Journal of Applied Toxicology

Cover image for Vol. 34 Issue 1

January 2014

Volume 34, Issue 1

Pages 1–112

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    1. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis (pages 1–18)

      M. E. Meek, A. Boobis, I. Cote, V. Dellarco, G. Fotakis, S. Munn, J. Seed and C. Vickers

      Version of Record online: 25 OCT 2013 | DOI: 10.1002/jat.2949

      The World Health Organization/International Programme on Chemical Safety mode of action/human relevance framework has been updated to reflect experience acquired in its application and extend its utility to emerging areas in toxicity testing and non-testing methods. This modified framework and accompanying roadmap and case examples are expected to contribute to improving transparency in explicitly addressing weight of evidence considerations in mode of action/species concordance analysis based on both conventional data sources and evolving methods.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Pro-apoptotic properties of morphine in neuroblastoma × glioma NG108-15 hybrid cells: modulation by yohimbine (pages 19–24)

      María José Polanco, Luis Fernando Alguacil and Carmen González-Martín

      Version of Record online: 12 SEP 2012 | DOI: 10.1002/jat.2817

      Morphine neurotoxicity has been studied in NG108-15 cells after 24 h incubation with 0.1 and 10 μM concentrations of the opioid. Images compatible with apoptosis and necrosis could be observed directly and after staining with methylene blue, crystal violet and propidium iodide/4′,6-diamidino-2-phenylindole. Quantification of caspase 3/7 activity and DNA fragmentation confirmed a modest but significant proapoptotic effect of morphine. Co-incubation with 10 μM yohimbine prevented all these changes, thus extending previous findings of a yohimbine-sensitive, neurotoxic effect of morphine on NG108-15 cells.

    2. The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice (pages 25–32)

      Cristiano R. Jesse, Cristiani F. Bortolatto, Ethel A. Wilhelm, Silvane Souza Roman, Marina Prigol and Cristina W. Nogueira

      Version of Record online: 14 SEP 2012 | DOI: 10.1002/jat.2818

      Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg–1). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg–1 day–1, per os (p.o.), starting 3 days before cisplatin injection.

    3. Absence of genotoxic effects of the coumarin derivative 4-methylesculetin in vivo and its potential chemoprevention against doxorubicin-induced DNA damage (pages 33–39)

      Rafael Palhano Fedato and Edson Luis Maistro

      Version of Record online: 10 OCT 2012 | DOI: 10.1002/jat.2823

      4-Methylesculetin (4-ME) is a potent synthetic antioxidant compound. This study investigated the in vivo genotoxicity of 4-ME and its potential antigenotoxicity against doxorubicin (DX) DNA damage. Doses of 500, 1000 and 2000 mg kg–1 were tested only or with a simultaneous injection of DX. A comet assay in different cells of mice and the micronucleus test were the endpoints analyzed. No differences were observed between the control and treated groups, indicating that it lacks genotoxic and cytotoxic effects. Moreover, 4-ME demonstrated protective effects against DX.

    4. Modified hydra bioassay to evaluate the toxicity of multiple mycotoxins and predict the detoxification efficacy of a clay-based sorbent (pages 40–48)

      K. A. Brown, T. Mays, A. Romoser, A. Marroquin-Cardona, N. J. Mitchell, S. E. Elmore and T. D. Phillips

      Version of Record online: 10 OCT 2012 | DOI: 10.1002/jat.2824

      Mycotoxin sorption efficacy of UPSN, a refined calcium montmorillonite clay, was examined in vitro and a rapid in vivo hydra bioassay was utilized to evaluate aflatoxin B1 and fumonisin B1 toxicity and confirm UPSN efficacy. UPSN sorbed both mycotoxins in vitro, although more FB1 bound at pH 2.0 than 6.5. Treatment with UPSN resulted in significant protection to mycotoxin-exposed hydra. Results indicate that this modified hydra bioassay can be used as an initial screen to predict toxin binding agent efficacy.

    5. Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression (pages 49–56)

      Yu Yamaguchi, Eiko Sakai, Hiroshi Sakamoto, Reiko Fumimoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto and Takayuki Tsukuba

      Version of Record online: 30 OCT 2012 | DOI: 10.1002/jat.2827

      Osteoclasts (OCLs) are multinucleated bone-resorbing cells. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ) on differentiation of macrophages into OCLs. tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) and impaired phosphorylation of several mitogen-activated protein kinases. And, tBHQ inhibited the release of high mobility group box 1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1/NFATc1 pathways.

    6. A 13-week toxicity study of acrylamide administered in drinking water to hamsters (pages 57–65)

      Toshio Imai and Tsukasa Kitahashi

      Version of Record online: 6 NOV 2012 | DOI: 10.1002/jat.2831

      Thirteen-week toxicity of (AA) was evaluated in Syrian hamsters, at concentrations of 0 (control), 20, 30 and 50 mg kg–1 body weight in drinking water. Treatment with AA caused peripheral nerve disorders in all AA-treated groups with dose dependence. In addition, testicular toxicity at 50 mg kg–1 and lowered body weights at 30 and 50 mg kg–1 were observed. These results indicated the maximum tolerated dose for long-term studies of AA to be 20 mg kg–1 or less in Syrian hamsters.

    7. Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation (pages 66–75)

      Debasish Halder, Ji Hyun Park, Mi Ran Choi, Jin Choul Chai, Young Seek Lee, Chanchal Mandal, Kyoung Hwa Jung and Young Gyu Chai

      Version of Record online: 4 FEB 2013 | DOI: 10.1002/jat.2832

      In the present study, we examined the role that chronic ethanol (EtOH) exposure plays in gene expression changes during early stage of embryonic differentiation. By employing a transcriptomic approach, we have identified genes, including GSC, which are vulnerable to EtOH exposure during the early stages of embryonic development. We reported that EtOH deregulates GSC expression by altering nodal signaling pathway, which may provide a new avenue for analyzing the molecular mechanisms behind EtOH teratogenicity in FASD individuals.

    8. Chronic exposure to low concentrations of strontium 90 affects bone physiology but not the hematopoietic system in mice (pages 76–86)

      Nicholas Synhaeve, Ndéye Marième Wade-Gueye, Stefania Musilli, Johanna Stefani, Line Grandcolas, Gaëtan Gruel, Maâmar Souidi, Isabelle Dublineau and Jean-Marc Bertho

      Version of Record online: 16 NOV 2012 | DOI: 10.1002/jat.2834

      The effect of chronic ingestion of strontium 90 was investigated in a mouse model, with strontium 90 concentrations representative of environmental contamination after a major nuclear accident. Results did not show evidence for modifications in the hematopoietic system. By contrast, a modification of bone metabolism was demonstrated, but was not linked to phosphocalcic homeostasis. This suggests a direct effect of strontium 90 storage in the bones on osteoblasts and/or osteoclasts.

    9. (E)-2-Benzylidene-4-phenyl-1,3-diselenole ameliorates signals of renal injury induced by cisplatin in rats (pages 87–94)

      Cristiani F. Bortolatto, Ethel A. Wilhelm, Silvane S. Roman and Cristina W. Nogueira

      Version of Record online: 10 DEC 2012 | DOI: 10.1002/jat.2837

      The protective effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) on renal injury induced by cisplatin in rats was investigated. BPD ameliorated renal injury and reduced plasma markers altered by cisplatin. BPD attenuated the reduction of renal AA and GSH content induced by cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was reversed by BPD. BPD was effective in attenuating the inhibition of δ-aminolevulinic dehydratase in kidneys of rats exposed to cisplatin.

    10. Exploration of effects of emodin in selected cancer cell lines: enhanced growth inhibition by ascorbic acid and regulation of LRP1 and AR under hypoxia-like conditions (pages 95–104)

      Shashank Masaldan and Vidhya V. Iyer

      Version of Record online: 5 DEC 2012 | DOI: 10.1002/jat.2838

      Ascorbic acid (AA) pre-treatment increased growth inhibition by emodin in AR-positive LNCaP, PC-3, HCT-15, MG-63 and A549 cancer cells, all with varying LRP1 levels, probably owing to ROS generation by emodin and the pro-oxidant activity of AA. Marked increase in LRP1 expression and growth inhibition of these cancer cells by emodin under hypoxia-like conditions may point to a strategy to target hypoxic tumors through the LRP1 protein by increased uptake of emodin, alone or along with other chemotherapeutic agents.

    11. Chrysin inhibits metastatic potential of human triple-negative breast cancer cells by modulating matrix metalloproteinase-10, epithelial to mesenchymal transition, and PI3K/Akt signaling pathway (pages 105–112)

      Bing Yang, Jing Huang, Tingxiu Xiang, Xuedong Yin, Xinrong Luo, Jianbo Huang, Fuling Luo, Hongyuan Li, Hongzhong Li and Guosheng Ren

      Version of Record online: 10 OCT 2013 | DOI: 10.1002/jat.2941

      The effect and mechanisms of chrysin on cancer metastasis still remain enigmatic. In this study, metastatic triple-negative breast cancer (TNBC) cell lines were used to evaluate the anti-metastatic acitivity of chrysin. The results showed that chrysin significantly suppressed TNBC cell migration and invasion in a dose-dependent manner. It was demonstrated that inhibiting Akt signaling pathway might play a central role in chrysin-induced anti-metastatic activity by regulating MMP-10 and EMT.

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