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  Subjects -> ENVIRONMENTAL STUDIES (Total: 772 journals)
    - ENVIRONMENTAL STUDIES (701 journals)
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ENVIRONMENTAL STUDIES (701 journals)            First | 1 2 3 4     

Showing 601 - 378 of 378 Journals sorted alphabetically
Revista de Direito Ambiental e Socioambientalismo     Open Access  
Revista de Direito e Sustentabilidade     Open Access  
Revista de Gestão Ambiental e Sustentabilidade - GeAS     Open Access  
Revista de Salud Ambiental     Open Access  
Revista Direito Ambiental e Sociedade     Open Access  
Revista Eletrônica de Gestão e Tecnologias Ambientais     Open Access  
Revista Eletrônica em Gestão, Educação e Tecnologia Ambiental     Open Access  
Revista Eletrônica TECCEN     Open Access  
Revista Geama     Open Access  
Revista Hábitat Sustenable     Open Access   (Followers: 1)
Revista Internacional de Ciências     Open Access   (Followers: 1)
Revista Meio Ambiente e Sustentabilidade     Open Access   (Followers: 1)
Revista Metropolitana de Sustentabilidade     Open Access  
Revista Monografias Ambientais     Open Access  
Revista Verde de Agroecologia e Desenvolvimento Sustentável     Open Access   (Followers: 2)
Ring     Open Access   (Followers: 1)
Riparian Ecology and Conservation     Open Access   (Followers: 7)
Rivista di Studi sulla Sostenibilità     Full-text available via subscription   (Followers: 1)
Russian Journal of Ecology     Hybrid Journal   (Followers: 1)
S.A.P.I.EN.S     Open Access   (Followers: 2)
Safety Science     Hybrid Journal   (Followers: 33)
San Francisco Estuary and Watershed Science     Open Access  
SAR and QSAR in Environmental Research     Hybrid Journal   (Followers: 1)
Saúde e Meio Ambiente : Revista Interdisciplinar     Open Access  
Scandinavian Journal of Work, Environment & Health     Partially Free   (Followers: 13)
Science of The Total Environment     Hybrid Journal   (Followers: 27)
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: 8)
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: 5)
Sriwijaya Journal of Environment     Open Access  
Stochastic Environmental Research and Risk Assessment     Hybrid Journal   (Followers: 4)
Strategic Behavior and the Environment     Full-text available via subscription   (Followers: 2)
Strategic Planning for Energy and the Environment     Hybrid Journal   (Followers: 4)
Studies in Conservation     Hybrid Journal   (Followers: 12)
Studies in Environmental Science     Full-text available via subscription   (Followers: 5)
Sustainability     Open Access   (Followers: 21)
Sustainability in Environment     Open Access   (Followers: 2)
Sustainability of Water Quality and Ecology     Hybrid Journal   (Followers: 4)
Sustainable Cities and Society     Hybrid Journal   (Followers: 23)
Sustainable Development     Hybrid Journal   (Followers: 16)
Sustainable Development Law & Policy     Open Access   (Followers: 8)
Sustainable Development Strategy and Practise     Open Access  
Sustainable Environment Research     Open Access  
Sustainable Technologies, Systems & Policies     Open Access   (Followers: 7)
TECHNE - Journal of Technology for Architecture and Environment     Open Access   (Followers: 8)
Tecnogestión     Open Access  
Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica     Open Access  
The Historic Environment : Policy & Practice     Hybrid Journal   (Followers: 5)
The International Journal on Media Management     Hybrid Journal   (Followers: 5)
Theoretical Ecology     Hybrid Journal   (Followers: 12)
Theoretical Ecology Series     Full-text available via subscription   (Followers: 1)
Toxicologic Pathology     Hybrid Journal   (Followers: 21)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 4)
Toxicological Sciences     Hybrid Journal   (Followers: 12)
Toxicology     Hybrid Journal   (Followers: 19)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 20)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 7)
Toxicology in Vitro     Hybrid Journal   (Followers: 13)
Toxicology Letters     Hybrid Journal   (Followers: 13)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 11)
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)
Transactions on Environment and Electrical Engineering     Open Access  
Transportation Research Part D: Transport and Environment     Hybrid Journal   (Followers: 27)
Transylvanian Review of Systematical and Ecological Research     Open Access  
Trends in Ecology & Evolution     Full-text available via subscription   (Followers: 224)
Trends in Environmental Analytical Chemistry     Hybrid Journal   (Followers: 3)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 26)
Tropicultura     Open Access  
UD y la Geomática     Open Access  
Universidad y Ciencia     Open Access   (Followers: 1)
Urban Studies     Hybrid Journal   (Followers: 57)
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: 9)
Water Environment Research     Full-text available via subscription   (Followers: 41)
Water International     Hybrid Journal   (Followers: 15)
Water, Air, & Soil Pollution     Hybrid Journal   (Followers: 23)
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: 18)
Weather, Climate, and Society     Full-text available via subscription   (Followers: 12)
Web Ecology     Open Access   (Followers: 5)
Wetlands     Hybrid Journal   (Followers: 24)
Wilderness & Environmental Medicine     Hybrid Journal   (Followers: 4)
Wildlife Australia     Full-text available via subscription   (Followers: 2)
Wiley Interdisciplinary Reviews - Climate Change     Hybrid Journal   (Followers: 17)
Wiley Interdisciplinary Reviews : Energy and Environment     Hybrid Journal   (Followers: 6)
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: 6)
World Journal of Environmental Engineering     Open Access   (Followers: 2)
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]   [16 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  [1589 journals]
  • Inhibition of germinal vesicle breakdown in Xenopus oocytes in vitro by a
           series of substituted glycol ethers
    • Authors: Douglas J. Fort; Michael B. Mathis, Patrick D. Guiney, John A. Weeks
      Abstract: A 24 hour in vitro Xenopus oocyte maturation (germinal vesicle breakdown [GVBD]) assay developed by Pickford and Morris (Environmental Health Perspectives, 1999, 107, 285–292) was used to screen a series of substituted glycol ethers (GEs). Substituted GEs included: ethylene glycol monomethyl ether (EGME); EG monoethyl ether (EGEE); EG monopropyl ether (EGPE); EG monobutyl ether (EGBE); EG monohexyl ether (EGHE); diethylene glycol monomethyl ether (DGME); triethylene glycol monomethyl ether (TGME); ethylene glycol monophenyl ether (EGPhE); EG monobenzyl ether (EGBeE); EG diphenyl ether (EGDPhE); and propylene glycol monophenyl ether (PGPhE). The GEs inhibited progesterone- or androstenedione-induced GVBD with the following relative potency: EGPhE> PGPhE> EGME>> EGEE ≥ EGBeE> EGPE>> EGBE>EGHE> EGDPhE>> DGME ≥ TGME, or EGPhE>> PGPhE>> EGBeE> EGDPhE> EGEE> EGME> EGPE> EGBE, EGHE, DGME and TGME, respectively. Further, [3H]progesterone or [3H]androstenedione binding affinities to the oocyte plasma membrane progesterone receptor (OMPR) or classical androgen receptor (AR) were: EGME> EGPhE ≥ PGPhE ≥ EGEE> EGBeE>> EGPE>> EGBE ≥ EGHE> EGDPhE, TGME, and DGME, or EGPhE> PGPhE>> EGBeE> EGDPhE>> EGEE ≥ EGME>> EGPE, EGBE, and EGHE> DGME and TGME, respectively. Binary joint mixture studies with the GVBD model using flutamide (AR antagonist) and EGPhE indicated that flutamide/EGPhE mixture acted in a concentration additive manner. The effects of substituted GE series, however, may be mediated through the OMPR; the potency of EGPhE may be the result of bimodal inhibition of both the OMPR and AR pathways.
      PubDate: 2017-12-04T03:00:26.792042-05:
      DOI: 10.1002/jat.3567
  • Integrated decision strategies for skin sensitization hazard
    • Authors: Judy Strickland; Qingda Zang, Nicole Kleinstreuer, Michael Paris, David M. Lehmann, Neepa Choksi, Joanna Matheson, Abigail Jacobs, Anna Lowit, David Allen, Warren Casey
      PubDate: 2017-11-29T00:50:26.923014-05:
      DOI: 10.1002/jat.3572
  • Lipopolysaccharide levels adherent to PM2.5 play an important role in
    • Authors: Cuiying He; Yuan Song, Takamichi Ichinose, Miao He, Kentaro Morita, Duo Wang, Tamotsu Kanazawa, Yasuhiro Yoshida
      Abstract: Epidemiological studies show that exposure to ambient particulate matter (PM) is associated with serious adverse health effects, including, but not limited to, those on the respiratory system. In the present study, we investigated the splenic response in mice administered PM of ≤ 2.5 μ m diameter (PM2.5). Male BALB/c mice (7 or 8 weeks old) were intratracheally administered PM2.5 (0.1 mg) four times, at 2 week intervals, and dissected 24 h after the final administration. The effect of six types of PM2.5, collected in Shenyang or Beijing (China) and Kitakyushu (Japan), on splenocytes was examined. Our results revealed a strong correlation between the levels of lipopolysaccharide (LPS), but not that of β-glucan and polycyclic aromatic hydrocarbons, attached to PM2.5 and the effect of PM2.5 on cell activity. PM2.5 with a low amount of LPS (PM2.5LL) reduced splenocyte mitogen-induced proliferation and cytokine production compared with that in control mice. The suppressive effects of PM2.5LL on proliferation and interleukin-2 production in splenocytes were rescued by the antioxidant N-acetylcysteine. Expression of heme oxygenase-1 was elevated after PM2.5LL administration, particularly in CD11b + cells, while no elevation was observed in CD4+, CD8+ or B220+ cells. Further, dissociation of the nuclear factor erythroid 2-related factor 2 from Kelch-like ECH-associating protein 1 was observed in splenocytes of PM2.5LL-administered mice. These data suggest that LPS attached to PM2.5 modulates the splenocyte immune responses to PM2.5.
      PubDate: 2017-11-29T00:45:39.289169-05:
      DOI: 10.1002/jat.3554
  • Liposomal encapsulation of silver nanoparticles enhances cytotoxicity and
           causes induction of reactive oxygen species-independent apoptosis
    • Authors: A. Yusuf; A. Brophy, B. Gorey, A. Casey
      Abstract: Silver nanoparticles (AgNP) are one of the most widely investigated metallic NPs due to their promising antibacterial activities. In recent years, AgNP research has shifted beyond antimicrobial use to potential applications in the medical arena. This shift coupled with the extensive commercial applications of AgNP will further increase human exposure and the subsequent risk of adverse effects that may result from repeated exposures and inefficient delivery, meaning research into improved AgNP delivery is of paramount importance. In this study, AgNP were encapsulated in a natural biosurfactant, dipalmitoylphosphatidylcholine, in an attempt to enhance the intracellular delivery and simultaneously mediate the associated cytotoxicity of the AgNP. It was noted that because of the encapsulation, liposomal AgNP (Lipo-AgNP) at 0.625 μg ml–1 induced significant cell death in THP1 cell lines a notably lower dose than that of the uncoated AgNP induced cytotoxicity. The induced cytotoxicity was shown to result in an increased level of DNA fragmentation resulting in a cell cycle interruption at the S phase. It was shown that the predominate form of cell death upon exposure to both uncoated AgNP and Lipo-AgNP was apoptosis. However, a reactive oxygen species-independent activation of the executioner caspases 3/7 occurred when exposed to the Lipo-AgNP. These findings showed that encapsulation of AgNP enhance AgNP cytotoxicity and mediates a reactive oxygen species-independent induction of apoptosis.
      PubDate: 2017-11-27T20:05:36.408376-05:
      DOI: 10.1002/jat.3566
  • Effects of triclosan on Japanese medaka (Oryzias latipes) during embryo
           development, early life stage and reproduction
    • Authors: Yoshifumi Horie; Takahiro Yamagishi, Hiroko Takahashi, Taisen Iguchi, Norihisa Tatarazako
      Abstract: Triclosan has been shown to have endocrine-disrupting effects in aquatic organisms. In 2016, the US Food and Drug Administration banned the use of triclosan in consumer soaps. Before the ban, triclosan was reported at low concentrations in the aquatic environment, although the effect of triclosan on reproduction in teleost fish species is yet to be clarified. Here we investigated the effects of triclosan on embryo development and reproduction, and during the early life stage, in Japanese medaka (Oryzias latipes) by using Organisation for Economic Co-operation and Development tests 229, 212 and 210, with minor modifications. In adult medaka, exposure to 345.7 μg l–1 suppressed fecundity and increased mortality but had no effect on fertility. Exposure to 174.1 or 345.7 μg l–1 increased liver vitellogenin concentration in females but decreased liver vitellogenin concentration in males. With triclosan exposure, mortality was increased dose dependently during the embryonic and early larval stages, and a particularly steep increase in mortality was observed soon after hatching. The lowest observed effect concentrations of triclosan in Japanese medaka obtained in the present study (mortality [embryonic and larval stages, 276.3 μg l–1; early life stage, 134.4 μg l–1; adult stage, 174.1 μg l–1], growth [134.4 μg l–1], vitellogenin [174.1 μg l–1], fecundity [345.7 μg l–1] and fertility [>345.7 μg l–1]) were at least 55 times (compared with the USA) and up to 13 400 times (compared with Germany) greater than the detected triclosan levels in the aquatic environment. These results suggest that triclosan may not be affecting fish populations in the aquatic environment.
      PubDate: 2017-11-27T20:00:38.239696-05:
      DOI: 10.1002/jat.3561
  • Graphene oxide induces cytotoxicity and oxidative stress in bluegill
           sunfish cells
    • Authors: Koigoora Srikanth; L. Syam Sundar, Eduarda Pereira, Armando Costa Duarte
      Abstract: Graphene oxide (GO) is considered a promising material for biological application due to its unique properties. However, the potential toxicity of GO to aquatic organism particularly bluegill sun fish cells (BF‐2) is unexplored or remains poorly understood. GO‐induced cytotoxicity and oxidative stress in BF‐2 cells were assessed using a battery of biomarkers. Two different biological assays (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide and neutral red uptake were used to evaluate the cytotoxicity of GO on BF‐2 cells. It was found that GO induced dose‐ and time‐dependent cytotoxicity on BF‐2 cells. BF‐2 cells exposed to lower concentration of GO (40 μg ml–1) for 24 induced morphological changes when compared to their respective controls. As evidence for oxidative stress lipid peroxidation, superoxide dismutase, catalase, reactive oxygen species and 8‐hydroxy‐2′‐deoxyguanosine levels were increased and glutathione levels were found to decline in BF‐2 cells after treatment with GO. Our findings demonstrate that GO when exposed to BF‐2 fish cells cause oxidative stress.
      PubDate: 2017-11-23T22:25:42.242341-05:
      DOI: 10.1002/jat.3557
  • Comparison of subchronic immunotoxicity of four different types of
           aluminum‐based nanoparticles
    • Authors: Eun-Jung Park; Sang Jin Lee, Gwang-Hee Lee, Dong-Wan Kim, Cheolho Yoon, Byoung-Seok Lee, Younghun Kim, Jaerak Chang, Kyuhong Lee
      Abstract: Nanoparticles (NPs) have recently emerged as an inhalable pollutant, owing to their applications, aluminum‐based NPs (Al‐NPs) have been prioritized for toxicity testing. In the current study, we compared the pulmonary biopersistence and subsequent toxicity of four different types of Al‐NPs (two rod‐type aluminum oxide NPs [AlONPs] with different aspect ratios [short (S)‐ and long (L)‐AlONPs], spherical aluminum cerium oxide NPs [AlCeO3, AlCeONPs] and spherical γ‐aluminum oxide hydroxide nanoparticles [AlOOHNPs]) 13weeks after a single intratracheal instillation, considering the importance of their properties in their toxicity. We found that the pulmonary biopersistence of Al‐NPs was strengthened by a high aspect ratio in the rod‐type AlONPs and by the presence of hydroxyl groups in the spherical‐type Al‐NPs. The highest toxicity was observed in the mice treated with AlOOHNPs, which showed low biostability. More importantly, we identified that the commercially available AlCeONPs were Al2O3‐coated CeO2 NPs, but not AlCeO3 NPs, although they have been sold under the trade name of AlCeONPs. In conclusion, the aspect ratio and biostability may be important factors in the determination of the biopersistence of NPs and the subsequent biological response. In addition, the physicochemical properties of NPs should be examined in detail before their release into the market to prevent unexpected adverse health effects.
      PubDate: 2017-11-23T04:50:55.535854-05:
      DOI: 10.1002/jat.3564
  • Effects of bergenin on methylglyoxal‐induced damage in osteoblastic
           MC3T3‐E1 cells
    • Authors: Kyung Hee Lee; Eun Mi Choi
      Abstract: Bergenin is the main chemical constituent of plants in the genus Bergenia, which are used in traditional medicines. Methylglyoxal (MG), a highly reactive dicarbonyl compound, is the major precursor for forming advanced glycation end products (AGEs). Pretreating MC3T3‐E1 cells with bergenin prevented MG‐induced protein adduct formation. Bergenin inhibited the MG‐induced soluble receptor for AGE (sRAGE), interleukin, reactive oxygen species and mitochondrial superoxide production. Additionally bergenin increased glyoxalase I activity, glutathione, heme oxygenase‐1 and nuclear factor erythroid 2‐related factor 2 levels in the presence of MG. Pretreatment with bergenin before MG exposure reduced MG‐induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation, loss of adenosine triphosphate and reduced adenosine monophosphate‐activated protein kinase. These results demonstrate that bergenin may prevent the development of diabetic osteopathy.
      PubDate: 2017-11-17T07:16:29.825801-05:
      DOI: 10.1002/jat.3565
  • Metabolic effects of p,p′‐DDE on Atlantic salmon hepatocytes
    • Authors: Pål A. Olsvik; Liv Søfteland
      Abstract: Decades after being banned in many countries, DDT and its metabolites are still considered major environmental hazards. The p,p′‐DDE isomer, the DDT metabolite found in highest concentration in aquaculture feeds, is an endocrine disruptor with demonstrated ability to induce epigenetic effects. This study aimed at examining the impact of p,p′‐DDE on Atlantic salmon. Primary hepatocytes were exposed to four concentrations of p,p′‐DDE (0.1, 1, 10, 100 μm) for 48 hours, and endpoints included cytotoxicity, global DNA methylation, targeted transcription and metabolomics profiling (100 μm). p,p′‐DDE was moderately cytotoxic at 100 μm. No impact was seen on global DNA methylation. Vtg1 and esr1 transcription, markers of endocrine disruption, was most strongly induced at 10 μm p,p′‐DDE, while ar showed strongest response at 100 μm. Metabolomics profiling showed that p,p′‐DDE at 100 μm most strongly affected carbohydrate metabolism, primary bile acid metabolism, leucine, isoleucine and valine metabolism, diacylglycerol and sphingolipid metabolism. Observed changes in lipid levels suggest that p,p′‐DDE interferes with phospholipid membrane biosynthesis. Elevation of bile acid levels in p,p′‐DDE‐exposed hepatocytes indicates upregulation of synthesis of bile acids after cytochrome P450 activation. Pathway analysis showed that the superpathway of methionine degradation was the most significantly affected pathway by p,p′‐DDE exposure, while endocrine system disorder topped the diseases and disorder ranking. In conclusion, this work predicts an endocrine response to p,p′‐DDE exposure, and demonstrates how this legacy pesticide might interfere with mechanisms linked to DNA methylation in Atlantic salmon hepatocytes.
      PubDate: 2017-11-17T07:10:37.308662-05:
      DOI: 10.1002/jat.3556
  • Arsenite downregulates H3K4 trimethylation and H3K9 dimethylation during
           transformation of human bronchial epithelial cells
    • Authors: Wei Tu; Yin Liu, Chengfeng Xie, Xue Zhou
      Abstract: Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic‐induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS‐2B) cells. After 16 weeks’ exposure, cells were transformed by 0.1, 0.5 and 1 μm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 μm arsenite at 12 weeks, and 0.5 and 1 μm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A. Global dimethylated H3K9 (H3K9me2) was also decreased after exposure to 0.5 μm arsenite for 4, 8, 12 and 16 weeks and 1.0 μm arsenite for 8 and 12 weeks, which was associated with an increase of HDM activities. Our findings indicated that arsenite decreased global H3K4me3 and H3K9me2 levels during cell transformation by modulating the enzymatic activities of histone methyltransferases and/or HDMs, and by upregulation of KDM5A protein levels for H3K4me3.
      PubDate: 2017-11-17T07:05:49.223045-05:
      DOI: 10.1002/jat.3555
  • Thirteen week toxicity study of dietary l‐tryptophan in rats with a
           recovery period of 5 weeks
    • Authors: Yusuke Shibui; Hideki Matsumoto, Yoko Masuzawa, Takumi Ohishi, Tsutomu Fukuwatari, Katsumi Shibata, Ryosei Sakai
      Abstract: Although l‐tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l‐tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague–Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l‐tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no‐observed‐adverse‐effect level of l‐tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l‐tryptophan: 779 mg kg–1 body weight day–1 [males] and 1765 mg kg–1 body weight day–1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l‐tryptophan, the no‐observed‐adverse‐effect level of overall l‐tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l‐tryptophan: 948 mg kg–1 body weight day–1 (males) and 1956 mg kg–1 body weight day–1 (females)). We conclude that l‐tryptophan has a low toxicity profile in terms of human use.
      PubDate: 2017-11-16T05:05:28.424417-05:
      DOI: 10.1002/jat.3562
  • γ‐H2AX formation in the urinary bladder of rats treated with two
           norharman derivatives obtained from o‐toluidine and aniline
    • Authors: T. Toyoda; Y. Totsuka, K. Matsushita, T. Morikawa, N. Miyoshi, K. Wakabayashi, K. Ogawa
      Abstract: Aminomethylphenylnorharman (AMPNH) and aminophenylnorharman (APNH) are mutagenic norharman derivatives obtained from o‐toluidine and aniline, respectively. APNH is carcinogenic to the urinary bladder of rats and present in urine samples of healthy volunteers, indicating that norharman derivatives may be associated with cancer development in the urinary bladder of humans. To evaluate the possible role of AMPNH and APNH in bladder carcinogenesis, we examined the formation of γ‐H2AX, a DNA damage response marker, in the urinary bladder of rats. Seven‐week‐old male F344 rats were treated with 400 ppm AMPNH or 40 ppm APNH in the diet for 4 weeks. Animals were killed at the end of administration or after 2 weeks of recovery, and immunohistochemistry for γ‐H2AX and Ki67, a cell proliferation marker, was performed. At week 4, γ‐H2AX formation in bladder epithelial cells was significantly increased by APNH treatment as compared with that in controls. AMPNH also induced upregulation of γ‐H2AX formation, although there was no statistical significance. After the recovery period, γ‐H2AX‐positive cells were reduced but remained significantly higher in AMPNH and APNH groups than in the control group. Ki67‐positive cells were significantly increased by AMPNH and APNH at week 4 and reduced to the same level as the control after 2 weeks of recovery. Expression of KRT14, a bladder stem cell marker, was also increased in the basal layer by the two norharman derivatives. Thus, AMPNH and APNH showed in vivo genotoxicity in the bladder epithelium of rats, and APNH may be a potent causative agent of bladder carcinogenesis.
      PubDate: 2017-11-16T05:00:58.068235-05:
      DOI: 10.1002/jat.3560
  • Drug interaction at hERG channel: In vitro assessment of the
           electrophysiological consequences of drug combinations and comparison
           against theoretical models
    • Authors: Barbara Wiśniowska; Bartosz Lisowski, Magdalena Kulig, Sebastian Polak
      Abstract: Drugs carry a proarrhythmic risk, which gets even greater when they are used in combination. In vitro assessment of the proarrhythmic potential of drugs is limited to one compound and thus neglects the potential of drug–drug interactions, including those involving active metabolites. Here we present the results of an in vitro study of potential drug–drug interactions at the level of the hERG channel for the combination of up to three compounds: loratadine, desloratadine and ketoconazole. Experiments were performed at room temperature on an automated patch‐clamp device CytoPatch 2, with the use of heterogeneously, stably transfected HEK cells. Single drugs, pairs and triplets were used. The results provided as the inhibition of the IKr current for pairs were compared against the calculated theoretical interaction. Models applied to calculate the combined effect of inhibitory actions of simultaneously given drugs include: (1) simple additive model with a maximal inhibition limit of 1 (all channels blocked in 100%); (2) Bliss independence; and (3) Loewe additivity. The observed IC50 values for loratadine, desloratadine and ketoconazole were 5.15, 1.95 and 0.74 μm respectively. For the combination of drugs tested in pairs, the effect was concentration dependent. In lower concentrations, the synergistic effect was observed, while for the highest tested concentrations it was subadditive. To triple the effect, it was subadditive regardless of concentrations. The square root of sum of squares of differences between the observed and predicted total inhibition was calculated to assess the theoretical interaction models. For most of the drugs, the allotopic model offered the best fit.
      PubDate: 2017-11-16T05:00:35.995898-05:
      DOI: 10.1002/jat.3552
  • Apoptotic and antiproliferative properties of
           3β‐hydroxy‐Δ5‐steroidal congeners from a partially purified column
           fraction of Dendronephthya gigantea against HL‐60 and MCF‐7 cancer
    • Authors: I. P. Shanura Fernando; K. K. Asanka Sanjeewa, Hyun-Soo Kim, Lei Wang, Won Woo Lee, You-Jin Jeon
      Abstract: Organisms belonging to the genus Dendronephthya are among a group of marine invertebrates that produce a variety of terpenoids with biofunctional properties. Many of these terpenoids have been proven effective as anticancer drugs. Here, we report the antiproliferative effect of 3β‐hydroxy‐Δ5‐steroidal congeners against the proliferation of HL‐60 human leukemia cells and MCF‐7 human breast cancer cells. The sterol‐rich fraction (DGEHF2‐1) inhibited the growth of HL‐60 and MCF‐7 cells with IC50 values of 13.59 ± 1.40 and 29.41 ± 0.87 μg ml–1 respectively. Treatment with DGEHF2‐1 caused a dose‐dependent increase in apoptotic body formation, DNA damage and the sub‐G1 apoptotic cell population. Moreover, DGEHF2‐1 downregulated the expression of Bcl‐xL while upregulating Bax, caspase‐9, and PARP cleavage in both HL‐60 and MCF‐7 cells. The steroid fraction was found to act via the mitochondria‐mediated apoptosis pathway. Identification of the sterols was performed via gas chromatography–tandem mass spectrometry analysis. Studying the mechanism of the anticancer effect caused by these sterol derivatives could lead to the identification of other natural products with anticancer properties.
      PubDate: 2017-11-16T04:56:12.621385-05:
      DOI: 10.1002/jat.3559
  • A toxicogenomics approach to screen chlorinated flame retardants
           tris(2‐chloroethyl) phosphate and tris(2‐chloroisopropyl) phosphate
           for potential health effects
    • Authors: Boris V. Krivoshiev; Gerrit T.S. Beemster, Katrien Sprangers, Ronny Blust, Steven J. Husson
      Abstract: Tris(2‐chloroethyl) phosphate (TCEP) is a pervasive flame retardant that has been identified as a chemical of concern given its health effects and therefore its use has since been tightly regulated. Tris(2‐chloroisopropyl) phosphate (TCIPP), an analogue of TCEP, is believed to be its replacement. However, compared to TCEP, little is known of the toxicological impacts of TCIPP. We used RNA sequencing as unbiased and sensitive tool to identify and compare effects on a transcriptome level of TCEP and TCIPP in the human hepatocellular carcinoma cell line, HepG2. We identified that compared to other flame retardants, TCEP and TCIPP had little cytotoxicity. Treatment with sub‐cytotoxic concentrations of the two compounds revealed that both chemicals elicited similar effects; both compounds were found to affect genes involved in immune responses and steroid hormone biosynthesis, while also affecting xenobiotic metabolism pathways in a similar manner. Specifically for effects on immune responses, both compounds were shown to alter the expression of the receptor of the potent and pleiotropic complement component, C5a. Additionally, expression of genes encoding for effector proteins involved in the complement cascade along with other potent inflammatory regulators were found altered in response to TCEP and TCIPP, further emphasizing their potential effects on immune function. Taken together, given that TCIPP elicited similar effects compared to TCEP, and at lower concentrations, the potential health effects of TCIPP need to be further studied for a complete risk assessment of the compound.
      PubDate: 2017-11-16T04:51:53.982287-05:
      DOI: 10.1002/jat.3553
  • A safety and immunogenicity study of a novel subunit plague vaccine in
           cynomolgus macaques
    • Authors: Li Liu; Dong Wei, Zhe Qu, Li Sun, Yufa Miao, Yanwei Yang, Jinbiao Lu, Weixin Du, Bingxiang Wang, Bo Li
      Abstract: Plague has led to millions of deaths in history and outbreaks continue to the present day. The efficacy limitations and safety concerns of the existing killed whole cell and live‐attenuated vaccines call for the development of new vaccines. In this study, we evaluated the immunogenicity and safety of a novel subunit plague vaccine, comprising native F1 antigen and recombinant V antigen. The cynomolgus macaques in low‐ and high‐dose vaccine groups were vaccinated at weeks 0, 2, 4 and 6, at dose levels of 15 μg F1 + 15 μg rV and 30 μg F1 + 30 μg rV respectively. Specific antibodies and interferon‐γ and interleukin‐2 expression in lymphocytes were measured. For safety, except for the general toxicity and local irritation, we made a systematic immunotoxicity study on the vaccine including immunostimulation, autoimmunity and anaphylactic reaction. The vaccine induced high levels of serum anti‐F1 and anti‐rV antibodies, and caused small increases of interferon‐γ and interleukin‐2 in monkeys. The vaccination led to a reversible increase in the number of peripheral blood eosinophils, the increases in serum IgE level in a few animals and histopathological change of granulomas at injection sites. The vaccine had no impact on general conditions, most clinical pathology parameters, percentages of T‐cell subsets, organ weights and gross pathology of treated monkeys and had passable local tolerance. The F1 + rV subunit plague vaccine can induce very strong humoral immunity and low level of cellular immunity in cynomolgus macaques and has a good safety profile.
      PubDate: 2017-11-14T01:21:23.722434-05:
      DOI: 10.1002/jat.3550
  • A mitochondrial targeting tetrapeptide Bendavia protects lateral line hair
           cells from gentamicin exposure
    • Authors: Xiao Kuang; Yanhui Sun, Zhenjie Wang, Shuang Zhou, Hongzhuo Liu
      Abstract: The hearing loss induced by aminoglycosides is caused by the permanent loss of mechanosensory hair cells of the inner ear. The aim of the present study is therefore to evaluate the protective effect of Bendavia, a novel antioxidant, on gentamicin‐induced hair cell damage in zebrafish lateral lines. The results demonstrated the pretreatment of Bendavia exhibited dose‐dependent protection against gentamicin in both acute and chronic exposure. We found that Bendavia at 150 μm conferred optimal protection from either acute or chronic exposure with ototoxin. Bendavia reduced uptake of fluorescent‐tagged gentamicin via mechanoelectrical transduction channels, suggesting its protective effects may be partially due to decreasing ototoxic molecule uptake. The intracellular death pathways inhibition triggered by gentamicin might be also included as no blockage of gentamicin was observed. Our data suggest that Bendavia represents a novel otoprotective drug that might provide a therapeutic alternative for patients receiving aminoglycoside treatment.
      PubDate: 2017-11-03T07:40:50.388452-05:
      DOI: 10.1002/jat.3547
  • Transcriptional profiling reveals gene expression changes associated with
           inflammation and cell proliferation following short‐term inhalation
           exposure to copper oxide nanoparticles
    • Authors: Pedro M. Costa; Ilse Gosens, Andrew Williams, Lucian Farcal, Daniele Pantano, David M. Brown, Vicki Stone, Flemming R. Cassee, Sabina Halappanavar, Bengt Fadeel
      Abstract: Our recent studies revealed a dose‐dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short‐term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post‐exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m−3 (low dose) and 13.2 mg m−3 (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high‐dose group and 200 in low‐dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation‐associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short‐term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.
      PubDate: 2017-11-02T05:41:20.28174-05:0
      DOI: 10.1002/jat.3548
  • Low‐level perfluorooctanoic acid enhances 3 T3‐L1 preadipocyte
           differentiation via altering peroxisome proliferator activated receptor
           gamma expression and its promoter DNA methylation
    • Authors: Yue Ma; Jie Yang, Yanjian Wan, Yang Peng, Shuai Ding, Yuanyuan Li, Bing Xu, Xi Chen, Wei Xia, Yuebin Ke, Shunqing Xu
      Abstract: Recent studies suggest that perfluorooctanoic acid (PFOA) can play a role in the development of obesity; however, the associated mechanisms are poorly understood. We investigated how PFOA exposure affected the differentiation of 3 T3‐L1 preadipocytes and the associated transcriptional and epigenetic mechanisms. Cells treated with different doses of PFOA (ranging from 0.01 to 100 μg ml–1) were assessed for proliferation, differentiation and triglyceride accumulation. The gene expression levels of peroxisome proliferator activated receptor gamma (PPARγ) and its target genes were measured. DNA methylation levels of PPARγ promoter and global DNA methylation levels were also tested. We found a concentration‐dependent enhancement of adipocyte proliferation and differentiation following PFOA exposure. PFOA also induced a significant concentration‐dependent increase in the accumulation of lipid and triglyceride. Increased gene expression was also observed for PPARγ, CCAAT/enhancer binding proteins α, fatty acid binding protein 2 and lipoprotein lipase in differentiated cells after PFOA exposure. The ability of PFOA to induce adipogenesis was blocked by GW9662, a known PPARγ antagonist. In addition, significant demethylation of the cytosine–phosphate–guanine sites in the PPARγ promoter was observed after exposure to PFOA. In addition, PFOA exposure resulted in decreased global DNA methylation and increased expression levels of DNA methyltransferases genes. We found that treatment with low levels of PFOA can induce adipogenic differentiation in preadipocytes, and the underlying mechanisms probably involve the activation of PPARγ transcription and demethylation of PPARγ promoter.
      PubDate: 2017-11-02T03:00:51.565166-05:
      DOI: 10.1002/jat.3549
  • Mechanisms of toxicity associated with six tyrosine kinase inhibitors in
           human hepatocyte cell lines
    • Authors: Cécile Mingard; Franziska Paech, Jamal Bouitbir, Stephan Krähenbühl
      Abstract: Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse‐XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady‐state plasma concentrations in humans. In HepaRG cells, pretreatment with rifampicin decreased membrane toxicity (measured as adenylate kinase release) and dissipation of adenosine triphosphate stores, indicating that toxicity was associated mainly with the parent drugs. Ponatinib strongly impaired oxidative metabolism but only weakly glycolysis, and induced apoptosis of HepG2 cells at concentrations higher than steady‐state plasma concentrations in humans. Crizotinib and dasatinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis of HepG2 cells. Pazopanib was associated with a weak increase in mitochondrial reactive oxygen species accumulation and inhibition of glycolysis without being cytotoxic. In conclusion, regorafenib and sorafenib are strong mitochondrial toxicants and inhibitors of glycolysis at clinically relevant concentrations. Ponatinib affects mitochondria and glycolysis at higher concentrations than reached in plasma (but possibly in liver), whereas crizotinib, dasatinib and pazopanib showed no relevant toxicity. Mitochondrial toxicity and inhibition of glycolysis most likely explain hepatotoxicity associated with regorafenib, sorafenib and possibly pazopanib, but not for the other compounds investigated.
      PubDate: 2017-10-26T05:10:38.151446-05:
      DOI: 10.1002/jat.3551
  • Integration of mechanistic and pharmacokinetic information to derive oral
           reference dose and margin‐of‐exposure values for hexavalent chromium
    • Authors: Chad M. Thompson; Christopher R. Kirman, Sean M. Hays, Mina Suh, Seneca E. Harvey, Deborah M. Proctor, Julia E. Rager, Laurie C. Haws, Mark A. Harris
      Abstract: The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg−1 day−1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg−1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg−1 day−1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg−1 day−1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.
      PubDate: 2017-10-24T05:55:40.680531-05:
      DOI: 10.1002/jat.3545
  • Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in
           myocardial H9c2 cells
    • Authors: Xin Chen; Long Chen, Shanxiang Jiang, Shile Huang
      Abstract: Maduramicin, a polyether ionophore antibiotic, is widely used as an anticoccidial agent in the poultry industry. It has been reported that maduramicin may cause heart and skeletal muscle cell damage, resulting in heart failure, skeletal muscle degeneration and even death in animals and humans, if improperly used. However, the molecular mechanism behind its capability to cause death of cardiac cells is not known. Here, we show that maduramicin induced apoptosis and necrosis in rat myocardial cells (H9c2). Maduramicin did not apparently upregulate the expression of pro‐apoptotic proteins (e.g., BAD, BAK and BAX) or downregulate the expression of anti‐apoptotic proteins (e.g. Bcl‐2, Bcl‐xL, Mcl‐1 and survivin). Interestingly, maduramicin increased the expression of DR4 and TRAIL, activating caspases 8/3 and triggering cleavage of poly ADP ribose polymerase (PARP). In addition, maduramicin induced nuclear translocation of apoptosis inducing factor. Furthermore, maduramicin blocked autophagic flux, as evidenced by inducing accumulation of both LC3‐II and p62/SQSTM1. Taken together, the above results suggest that maduramicin executes its toxicity in the myocardial cells at least by inducing caspase‐dependent cell death through TRAIL/DR4‐mediated extrinsic pathway and caspase‐independent cell death by inducing apoptosis inducing factor nuclear translocation and blocking autophagic flux. Our findings provide a new insight into the molecular mechanism of maduramicin's toxicity in myocardial cells.
      PubDate: 2017-10-19T03:16:14.582201-05:
      DOI: 10.1002/jat.3546
  • Protective roles of hepatic gamma‐aminobutyric acid signaling in acute
           ethanol exposure‐induced liver injury
    • Authors: Shuanglian Wang; Shaofeng Sui, Zhiyan Liu, Cheng Peng, Jia Liu, Dan Luo, Xinhuan Fan, Chuanyong Liu, Wei-Yang Lu
      Abstract: Alcoholic liver disease (ALD) is a consequence of heavy and prolonged alcohol consumptions. We previously demonstrated a hepatic gamma‐aminobutyric acid (GABA) signaling system that protects the liver from toxic injury. The present study was designed to investigate the role of the hepatic GABA signaling system in the process of acute ethanol exposure‐induced liver injury. Our results showed that the expression of GABA synthesizing enzyme glutamic acid decarboxylase and type A GABA receptor (GABAAR) subunits was upregulated in ethanol‐treated mice compared with saline‐treated controls. Remarkably, pretreatment of mice with GABA (1.5 mg kg−1 body weight, intraperitoneal injection [i.p.]) or with the GABAAR agonist muscimol (1.2 mg kg−1 body weight, i.p.) protected the liver against ethanol toxicity and improved liver function, whereas pretreatment of mice with the GABAAR antagonist bicuculline (2.0 mg kg−1 body weight, i.p.) worsened the liver function. Further analyses suggest that GABAAR‐mediated signaling protects the liver from ethanol injury by, at least partially, inhibiting the IRE1α‐ASK1‐JNK pro‐apoptotic pathway in hepatocytes in the process of ethanol‐induced endoplasmic reticulum stress response.
      PubDate: 2017-10-17T05:28:03.842324-05:
      DOI: 10.1002/jat.3544
  • Protective effect of metoclopramide against organophosphate‐induced
           apoptosis in the murine skin fibroblast L929
    • Authors: Basem M. Jaber; Georg A. Petroianu, Syed A. Rizvi, Anwar Borai, Nada A. Saleh, Sharif M. Hala, Ayman M. Saleh
      Abstract: This study was performed to evaluate the protective efficacy of metoclopramide (MCP) against the organophosphates paraoxon (POX)‐ and malathion (MLT)‐induced apoptosis in the murine L929 skin fibroblasts. L929 cells were exposed to either POX (10 nm) or 1.0 μm MLT in the absence and presence of increased concentrations of MCP. The protective effect of MCP on these organophosphate‐stimulated apoptotic events was evaluated by flow cytometry analysis after staining with annexin‐V/propidium iodide, processing and activation of the executioner caspase‐3, cleavage of the poly‐ADP ribose polymerase, fragmentation of the nucleosomal DNA and disruption of the mitochondrial membrane potential (Δψ). Our results showed that increased doses of MCP alone (≥10 μm) did not induce apoptosis or activation of caspase‐3. Pretreatment of the cells with MCP attenuated all the apoptotic events triggered by the organophosphate compounds in a dose‐dependent manner reaching ~70–80% protection when they were preincubated at 1 and 5 μm of the drug before the addition of POX and MLT, respectively. Interestingly, MCP did not offer a significant protective effect against the cytotoxicity of tumor necrosis factor‐α, cisplatinum, etoposide or paclitaxel, which stimulate apoptosis by various mechanisms, suggesting that the anti‐apoptotic effect of the drug is specific to organophosphates. The strong and specific anti‐apoptotic activity of subclinical doses of MCP against the cytotoxicity of organophosphate compounds suggests its potential clinical application in treating their poisoning.
      PubDate: 2017-10-13T00:26:08.495857-05:
      DOI: 10.1002/jat.3543
  • Development of an alternative zebrafish model for drug‐induced
           intestinal toxicity
    • Authors: Bokyeong Ryu; C-Yoon Kim, Hanseul Oh, Ukjin Kim, Jin Kim, Cho-Rok Jung, Byoung-Hee Lee, Seungki Lee, Seo-Na Chang, Ji Min Lee, Hyung-Min Chung, Jae-Hak Park
      Abstract: An evaluation of intestinal toxicity is important because the mucosal lining of the gastrointestinal tract is the first barrier for oral xenobiotics. Until now, a rat model has been recommended as the standard intestinal toxicity model and the Caco‐2 cell line, originated from a human colon adenocarcinoma, has been used as an alternative to this model, but there are limitations regarding cost‐effectiveness and the need for mimicry of the human system. In this study, we investigated whether zebrafish could be a valid alternative to rats and Caco‐2 cells as an intestinal toxicity model. We focused on intestinal gene expression of cytochrome P450 3A65, oxidative stress, apoptosis, inflammation, and intestinal function. Reverse transcription–quantitative polymerase chain reaction analysis was conducted using three models: zebrafish, Sprague–Dawley rats and Caco‐2 cells, and the transcript levels and patterns of indicator genes were analyzed in conjunction with histopathological changes. Our results suggested that representative intestinal toxicants, indomethacin, diclofenac and methotrexate, induced significant transcript level changes in marker genes such as CYP3A, inducible nitric oxide synthase, heme oxygenase 1, superoxide dismutase 1, glutathione peroxidase 1, BCL2 associated X, B‐cell lymphoma 2, caspase 9, tumor protein p53, nuclear factor‐κB, interleukin‐1β, tumor necrosis factor‐alphaα and toll‐like receptor 2 in the zebrafish model as in the rat and Caco‐2 cells models. These results suggest that zebrafish model is sufficiently worth developing as an intestinal toxicity model that can replace or compensate the rat model or Caco‐2 cell model.
      PubDate: 2017-10-13T00:20:49.461779-05:
      DOI: 10.1002/jat.3520
  • The percutaneous toxicokinetics of VX in a damaged skin porcine model and
           the evaluation of WoundStat™ as a topical decontaminant
    • Authors: Helen Lydon; Charlotte Hall, Hazem Matar, Christopher Dalton, J. Kevin Chipman, John S. Graham, Robert P. Chilcott
      Abstract: This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for the decontamination of superficial, nerve agent‐contaminated wounds. Anaesthetized animals were randomly assigned to either control (n = 7), no decontamination (n = 12) or WoundStat™ (n = 12) treatment groups. Pigs were exposed to a 5× LD50 dose of neat, radiolabelled S‐[2‐(diisopropylamino)ethyl]‐O‐ethyl methyl‐phosphonothioate (VX; or equivalent volume of sterile saline for the control group) via an area of superficially damaged skin on the ear. WoundStat™ was applied at 30 seconds post‐exposure to assigned animals. The VX contaminant (or saline) and decontaminant remained in place for the duration of the study (up to 6 hours). Physiological parameters and signs of intoxication were recorded during the exposure period. Skin and organ samples were taken post mortem for 14C–VX distribution analyses. Blood samples were taken periodically for toxicokinetic and whole‐blood acetylcholinesterase (AChE) activity analyses. VX exposure was accompanied by a rapid decrease in AChE activity in all animals, regardless of decontamination. However, decontamination significantly improved survival rate and time and reduced the severity of signs of intoxication. In addition, the distribution of 14C–VX in key internal organs and post mortem blood samples was significantly lower in the WoundStat™ treatment group. This study demonstrates that WoundStat™ may be a suitable medical countermeasure for increasing both survival rate and time following VX exposure. The results also suggest that AChE activity is not a useful prognostic indicator.
      PubDate: 2017-10-10T07:15:33.915626-05:
      DOI: 10.1002/jat.3542
  • Effects of exposure to six chemical ultraviolet filters commonly used in
           personal care products on motility of MCF‐7 and MDA‐MB‐231 human
           breast cancer cells in vitro
    • Authors: Maha Alamer; Philippa D. Darbre
      Abstract: Benzophenone (BP)‐1, BP‐2, BP‐3, octylmethoxycinnamate (OMC), 4‐methylbenzilidenecamphor and homosalate are added to personal care products to absorb ultraviolet light. Their presence in human milk and their oestrogenic activity suggests a potential to influence breast cancer development. As metastatic tumour spread is the main cause of breast cancer mortality, we have investigated the effects of these compounds on migration and invasion of human breast cancer cell lines. Increased motility of oestrogen‐responsive MCF‐7 human breast cancer cells was observed after long‐term exposure (>20 weeks) to each of the six compounds at ≥10−7 m concentrations using three independent assay systems (scratch assay, live cell imaging, xCELLigence technology) and increased invasive activity was observed through matrigel using the xCELLigence system. Increased motility of oestrogen‐unresponsive MDA‐MB‐231 human breast cancer cells was observed after 15 weeks of exposure to each of the six compounds by live cell imaging and xCELLigence technology, implying the increased migratory activity was not confined to oestrogen‐responsive cells. Molecular mechanisms varied between compounds and cell lines. Using MCF‐7 cells, reduction in E‐cadherin was observed following 24 weeks' exposure to 10−5 m BP‐1 and 10−5 m homosalate, and reduction in β‐catenin was noted following 24 weeks' exposure to 10−5 m OMC. Using MDA‐MB‐231 cells, increased levels of matrix metalloproteinase 2 were observed after 15 weeks exposure to 10−7 m OMC and 10−7 m 4‐methylbenzilidenecamphor. Although molecular mechanisms differ, these results demonstrate that exposure to any of these six compounds can increase migration and invasion of human breast cancer cells.
      PubDate: 2017-10-09T02:15:58.873092-05:
      DOI: 10.1002/jat.3525
  • A genomic characterization of the influence of silver nanoparticles on
           bone differentiation in MC3T3‐E1 cells
    • Authors: Tao Qing; Meena Mahmood, Yuanting Zheng, Alexandru S. Biris, Leming Shi, Daniel A. Casciano
      Abstract: Silver nanoparticles (AgNPs) have been widely used in a variety of biomedical applications. Previous studies demonstrated that AgNPs significantly enhanced bone cell mineralization and differentiation in MC3T3–1 cells, a model in vitro system, when compared to several other NPs. This increased bone deposition was evaluated by phenotypic measurements and assessment of the expression of miRNAs associated with regulation of bone morphogenic proteins. In the present study, we used RNA‐seq technology, a more direct measurement of gene expression, to investigate further the mechanisms of bone differentiation induced by AgNP treatment. Key factors associated with the osteoclast pathway were significantly increased in response to AgNP exposure including Bmp4, Bmp6 and Fosl1. In addition, genes of metabolism and toxicity pathways were significantly regulated as well. Although this study suggests the potential for AgNPs to influence bone morphogenesis in injury or disease applications, further investigation into the efficacy and safety of AgNPs in bone regeneration is warranted.
      PubDate: 2017-10-04T00:55:27.446787-05:
      DOI: 10.1002/jat.3528
  • Diethylstilbestrol impaired oogenesis of yellow catfish juveniles through
           disrupting hypothalamic–pituitary–gonadal axis and germ cell
    • Authors: Yaqin Wang; Yingwen Li, Qiliang Chen, Zhihao Liu
      Abstract: Diethylstilbestrol (DES), a non‐steroidal estrogen, has been found to cause altered germ cell development and disordered ovarian development in fish females. However, the mechanisms that might be involved are poorly understood. In this study, female juveniles of yellow catfish (Pelteobagrus fulvidraco) (120 days post‐hatching) were exposed to two doses (10 and 100 ng l−1) of DES for 28 days. After the endpoint of exposure, decreased ovary weight and gonadosomatic index, as well as various ovarian impairments were observed in response to DES. Besides, DES elevated the mRNA levels of vitellogenin 1 (vtg 1) and estrogen receptor 1 (esr 1) in liver and decreased 17β‐estradiol level in plasma. Correspondingly, suppressed mRNA levels of the key genes in the hypothalamic–pituitary–gonadal axis (such as cyp19a1b, gnrh‐II, fshβ and lhβ in brain and fshr, lhr and cyp19a1a in ovary) after DES exposure were also observed. The declined level of plasma 17β‐estradiol and altered gene expressions of genes in the hypothalamic–pituitary–gonadal axis were thus supposed to be closely related to the disrupted oogenesis in DES‐treated fish. Analyses further demonstrated that, higher concentration of DES elevated the expression ratio of bax/bcl‐2, indicating the enhanced apoptosis occurred in ovary. Moreover, DES upregulated the expressions of genes involved in proliferation (cyclin d1 and pcna), meiotic entry (cyp26a1 and scp3) and meiotic maintenance (dmc1), resulting in arrested oogenesis in catfish. The present study greatly extended our understanding on the mechanisms underlying of reproductive toxicity of DES on fish oogenesis.
      PubDate: 2017-09-28T04:10:43.22491-05:0
      DOI: 10.1002/jat.3529
  • Aberrant expression of miR‐451a contributes to
           1,2‐dichloroethane‐induced hepatic glycerol gluconeogenesis disorder
           by inhibiting glycerol kinase expression in NIH Swiss mice
    • Authors: Ni Zeng; Hongmei Jiang, Qiming Fan, Ting Wang, Weifeng Rong, Guoliang Li, Ruobi Li, Dandan Xu, Tao Guo, Fei Wang, Lihai Zeng, Manqi Huang, Jiewei Zheng, Fengrong Lu, Wen Chen, Qiansheng Hu, Zhenlie Huang, Qing Wang
      Abstract: The identification of aberrant microRNA (miRNA) expression during chemical‐induced hepatic dysfunction will lead to a better understanding of the substantial role of miRNAs in liver diseases. 1,2‐Dichloroethane (1,2‐DCE), a chlorinated organic toxicant, can lead to hepatic abnormalities in occupationally exposed populations. To explore whether aberrant miRNA expression is involved in liver abnormalities mediated by 1,2‐DCE exposure, we examined alterations in miRNA expression patterns in the livers of NIH Swiss mice after dynamic inhalation exposure to 350 or 700 mg m–3 1,2‐DCE for 28 days. Using a microarray chip, we discovered that only mmumiR‐451a was significantly upregulated in the liver tissue of mice exposed to 700 mg m–3 1,2‐DCE; this finding was validated by quantitative real‐time polymerase chain reaction. In vitro study revealed that it was metabolite 2‐chloroacetic acid, not 1,2‐DCE that resulted in the upregulation of mmu‐miR‐451a in the mouse AML12 cell line. Furthermore, our data showed that the upregulation of mmu‐miR‐451a induced by 2‐chloroacetic acid could suppress the expression of glycerol kinase and lead to the inhibition of glycerol gluconeogenesis in mouse liver tissue and AML12 cells. These observations provide evidence that hepatic mmu‐miR‐451a responds to 1,2‐DCE exposure and might induce glucose metabolism disorders by suppressing the glycerol gluconeogenesis process.
      PubDate: 2017-09-28T04:05:34.15541-05:0
      DOI: 10.1002/jat.3526
  • A practical approach to assess inhalation toxicity of metal oxide
           nanoparticles in vitro
    • Authors: Anita C. A. Dankers; C. Frieke Kuper, Anja J. Boumeester, Babs O. Fabriek, Ingeborg M. Kooter, Mariska Gröllers-Mulderij, Peter Tromp, Inge Nelissen, Esther K. Zondervan-Van Den Beuken, Rob J. Vandebriel
      Abstract: Exposure of humans to metal oxide nanoparticles (NPs) occurs mainly via air, and inhaled metal oxide NPs may generate inflammation. The aim of this study was to investigate the proinflammatory potential of six metal oxide NPs (CeO2, Mn2O3, CuO, ZnO, Co3O4 and WO3; 27–108 μg ml−1) using human primary 3‐dimensional airway epithelium (MucilAir™) and dendritic cell (DC) models. Metal oxide NPs were mainly aggregated/agglomerated in the cell media, as determined by dynamic light scattering, scanning electron microscopy and differential centrifugal sedimentation. WO3 and ZnO were highly soluble, both with and without respiratory mucus. Proinflammatory signalling by the epithelium was evaluated after a 24 hour exposure by increased interleukin‐6 and ‐8 and monocyte chemoattractant protein 1 cytokine release, which occurred only for CuO. Moreover, maturation of immature human DCs, which play a key role in the lung immune system, were evaluated by expression of surface markers HLA‐DR, CD80, CD83 and CD86 after a 48 hour exposure. Only Mn2O3 consistently upregulated DC maturation markers. Furthermore, by addition of medium from metal oxide NP‐exposed 3‐dimensional airway cultures to metal oxide NP‐exposed DC cultures, the interplay between lung epithelium and DCs was studied. Such an interplay was again only observed for Mn2O3 and in one of five DC donors. Our results show that, even when using dosages that represent very high in vivo exposure levels, up to 27 hours of constant human airway exposure, metal oxide NPs cause minimal proinflammatory effects and that epithelial cells not necessarily interfere with DC maturation upon metal oxide NP exposure. The present approach exemplifies a relevant translation towards human safety assessment.
      PubDate: 2017-09-28T04:01:14.253214-05:
      DOI: 10.1002/jat.3518
  • Preventive effects of fructose and N‐acetyl‐L‐cysteine against
           cytotoxicity induced by the psychoactive compounds
           N‐methyl‐5‐(2‐aminopropyl)benzofuran and
           3,4‐methylenedioxy‐N‐methamphetamine in isolated rat hepatocytes
    • Authors: Yoshio Nakagawa; Toshinari Suzuki, Akiko Inomata
      Abstract: Psychoactive compounds, N‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB) and 3,4‐methylenedioxy‐N‐methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N‐acetyl‐l‐cysteine (NAC) on 5‐MAPB‐ and MDMA‐induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration‐dependent (0–4 mm) and time‐dependent (0–3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5‐MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5‐MAPB−/MDMA‐induced cytotoxicity. In addition, the exposure of hepatocytes to 5‐MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5‐MAPB−/MDMA‐induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5‐MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress.
      PubDate: 2017-09-26T04:35:27.090999-05:
      DOI: 10.1002/jat.3523
  • Allopurinol suppresses expression of the regulatory T‐cell migration
           factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of
           nuclear factor‐κB activation
    • Authors: Makoto Osabe; Toshiyuki Tajika, Masahiro Tohkin
      Abstract: Recent studies have shown that sparse distribution of regulatory T cells (Tregs) in the skin might be involved in the onset of severe cutaneous adverse drug reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis. Treg migration toward epithelial cells is regulated by certain chemokines, including TARC/CCL17 and MDC/CCL22. In this study, we analyzed the effect of allopurinol (APN), a drug known to cause severe adverse reactions, on the expression of factors affecting Treg migration and the mechanisms involved. APN inhibited the tumor necrosis factor (TNF)‐α‐ and interferon (IFN)‐γ‐associated expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells in a dose‐dependent manner. Consistent with this, APN also suppressed TNF‐α‐ and IFN‐γ‐induced production of TARC/CCL17 and MDC/CCL22 proteins and the migration of C‐C chemokine receptor type 4‐positive cells. Activity of the transcription factors NF‐κB and STAT1, which are involved in TARC/CCL17 and MDC/CCL22 expression, was also investigated. APN inhibited activation of NF‐κB, but not that of STAT1. Furthermore, it restricted p38 MAPK phosphorylation. These results suggest that APN inhibits TNF‐α‐ and IFN‐γ‐induced TARC/CCL17 and MDC/CCL22 production through downregulation of p38 MAPK and NF‐κB signaling, resulting in the sparse distribution of Tregs in the skin of patients with APN‐associated Stevens–Johnson syndrome/toxic epidermal necrolysis.
      PubDate: 2017-09-26T04:25:30.613698-05:
      DOI: 10.1002/jat.3522
  • Potential hazards of fenvalerate in massive pollution influence the
           apoptosis sensitivity
    • Authors: Zheng-Guo Cui; Yu-Jie Jin, Lu Sun, Shahbaz Ahmad Zakki, Meng-Ling Li, Qian-Wen Feng, Takashi Kondo, Ryohei Ogawa, Hidekuni Inadera
      Abstract: Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)‐induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 μm cadmium chloride (CdCl2) with or without Fen pretreatment at 1–50 μm. Apoptosis was evaluated by externalization of phosphatidylserine on the plasma membrane. The expression levels of apoptosis‐related proteins, including Bcl‐2 family members were determined by western blot analysis. The results revealed that pretreatment with Fen at 20 μm for 12 hours significantly inhibited Cd‐induced apoptosis. Decreased expression of pro‐apoptotic Bcl‐2 family proteins (Noxa and Bid) and increased expression of anti‐apoptotic proteins (Bcl‐xL, Mcl‐1 and XIAP) were observed after combined treatment with Fen and CdCl2. Phosphorylation of ERK and AKT was increased, while phosphorylation of JNK was decreased by the combined treatment, compared with CdCl2 treatment alone. In conclusion, Fen decreased apoptotic sensitivity induced by Cd in U937 cells. This effect was associated with activation of ERK and AKT, suppression of JNK and changes in expression of Bcl‐2 family proteins and XIAP. The present findings suggest a potential influence of Fen on Cd toxicity via suppression of apoptosis. Fen decreased apoptotic sensitivity induced by Cd, and thus it may contribute carcinogenic risk and influence on cancer therapy.
      PubDate: 2017-09-26T04:15:29.539493-05:
      DOI: 10.1002/jat.3517
  • Cytoprotective effects of xanthohumol against methylglyoxal‐induced
           cytotoxicity in MC3T3‐E1 osteoblastic cells
    • Authors: Kwang Sik Suh; Suk Chon, Eun Mi Choi
      Abstract: Methylglyoxal (MG) has been suggested to be a major source of intracellular reactive carbonyl compounds, and has been implicated in increasing the levels of advanced glycation end products in age‐related diseases. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. In the present study, we investigated the effects of xanthohumol on MG‐induced cytotoxicity in osteoblastic MC3T3‐E1 cells. Xanthohumol attenuated MG‐induced cytotoxicity, as evidenced by improved cell viability, and prevented MG‐induced MG‐protein adducts, inflammatory cytokines, reactive oxygen species and mitochondrial superoxide production. In addition, xanthohumol increased glyoxalase I activity, glutathione, heme oxygenase‐1 and nuclear factor erythroid 2‐related factor 2 levels in the presence of MG. Pretreatment with xanthohumol before MG exposure reduced MG‐induced mitochondrial dysfunction. Furthermore, xanthohumol treatment resulted in a significant reduction in the levels of endoplasmic reticulum stress and autophagy induced by MG. Notably, the autophagy‐reducing effect of xanthohumol was abolished after the addition of Ex527, a selective inhibitor of sirtuin 1, suggesting that xanthohumol is an effective sirtuin 1 activator for reducing autophagy. Taken together, our findings suggest xanthohumol as a promising new strategy for preventing diabetic osteopathy.
      PubDate: 2017-09-20T20:16:03.574717-05:
      DOI: 10.1002/jat.3521
  • Long‐term exposure to bisphenol S damages the visual system and reduces
           the tracking capability of male zebrafish (Danio rerio)
    • Authors: Wenmin Liu; Xiaona Zhang, Penghao Wei, Hua Tian, Wei Wang, Shaoguo Ru
      Abstract: Bisphenol S (BPS) is widely detected in aquatic environments and in human bodies. BPS has reproductive and thyroid disrupting effects, but its effect on the visual system remains unknown. In the present study, zebrafish embryos were exposed to BPS at concentrations of 1, 10, 100 and 1000 μg l−1 until 120 days post‐fertilization in a semistatic system, and the effect of BPS on the visual behavior was examined using the optokinetic response and the optomotor response tests in male zebrafish. The retinal histology, mRNA expression of photoreceptor opsin genes (zfrho, zfblue, zfgr1, zfred and zfuv) and apoptosis‐related genes (bax and bcl‐2) were also assessed. Long‐term BPS exposure decreased the tracking capability of male zebrafish, consistent with structural damage to the retina. BPS induced different amounts of vacuoles in the retinal pigment epithelium, and 1000 μg l−1 BPS exposure decreased the length of the inner plexiform layer, ganglion cell layer and retina, and induced an irregular arrangement of photoreceptor cells. The expression levels of the opsin genes (zfred, zfgr1 and zfrho) were significantly elevated, indicating an enhanced spectral sensitivity to red, green and dim light to compensate for the reduction of the optomotor response. Together, the results showed for the first time that long‐term exposure to BPS damaged the structure of male zebrafish retina and reduced their tracking capability.
      PubDate: 2017-09-11T10:02:18.268303-05:
      DOI: 10.1002/jat.3519
  • Effect of cadmium on kitl pre‐mRNA alternative splicing in murine
           ovarian granulosa cells and its associated regulation by miRNAs
    • Authors: Wenxiang Wang; Jie Chen, Lingfeng Luo, Yuchen Li, Jin Liu, Wenchang Zhang
      Abstract: In this study, we established an in vitro exposure model of murine ovarian granulosa cells to observe the effect of Cd on alternative splicing of the kitl pre‐mRNA and subsequently to explore the role of kitl gene expression regulation‐related miRNAs through miRNA prediction, miRNA chip, bioinformatics and real‐time quantitative polymerase chain reaction analyses. Our results showed that the kitl1/kitl2 mRNA ratio was significantly different (P 
      PubDate: 2017-09-11T09:59:58.841276-05:
      DOI: 10.1002/jat.3516
  • Relationship between peroxisome proliferator-activated receptor alpha
           activity and cellular concentration of 14 perfluoroalkyl substances in
           HepG2 cells
    • Authors: Anna Kjerstine Rosenmai; Lutz Ahrens, Théo Godec, Johan Lundqvist, Agneta Oskarsson
      Abstract: Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARα activity. We investigated the relationship between PPARα activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography–tandem mass spectrometry and PPARα activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04–4.1%) with absolute cellular concentrations in the range 4–2500 ng mg−1 protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARα activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARα activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARα activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARα activities >2.5-fold compared to controls. The concentration–response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound-specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARα activity and cellular concentration of a broad range of PFASs.
      PubDate: 2017-08-31T05:40:32.815782-05:
      DOI: 10.1002/jat.3515
  • Butyltin compounds alter secretion of interleukin 6 from human immune
    • Authors: Shyretha Brown; Wendy Wilburn, Tyesha Martin, Margaret Whalen
      Abstract: Butyltins (BTs), tributyltin (TBT) and dibutyltin (DBT) are organotin compounds that have been used in a variety of industrial applications; as a result, these compounds have been found in human blood. Interleukin (IL)-6 is a proinflammatory mediator that is produced by T lymphocytes and monocytes. It is responsible for immune response regulation as well as tissue repair and cellular growth. Both BTs decrease the ability of human natural killer cells to destroy tumor cells and alter the secretion of proinflammatory cytokines tumor necrosis factor alpha, interferon gamma and IL-1 beta (β) from human lymphocytes ex vivo. Here, we show that BTs alter the secretion of IL-6 from increasingly reconstituted preparations of human immune cells. IL-6 secretion was examined after 24 hour, 48 hour or 6 day exposures to TBT and DBT in highly enriched human natural killer cells, monocyte-depleted peripheral blood mononuclear cells (PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs + granulocytes). The results indicated that both BTs altered IL-6 secretion from all cell preparations. Significant decreases of IL-6 secretion were seen at the highest concentration of TBT (200 nm) and DBT (5–2.5 μm) while the lower concentrations of DBT (0.05 and 0.1 μm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence.
      PubDate: 2017-08-24T22:10:41.000141-05:
      DOI: 10.1002/jat.3514
  • A novel endpoint for the assessment of chemotherapy-induced peripheral
           neuropathy in rodents: biomechanical properties of peripheral nerve
    • Authors: Chang-Ning Liu; Edwin Berryman, David Zakur, Ahmed M. Shoieb, Ingrid D. Pardo, Magalie Boucher, Chris J. Somps, Chedo M. Bagi, Jon C. Cook
      Abstract: Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 μg kg−1 day−1, i.p., for 10 days in rats and 100 μg kg−1 day−1, i.p., for 11 days in mice, respectively) were employed as the CiPN models. Behavioral changes were assessed during the dosing phase. At necropsy, the sural or sciatic nerve was harvested from the rats and mice, respectively, and assessed for mechanical and histopathological endpoints. It was found that the maximal load and the load/extension ratio were significantly decreased in the nerves collected from the animals dosed with vincristine compared with the vehicle-treated animals (P 
      PubDate: 2017-08-16T05:00:30.380633-05:
      DOI: 10.1002/jat.3513
  • Issue Information
    • First page: 1
      Abstract: No abstract is available for this article.
      PubDate: 2017-11-24T05:03:25.586208-05:
      DOI: 10.1002/jat.3530
  • Potential applications and human biosafety of nanomaterials used in
    • Authors: Hong Su; Yafei Wang, Yuanliang Gu, Linda Bowman, Jinshun Zhao, Min Ding
      First page: 3
      Abstract: With the rapid development of nanotechnology, potential applications of nanomaterials in medicine have been widely researched in recent years. Nanomaterials themselves can be used as image agents or therapeutic drugs, and for drug and gene delivery, biological devices, nanoelectronic biosensors or molecular nanotechnology. As the composition, morphology, chemical properties, implant sites as well as potential applications become more and more complex, human biosafety of nanomaterials for clinical use has become a major concern. If nanoparticles accumulate in the human body or interact with the body molecules or chemical components, health risks may also occur. Accordingly, the unique chemical and physical properties, potential applications in medical fields, as well as human biosafety in clinical trials are reviewed in this study. Finally, this article tries to give some suggestions for future work in nanomedicine research. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-06-06T22:15:35.208541-05:
      DOI: 10.1002/jat.3476
  • Review of the effects of manufactured nanoparticles on mammalian target
    • Authors: Tianshu Wu; Meng Tang
      First page: 25
      Abstract: Nanotechnology had matured significantly during the last two decades as it has transitioned from bench top science to applied technology. Even though the issue of safety of nanotechnology has been raised nearly one decade ago, the rapid progress in development and use of nanomaterials has not yet been matched by toxicological investigations. Many recent studies have simply outlined the toxic effects of nanoparticles (NPs), but few have systematically addressed their potentially adverse biological effects on target organs. Some animal models have shown that NPs could be accumulated in various organs. These accumulations can access the vasculature and target other organs, resulting in a potential health risks. After the brief description of current knowledge on the wide applications of several common NPs, their applications and the toxicokinetics, this review focused on effects of NPs on organ functions and mammal health after acute or chronic exposure, and potential mechanisms of action. Due to their physical properties, the liver, kidneys and lung are the main target organs of NPs. Most of NPs show slight toxicity when exposed to animals, while certain toxic effects like oxidative stress generation, inflammation and DNA damage are commonly observed. The severity of NPs toxicity is dependent upon several factors, including exposure dose and administration, NPs chemistry, size, shape, agglomeration state, and electromagnetic properties, which could provide useful information necessary to control the toxicity of NPs. Finally, the safety evaluation of nanotoxicity was addressed.
      PubDate: 2017-08-11T05:35:45.039751-05:
      DOI: 10.1002/jat.3499
  • Non-animal assessment of skin sensitization hazard: Is an integrated
           testing strategy needed, and if so what should be integrated'
    • Authors: David W. Roberts; Grace Patlewicz
      First page: 41
      Abstract: There is an expectation that to meet regulatory requirements, and avoid or minimize animal testing, integrated approaches to testing and assessment will be needed that rely on assays representing key events (KEs) in the skin sensitization adverse outcome pathway. Three non-animal assays have been formally validated and regulatory adopted: the direct peptide reactivity assay (DPRA), the KeratinoSens™ assay and the human cell line activation test (h-CLAT). There have been many efforts to develop integrated approaches to testing and assessment with the “two out of three” approach attracting much attention. Here a set of 271 chemicals with mouse, human and non-animal sensitization test data was evaluated to compare the predictive performances of the three individual non-animal assays, their binary combinations and the “two out of three” approach in predicting skin sensitization potential. The most predictive approach was to use both the DPRA and h-CLAT as follows: (1) perform DPRA – if positive, classify as sensitizing, and (2) if negative, perform h-CLAT – a positive outcome denotes a sensitizer, a negative, a non-sensitizer. With this approach, 85% (local lymph node assay) and 93% (human) of non-sensitizer predictions were correct, whereas the “two out of three” approach had 69% (local lymph node assay) and 79% (human) of non-sensitizer predictions correct. The findings are consistent with the argument, supported by published quantitative mechanistic models that only the first KE needs to be modeled. All three assays model this KE to an extent. The value of using more than one assay depends on how the different assays compensate for each other's technical limitations. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-05-24T06:15:26.796918-05:
      DOI: 10.1002/jat.3479
  • Effect of bisphenol A on reproductive processes: A review of in vitro, in
           vivo and epidemiological studies
    • Authors: Agnieszka Tomza-Marciniak; Paulina Stępkowska, Jarosław Kuba, Bogumiła Pilarczyk
      First page: 51
      Abstract: As bisphenol A (BPA) is characterized by a pronounced influence on human hormonal regulation, particular attention has been aimed at understanding its role in reproductive processes in males and females, as well as on fetal development. Owing to the increasing number of alarming reports on the negative consequences of the presence of BPA in human surroundings, more and more studies are being undertaken to clarify the negative effects of BPA on human reproductive processes. The aim of this work was to collect and summarize data on the influence of BPA exposure on reproductive health. Based on an analysis of selected publications it was stated that there is strong proof confirming that BPA is an ovarian, uterine and prostate toxicant at a level below the lowest observed adverse effect level (50 mg kg−1 bodyweight) as well as a level below the proposed safe level (4 μg kg−1 bodyweight). It seems there is also reliable evidence in relation to the negative effect of BPA on sperm quality and motility. Limited evidence also pertains to the case of the potential of BPA to affect polycystic ovary syndrome occurrence. Although in epidemiological studies this disease was common, in studies on animal models such results were still not confirmed. No unambiguous results of epidemiological studies and with animal models were obtained in relation to the evaluation of associations between BPA and implantation failure in women, evaluation of associations between BPA and sexual dysfunction in men, and impact of BPA on birth rate, birth weight and length of gestation. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-06-13T03:25:23.029446-05:
      DOI: 10.1002/jat.3480
  • Combinations of genotoxic tests for the evaluation of group 1 IARC
    • Authors: Jacky Bhagat
      First page: 81
      Abstract: Many of the known human carcinogens are potent genotoxins that are efficiently detected as carcinogens in human populations but certain types of compounds such as immunosuppressants, sex hormones, etc. act via non-genotoxic mechanism. The absence of genotoxicity and the diversity of modes of action of non-genotoxic carcinogens make predicting their carcinogenic potential extremely challenging. There is evidence that combinations of different short-term tests provide a better and efficient prediction of human genotoxic and non-genotoxic carcinogens. The purpose of this study is to summarize the in vivo and in vitro comet assay (CMT) results of group 1 carcinogens selected from the International Agency for Research on Cancer and to discuss the utility of the comet assay along with other genotoxic assays such as Ames, in vivo micronucleus (MN), and in vivo chromosomal aberration (CA) test. Of the 62 agents for which valid genotoxic data were available, 38 of 61 (62.3%) were Ames test positive, 42 of 60 (70%) were in vivo MN test positive and 36 of 45 (80%) were positive for the in vivo CA test. Higher sensitivity was seen in in vivo CMT (90%) and in vitro CMT (86.9%) assay. Combination of two tests has greater sensitivity than individual tests: in vivo MN + in vivo CA (88.6%); in vivo MN + in vivo CMT (92.5%); and in vivo MN + in vitro CMT (95.6%). Combinations of in vivo or in vitro CMT with other tests provided better sensitivity. In vivo CMT in combination with in vivo CA provided the highest sensitivity (96.7%).
      PubDate: 2017-07-11T04:35:33.876311-05:
      DOI: 10.1002/jat.3496
  • Maternal alcohol consumption and altered miRNAs in the developing fetus:
           Context and future perspectives
    • Authors: Chanchal Mandal; Debasish Halder, Kyoung Hwa Jung, Young Gyu Chai
      First page: 100
      Abstract: Alcohol is a teratogenic agent that can cause a wide range of developmental disorders, and sometimes, the effects persist throughout an individual's lifetime. Researchers have shown the involvement of epigenetic mechanisms in alcohol-mediated disorders. Non-coding RNAs are one of the major sources of epigenetic modifications, especially microRNAs. The association of microRNAs with alcohol consumption leads to a new focus on finding the molecular mechanisms of alcohol toxicity. It has been suggested that alcohol alters the relative expression of microRNAs and regulates target mRNA expression in both in vitro and in vivo models. Currently, we lack information regarding the relationship between altered microRNA expression and disease phenotypes in alcohol-mediated disorders. In this review, we tried to gather all of the available information about the alcohol-mediated dysregulation of microRNA expression in utero. We hope that our efforts will help future researchers identify major microRNAs in the field of prenatal alcohol toxicity and related therapeutics.
      PubDate: 2017-07-05T05:35:22.374338-05:
      DOI: 10.1002/jat.3504
  • Dermatotoxicology of sulfur mustard: Historical perspectives from World
           War I
    • Authors: Austin Jiang; Howard Maibach
      First page: 108
      Abstract: Sulfur mustard has been used as a chemical warfare agent for the past century. After its introduction by the Germans in World War I, investigators quickly began studying its impact on the human body including its deleterious effects on skin. This review focuses on two groups in particular who conducted experiments from 1917 to 1918: the United States Army at the American University Experiment Station Laboratories and Torald Sollmann at Western Reserve University. Through this work, these researchers proved far ahead of their time by anticipating dermatologic phenomena not described in the literature until later in the twentieth century. These include regional variation of percutaneous penetration, effect of vehicle on penetration and predicting immunologic contact urticaria. The work conducted by these researchers set the groundwork for much of twentieth century dermatotoxicology.
      PubDate: 2017-09-19T21:20:30.460833-05:
      DOI: 10.1002/jat.3524
  • Chemical warfare agent simulants for human volunteer trials of emergency
           decontamination: A systematic review
    • Authors: Thomas James; Stacey Wyke, Tim Marczylo, Samuel Collins, Tom Gaulton, Kerry Foxall, Richard Amlôt, Raquel Duarte-Davidson
      First page: 113
      Abstract: Incidents involving the release of chemical agents can pose significant risks to public health. In such an event, emergency decontamination of affected casualties may need to be undertaken to reduce injury and possible loss of life. To ensure these methods are effective, human volunteer trials (HVTs) of decontamination protocols, using simulant contaminants, have been conducted. Simulants must be used to mimic the physicochemical properties of more harmful chemicals, while remaining non‐toxic at the dose applied. This review focuses on studies that employed chemical warfare agent simulants in decontamination contexts, to identify those simulants most suitable for use in HVTs of emergency decontamination. Twenty‐two simulants were identified, of which 17 were determined unsuitable for use in HVTs. The remaining simulants (n = 5) were further scrutinized for potential suitability according to toxicity, physicochemical properties and similarities to their equivalent toxic counterparts. Three suitable simulants, for use in HVTs were identified; methyl salicylate (simulant for sulphur mustard), diethyl malonate (simulant for soman) and malathion (simulant for VX or toxic industrial chemicals). All have been safely used in previous HVTs, and have a range of physicochemical properties that would allow useful inference to more toxic chemicals when employed in future studies of emergency decontamination systems.
      PubDate: 2017-10-09T02:31:02.022889-05:
      DOI: 10.1002/jat.3527
  • Chronic arsenic intoxication diagnostic score (CAsIDS)
    • Authors: Sergio Ulhoa Dani; Gerhard Franz Walter
      First page: 122
      Abstract: Arsenic and its compounds are well-established, potent, environmentally widespread and persistent toxicants with metabolic, genotoxic, mutagenic, teratogenic, epigenetic and carcinogenic effects. Arsenic occurs naturally in the Earth's crust, but anthropogenic arsenic emissions have surmounted the emissions from important natural sources such as volcanism. Inorganic arsenicals exhibit acute and chronic toxicities in virtually all cell types and tissues, and hence arsenic intoxication affects multiple systems. Whereas acute arsenic intoxication is rare and relatively easy to diagnose, chronic arsenic intoxication (CAsI) is common but goes often misdiagnosed. Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication. CAsIDS can help physicians establish the diagnosis of CAsI and associated conditions.
      PubDate: 2017-08-31T04:37:16.988043-05:
      DOI: 10.1002/jat.3512
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