Journal of Applied Toxicology

Cover image for Vol. 34 Issue 12

December 2014

Volume 34, Issue 12

Pages 1271–1442

  1. Research Articles

    1. Top of page
    2. Research Articles
    1. CKD-501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks (pages 1271–1284)

      Kyoung-Sik Moon, Ji-Eun Lee, Hee Su Lee, In-Chang Hwang, Dal-Hyun Kim, Hyun-Kyu Park, Hyun-Ji Choi, Woori Jo, Woo-Chan Son and Hyo-In Yun

      Article first published online: 11 SEP 2013 | DOI: 10.1002/jat.2918

      CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for diabetes. Carcinogenicity study was conducted over a period of 104 weeks in ICR mice with three groups, each consisting of 60 mice in both sexes, received oral dosages of 0.2, 1.0 or 6.0 mg/kg/day. No significant treatment-related effects were observed on the survival rates. Expected non-neoplastic findings for this class of compound (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy) were seen. No treatment-related neoplastic changes were observed.

    2. Alteration in cellular viability, pro-inflammatory cytokines and nitric oxide production in nephrotoxicity generation by Amphotericin B: involvement of PKA pathway signaling (pages 1285–1292)

      F. D. França, A. F. Ferreira, R. C. Lara, J. V. Rossoni Jr, D. C. Costa, K. C. M. Moraes, C. A. Tagliati and M. M. Chaves

      Article first published online: 18 SEP 2013 | DOI: 10.1002/jat.2927

      The use of Amphotericin B is often limited as a result of adverse effects, especially nephrotoxicity. In this study we evaluate that the inhibition of the PKA pathway decreases cell death, changes in the production of pro-inflammatory cytokines and nitric oxide in LLC-PK1 and MDCK cell lines. Therefore, the inhibition of the PKA pathway can help decrease nephrotoxicity caused by Amphotericin B.

    3. Histopathological findings on Carassius auratus hepatopancreas upon exposure to acrylamide: correlation with genotoxicity and metabolic alterations (pages 1293–1302)

      Miguel Larguinho, Pedro M. Costa, Gonçalo Sousa, Maria H. Costa, Mário S. Diniz and Pedro V. Baptista

      Article first published online: 7 OCT 2013 | DOI: 10.1002/jat.2936

      The toxicity of acrylamide to aquatic organisms is scarcely known. Goldfish were exposed to several concentrations of waterborne acrylamide and the results showed a dose-dependent increase in genotoxicity endpoints and in the levels of hepatic CYP1A and GST activity. In addition, acrylamide induced more histopathological changes to pancreatic acini than to the hepatic parenchyma. Overall, the findings suggest a specific mode of action that overran the defences against acrylamide a rather than causing a general systemic failure.

    4. Deltamethrin induced an apoptogenic signalling pathway in murine thymocytes : exploring the molecular mechanism (pages 1303–1310)

      Anoop Kumar, D. Sasmal and Neelima Sharma

      Article first published online: 12 NOV 2013 | DOI: 10.1002/jat.2948

      The immunotoxic effects of DLM on mammalian system and its mechanism is still unclear. This study has been designed to first observe the binding affinity of DLM to immune cells and its effects on immune system. The results imply that DLM has a strong binding affinity towards the CD4 and CD8 receptors. DLM induces apoptosis in murine thymocytes in a concentration-dependent manner. Caspase, ROS and GSH act as critical mediators in DLM-induced apoptosis. The posibility of caspase-independent pathways also exists.

    5. Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro (pages 1311–1319)

      Valérian Bunel, Marie-Hélène Antoine, Joëlle Nortier, Pierre Duez and Caroline Stévigny

      Article first published online: 24 OCT 2013 | DOI: 10.1002/jat.2951

      Schizandrin and schizandrin B were tested on HK-2 cells for potential alleviation of cisplatin-mediated nephrotoxicity. Both compounds enhanced cell survival via reducing apoptosis rate. Schizandrin showed moderate effects towards modulation of regeneration capacities of healthy cells. Both Schi and Schi B limited extracellular matrix deposition and could help preventing dedifferentiation processes via the β-catenin pathway. Schizandrin and Schizandrin B present promising activities for future development of protective agents against CisPt nephrotoxicity.

    6. Hepatic fibrogenesis and transforming growth factor/Smad signaling activation in rats chronically exposed to low doses of lead (pages 1320–1331)

      Rossana C. Perez Aguilar, Stella M. Honoré, Susana B. Genta and Sara S. Sánchez

      Article first published online: 6 NOV 2013 | DOI: 10.1002/jat.2955

      The present work describes the role of lead in promoting liver fibrogenesis and suggests mechanisms in the underlying process. Our results report for the first time, that chronic exposure to low doses of lead could trigger the phenotypic transformation of hepatic stellate cells, secretion of the extracelular matrix and upregulated expression of TGFβ1/Smad signaling. Taken together, these results suggest a role of lead in promoting a fibrogenic state with altered hepatic structure.

    7. Combined antitumor effects of bee venom and cisplatin on human cervical and laryngeal carcinoma cells and their drug resistant sublines (pages 1332–1341)

      Goran Gajski, Tamara Čimbora-Zovko, Sanjica Rak, Marko Rožman, Maja Osmak and Vera Garaj-Vrhovac

      Article first published online: 12 NOV 2013 | DOI: 10.1002/jat.2959

      The present study investigated the possible combined anticancer ability of bee venom (BV) and cisplatin towards two pairs of tumour cell lines: parental cervical carcinoma HeLa cells and their cisplatin-resistant HeLa CK subline, as well as laryngeal carcinoma HEp-2 cells and their cisplatin-resistant CK2 subline. Our results suggest that combined treatment with BV could be useful from the point of minimizing the cisplatin concentration during chemotherapy, consequently reducing and/or postponing the development of cisplatin resistance.

    8. Proteomic analysis of perfluorooctane sulfonate-induced apoptosis in human hepatic cells using the iTRAQ technique (pages 1342–1351)

      Qingyu Huang, Jie Zhang, Siyuan Peng, Miaomiao Du, Sawyen Ow, Hai Pu, Chensong Pan and Heqing Shen

      Article first published online: 3 DEC 2013 | DOI: 10.1002/jat.2963

      Environmental perfluorooctane sulfonate (PFOS) exposure has been associated with a number of adverse health effects. However, the mechanisms associated with PFOS toxicity remain unclear. In the current proteomic study, 18 differential proteins with dose-dependent changes were identified in PFOS-exposed L-02 cells by iTRAQ-labeling and nanoLC-MS/MS. Furthermore, induction of apoptosis was proposed as a key mechanism for PFOS cytotoxicity. These results may provide useful insights into the mechanisms of PFOS-mediated hepatotoxicity and assist in the development of biomarkers indicative of PFOS exposure.

    9. Identification of differentially expressed proteins related to organophosphorus-induced delayed neuropathy in the brains of hens (pages 1352–1360)

      Ying Jiang, Xiaohui Liu, Shuangyue Li, Yanning Zhang, Fengyuan Piao and Xiance Sun

      Article first published online: 12 DEC 2013 | DOI: 10.1002/jat.2965

      In this study, eight differentially expressed proteins related to organophosphate-induced delayed neuropathy (OPIDN) were identified in the brains of hens on day 5. Among these proteins, downregulated expression of glutamine synthetase (GS) was further confirmed. Moreover, TOCP exposure increased the levels of glutamate and [Ca2+]i, and decreased the level of glutamine, which indicates that the downregulated expression of GS might be associated with OPIDN through the disruption of homeostasis of the glutamate–glutamine cycle and [Ca2+]i in the early stage after TOCP administration.

    10. The immunosuppressant tributyltin oxide blocks the mTOR pathway, like rapamycin, albeit by a different mechanism (pages 1361–1367)

      Ahmed M. Osman and Henk van Loveren

      Article first published online: 26 DEC 2013 | DOI: 10.1002/jat.2966

      We report here that tributyltin oxide (TBTO) inhibits, like rapamycin, the p70S6k1 pathway, though by a different mechanism in EL4 cell line. Both TBTO and rapamycin downregulated the phosphorylation state of S6k1 assessed at Ser421/Thr424, but in contrast to rapamycin, TBTO decreased the total S6k1 protein. In addition, TBTO reduced the levels of RPS6 (Ser236) and eIF4B (Ser422), downstream substrates of S6k1. Further, TBTO and rapamycin differentially affected 4E-binding protein 1, a repressor of the cap-binding protein eIF4E.

    11. A longitudinal study assessing lens thickness changes in the eye of the growing beagle using ultrasound scanning: relevance to age of dogs in regulatory toxicology studies (pages 1368–1372)

      Juliana Maynard, Angela Sykes, Helen Powell, Guy Healing, Marietta Scott, Andrew Holmes, Sally-Ann Ricketts, Jane Stewart and Stewart Davis

      Article first published online: 16 JAN 2014 | DOI: 10.1002/jat.2967

      The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770.

    12. Use of the mouse ear vesicant model to evaluate the effectiveness of ebselen as a countermeasure to the nitrogen mustard mechlorethamine (pages 1373–1378)

      Anju Lulla, Sandra Reznik, Louis Trombetta and Blase Billack

      Article first published online: 17 DEC 2013 | DOI: 10.1002/jat.2969

      The goal of the present study was to demonstrate for the first time the effectiveness of ebselen (EB-1) as a vesicant countermeasure in an in vivo model. Using the mouse ear vesicant model (MEVM), HN2, applied topically, showed a dose-dependent injury. To examine HN2 countermeasure activity, either hydrocortisone (HC) or EB-1 was administered as three topical treatments after HN2 exposure. Both HC and EB-1 were found to reduce tissue swelling associated with HN2 toxicity 24 h after vesicant exposure.

    13. Characterization of the biochemical effects of naphthalene on the mouse respiratory system using NMR-based metabolomics (pages 1379–1388)

      Jia-Huei Hong, Wen-Ching Lee, Yu-Ming Hsu, Hao-Jan Liang, Cho-Hua Wan, Chung-Liang Chien and Ching-Yu Lin

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2970

      Naphthalene, a ubiquitous environmental pollutant, has been shown to cause bronchiolar epithelial necrosis in the mouse airway. Metabolic variations in the bronchoalveolar lavage fluid and the lung tissues of naphthalene-treated mice and controls were examined using NMR-based metabolomics to identify the toxic mechanism. The metabolic changes may be related to lipid peroxidation, disruptions of membrane components, and imbalanced energy supply, and these results may partially explain the loss of cell membrane integrity in the airway epithelial cells of naphthalene-treated mice.

    14. Gene expression profile of brain regions reflecting aberrations in nervous system development targeting the process of neurite extension of rat offspring exposed developmentally to glycidol (pages 1389–1399)

      Hirotoshi Akane, Fumiyo Saito, Ayako Shiraki, Nobuya Imatanaka, Yumi Akahori, Megu Itahashi, Liyun Wang and Makoto Shibutani

      Article first published online: 7 JAN 2014 | DOI: 10.1002/jat.2971

      Glycidol has shown effects on hippocampal neurogenesis after developmental exposure to rats. In this study, pregnant rats were given drinking water containing glycidol, and offspring were subjected to region-specific microarray analysis in four different brain areas. Gene expression alterations suggesting effects on neuronal plasticity were observed in all brain areas at 1000 ppm. Among them, genes in the hippocampal dentate gyrus were downregulated at ≥ 300 ppm, suggesting that neurogenesis might be the sensitive target of this type of toxicity.

    15. Application of the SOS/umu test and high-content in vitro micronucleus test to determine genotoxicity and cytotoxicity of nine benzothiazoles (pages 1400–1408)

      Yan Ye, Jiang Weiwei, Li Na, Ma Mei, Rao Kaifeng and Wang Zijian

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2972

      Cytotoxicity of BTs in both bacterial Salmonella typhimurium TA1535/pSK1002, MGC-803 and A549 cells was observed in a dose-dependent manner, and activation and inactivation were found for specific BTs after metabolism. Six of nine BTs were found to be genotoxic to either bacteria or cells or both, and structure alerts including heterocyclic amine and hacceptor-path3-hacceptor may contribute to the underlying genotoxic mechanism for 2-Aminobenzothiazole and 2-Hydroxy-benzothiazole respectively.

    16. Absence of mature microRNAs inactivates the response of gene expression to carcinogenesis induced by N-ethyl-N-nitrosourea in mouse liver (pages 1409–1417)

      Yang Luan, Xinming Qi, Liang Xu, Jin Ren and Tao Chen

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2973

      This study evaluates the role of microRNAs in chemical tumorigenesis by evaluating genomic gene expression in microRNA knockout mice treated with carcinogen N-ethyl-N-nitrosourea. The results demonstrate that the mouse liver in the absence of mature microRNAs could not appropriately respond to the carcinogenic insults to suppress the carcinogenesis induced by the carcinogen. Many tumor-suppressor functions, especially BRCA1 and P53 signaling pathways, were lost due to the absence of mature microRNAs. Thus, microRNAs play a critical role in chemical carcinogenesis.

    17. Evaluation of electric arc furnace-processed steel slag for dermal corrosion, irritation, and sensitization from dermal contact (pages 1418–1425)

      Mina Suh, Matthew J. Troese, Debra A. Hall, Blair Yasso, John J. Yzenas and Debora M. Proctor

      Article first published online: 7 JAN 2014 | DOI: 10.1002/jat.2974

      Electric arc furnace (EAF) steel slag is alkaline and contains metals and thus has potential to cause dermal effects. To assess dermal irritation, corrosion, and sensitizing potential of EAF slag, in vitro and in vivo dermal toxicity assays were conducted. EAF slag was not corrosive, irritating, or sensitizing in any tests. These findings are supported by the observation that metals in EAF slag occur as oxides of low solubility with leachates that are well below toxicity characteristic leaching procedure limits.

    18. Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds (pages 1426–1435)

      Galina F. Makhaeva, Elena V. Rudakova, Nichole D. Hein, Olga G. Serebryakova, Nadezhda V. Kovaleva, Natalia P. Boltneva, John K. Fink and Rudy J. Richardson

      Article first published online: 7 JAN 2014 | DOI: 10.1002/jat.2977

      Although the mouse does not readily exhibit clinical signs of organophosphorus compound-induced delayed neurotoxicity (OPIDN), it displays axonal lesions and expresses brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE). The present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess OPIDN potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Our results support this hypothesis.

    19. Lipopolysaccharide exposure augments isoniazide-induced liver injury (pages 1436–1442)

      Yijing Su, Yun Zhang, Mi. Chen, Zhenzhou Jiang, Lixin Sun, Tao Wang and Luyong Zhang

      Article first published online: 6 FEB 2014 | DOI: 10.1002/jat.2979

      The results of this study demonstrate that LPS-induced inflammation makes rats more susceptible to INH hepatotoxicity. INH/LPS coadministration resulted in damage on bile acid metabolism, and cholestasis is considered as the main pattern of INH/LPS induced hepatotoxicity. TNF-α may be a factor in the ability of LPS to enhance the hepatotoxicity of INH. These results may have implications in idiosyncratic research attempting to improve the safety of INH.