatocytes. 5‐MAPB caused not only concentration‐dependent (0–4.0 mm) and time‐dependent (0–3 h) cell death accompanied by the depletion of cellular ATP and reduced glutathione and protein thiol levels, but also accumulation of oxidized glutathione. Of the other analogues examined at a concentration of 4 mm, 5‐MAPB/5‐APB‐induced cytotoxicity with the production of reactive oxygen species and loss of mitochondrial membrane potential was greater than that induced by MDMA. In isolated rat liver mitochondria, the benzofurans resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA, with a decrease in the rate of state 3 oxygen consumption. Furthermore, the benzofurans caused more of a rapid mitochondrial swelling dependent on the mitochondrial permeability transition than MDMA. 5‐MAPB at a weakly toxic level (1 mm) was metabolized slowly: levels of 5‐MAPB and 5‐APB were approximately 0.9 mm and 50 μm, respectively, after 3 h incubation. Taken collectively, these results indicate that mitochondria are target organelles for the benzofuran analogues and MDMA, which elicit cytotoxicity through mitochondrial failure, and the onset of cytotoxicity may depend on the initial and/or residual concentrations of 5‐MAPB rather than on those of its metabolite 5‐APB. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-06-13T01:10:49.273901-05:
      DOI: 10.1002/jat.3351
       
  • Detection of exposure effects of mixtures of heavy polycyclic aromatic
           hydrocarbons in zebrafish embryos
    • Authors: Alejandro Barranco; Laura Escudero, Jon Sanz Landaluze, Sandra Rainieri
      Abstract: In this study we evaluated the exposure effects of mixtures of five polycyclic aromatic hydrocarbons (PAHs); namely, benzo[a]anthracene, benzo[a]pyrene, benzo[b]fluoranthene, benzo[k]fluoranthene and chrysene on zebrafish embryos. Supplementation of the exposure media with 0.45% dimethyl sulfoxide and 50 ppm of Tween 20 could guarantee the solubilization and stabilization of the PAHs up to 24 h without affecting the embryos development. The exposure effects were tested by detecting the differential expression of a number of genes related to the aryl hydrocarbon receptor gene battery. Effects were detectable already after 6 h of exposure. After 24 h of exposure, all PAHs, except for benzo[a]anthracene, acted as potent inducers of the gene cyp1a1. Benzo[k]fluoranthene was the major inducer; the effect caused by the mixture at the lower concentration tested (1 ng ml−1) was dominated by its presence. However, in the mixture at the highest concentration tested (10 ng ml−1) it caused less induction and was not dominant. No significant bioaccumulation values were detected on embryos exposed to the PAHs tested in this study; however, the results obtained, indicated that PAHs undergo a very rapid metabolization inside the embryos, and that those biotransformation products yield changes on the expression of genes involved in the aryl hydrocarbon receptor pathway. Future work should focus on identification of the PAH metabolization products and on the effect of these metabolites on toxicity. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-06-10T01:25:31.717541-05:
      DOI: 10.1002/jat.3353
       
  • Comparative oral dose toxicokinetics of sodium selenite and
           selenomethionine
    • Authors: T. Zane Davis; Asheesh K. Tiwary, Bryan L. Stegelmeier, James A. Pfister, Kip E. Panter, Jeffery O. Hall
      Abstract: Selenium (Se) poisoning by different forms of Se occurs in the United States. However, the toxicokinetics of different selenocompounds after oral ingestion is not well documented. In this study the toxicokinetics of Se absorption, distribution and elimination were determined in serum and whole blood of lambs that were orally dosed with increasing doses of Se as sodium selenite (inorganic Se) or selenomethionine (SeMet, organic Se). Thirty‐two lambs were randomly assigned to eight treatment groups, with four animals per group. Se was administered at 1, 2 or 3 mg kg−1 body weight, as either sodium selenite or SeMet with proper control groups. Blood and serum were collected at predetermined time points for 7 days post‐dosing. Resulting Se concentrations in both serum and whole blood from SeMet treatment groups were significantly greater than those given equimolar doses of Se as sodium selenite. Se concentrations in serum and whole blood of lambs dosed with SeMet peaked at significantly greater concentrations when compared with lambs dosed with equimolar doses of sodium selenite. Based on the serum and whole blood kinetics, the rate of Se absorption was greater for SeMet than for sodium selenite although rates of absorption for both Se forms decreased with increasing dose. The rates of Se elimination increased with dose. These results demonstrate that SeMet has a greater absorption rate and a similar retention time resulting in a greater area under the curve and thus bioavailability than sodium selenite, which must be considered in both overdose and nutritional exposures. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2016-06-10T01:05:25.404061-05:
      DOI: 10.1002/jat.3350
       
  • Preclinical safety study of a recombinant Streptococcus pyogenes vaccine
           formulated with aluminum adjuvant
    • Authors: Harm HogenEsch; Anisa Dunham, Elodie Burlet, Fangjia Lu, Yung‐Yi C. Mosley, Garry Morefield
      Abstract: A recombinant vaccine composed of a fusion protein formulated with aluminum hydroxide adjuvant is under development for protection against diseases caused by Streptococcus pyogenes. The safety and local reactogenicity of the vaccine was assessed by a comprehensive series of clinical, pathologic and immunologic tests in preclinical experiments. Outbred mice received three intramuscular injections of 1/5th of the human dose (0.1 ml) and rabbits received two injections of the full human dose. Control groups received adjuvant or protein antigen. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. There was a transient increase of peripheral blood neutrophils after the third vaccination of mice. In addition, the concentration of acute phase proteins serum amyloid A and haptoglobin was significantly increased 1 day after injection of the vaccine in mice. There was mild transient swelling and erythema of the injection site in both mice and rabbits. Treatment‐related pathology was limited to inflammation at the injection site and accumulation of adjuvant‐containing macrophages in the draining lymph nodes. In conclusion, the absence of clinical toxicity in two animal species suggest that the vaccine is safe for use in a phase I human clinical trial. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-30T21:05:44.533104-05:
      DOI: 10.1002/jat.3349
       
  • Lithium limits trimethyltin‐induced cytotoxicity and proinflammatory
           response in microglia without affecting the concurrent autophagy
           impairment
    • Authors: Cinzia Fabrizi; Elena Pompili, Francesca Somma, Stefania De Vito, Viviana Ciraci, Marco Artico, Paola Lenzi, Francesco Fornai, Lorenzo Fumagalli
      Abstract: Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic system both in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT‐intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3. Consistent with autophagy impairment we observe in TMT‐treated microglia the accumulation of p62/SQSTM1, a protein specifically degraded through this pathway. Lithium has been proved effective in limiting neurodegenerations and, in particular, in ameliorating symptoms of TMT intoxication in rodents. In our in vitro model, lithium displays a pro‐survival and anti‐inflammatory action reducing both cell death and the proinflammatory response of TMT‐treated microglia. In particular, lithium exerts these activities without reducing TMT‐induced accumulation of light chain 3 protein. In fact, the autophagic block imposed by TMT is unaffected by lithium administration. These results are of interest as defects in the execution of autophagy are frequently observed in neurodegenerative diseases and lithium is considered a promising therapeutic agent for these pathologies. Thus, it is relevant that this cation can still maintain its pro‐survival and anti‐inflammatory role in conditions of autophagy block. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-25T23:20:33.492046-05:
      DOI: 10.1002/jat.3344
       
  • Toxic effects of chemical dispersant Corexit 9500 on water flea Daphnia
           magna
    • Authors: Kenji Toyota; Nicole A. McNabb, Demetri D. Spyropoulos, Taisen Iguchi, Satomi Kohno
      Abstract: In 2010, approximately 2.1 million gallons of chemical dispersants, mainly Corexit 9500, were applied in the Gulf of Mexico to prevent the oil slick from reaching shorelines and to accelerate biodegradation of oil during the Deepwater Horizon oil spill. Recent studies have revealed toxic effects of Corexit 9500 on marine microzooplankton that play important roles in food chains in marine ecosystems. However, there is still little known about the toxic effects of Corexit 9500 on freshwater zooplankton, even though oil spills do occur in freshwater and chemical dispersants may be used in response to these spills. The cladoceran crustacean, water flea Daphnia magna, is a well‐established model species for various toxicological tests, including detection of juvenile hormone‐like activity in test compounds. In this study, we conducted laboratory experiments to investigate the acute and chronic toxicity of Corexit 9500 using D. magna. The acute toxicity test was conducted according to OECD TG202 and the 48 h EC50 was 1.31 ppm (CIs 0.99–1.64 ppm). The reproductive chronic toxicity test was performed following OECD TG211 ANNEX 7 and 21 days LOEC and NOEC values were 4.0 and 2.0 ppm, respectively. These results indicate that Corexit 9500 has toxic effects on daphnids, particularly during the neonatal developmental stage, which is consistent with marine zooplankton results, whereas juvenile hormone‐like activity was not identified. Therefore, our findings of the adverse effects of Corexit 9500 on daphnids suggest that application of this type of chemical dispersant may have catastrophic impacts on freshwater ecosystems by disrupting the key food chain network. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-25T23:10:32.196468-05:
      DOI: 10.1002/jat.3343
       
  • Acetyl L‐carnitine targets adenosine triphosphate synthase in protecting
           zebrafish embryos from toxicities induced by verapamil and ketamine: An in
           vivo assessment
    • Authors: Xiaoqing Guo; Melanie Dumas, Bonnie L. Robinson, Syed F. Ali, Merle G. Paule, Qiang Gu, Jyotshna Kanungo
      Abstract: Verapamil is a Ca2+ channel blocker and is highly prescribed as an anti‐anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca2+‐permeable N‐methyl‐d‐aspartate‐type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l‐carnitine (ALCAR) reverses ketamine‐induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48 h post‐fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4 h. Heart beat and overall development were monitored in vivo. In 48 h post‐fertilization embryos, 2 mm ketamine reduced heart rate in a 2 or 4 h exposure and 0.5 mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca2+ entry through L‐type Ca2+ channels that ALCAR is known to activate. Hence, we used verapamil to block the L‐type Ca2+ channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5‐trimethoxybenzoic acid 8‐(diethylamino)octyl ester, an inhibitor of intracellular Ca2+ release suggesting that ALCAR acts via effectors downstream of Ca2+. In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca2+ during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine‐ and verapamil‐induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2016-05-18T07:05:10.31434-05:0
      DOI: 10.1002/jat.3340
       
  • Dibutyltin‐induced alterations of interleukin 1beta secretion from
           human immune cells
    • Authors: Shyretha Brown; Shahin Tehrani, Margaret M. Whalen
      Abstract: Dibutyltin (DBT) is used to stabilize polyvinyl chloride plastics (including pipes that distribute drinking water) and as a de‐worming agent in poultry. DBT is found in human blood, and DBT exposures alter the secretion of tumor necrosis factor alpha and interferon gamma from lymphocytes. Interleukin (IL)‐1β is a proinflammatory cytokine that regulates cellular growth, tissue restoration and immune response regulation. IL‐1β plays a role in increasing invasiveness of certain tumors. This study reveals that exposures to DBT (24 h, 48 h and 6 days) modify the secretion of IL‐1β from increasingly reconstituted preparations of human immune cells (highly enriched human natural killer cells, monocyte‐depleted [MD] peripheral blood mononuclear cells [PBMCs], PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes). DBT altered IL‐1β secretion from all cell preparations. Higher concentrations of DBT (5 and 2.5 μm) decreased the secretion of IL‐1β, while lower concentrations of DBT (0.1 and 0.05 μm) increased the secretion of IL‐1β. Selected signaling pathways were examined in MD‐PBMCs to determine if they play a role in DBT‐induced elevations of IL‐1β secretion. Pathways examined were IL‐1β converting enzyme (caspase 1), mitogen‐activated protein kinases and nuclear factor kappa B. Caspase 1 and mitogen‐activated protein kinase pathways appear to be utilized by DBT in increasing IL‐1β secretion. These results indicate that DBT alters IL‐1β secretion from human immune cells in an ex. vivo system utilizing several IL‐1β regulating signaling pathways. Thus, DBT may have the potential to alter IL‐1β secretion in an in vivo system. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-17T01:35:28.9227-05:00
      DOI: 10.1002/jat.3339
       
  • Non‐clinical safety assessment of single and repeated administration of
           gE/AS01 zoster vaccine in rabbits
    • Authors: Giulia Giordano; Lawrence Segal, Menk Prinsen, Marcel V. W. Wijnands, Nathalie Garçon, Eric Destexhe
      Abstract: HZ/su is an investigational recombinant subunit vaccine for the prevention of shingles, a disease resulting from the reactivation of varicella zoster virus. The vaccine is composed of recombinant varicella zoster virus glycoprotein E (gE), and liposome‐based Adjuvant System AS01. To evaluate the potential local and systemic effects of this vaccine, three studies were performed in rabbits. In the first two studies, rabbits received a single intramuscular (IM; study 1) or subcutaneous (SC; study 2) dose of gE/AS01, AS01 alone (in study 2 only) or saline, and the local tolerance was evaluated up to 3 days after administration. Under these conditions, only local inflammatory reactions at the injection sites were detected by microscopic evaluation. In the third study, gE/AS01, AS01 alone or saline, were injected SC or IM on four occasions at 2 week intervals. General health status, local tolerance, ophthalmology, haematology and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed after termination of the study. The only treatment‐related changes included a transient increase in neutrophils, C‐reactive protein and fibrinogen levels and microscopic signs of inflammation at the injection sites, which are expected observations related to the elicited inflammatory reaction. The SC and IM routes of administration produced similar systemic effects. However, microscopic findings at the injection sites differed. One month after the last injection, recovery was complete in all groups. In conclusion, the single and repeated SC and IM administration of the gE/AS01 vaccine were locally and systemically well‐tolerated in rabbits and support the clinical development of the vaccine. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-12T08:03:54.99173-05:0
      DOI: 10.1002/jat.3329
       
  • 4‐Nitrophenol exposure alters the AhR signaling pathway and related gene
           expression in the rat liver
    • Authors: Ruonan Li; Meiyan Song, Zhi Li, Yansen Li, Gen Watanabe, Kentaro Nagaoka, Kazuyoshi Taya, Chunmei Li
      Abstract: 4‐Nitrophenol (PNP) is well known as an environmental endocrine disruptor. The aim of this study was to clarify the mechanism of PNP‐induced liver damage and determine the regulatory involvement of the aryl hydrocarbon receptor (AhR) signaling pathway and associated gene expression. Immature male Wistar–Imamichi rats (28 days old) were randomly divided into control and PNP groups, which consisted of 1‐ and 3‐day exposure (1 DE and 3 DE, respectively) and 3‐day exposure followed by 3‐day recovery (3 DE + 3 DR), groups. Each group was administered the vehicle or PNP (200 mg kg–1 body weight). The body and liver weight were significantly decreased in the 3 DE group. The mRNA expression levels of estrogen receptor‐α (ERα), glutathione S‐transferase (GST) and AhR exhibited a significant increase in the 1 DE group whereas, in contrast, that of cytochrome P450 (CYP) 1A1 decreased significantly in the 3 DE +3 DR group. AhR and CYP1A1 proteins were detected in the cytoplasm of hepatocytes of the 1 DE and 3 DE +3 DR groups whereas the ERα protein was found in the hepatocyte nuclei of the 1 DE and 3 DE groups. The present study demonstrates that PNP activated the AhR signaling pathway and regulated related CYP1A1 and GST gene expression in the liver. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-12T07:51:04.421728-05:
      DOI: 10.1002/jat.3332
       
  • Lack of genotoxic mechanisms in early‐stage furan‐induced
           hepatocellular tumorigenesis in gpt delta rats
    • Authors: Daisuke Hibi; Yu Yokoo, Yuta Suzuki, Yuji Ishii, Meilan Jin, Aki Kijima, Takehiko Nohmi, Akiyoshi Nishikawa, Takashi Umemura
      Abstract: Furan has been used as an intermediate in the chemical‐manufacturing industry and has been shown to contaminate various foods. Although furan induces hepatocellular tumors in rodents, equivocal results from in vitro and in vivo mutagenicity tests have caused controversy regarding the involvement of genotoxic mechanisms in furan‐induced carcinogenesis. In the present study, to elucidate the possible mechanisms underlying furan‐induced hepatocarcinogenesis, a comprehensive medium‐term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. In the liver, the frequencies of gpt and Spi‐ mutants derived mainly from point and deletion mutations, respectively, were not changed, and there were no furan‐specific gpt mutations in furan‐treated rats. In contrast, the number and area of glutathione S‐transferase placental form (GST‐P)‐ positive foci were significantly increased in the high‐dose group. Also, the ratio of PCNA‐positive hepatocytes was significantly elevated in the same group, as supported by significant increases in cyclin d1 and cyclin e1 mRNA levels. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to the development of GST‐P foci in furan‐treated rats. Based on the close relationship between GST‐P and neoplastic hepatocytes, these data allowed us to hypothesize that cell proliferation following signal transduction other than the mitogen‐activated protein kinase (MAPK)/ERK pathway may play a crucial role in early‐stage furan‐induced hepatocarcinogenesis. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-03T07:51:06.035242-05:
      DOI: 10.1002/jat.3331
       
  • Characterization of three human cell line models for high‐throughput
           neuronal cytotoxicity screening
    • Authors: Zhi‐Bin Tong; Helena Hogberg, David Kuo, Srilatha Sakamuru, Menghang Xia, Lena Smirnova, Thomas Hartung, David Gerhold
      Abstract: More than 75 000 man‐made chemicals contaminate the environment; many of these have not been tested for toxicities. These chemicals demand quantitative high‐throughput screening assays to assess them for causative roles in neurotoxicities, including Parkinson's disease and other neurodegenerative disorders. To facilitate high throughput screening for cytotoxicity to neurons, three human neuronal cellular models were compared: SH‐SY5Y neuroblastoma cells, LUHMES conditionally‐immortalized dopaminergic neurons, and Neural Stem Cells (NSC) derived from human fetal brain. These three cell lines were evaluated for rapidity and degree of differentiation, and sensitivity to 32 known or candidate neurotoxicants. First, expression of neural differentiation genes was assayed during a 7‐day differentiation period. Of the three cell lines, LUHMES showed the highest gene expression of neuronal markers after differentiation. Both in the undifferentiated state and after 7 days of neuronal differentiation, LUHMES cells exhibited greater cytotoxic sensitivity to most of 32 suspected or known neurotoxicants than SH‐SY5Y or NSCs. LUHMES cells were also unique in being more susceptible to several compounds in the differentiating state than in the undifferentiated state; including known neurotoxicants colchicine, methyl‐mercury (II), and vincristine. Gene expression results suggest that differentiating LUHMES cells may be susceptible to apoptosis because they express low levels of anti‐apoptotic genes BCL2 and BIRC5/survivin, whereas SH‐SY5Y cells may be resistant to apoptosis because they express high levels of BCL2, BIRC5/survivin, and BIRC3 genes. Thus, LUHMES cells exhibited favorable characteristics for neuro‐cytotoxicity screening: rapid differentiation into neurons that exhibit high level expression neuronal marker genes, and marked sensitivity of LUHMES cells to known neurotoxicants. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-05-03T07:44:26.906766-05:
      DOI: 10.1002/jat.3334
       
  • Regucalcin counteracts tert‐butyl hydroperoxide and cadmium‐induced
           oxidative stress in rat testis
    • Authors: Sara Correia; Cátia V. Vaz, Ana M. S. Silva, José E. Cavaco, Sílvia Socorro
      Abstract: Regucalcin (RGN) is a calcium (Ca2+)‐binding protein with multiple physiological roles and has also been linked to the suppression of oxidative stress. It is widely known that oxidative stress adversely affects spermatogenesis, disrupting the development of germ cells, and interfering with sperm function. The present study aims to analyze the role of RGN modulating testicular oxidative stress. To address this issue, seminiferous tubules (SeT) from transgenic rats overexpressing RGN (Tg‐RGN) and wild‐type (WT) were cultured ex vivo for 24 h in the presence/absence of pro‐oxidant stimuli, tert‐butyl hydroperoxide (TBHP, 250 and 500 μM) and cadmium chloride (Cd, 10 and 20 μM). Noteworthy, SeT from Tg‐RGN animals displayed a significantly higher antioxidant capacity and diminished levels of thiobarbituric acid reactive substances relatively to their WT counterparts, both in control and experimental conditions. Regarding the antioxidant defense systems, a significant increase in the activity of glutathione‐S‐transferase was found in the SeT of Tg‐RGN whereas no differences were observed in superoxide dismutase activity throughout experimental conditions. The activity of apoptosis executioner caspase‐3 was significantly increased in the SeT of WT rats treated with 250 μM of TBHP or 10 μM of Cd, an effect not seen in Tg‐RGN animals. These results showed that the SeT of Tg‐RGN animals displayed lower levels of oxidative stress and increased antioxidant defenses, exhibiting protection against oxidative damage and apoptosis. Moreover, the present findings support the antioxidant role of RGN in spermatogenesis, which may be an important issue of further research in the context of male infertility. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-04-25T02:46:48.66054-05:0
      DOI: 10.1002/jat.3333
       
  • Issue Information - TOC
    • First page: 1
      Abstract: No abstract is available for this article.
      PubDate: 2016-11-16T19:27:53.288196-05:
      DOI: 10.1002/jat.3398
       
  • Biologic activity of cyclic and caged phosphates: a review
    • Authors: Dietrich E. Lorke; Anka Stegmeier‐Petroianu, Georg A. Petroianu
      First page: 13
      Abstract: The recognition in the early 1960s by Morifusa Eto that tri‐o‐cresyl phosphate (TOCP) is hydroxylated by the cytochrome P450 system to an intermediate that spontaneously cyclizes to a neurotoxic phosphate (saligenin phosphate ester) ignited the interest in this group of compounds. Only the ortho isomer can cyclize and clinically cause Organo Phosphate Induced Delayed Neurotoxicity (OPIDN); the meta and para isomers of tri‐cresyl phosphate are not neuropathic because they are unable to form stable cyclic saligenin phosphate esters. This review identifies the diverse biological effects associated with various cyclic and caged phosphates and phosphonates and their possible use. Cyclic compounds that inhibit acetylcholine esterase (AChE), such as salithion, can be employed as pesticides. Others are neurotoxic, most probably because of inhibition of neuropathy target esterase (NTE). Cyclic phosphates that inhibit lipases, the cyclipostins, possibly represent promising therapeutic avenues for the treatment of type 2 diabetes mellitus and/or microbial infections; those compounds inhibiting β‐lactamase may prevent bacterial resistance against β‐lactam antibiotics. Naturally occurring cyclic phosphates, such as cyclic AMP, cyclic phosphatidic acid and the ryanodine receptor modulator cyclic adenosine diphosphate ribose, play an important physiological role in signal transduction. Moreover, some cyclic phosphates are GABA‐antagonists, while others are an essential component of Molybdenum‐containing enzymes. Some cyclic phosphates (cyclophosphamide, ifosfamide) are clinically used in tumor therapy, while the coupling of therapeutic agents with other cyclic phosphates (HepDirect® Technology) allows drugs to be targeted to specific organs. Possible clinical applications of these compounds are considered. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-09T11:17:34.349526-05:
      DOI: 10.1002/jat.3369
       
  • Anthophyllite asbestos: state of the science review
    • Authors: Shannon H. Gaffney; Matthew Grespin, Lindsey Garnick, Derek A. Drechsel, Rebecca Hazan, Dennis J. Paustenbach, Brooke D. Simmons
      First page: 38
      Abstract: Anthophyllite is an amphibole form of asbestos historically used in only a limited number of products. No published resource currently exists that offers a complete overview of anthophyllite toxicity or of its effects on exposed human populations. We performed a review focusing on how anthophyllite toxicity was understood over time by conducting a comprehensive search of publicly available documents that discussed the use, mining, properties, toxicity, exposure and potential health effects of anthophyllite. Over 200 documents were identified; 114 contained relevant and useful information which we present chronologically in this assessment. Our analysis confirms that anthophyllite toxicity has not been well studied compared to other asbestos types. We found that toxicology studies in animals from the 1970s onward have indicated that, at sufficient doses, anthophyllite can cause asbestosis, lung cancer and mesothelioma. Studies of Finnish anthophyllite miners, conducted in the 1970s, found an increased incidence of asbestosis and lung cancer, but not mesothelioma. Not until the mid‐1990s was an epidemiological link with mesothelioma in humans observed. Its presence in talc has been of recent significance in relation to potential asbestos exposure through the use of talc‐containing products. Characterizing the health risks of anthophyllite is difficult, and distinguishing between its asbestiform and non‐asbestiform mineral form is essential from both a toxicological and regulatory perspective. Anthophyllite toxicity has generally been assumed to be similar to other amphiboles from a regulatory standpoint, but some notable exceptions exist. In order to reach a more clear understanding of anthophyllite toxicity, significant additional study is needed. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-11T03:05:57.857656-05:
      DOI: 10.1002/jat.3356
       
  • The C. elegans model in toxicity testing
    • Authors: Piper Reid Hunt
      First page: 50
      Abstract: Caenorhabditis elegans is a small nematode that can be maintained at low cost and handled using standard in vitro techniques. Unlike toxicity testing using cell cultures, C. elegans toxicity assays provide data from a whole animal with intact and metabolically active digestive, reproductive, endocrine, sensory and neuromuscular systems. Toxicity ranking screens in C. elegans have repeatedly been shown to be as predictive of rat LD50 ranking as mouse LD50 ranking. Additionally, many instances of conservation of mode of toxic action have been noted between C. elegans and mammals. These consistent correlations make the case for inclusion of C. elegans assays in early safety testing and as one component in tiered or integrated toxicity testing strategies, but do not indicate that nematodes alone can replace data from mammals for hazard evaluation. As with cell cultures, good C. elegans culture practice (GCeCP) is essential for reliable results. This article reviews C. elegans use in various toxicity assays, the C. elegans model's strengths and limitations for use in predictive toxicology, and GCeCP. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2016-07-22T01:45:37.492847-05:
      DOI: 10.1002/jat.3357
       
  • Gender and geographical variability in the exposure pattern and metabolism
           of deoxynivalenol in humans: a review
    • Authors: Liangkai Chen; Miao Yu, Qinghua Wu, Zhao Peng, Di Wang, Kamil Kuča, Ping Yao, Hong Yan, Andreas K. Nüssler, Liegang Liu, Wei Yang
      First page: 60
      Abstract: Deoxynivalenol (DON, also known as vomitoxin) is a common mycotoxin found worldwide, especially in contaminated food. DON is toxic to a variety of cells and tissues in humans. Three kinds of conjugated products (DON‐3‐glucuronide, DON‐15‐glucuronide and DON‐7‐glucuronide) can be found as major metabolites in human urine. Females and males show different patterns of exposure levels, and human exposure to DON also shows some geographical differences because of different DON levels in cereal‐based foods, food intake habits and UDP‐glucuronosyltransferase expression. Specifically, the C12, 13‐deepoxy metabolite was found predominantly in French adults but was rarely detected in UK adults. However, a cohort of Spanish individuals demonstrated even lower DON levels than the levels in the UK populations, whereas a very high DON exposure level was detected in South Africa and Linxian, China. Recent publications have further indicated that DON could be detected in the urine of pregnant women from different countries, which suggests that there is a potential risk to both mothers and foetuses. Additionally, phytochemicals have been shown to be less toxic to cells and laboratory animals in research studies and may also be used as food additives for reducing the toxic effects of DON. In this review, we provide global information on DON metabolism, human exposure and gender differences in humans. Also, control strategies for this mycotoxin are discussed. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-07-26T03:56:47.324771-05:
      DOI: 10.1002/jat.3359
       
  • The inadequacies of pre-market chemical risk assessment's toxicity
           studies—the implications
    • Authors: Anthony C. Tweedale
      First page: 92
      Abstract: Industry provides essentially all the data for most (pre-market) chemical risk assessments (RA); academics study a chemical once it is marketed. For two randomly-chosen high production chemicals, despite new European Union mandates to evaluate all data, just 13% of the herbicide bentazon and 15% of the flame-retardant hexabromocyclododecane's published toxicity studies were found in their pre-market RA, and a systematic review on bentazon concludes it has greater hazards than indicated in its RA. More important, for both, academia's toxicity studies were designated as lower quality than industries were, despite showing hazards at lower doses. The accuracy of industry's test methods is analyzed and found to be replicable but insensitive, thus inaccurate. The synthetic pharmaceutical industry originated them, and by 1983 the Organization for Economic Cooperation & Development mandated their test guidelines (TG) methods be accepted for any new study for pre-market RA. For existing studies, industry's “Klimisch” criterion is universally used to evaluate quality, but it only states that TG studies produce the best data. However, no TG can answer the realistic exposure effect hypotheses of academics; therefore, crucially in pre-market RA, tens of thousands of published experimental findings (increasingly at low dose) are ignored to determine the safe dose. Few appreciate this, so scientific debate on the most accurate elements of toxicity tests is urgently indicated. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-10-26T23:31:11.279287-05:
      DOI: 10.1002/jat.3396
       
  • What determines skin sensitization potency: Myths, maybes and realities.
           The 500 molecular weight cut‐off: An updated analysis
    • Authors: Jeremy M. Fitzpatrick; David W. Roberts, Grace Patlewicz
      First page: 105
      Abstract: It is widely accepted that substances must have a molecular weight (MW)  500, five were sensitizers. This provided good evidence to refute such a MW 500 threshold. While Roberts et al. (2012) made a convincing case that the MW > 500 cut‐off was not a true requirement for sensitization, the number of counter examples identified were too few to draw any statistical conclusions. This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW > 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings. The study also assessed whether the same reaction chemistry principles established for low MW sensitizers applied to chemicals with a MW > 500. The existing reaction chemistry considerations were found appropriate to rationalize the sensitization behaviour of the 14 sensitizers with a MW > 500. The existence of the MW 500 threshold, based on the widespread misconception that the ability to penetrate efficiently the stratum corneum is a key determinant of skin sensitization potential and potency, was refuted. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-06-10T01:15:33.619414-05:
      DOI: 10.1002/jat.3348
       
  • Is skin penetration a determining factor in skin sensitization potential
           and potency' Refuting the notion of a LogKow threshold for skin
           sensitization
    • Authors: Jeremy M. Fitzpatrick; David W. Roberts, Grace Patlewicz
      First page: 117
      Abstract: It is widely accepted that substances that cannot penetrate through the skin will not be sensitizers. LogKow and molecular weight (MW) have been used to set thresholds for sensitization potential. Highly hydrophilic substances e.g. LogKow ≤ 1 are expected not to penetrate effectively to induce sensitization. To investigate whether LogKow >1 is a true requirement for sensitization, a large dataset of substances that had been evaluated for their skin sensitization potential under Registration, Evaluation, Authorisation and restriction of CHemicals (REACH), together with available measured LogKow values was compiled using the OECD eChemPortal. The incidence of sensitizers relative to non‐sensitizers above and below a LogKow of 1 was explored. Reaction chemistry principles were used to explain the sensitization observed for the subset of substances with a LogKow ≤0. 1482 substances were identified with skin sensitization data and measured LogKow values. 525 substances had a measured LogKow ≤ 1, 100 of those were sensitizers. There was no significant difference in the incidence of sensitizers above and below a LogKow of 1. Reaction chemistry principles that had been established for lower MW and more hydrophobic substances were found to be still valid in rationalizing the skin sensitizers with a LogKow ≤ 0. The LogKow threshold arises from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potential and potency. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-06-29T20:40:33.379277-05:
      DOI: 10.1002/jat.3354
       
  • Evidence for direct effects of glyphosate on ovarian function: glyphosate
           influences steroidogenesis and proliferation of bovine granulosa but not
           theca cells in vitro
    • 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 
       
  • Comparative in vitro toxicity assessment of perfluorinated carboxylic
           acids
    • 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.
       
  • Activation of interleukin-6 and -8 expressions by methylmercury in human
           U937 macrophages involves RelA and p50
    • 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.
       
  • Responses of A549 human lung epithelial cells to cristobalite and
           α-quartz exposures assessed by toxicoproteomics and gene expression
           analysis
    • 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.
       
  • Relationship between increasing concentrations of two carcinogens and
           statistical image descriptors of foci morphology in the cell
           transformation assay
    • 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.
       
  • Developmental toxicity of auranofin in zebrafish embryos
    • 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.
       
  • Antagonistic effect of N-ethylmaleimide on arsenic-mediated oxidative
           stress-induced poly(ADP-ribosyl)ation and cytotoxicity
    • 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.
       
  • Cytotoxicity, oxidative stress and inflammation induced by ZnO
           nanoparticles in endothelial cells: interaction with palmitate or
           lipopolysaccharide
    • 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.
       
  • Effects of oral exposure to the phthalate substitute acetyl tributyl
           citrate on female reproduction in mice
    • 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.
       
  • 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
    • 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
       
  • Immunotoxic effects of in vitro exposure of dolphin lymphocytes to
           Louisiana sweet crude oil and Corexit™
    • 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.
       
  • Lack of in vivo mutagenicity of 1,2-dichloropropane and dichloromethane in
           the livers of gpt delta rats administered singly or in combination
    • 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.
       
  • Zebrafish larva as a reliable model for in vivo assessment of membrane
           remodeling involvement in the hepatotoxicity of chemical agents
    • 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.
       
 
 
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