Journal of Applied Toxicology

Cover image for Vol. 35 Issue 7

July 2015

Volume 35, Issue 7

Pages 695–869

  1. Review Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. You have free access to this content
      T-helper cell-mediated factors in drug-induced liver injury (pages 695–700)

      Xinzhi Wang, Luyong Zhang and Zhenzhou Jiang

      Article first published online: 6 MAR 2015 | DOI: 10.1002/jat.3115

      T-helper cell-mediated immune responses can contribute to drug-induced liver injury (DILI). This review summarizes recent advances in the T-helper cell-mediated factors in DILI and potential mechanisms, which may lead to a better understanding of DILI.

  2. Research Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells (pages 709–716)

      Dongxu Zhao, Congcong Wang, Shusheng Tang, Chaoming Zhang, Shen Zhang, Yan Zhou and Xilong Xiao

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3022

      Olaquindox has been demonstrated to inhibit cell growth and induce cell death in a variety of cell lines. Recently, we reported that olaquindox can induce apoptosis of HepG2 cells in a mitochondria-dependent pathway. In this study, we demonstrated that olaquindox can induce autophagy. In addition, we also found that the autophagy inhibitor 3-MA enhances olaquindox-induced apoptotic cell death. Furthermore, ROS-dependent JNK activation may be involved in the negative regulation of olaquindox-induced autophagy in HepG2 cells.

    2. You have full text access to this OnlineOpen article
      Non-clinical safety evaluation of single and repeated intramuscular administrations of MAGE-A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys (pages 717–728)

      Eric Destexhe, Emilie Grosdidier, Nathalie Baudson, Roy Forster, Catherine Gerard, Nathalie Garçon and Lawrence Segal

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3025

      We evaluated the potential local and systemic toxic effects induced by single (rabbits) or 25 repeated (monkeys) injections of MAGE-A3 Cancer Immunotherapeutic, compared with control saline. Immune responses were assessed in monkeys. Single and repeated (up to 4x at the same site) injections were well-tolerated. Following 5–7 repeated injections, limb circumferences increased up to 26% (5h post-injection), but returned to normal after 1–8 days. MAGE-A3 Cancer Immunotherapeutic induced MAGE-A3-specific antibody and T-cell responses in all monkeys.

    3. The relationship between chemical-induced kidney weight increases and kidney histopathology in rats (pages 729–736)

      Evisabel A. Craig, Zhongyu Yan and Q. Jay Zhao

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3036

      We examined the relationship between chemically-induced kidney weight changes and renal histopathological alterations in rats to better understand the utility of kidney weight measurements in predicting renal toxicity. We found that statistically significant increases in absolute, but not relative, kidney weight correlate well with renal histopathology irrespective of whether kidney weight changes reach 10% and independently of a chemical's effect on body weight. This suggests that absolute kidney weight measurements should be routinely analyzed to identify potential renal toxicants.

    4. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain (pages 737–751)

      Sara Paradells, Brenda Rocamonde, Cristina Llinares, Vicente Herranz-Pérez, Misericordia Jimenez, Jose Manuel Garcia-Verdugo, Ivan Zipancic, Jose Miguel Soria and Ma. Angeles Garcia-Esparza

      Article first published online: 25 SEP 2014 | DOI: 10.1002/jat.3061

      Ochratoxin A (OTA) is a common contaminant in food and feedstuffs. In the present study we investigated, in vitro and in vivo, the effect of OTA exposure on the subventricular zone (SVZ) and on neural precursors obtained from this neurogenic niche in the adult brain. We demonstrate how OTA could be a threat to SVZ precursors and adult SVZ neurogenic niche through its impact in cell viability, proliferation and differentiation in a dose-dependent manner.

    5. Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice (pages 759–765)

      Mayra Gisel Flores-Montoya and Christina Sobin

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3064

      Research has suggested that chronic low-level lead exposure diminishes children's neurocognitive function. Animal models are needed in order to understand how chronic low-level lead disrupts behavior and the brain. C57BL/6J mice (N = 61) were exposed chronically to low-level lead or sodium from birth until PND 28 and were tested behaviorally. As blood lead level increased, exploratory activity decreased. This is the first study to show behavioral effects of chronic low-level lead exposure in pre-adolescent C57BL/6J mice.

    6. RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights (pages 766–780)

      Scott S. Auerbach, Dhiral P. Phadke, Deepak Mav, Stephanie Holmgren, Yuan Gao, Bin Xie, Joo Heon Shin, Ruchir R. Shah, B. Alex Merrick and Raymond R. Tice

      Article first published online: 6 NOV 2014 | DOI: 10.1002/jat.3068

      Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE rat liver samples exposed to aflatoxin B1. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples.

    7. Comparison of the kinetics of various biomarkers of benzo[a]pyrene exposure following different routes of entry in rats (pages 781–790)

      Marjory Moreau and Michèle Bouchard

      Article first published online: 27 OCT 2014 | DOI: 10.1002/jat.3070

      This study provides insights on kinetic differences of biomarkers of exposure to carcinogenic polycyclic aromatic hydrocarbons and route-dependent variations in their excretion time courses based on experimental studies in rats. We confirmed the interest of measuring multiple metabolites due to route-to-route differences in the relative excretion of the different biomarkers and in the time courses of diolBaPs versus OHBaPs. Concentration ratios of the different metabolites may help indicate time and main route of exposure.

    8. d-α-tocopheryl polyethylene glycol 1000 succinate-containing vehicles provide no detectable chemoprotection from oxidative damage (pages 791–798)

      Bethany R. Baumgart, Terry R. Van Vleet, Damir Simic, Theodora W. Salcedo, Kimberley Lentz, Michael Donegan, Marc H. Davies, Roderick T. Bunch, Thomas P. Sanderson and Robert W. Lange

      Article first published online: 27 OCT 2014 | DOI: 10.1002/jat.3072

      The objective of this study was to evaluate potential protective effects of vehicles containing d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), which may impact nonclinical safety assessments of oxidative processes. This was achieved by evaluating rat plasma, liver and adrenal gland concentrations of d-α-tocopheryl succinate (TS) and d-α-tocopherol as well as oxidative status of plasma following oral dosing of TPGS-containing vehicles, intraperitoneal (IP) dosing of TS or ex vivo treatment of blood with H2O2

    9. Assessment of temperature-induced hERG channel blockade variation by drugs (pages 799–805)

      Rahul R. Kauthale, Shruta S. Dadarkar, Raghib Husain, Vikas V. Karande and Madhumanjiri M. Gatne

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3074

      Prolongation of QT interval can be induced by drugs interacting with the cardiac potassium channel hERG. hERG channel blockade of certain drugs was evaluated at ambient and physiological temperatures. Amiodarone and β-estradiol showed a dose-dependent IKr blockade with higher blockade at 37°C. Whereas, ivermectin and frusemide showed a dose-dependent IKr blockade with lower blockade at 37°C. Gentamicin, enrofloxacin, xylazine and albendazole lacked effect. Thus, effect of temperature variation should be taken into consideration during the evaluation of hERG blockade potential.

    10. Long-term exposures to di-n-butyl phthalate inhibit body growth and impair gonad development in juvenile Murray rainbowfish (Melanotaenia fluviatilis) (pages 806–816)

      Harpreet Bhatia, Anupama Kumar, John C. Chapman and Mike J. McLaughlin

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3076

      Juvenile Murray rainbowfish were exposed to 5-15 µg/L di-n-butyl phthalate for upto 90 days. Complete feminization of the gonad was noted in fish exposed to 5 µg/L for 90 days and to 15 and 50 µg/L of DnBP for 30 or 60 days. The E2/11-KT ratio was higher only after exposures to 5 µg/L for 90 days and to 50 µg/L for 30 days. Exposures to 5 µg/L DnBP for 30 days did not have profound effects on body growth and gonadal differentiation of fish.

    11. All-cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non-polluted areas (pages 817–823)

      Yasushi Suwazono, Kazuhiro Nogawa, Yuko Morikawa, Muneko Nishijo, Etsuko Kobayashi, Teruhiko Kido, Hideaki Nakagawa and Koji Nogawa

      Article first published online: 22 DEC 2014 | DOI: 10.1002/jat.3077

      To evaluate the effect of environmental cadmium exposure on all-cause mortality, we conducted a 19-year cohort study in 1067 men and 1590 women aged 50 years or older who lived in three cadmium non-polluted areas in Japan. Continuous urinary cadmium and quartiles of urinary cadmium (Cd) were significantly related to the all-cause mortality in men and women. These results emphasized the necessity of further evaluation concerning the adoption of measures to protect the general population from environmental Cd exposure.

    12. Acute toxicity of 50 metals to Daphnia magna (pages 824–830)

      Akira Okamoto, Masumi Yamamuro and Norihisa Tatarazako

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3078

      In this study, we conducted acute toxicity testing of 50 metals in Daphnia magna. The acute toxicity results of 40 elements, obtained in this study, were not correlated with electronegativity. Similarly, the acute toxicity results of metals including the rare metals were also not correlated with other physicochemical constants, and the metal toxicity was not able to be explained by some parameters. In the future, our data will be required in judging with metal toxicity in environment.

    13. Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro (pages 831–841)

      Peter C. J. Schmeits, Jia Shao, Danique A. van der Krieken, Oscar L. Volger, Henk van Loveren, Ad. A. C. M. Peijnenburg and Peter J. M. Hendriksen

      Article first published online: 25 NOV 2014 | DOI: 10.1002/jat.3079

      Genomic biomarkers for direct immunotoxicity that were previously identified in human Jurkat T cells were tested using new compounds and compound classes. RNA isolated from exposures of Jurkat cells with subcytotoxic concentrations of compounds were subjected to Fluidigm high throughput analysis. The sensitivity (100%), specificity (80%) and accuracy (93%) were all higher than before. This Jurkat screening assay holds great promise to be applied in an animal-free testing strategy for human immunotoxicity.

    14. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues (pages 842–850)

      Anders Lundby, Pernille Bolvig, Anne Charlotte Hegelund, Bo F. Hansen, Jesper Worm, Anne Lützen, Nils Billestrup, Christine Bonnesen and Martin B. Oleksiewicz

      Article first published online: 21 NOV 2014 | DOI: 10.1002/jat.3082

      In a panel of five cell lines, we investigated correlations between surface expression levels of insulin receptors, IGF-I receptors and hybrid receptors and the mitogenic potency of insulin, the hyper-mitogenic insulin X10 and IGF-I. Mitogenicity modes of action were explored by siRNA-mediated receptor knockdown. Our results show that the insulin receptors (IR) as well as insulin-like growth factor 1 receptor (IGF-IR) may contribute to the mitogenic effects of insulin. These results are relevant for preclinical carcinogenicity safety assessment of developmental insulin analogues.

    15. 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin induces premature senescence of astrocytes via WNT/β-catenin signaling and ROS production (pages 851–860)

      Xiaoke Nie, Lingwei Liang, Hanqing Xi, Shengyang Jiang, Junkang Jiang, Cuiying Tang, Xipeng Liu, Suyi Liu, Chunhua Wan, Jianya Zhao and Jianbin Yang

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3084

      2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms.

    16. Impact of di-ethylhexylphthalate exposure on metabolic programming in P19 ECC-derived cardiomyocytes (pages 861–869)

      Kristina Schaedlich, Juliane-Susanne Schmidt, Wing Yee Kwong, Kevin D. Sinclair, Randy Kurz, Heinz-Georg Jahnke and Bernd Fischer

      Article first published online: 29 OCT 2014 | DOI: 10.1002/jat.3085

      Di(2-ethylhexyl)phthalate (DEHP) is a commonly used plasticizer in plastic devices of everyday use, primarily known to impair male gonadal development and fertility. Rising environmental pollution during the last centuries coincides with an increasing prevalence of cardiovascular and metabolic diseases. We have investigated the effects of early embryonic DEHP exposure on cardiomyogenesis in vitro, using the murine P19 embryonic carcinoma cell line (P19 ECC). Early DEHP exposure of P19 ECC altered the expression of genes associated with cellular metabolism and the functional features of cardiomyocytes.

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