Journal of Applied Toxicology

Cover image for Vol. 34 Issue 8

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Philip W. Harvey

Impact Factor: 2.597

ISI Journal Citation Reports © Ranking: 2012: 37/85 (Toxicology)

Online ISSN: 1099-1263

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  1. 1 - 73
  1. Review Articles

    1. Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status

      Philippa D. Darbre and Philip W. Harvey

      Article first published online: 22 JUL 2014 | DOI: 10.1002/jat.3027

      This review summarises evidence that parabens can lead in human breast epithelial cells to development of 4/6 of the hallmarks, 1/2 of the emerging hallmarks and 1/2 of the enabling characterstics of cancer cells as defined by Hanahan and Weinberg in 2011 and can do so at concentrations which are not incompatible with levels measurable in some human breast tissues. Results are discussed in the context of new exposure data and the regulatory status of parabens.

  2. Research Articles

    1. Cytotoxic and apoptotic activities of the plancitoxin I from the venom of crown-of-thorns starfish (Acanthaster planci) on A375.S2 cells

      Chi-Chiu Lee, Hernyi Justin Hsieh and Deng-Fwu Hwang

      Article first published online: 21 JUL 2014 | DOI: 10.1002/jat.3034

      This study reports a cytotoxic toxin derived from the venom of the crown-of-thorns starfish Acanthaster planci (CAV). The CAV was identified as plancitoxin I protein. The results indicated that after incubation with CAV, cells significantly decreased in A375.S2 cell viability. The assays indicated that CAV toxin promoted ROS production, lost mitochondrial membrane potential and induced inter-nucleosomal DNA fragmentation in A375.S2 cells. The results suggested that CAV toxin induced a cytotoxic effect in A375.S2 cells via the apoptotic procedure.

    2. You have full text access to this OnlineOpen article
      Elevated levels of antibodies against xenobiotics in a subgroup of healthy subjects

      Aristo Vojdani, Datis Kharrazian and Partha Sarathi Mukherjee

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3031

      Some environmental chemicals, acting as haptens, can bind to a high-molecular-weight carrier protein such as human serum albumin (HSA), causing the immune system to launch a defensive response against self-tissue, leading to autoimmunity. In this study we measured antibodies against 12 different chemicals bound to HSA in serum from 400 blood donors. We found that a substantial percentage of tested individuals showed significant antibody elevation against chemical adducts, which may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals. This protein adduct formation could be one of the mechanisms by which environmental chemicals induce autoimmune reactivity in a significant percentage of the population.

    3. Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells

      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.

    4. Inhibitory effect of apocynin on methylglyoxal-mediated glycation in osteoblastic MC3T3-E1 cells

      Kwang Sik Suh, Sang Youl Rhee, Young Seol Kim and Eun Mi. Choi

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3016

      The present study investigated the effects of apocynin on the mechanisms associated with methylglyoxal (MG) toxicity in osteoblastic MC3T3-E1 cells. Pretreatment with apocynin prevented the MG-induced protein glycation and formation of intracellular reactive oxygen species and mitochondrial superoxide in cells. In addition, apocynin increased glutathione level and restored the activity of glyoxalase I inhibited by MG. Apocynin treatment decreased the levels of TNF-a and IL-6 induced by MG. Additionally, the nitric oxide level reduced by MG was increased by apocynin.

    5. Renal cells exposed to cadmium in vitro and in vivo: normalizing gene expression data

      A. R. Nair, K. Smeets, E. Keunen, W.-K. Lee, F. Thévenod, E. Van Kerkhove and A. Cuypers

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3047

      The choice of reference genes for gene quantification is an important pre-requisite for carrying out new studies. A good normalization leads to biological relevant data interpretation as the detected variation in gene expression originates from biological rather than technical differences. The present study therefore serves as a baseline for renal cadmium (Cd) toxicity studies both in vitro and in vivo and the selected pool of reference genes that proved to be stable can be included in new experimental setups.

    6. Toxicity of new emerging pollutant tris-(2,3-dibromopropyl) isocyanurate on BALB/c mice

      Juan Li, Xu Zhang, Jieqing Bao, Yuchen Liu, Junfeng Li, Jia Li, Yong Liang, Jie Zhang and Aiqian Zhang

      Article first published online: 17 JUL 2014 | DOI: 10.1002/jat.3026

      Tris-(2,3-dibromopropyl) isocyanurate (TBC) exposure had no effects on basic growth or food intake of mice, whereas significantly increased alanine aminotransferase serum levels. TBC exposure induced p53 expression in mouse liver, and altered the ultrastructure in liver and lung. Results also indicated that mitochondria are one of the major target cytoplasmic organelles for TBC. These findings suggest that damage in mitochondria is one of the pathways that lead to toxic effects in the liver and lung of TBC-treated groups.

    7. Toxicity profiles and solvent–toxicant interference in the planarian Schmidtea mediterranea after dimethylsulfoxide (DMSO) exposure

      An-Sofie Stevens, Nicky Pirotte, Michelle Plusquin, Maxime Willems, Thomas Neyens, Tom Artois and Karen Smeets

      Article first published online: 25 JUN 2014 | DOI: 10.1002/jat.3011

      The solvent dimethylsulfoxide (DMSO) is used to investigate the toxicity of hydrophobic test compounds, but can bias the interpretation of test compound-induced responses. We assessed the effects of low DMSO concentrations on the planarian Schmidtea mediterranea, paying special attention to long-term exposures and stem cell responses, two important parameters in carcinogenicity assays. Above 500 µ l−1, DMSO affected different biological levels. We propose to avoid higher DMSO concentrations, or statistically take into account DMSO-induced effects and solvent–toxicant interactions.

    8. Comparative genotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells evaluated by fluorescent microscopy of cytochalasin B-blocked micronucleus formation

      Saura C. Sahu, Shambhu Roy, Jiwen Zheng, Jeffrey J. Yourick and Robert L. Sprando

      Article first published online: 6 JUN 2014 | DOI: 10.1002/jat.3028

      This report evaluates two in vitro cell culture models, human liver HepG2 cells and colon Caco2 cells, for screening the potential genotoxicity of food-related nanoparticles. It compares the genotoxic potential of 20-nm silver in these two cell types. Nanosilver is genotoxic to both cell types as shown by the in vitro micronucleus assay with HepG2 cells being more sensitive than Caco2 cells. Both of these cell types show promise as in vitro predictive screens for the potential genotoxicity of nanomaterials by in vitro micronucleus assay.

  3. Short Communications

    1. Time-dependent bioaccumulation of distinct rod-type TiO2 nanoparticles: Comparison by crystalline phase

      Eun-Jung Park, Gwang-Hee Lee, Cheolho Yoon, Min-Sung Kang, Soo Nam Kim, Myung-Haing Cho, Jae-Ho Kim and Dong-Wan Kim

      Article first published online: 29 MAY 2014 | DOI: 10.1002/jat.3006

      In this study, we compared the distribution in in mice over time of 2 rod-type titanium dioxide nanoparticles (TiNPs) that feature distinct phases, anatase (ATO) and brookite (BTO). Both TiNPs were rapidly distributed into tissues after injection. At 4 weeks after injection, both TiNPs were maximally accumulated in the spleen, followed by the liver, but the total accumulation of ATO in tissues measured in this study was more than that of BTO.

  4. Research Articles

    1. Vascular endothelial growth factor mRNA levels as a biomarker for short-term N-butyl-N-(4-hydroxybutyl) nitrosamine-induced rat bladder carcinogenesis bioassay

      Shin Wakui, Tomoko Mutou, Hiroyuki Takahashi, Masahiro Ikegami, Hideki Wanibuchi and Shoji Fukushima

      Article first published online: 28 MAY 2014 | DOI: 10.1002/jat.3021

      To establish a short-term rat bladder carcinogenic bioassay, the correlations analyzed between VEGF, VEGF mRNA, and bladder lesions inductions after BBN treatment. Wistar rats were given 0.05% BBN for 4, 10, or 26 weeks. VEGF mRNA levels of rat bladders at 10 weeks BBN treatment revealed a strong significant correlation with the incidence of bladder lesions at 26 weeks treatment. we suggest that quantitative VEGF mRNA levels are a good biomarker for a short-term BBN-induced rat bladder carcinogenesis bioassay.

    2. Developmental toxicity assay using high content screening of zebrafish embryos

      Susan Lantz-McPeak, Xiaoqing Guo, Elvis Cuevas, Melanie Dumas, Glenn D. Newport, Syed F. Ali, Merle G. Paule and Jyotshna Kanungo

      Article first published online: 28 MAY 2014 | DOI: 10.1002/jat.3029

      High content assay quantifies developmental toxicity in zebrafish embryos.

    3. Cardiotoxicity evaluation of anthracyclines in zebrafish (Danio rerio)

      Ying Han, Jing-pu Zhang, Jian-qin Qian and Chang-qin Hu

      Article first published online: 22 MAY 2014 | DOI: 10.1002/jat.3007

      Drug-induced cardiotoxicity is a leading factor for drug withdrawals, and limits drug efficacy and clinical use. Therefore, new alternative animal models and methods for drug safety evaluation have been given great attention. Anthracyclines (ANTs) are widely prescribed anticancer agents that have a cumulative dose relationship with cardiotoxicity. We performed experiments to study the toxicity of ANTs in early developing zebrafish embryos, especially their effects on the heart. LC50 values for daunorubicin, pirarubicin, doxorubicin (DOX), epirubicin and DOX-liposome at 72 h post-fertilization were 122.7 μM, 111.9 μM, 31.2 μM, 108.3 μM and 55.8 μM, respectively.

    4. A trivalent approach for determining in vitro toxicology: Examination of oxime K027

      Adriana Prado, Georg A. Petroianu, Dietrich E. Lorke and Jeremy W. Chambers

      Article first published online: 22 MAY 2014 | DOI: 10.1002/jat.3013

      Correlating in vitro toxicity to in vivo and clinical outcomes is of paramount importance to drug discovery. Our proposed approach measuring metabolism, mitochondrial stress, and viability may predict the extent of drug toxicity in vivo. Our panel of assays was examined using drugs of known in vivo toxicity to validate this methodology as a toxicity prediction tool. This approach may be useful for streamlining compounds introduced into pre-clinical studies and ultimately reduce animal numbers, costs, and time spent during development.

    5. Synergistic cytotoxicity and DNA strand breaks in cells and plasmid DNA exposed to uranyl acetate and ultraviolet radiation

      Janice Wilson, Mary C. Zuniga, Filbert Yazzie and Diane M. Stearns

      Article first published online: 15 MAY 2014 | DOI: 10.1002/jat.3015

      The photoactivation of uranyl ion by UV radiation was investigated as a chemical mechanism of uranium genotoxicity. The ability of UVB- and UVA-activated uranyl ion to generate strand breaks was measured in plasmid DNA, and the cytotoxicity of UVB-activated uranyl ion was measured in repair-proficient and repair-deficient Chinese hamster ovary cells, and human keratinocyte HaCaT cells. Results suggested that photoactivated uranyl ion is chemically genotoxic, and a case is made that skin is an overlooked target organ for uranium exposure.

    6. Endocrine disruption effects of p,p′-DDE on juvenile zebrafish

      Marta Sofia Monteiro, Maria Pavlaki, Augusto Faustino, Alexandra Rêma, Mariana Franchi, Letícia Gediel, Susana Loureiro, Inês Domingues, Jaime Rendón von Osten and Amadeu Mortágua Velho Maia Soares

      Article first published online: 15 MAY 2014 | DOI: 10.1002/jat.3014

      Potential endocrine effects of p,p'-DDE, the major metabolite of the insecticide DDT, were investigated in zebrafish during gonad differentiation. Juveniles were exposed to sub-lethal concentrations during 14 days and maintained in control water for further 4 months. An increase in vtg production was observed in exposed juveniles. Female gonads presented histopathological changes, which might impair their successful reproduction. These results demonstrate the ability of p,p'-DDE to cause endocrine disruption during gonad differentiation of zebrafish.

    7. Dimethylarsinic acid (DMAv) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder

      Zhang Lin, Liu Shengnan, Wang Fei, Song Yingli, Sun Qingshan, Sheng Wei, Xi. Shuhua and Sun Guifan

      Article first published online: 15 MAY 2014 | DOI: 10.1002/jat.3001

      The present study showed that DMAV administered to rats produced chronic inflammation and urothelial ultrastructural changes. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. 200 ppm DMAV treatment increased TGF-β1 secretion and decreased TNF-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMAV-treated rats.

    8. The in Vitro estrogenic activities of triclosan and triclocarban

      Hongyu Huang, Guizhen Du, Wei Zhang, Jialei Hu, Di. Wu, Ling Song, Yankai Xia and Xinru Wang

      Article first published online: 16 APR 2014 | DOI: 10.1002/jat.3012

      In the present study, we found that triclosan (TCS) and triclocarban (TCC) could induce the luciferase activities in the ER reporter gene assay, stimulate the proliferation of MCF-7 cells and change the expression of ERα and pS2 in MCF-7 cells. Moreover, TCS and TCC could alter the expression of multiple microRNAs (mir-22, mir-206 and mir-193b) in MCF-7 cells, which would help to understand the mechanisms of their estrogenic effects on regulating the expression of ERα.

    9. Usefulness of urinary kidney injury molecule-1 (Kim-1) as a biomarker for cisplatin-induced sub-chronic kidney injury

      Ken-ichiro Nan-ya, Masatomo Kajihara, Natsuki Kojima and Masakuni Degawa

      Article first published online: 16 APR 2014 | DOI: 10.1002/jat.2999

      We explored biomarkers suitable for monitoring sub-chronic kidney injury using rat models of kidney injury induced by cisplatin (CDDP). CDDP was intravenously administered to rats at 1.5 mg kg–1 for 4 days at 24-h intervals and for up to 10 weeks at weekly intervals, and the changes in blood and urine components were examined together with the histopathological changes in renal tissues. The present findings indicate that urinary kidney injury molecule-1 (Kim-1) is the most useful biomarker for CDDP-induced rat sub-chronic kidney injury.

    10. Evaluation of developmental toxicity using undifferentiated human embryonic stem cells

      Eui-Man Jung, Yeo-ul Choi, Hong-Seok Kang, Hyun Yang, Eui-Ju Hong, Beum-Soo An, Jun-young Yang, Ki. Hwan Choi and Eui-Bae Jeung

      Article first published online: 16 APR 2014 | DOI: 10.1002/jat.3010

      An embryonic stem cell test (EST) has been developed to evaluate the potential of chemicals with an in vitro system. In the present study, novel methods to screen toxic chemicals during the developmental process were evaluated using undifferentiated human embryonic stem (hES) cells. The embryotoxic chemicals influence their response to pluripotent ES cell markers. Our microarray data may be used as indicators for assessment of new chemicals. We define the hES cell viability and embryonic-specific differentiation by chemicals.

    11. Serum enhanced cytokine responses of macrophages to silica and iron oxide particles and nanomaterials: a comparison of serum to lung lining fluid and albumin dispersions

      David M. Brown, Helinor Johnston, Eva Gubbins and Vicki Stone

      Article first published online: 16 APR 2014 | DOI: 10.1002/jat.2998

      The effect of amorphous silica and iron oxide particles and nanoparticles (NPs) dispersed in cell culture medium supplemented with bovine serum albumin (BSA), lung lining fluid (LLF) or serum were examined in terms of macrophage viability and cytokine production. Silica induced a dose dependent increase in LDH release with evidence of a size difference between particles in some treatments. These data suggest that serum is very potent at enhancing macrophage responses to silica and iron oxide NPs and particles.

    12. In vitro exposure of DE-71, a penta-PBDE mixture, on immune endpoints in bottlenose dolphins (Tursiops truncatus) and B6C3F1 mice

      Jena R. Wirth, Margie M. Peden-Adams, Natasha D. White, Gregory D. Bossart and Patricia A. Fair

      Article first published online: 7 APR 2014 | DOI: 10.1002/jat.3008

      Following in vitro exposure to environmentally relevant DE-71, a penta-PBDE commercial mixture, concentrations (0–50 µg ml–1) in dolphin peripheral blood leukocytes (PBLs) and adult female B6C3F1 mouse splenocytes, lymphocyte proliferation and natural killer cell activity was measured.  Risk assessment using a parallelogram approach indicated that dolphin PBLs exhibited similar results to correlative field studies and mice were generally more sensitive than dolphins. The parallelogram approach was predictive for the immune endpoints in this study.

    13. Impact of acute arsenic and cadmium exposure on the expression of two haeme oxygenase genes and other antioxidant markers in common carp (Cyprinus carpio)

      Zsanett Jancsó and Edit Hermesz

      Article first published online: 7 APR 2014 | DOI: 10.1002/jat.3000

      The response of an organism to exposure to toxic metals is in many cases brought about by changes at the level of gene expression. In this study, the heme oxygenases genes (ho-1 and ho-2) of common carp Cyprinus carpio were identified, and the changes in gene expressions were analyzed from the aspect of Cd and As accumulation. Both ho-1 and ho-2 are transcriptionally induced by Cd and As, but their inductions differ in time course, dose response and tissue specificity.

    14. Usefulness of optical coherence tomography to detect central serous chorioretinopathy in monkeys

      Hyun-Kyu Park, Woori Jo, Hyun-Ji Choi, Bongcheol Kim, Gilnam Lee, Jeongbeob Seo, Suk Young Cho, Choung-Soo Kim, Eun Kyung Choi, Jung Jin Hwang, Joo Yong Lee, Young Hee Yoon and Woo-Chan Son

      Article first published online: 28 MAR 2014 | DOI: 10.1002/jat.3009

      It is difficult to detect ocular toxicity owing to the lack of appropriate evaluation methods and application of imaging tools to preclinical studies provides more information. Optical coherence tomography (OCT) is a valuable imaging method to screen drug-induced central serous chorioretinopathy (CSC), and will be useful to detect ocular toxicity in preclinical trials. To our knowledge, this is the first study to demonstrate CSC using OCT in a monkey model.

    15. Involvement of immune- and inflammatory-related factors in flucloxacillin-induced liver injury in mice

      Shohei Takai, Satonori Higuchi, Azusa Yano, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi

      Article first published online: 20 MAR 2014 | DOI: 10.1002/jat.3002

      Flucloxacillin (FLX), which is a β-lactam antibiotic of the penicillin class, rarely causes drug-induced liver injury. The purpose of this study was to elucidate the mechanisms of FLX-induced liver injury in vivo. Toll-like receptor 4 (TLR4) ligands and inflammatory factors were significantly increased in FLX-administered mice. IL-17-related transcriptional factors and cytokines were increased, and the administration of recombinant IL-17 resulted in an exacerbation of the FLX-induced liver injury.TLR4-associated-signal transduction and IL-17 may be involved in FLX-induced liver injury.

    16. Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

      Sugandha Khanna, Philip R. Dash and Philippa D. Darbre

      Article first published online: 20 MAR 2014 | DOI: 10.1002/jat.3003

      Alkyl esters of p–hydroxybenzoic acid (parabens) are used widely as preservatives in consumer products. They have been measured in human breast tissue and can stimulate proliferation of oestrogen-responsive human breast cancer cells. We report here for the first time that long-term exposure (20 ± 2 weeks) to concentrations of methylparaben, n-propylparaben or n-butylparaben which give a maximal proliferative response also increased migratory and invasive properties of human breast cancer cell lines (MCF-7, T-47-D and ZR-75-1) in vitro.

    17. Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

      Nicola Bocchini, Mery Giantin, Federica Crivellente, Serena Ferraresso, Ivo Faustinelli, Mauro Dacasto and Patrizia Cristofori

      Article first published online: 18 FEB 2014 | DOI: 10.1002/jat.2992

      A set of phospholipidosis (PLD) biomarkers was identified in the blood and hearts of rats treated with amiodarone (AMD) using DNA microarrays. Overall, 545 and 8218 genes were modulated by AMD in hearts and blood, respectively; furthermore, some genes implicated in cellular phospholipid accumulation showed similar alterations. The usefulness of seven candidate genes was screened and confirmed by quantitative Real-Time PCR analysis. Presented data underscore the importance of transcriptional profiling in preclinical studies. Blood may be a surrogate tissue of cardiomyocyte PLD.

    18. Preliminary safety evaluation of a taurocholate-conjugated low-molecular-weight heparin derivative (LHT7): a potent angiogenesis inhibitor

      Farzana Alam, Seung Woo Chung, Seung Rim Hwang, Ji-young Kim, Jooho Park, Hyun Tae Moon and Youngro Byun

      Article first published online: 16 FEB 2014 | DOI: 10.1002/jat.2995

      In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight heparin derivative (LHT7) showed promising anti-angiogenic effects. For the development of this drug, LHT7, evaluation of its biological safety with mechanism-related side effects were performed. From this study, no other side effects have been found except for LHT7's accumulation in the liver and kidney owing its affinity to vascular endothelial growth factor (VEGF) and its saturation with TA at high doses.

    19. Interaction of citrate-coated silver nanoparticles with earthworm coelomic fluid and related cytotoxicity in Eisenia andrei

      Jin Il Kwak, Woo-Mi Lee, Shin Woong Kim and Youn-Joo An

      Article first published online: 16 FEB 2014 | DOI: 10.1002/jat.2993

      The earthworm Eisenia andrei was exposed to citrate-coated silver nanoparticles (cAgNPs), and the interaction of cAgNPs with earthworm coelomic fluid (ECF), the cytotoxicity of cAgNPs in earthworm coelomocytes was assessed. The aggregation and dissolution of cAgNPs increased in ECF, which contains various electrolytes that alter the properties of nanoparticles, and their subsequent toxicity. Microscopic and dissolution studies demonstrated that the aggregation of cAgNPs rapidly increased, and readily dissolved in ECF. The bioavailability of cAgNPs to earthworms induced lysosomal cytotoxicity.

    20. Carbon-based nanomaterials accelerate arteriolar thrombus formation in the murine microcirculation independently of their shape

      Martin Holzer, Peter Bihari, Marc Praetner, Bernd Uhl, Christoph Reichel, Janos Fent, Minnamari Vippola, Susan Lakatos and Fritz Krombach

      Article first published online: 14 FEB 2014 | DOI: 10.1002/jat.2996

      The aim of this study was to compare the acute effects of two differently shaped CBNs, fiber-shaped single-walled carbon nanotubes (SWCNT) and spherical ultrafine carbon black (CB), on thrombus formation as well as on leukocyte–endothelial cell interactions and leukocyte transmigration in the murine microcirculation upon systemic administration in vivo. The findings from this study suggest that systemic administration of CBNs accelerates arteriolar thrombus formation independently of the CBNs' shape, but does not induce leukocyte–endothelial cell interactions or leukocyte transmigration.

    21. Development and utilization of an ex vivo bromodeoxyuridine local lymph node assay protocol for assessing potential chemical sensitizers

      W. C. Williams, C. Copeland, E. Boykin, S. J. Quell and D. M. Lehmann

      Article first published online: 14 FEB 2014 | DOI: 10.1002/jat.2983

      The murine local lymph node assay (LLNA) is widely used to identify chemicals that may cause allergic contact dermatitis. We developed an ex vivo BrdU-labeling procedure eliminating the need for in vivo injections. The ex vivo BrdU LLNA accurately predicted the sensitization potential of known sensitizers and non-sensitizers. This ex vivo BrdU labeling method offers predictive capacity comparable to previously established LLNA protocols while eliminating animal injections and the use of radioisotope.

    22. Comparative cytotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells in culture

      Saura C. Sahu, Jiwen Zheng, Lesley Graham, Lynn Chen, John Ihrie, Jeffrey J. Yourick and Robert L. Sprando

      Article first published online: 12 FEB 2014 | DOI: 10.1002/jat.2994

      This report evaluates two in vitro cell culture models, human liver HepG2 cells and colon Caco2 cells, for screening the potential cytotoxicity of silver nanoparticles. It compares the cytotoxic potential of 20-nm silver in these two cell types. The nanosilver is cytotoxic to both the cell types, HepG2 being more sensitive. However, both the cell types are excellent in vitro systems for screening cytotoxicity of nanosilver.

    23. Fish multigeneration test with preliminary short-term reproduction assay for estrone using Japanese medaka (Oryzias latipes)

      Ataru Nakamura, Ikumi Tamura, Hitomi Takanobu, Masumi Yamamuro, Taisen Iguchi and Norihisa Tatarazako

      Article first published online: 12 FEB 2014 | DOI: 10.1002/jat.2981

      The long-term adverse effects of estrone on aquatic wildlife is of great concern. We exposed Japanese medaka (Oryzias latipes) to estrone (5.74-91.4 ng l–1) for 27 weeks across three generations. We found a decline in egg production and fertility in the second generation exposed to 91.4 ng l–1, much lower than known concentrations in urban rivers. Furthermore, histopathological abnormalities observed in the third generation exposed to 47.1 ng l–1 suggest that estrone exerts severe effects on the third or later generations.

    24. You have full text access to this OnlineOpen article
      Microvesicle-associated microRNA expression is altered upon particulate matter exposure in healthy workers and in A549 cells

      Valentina Bollati, Laura Angelici, Giovanna Rizzo, Laura Pergoli, Federica Rota, Mirjam Hoxha, Francesco Nordio, Matteo Bonzini, Letizia Tarantini, Laura Cantone, Angela C. Pesatori, Pietro Apostoli, Andrea A. Baccarelli and Pier Alberto Bertazzi

      Article first published online: 7 FEB 2014 | DOI: 10.1002/jat.2987

      Cell-derived microvesicles (MVs) are found in plasma and may transfer signals between tissues. In this article, we report in-vivo and in-vitro studies demonstrating that Particulate Matter (PM) affects systemic MV signaling by inducing MV release from alveolar cells into plasma. In-vivo microRNA screening showed increased miR-128 level in plasma MVs after PM exposure. In-vitro experiments confirmed PM-induced release of miR-128 in MVs from A549 alveolar cells. Future studies are warranted to determine the roles of MVs in mediating PM effects.

    25. Lipopolysaccharide exposure augments isoniazide-induced liver injury

      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.

    26. Development of a multiparametric in vitro model of skin sensitization

      Muriel Guyard-Nicodème, Eloise Gerault, Marion Platteel, Olivier Peschard, Wilfried Veron, Philippe Mondon, Svinareff Pascal and Marc G. J. Feuilloley

      Article first published online: 3 FEB 2014 | DOI: 10.1002/jat.2986

      A new in vitro model of skin sensitizing potential based on the measure of 4 parameters, i.e. trans-cutaneous permeation (Factor A), haptenation (Factor B), sensitization cytokines production (Factor C) and acute toxicity (Factor D) was described. A total of 32 compounds regularly employed in cosmetics were tested in this model. The correlation with in vivo assays reached 81.2% and the safety of the test (risk of false negative) reached 96.8 %.

    27. Differential effect of methyl-, butyl- and propylparaben and 17β-estradiol on selected cell cycle and apoptosis gene and protein expression in MCF-7 breast cancer cells and MCF-10A non-malignant cells

      Anna Maria Wróbel and Ewa Łucja Gregoraszczuk

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2978

      Parabens are alkyl esters of p-hydroxybenzoic acid used as antimicrobial preservatives in pharmaceuticals, foods and cosmetics. The present study was undertaken to determine the effect of methyl, butyl- and propylparaben, and 17β-estradiol as positive control, on cell cycle and apoptotic gene and protein expression in MCF-7 breast cancer and MCF-10A breast epithelial cells. The present results show differences between parabens and 17β-estradiol mechanisms of action in MCF-7, while similar to that of 17β-estradiol in non-transformed MCF-10A cells.

    28. Characterization of the biochemical effects of naphthalene on the mouse respiratory system using NMR-based metabolomics

      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.

    29. Effects of cylindrospermopsin on a common carp leucocyte cell line

      Anna Sieroslawska and Anna Rymuszka

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2990

      Cylindrospermopsin (CYN) is a cytotoxin produced by different cyanobacterial species. The aim of the study was to elucidate the impact of cylindrospermopsin on a common carp (Cyprinus carpio L.) leucocyte cell line (CLC). The toxin at 10 and 1 µg ml–1 occurred to be evidently cytotoxic whereas at 0.1 µg ml–1 there were no effects on cell viability or cell number; however, a strong reduction of bacteria uptake was detected. The obtained results indicate that cylindrospermopsin may interfere with the basic functions of fish phagocytic cells.

    30. Benchmark dose of cadmium concentration in rice for renal effects in a cadmium-polluted area in Japan

      Kazuhiro Nogawa, Teruhiko Kido, Muneko Nishijo, Hideaki Nakagawa and Yasushi Suwazono

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2982

      We applied an updated hybrid approach to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) of cadmium concentration in rice for renal effects in humans. The BMDL of cadmium in rice for β2-microglobulin was 0.25 mg/kg in men and 0.24 mg/kg in women. These estimated BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure especially in terms of the food standard of cadmium concentration in rice.

    31. The effect of diesel exhaust exposure on blood–brain barrier integrity and function in a murine model

      Sayeh Heidari Nejad, Ryusuke Takechi, Benjamin J. Mullins, Corey Giles, Alexander N. Larcombe, Dean Bertolatti, Krassi Rumchev, Satvinder Dhaliwal and John Mamo

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2985

      Epidemiological studies indicate that exposure to diesel exhaust (DE) is associated with vascular-based disorders. An in vivo murine model was utilized to determine the effect of DE inhalation on neurovascular integrity. The study demonstrated that exposure to DE compromises the integrity and function of cerebral capillary vessels. Heightened neurovascular inflammation as a consequence of sub-chronic DE exposure may contribute to risk for neurovascular based disorders.

    32. Absence of mature microRNAs inactivates the response of gene expression to carcinogenesis induced by N-ethyl-N-nitrosourea in mouse liver

      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.

    33. Application of the SOS/umu test and high-content in vitro micronucleus test to determine genotoxicity and cytotoxicity of nine benzothiazoles

      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.

    34. Establishment of a short-term, in vivo screening method for detecting chemicals with juvenile hormone activity using adult Daphnia magna

      Ryoko Abe, Haruna Watanabe, Masumi Yamamuro, Taisen Iguchi and Norihisa Tatarazako

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2989

      Juvenile hormone (JH) and JH agonists have been shown to induce male offspring production in Daphnia using OECD TG211. The critical period for JH action to induce male offspring is 7-8 h (only 1 h) before ovulation. For the purpose of the detection of JH-like chemicals, we improved and simplified TG211 Annex7 and enabled us to save time and effort. The validity of a new testing method was verified by the test of positive and negative control chemicals.

    35. Zinc sulfide nanoparticles selectively induce cytotoxic and genotoxic effects on leukemic cells: involvement of reactive oxygen species and tumor necrosis factor alpha

      Sandeep Kumar Dash, Totan Ghosh, Soumyabrata Roy, Sourav Chattopadhyay and Debasis Das

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2976

      The present study describes the anti-cancer efficacy of synthesized zinc sulphide nanoparticles (ZnS NPs) on KG-1A cell line. pH dependent dissolution study of ZnS NPs showed selective internalization activity for leukemic cells and killed the cells by induction of apoptosis. Pre-treatment with ROS and TNF-α inhibitor confirmed that these nanoparticles were able to kill leukemic cells by generating an excess amount of ROS and thereby initiated TNF-α mediated apoptosis pathway.

    36. 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

      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.

    37. Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds

      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.

    38. 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

      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.

    39. Evaluation of electric arc furnace-processed steel slag for dermal corrosion, irritation, and sensitization from dermal contact

      Mina Suh, Matthew J. Troese, Debra A. Hall, Blair Yasso, John J. Yzenas and Deborah 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.

    40. The immunosuppressant tributyltin oxide blocks the mTOR pathway, like rapamycin, albeit by a different mechanism

      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.

    41. Use of the mouse ear vesicant model to evaluate the effectiveness of ebselen as a countermeasure to the nitrogen mustard mechlorethamine

      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.

    42. Identification of differentially expressed proteins related to organophosphorus-induced delayed neuropathy in the brains of hens

      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.

    43. Proteomic analysis of perfluorooctane sulfonate-induced apoptosis in human hepatic cells using the iTRAQ technique

      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.

    44. Deltamethrin induced an apoptogenic signalling pathway in murine thymocytes : exploring the molecular mechanism

      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.

    45. Combined antitumor effects of bee venom and cisplatin on human cervical and laryngeal carcinoma cells and their drug resistant sublines

      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.

    46. Hepatic fibrogenesis and transforming growth factor/Smad signaling activation in rats chronically exposed to low doses of lead

      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.

    47. Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro

      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.

    48. Borrelidin has limited anti-cancer effects in bcl-2 overexpressing breast cancer and leukemia cells and reveals toxicity in non-malignant breast epithelial cells

      Diana Gafiuc, Marlene Weiß, Ioannis Mylonas and Ansgar Brüning

      Article first published online: 24 OCT 2013 | DOI: 10.1002/jat.2946

      Borrelidin is a macrolide antibiotic with selective cytotoxicity against endothelial cells and leukemia cells. While testing the efficacy of borrelidin on breast cancer cells, we noticed the occurrence of non-specific toxicity in non-malignant cells and pre-existing resistance mechanisms against borrelidin in breast cancer and leukemia cell lines. This may limit the use of borrelidin as a possible new anti-cancer drug and raises concerns about possible unspecific toxicities.

    49. Prophylactic administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone

      Dietrich E. Lorke, Syed M. Nurulain, Mohamed Y. Hasan, Kamil Kuča and Georg A. Petroianu

      Article first published online: 17 OCT 2013 | DOI: 10.1002/jat.2939

      In search of a broad-spectrum prophylactic agent for organophosphate poisoning, the reversible AChE-inhibitors pyridostigmine, physostigmine, ranitidine, tacrine and K-27 (an experimental oxime) were tested as a pre-treatment before exposure to the organophosphate AChE-inhibitor terbufos sulfone. Their efficacy in reducing organophosphorus compound-induced mortality was assessed by Cox survival analysis. Best in vivo protection from terbufos sulfone-induced mortality was achieved by K-27. Prophylactic administration of an oxime, such as K-27, in case of imminent organophosphorus compound exposure may be a viable option.

    50. Rapid determination of quetiapine in blood by gas chromatography–mass spectrometry. Application to post-mortem cases

      Olga López-Guarnido, María Jesús Tabernero, Antonio F. Hernández, Lourdes Rodrigo and Ana M. Bermejo

      Article first published online: 11 OCT 2013 | DOI: 10.1002/jat.2944

      A simple, fast and sensitive method for the determination of quetiapine (QTP) in human blood has been developed and validated. The method involved a basic liquid-liquid extraction procedure and subsequent analysis by gas chromatography-mass spectrometry (GC/MS), previous derivatization with bis(trimethylsilyl)-trifluoroacetamide (BSTFA) and chorotrimethylsilane (TMCS) (99:1). The method validation included linearity with a correlation coefficient >0.99 over the range 0.02–1 µg mL-1.The limit of detection was 0.005 µg mL-1. The procedure was further applied to post mortem cases.

    51. Histopathological findings on Carassius auratus hepatopancreas upon exposure to acrylamide: correlation with genotoxicity and metabolic alterations

      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.

    52. Towards an integrated in vitro strategy for estrogenicity testing

      Si Wang, Jac M. M. J. G. Aarts, Laura H. J. de Haan, Dimitrios Argyriou, Ad A. C. M. Peijnenburg, Ivonne M. C. M. Rietjens and Toine F. H. Bovee

      Article first published online: 30 SEP 2013 | DOI: 10.1002/jat.2928

      In order to define an in vitro integrated testing strategy (ITS) for estrogenicity, a set of 23 reference compounds representing diverse chemical classes were tested in a series of in vitro assays including proliferation and reporter gene assays. All in vitro assays used revealed a reasonable to good correlation (R2 = 0.62–0.87) with the in vivo uterotrophic assay but the combination of the yeast estrogen bioassay with the U2OS ERα-CALUX assay seems most promising for an ITS for in vitro estrogenicity testing.

    53. Long-term maintenance of HepaRG cells in serum-free conditions and application in a repeated dose study

      Sebastian Klein, Daniel Mueller, Valery Schevchenko and Fozia Noor

      Article first published online: 30 SEP 2013 | DOI: 10.1002/jat.2929

      HepaRG cells were maintained viable with constant CYP activities and liver-specific functions for 30 days in serum-free medium (SFM). The long-term viability and CYP activities were superior to those reported for primary human hepatocytes in vitro. Metabolic flux analysis indicates that the central carbon metabolism in SFM is comparable to standard conditions. This system can be applied for repeated dose toxicity assessments and will pave way for application on high content ‘omics’ platform in systems toxicology.

    54. Identification of metabolomic biomarkers for drug-induced acute kidney injury in rats

      Takeki Uehara, Akira Horinouchi, Yuji Morikawa, Yutaka Tonomura, Keiichi Minami, Atsushi Ono, Jyoji Yamate, Hiroshi Yamada, Yasuo Ohno and Tetsuro Urushidani

      Article first published online: 30 SEP 2013 | DOI: 10.1002/jat.2933

      Metabolomics involves the comprehensive and simultaneous determination of endogenous or exogenous metabolites in biological samples. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using CE-TOFMS on rat plasma treated with several nephrotoxicants. Among a total of 169 metabolites identified, 3-methylhistidine, 3-indoxyl sulfate, and guanidoacetate were selected as candidate biomarkers, which may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats.

    55. RBE4 cells are highly resistant to paraquat-induced cytotoxicity: studies on uptake and efflux mechanisms

      V. Vilas-Boas, R. Silva, P. Guedes-de-Pinho, F. Carvalho, M. L. Bastos and F. Remião

      Article first published online: 18 SEP 2013 | DOI: 10.1002/jat.2926

      The effects of the toxic herbicide paraquat (PQ) to the blood–brain barrier (BBB) have been scarcely studied. It is shown that RBE4 cells (in vitro model of a rat's BBB) were highly resistant to PQ-induced cytotoxicity and that PQ used the choline-uptake system to enter RBE4 cells instead of the transporters of basic or neutral amino acids or the polyamines. Furthermore, PQ was extruded back to the extracellular medium by P-glycoprotein. However, these uptake/efflux studies only partially explain RBE4 resistance to PQ.

    56. Alteration in cellular viability, pro-inflammatory cytokines and nitric oxide production in nephrotoxicity generation by Amphotericin B: involvement of PKA pathway signaling

      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.

    57. Prenatal exposure to bisphenol A at the reference dose impairs mitochondria in the heart of neonatal rats

      Ying Jiang, Juan Liu, Yuanyuan Li, Huailong Chang, Gengqi Li, Bing Xu, Xi Chen, Weiyong Li, Wei Xia and Shunqing Xu

      Article first published online: 18 SEP 2013 | DOI: 10.1002/jat.2924

      Bisphenol A exposure is epidemiologically associated with heart disease. We found prenatal exposure to BPA at the reference dose induced mild ultrastructure changes in myocardial mitochondria at birth day. Mitochondrial membrane potential and the activity of respiratory chain complex II were significantly decreased. The expression levels of key regulators involved in mitochondria energy metabolism and ATP-generating pathways were down-regulated. The study demonstrated that prenatal exposure to BPA at the reference dose could impair mitochondria in the hearts of neonatal rats.

    58. Differential responses to JNJ-37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

      Eric J. de Waal, Maria Desmidt, Sven Korte, Marc Niehoff, Kevan Chase, Wayne Arrowsmith and Ann Lampo

      Article first published online: 16 SEP 2013 | DOI: 10.1002/jat.2916

      JNJ-378226 81 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Differences between Cynomolgus monkeys and Sprague-Dawley rats were noted in their response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Overall the Cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in schizophrenia patients than the Sprague-Dawley rat.

    59. CKD-501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks

      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.

    60. Effects of butyltins on mitogen-activated-protein kinase kinase kinase and Ras activity in human natural killer cells

      Lindsay J. Celada and Margaret M. Whalen

      Article first published online: 5 SEP 2013 | DOI: 10.1002/jat.2921

      Butyltins (BTs) contaminate the environment and are found in human blood. Natural killer (NK) cells defend against tumors and virally-infected cells. Mitogen-activated protein kinases (MAPKs) regulate NK cells. BTs activate MAPKs in human NK cells. The current study examined if BT-induced activation of MAPK kinase kinases (MAP3Ks) caused MAPK activation. Tributyltin (TBT) activated the MAP3K, c-Raf, within 10 minutes and the MAP3K, ASK1, after one hour. Results suggest that both TBT and dibutyltin (DBT) are impacting the regulation of c-Raf.

    61. Comparison of inhibitory effects between acetaminophen–glutathione conjugate and reduced glutathione in human glutathione reductase

      Erika Nýdlová, Martina Vrbová, Petr Česla, Barbora Jankovičová, Karel Ventura and Tomáš Roušar

      Article first published online: 5 SEP 2013 | DOI: 10.1002/jat.2914

      Acetaminophen overdose is the most frequent cause of acute liver injury. The oxidation product reacts with glutathione generating acetaminophen-glutathione conjugate (APAP-SG). The aim of our study was to estimate the toxicity of APAP-SG by characterizing the inhibitory effect in glutathione reductase (GR) and comparing that to the inhibitory effect of reduced glutathione. Our results show that GR was significantly inhibited in the presence of both substances. The type of enzyme inhibition was observed to be competitive in the both cases.

    62. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

      Rachel P. L. van Swelm, Mackenzie Hadi, Coby M. M. Laarakkers, Rosalinde Masereeuw, Geny M. M. Groothuis and Frans G. M. Russel

      Article first published online: 30 AUG 2013 | DOI: 10.1002/jat.2917

      Drug-induced liver injury often leads to drug withdrawal. Proteins released from human, mouse and rat precision-cut liver slices (PCLS) exposed to several hepatotoxicants were profiled using MALDI-TOF MS. Following acetaminophen treatment, similar changes in protein profiles (including the key proteins SOD1, CA3 and calmodulin) were demonstrated as previously found in vivo in mouse urine. Incubation with diclofenac resulted in the same toxicity parameters as observed for acetaminophen. In conclusion, proteomics can be applied to identify potential translational biomarkers in PCLS.

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