Journal of Applied Toxicology

Cover image for Vol. 34 Issue 12

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 3.174

ISI Journal Citation Reports © Ranking: 2013: 24/87 (Toxicology)

Online ISSN: 1099-1263


  1. 1 - 60
  1. Review Articles

    1. Mini review on blood–brain barrier penetration of pyridinium aldoximes

      H. Kalász, S. M. Nurulain, G. Veress, S. Antus, F. Darvas, E. Adeghate, A. Adem, F. Hashemi and K. Tekes

      Article first published online: 7 OCT 2014 | DOI: 10.1002/jat.3048

      This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This review gives a description for the characterization of BBB penetration of established and novel pyridinium aldoximes.

  2. Research Articles

    1. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain

      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.

    2. Oral cadmium exposure during rat pregnancy: assessment of transplacental micronutrient transport and steroidogenesis at term

      Anja Mikolić, Martina Piasek, Antonija Sulimanec Grgec, Veda M. Varnai, Sandra Stasenko and Saša Kralik Oguić

      Article first published online: 25 SEP 2014 | DOI: 10.1002/jat.3055

      Biomarkers of Cd exposure, maternal and foetal micronutrients, and steroid hormones were evaluated after oral exposure to 50 mg Cd l–1 from pregnancy day 1 to 20. Non-pregnant rats were exposed under the same conditions. The Cd load was higher in pregnant rats. Progesterone and testosterone in placenta and serum were unchanged. Liver zinc increased in all exposed rats. Zinc decreased in maternal kidney and placenta, iron decreased in the maternal organs and foetus; hence micronutrient handover to the foetus was disrupted.

    3. Evaluation and refinement of a field-portable drinking water toxicity sensor utilizing electric cell–substrate impedance sensing and a fluidic biochip

      Mark W. Widder, Linda M. Brennan, Elizabeth A. Hanft, Mary E. Schrock, Ryan R. James and William H. van der Schalie

      Article first published online: 18 SEP 2014 | DOI: 10.1002/jat.3017

    4. Characteristic molecular and proteomic signatures of drug-induced liver injury in a rat model

      Jung Woo Eun, Hyun Jin Bae, Qingyu Shen, Se Jin Park, Hyung Seok Kim, Woo Chan Shin, Hee Doo Yang, Chan Young Jin, Jueng Soo You, Hyun Joo Kang, Hoguen Kim, Young Min Ahn, Won Sang Park, Jung Young Lee and Suk Woo Nam

      Article first published online: 18 SEP 2014 | DOI: 10.1002/jat.3062

      Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data.

    5. Chronic trimethyltin chloride exposure and the development of kidney stones in rats

      Xuefeng Ren, Xin Wu, Gang Sui, Zhihong Gong, Emmanuel Yawson, Banghua Wu, Guanchao Lai, Xiaolin Ruan, Hongbin Gao, Feng Zhou, Bing Su, James R. Olson and Xiaojiang Tang

      Article first published online: 16 SEP 2014 | DOI: 10.1002/jat.3054

      We previously reported that occupational trimethyltin (TMT) exposure is a risk factor for developing kidney stones. Here we performed a 180-day animal study and showed that chronic TMT exposure can significantly inhibit the activity of renal H+/K+-ATPase and subsequently lead to an increase in urinary pH. We observed a dose-dependent increase in the incidence of kidney/urinary tract stones and the pathological changes in the kidneys of rats with TMT exposure compared with the rats in the control group.

    6. 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

      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.

    7. Graphene supports in vitro proliferation and osteogenic differentiation of goat adult mesenchymal stem cells: potential for bone tissue engineering

      Hoda Elkhenany, Lisa Amelse, Andersen Lafont, Shawn Bourdo, Marc Caldwell, Nancy Neilsen, Enkeleda Dervishi, Oshin Derek, Alexandru S. Biris, David Anderson and Madhu Dhar

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3024

      Current treatments for bone loss injuries involve autologous and allogenic bone grafts, metal alloys, and ceramics. Although these therapies have proved to be useful, they suffer from inherent challenges, hence, an adequate bone replacement therapy has not yet been found. We hypothesize that graphene may be a useful nanoscaffold for mesenchymal stem cells and will promote proliferation and differentiation into bone progenitor cells. In this study we evaluate a combination of graphene and goat mesenchymal stem cells for bone regeneration.

    8. Exposure to MnCl2 · 4H2O during development induces activation of microglial and perivascular macrophage populations in the hippocampal dentate gyrus of rats

      Hajime Abe, Takumi Ohishi, Fumiyuki Nakane, Ayako Shiraki, Takeshi Tanaka, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3059

      This study was performed to clarify whether Mn exposure during development causes proinflammatory responses in the hippocampal dentate gyrus of offspring, involving the Mn-induced disruption of neurogenesis. Pregnant rats were treated with dietary MnCl2 · 4H2O during gestation and lactation. Their offspring showed increased activated microglia and perivascular macrophages in the dentate hilus and increased proinflammatory cytokines in the hippocampal tissue after 800 ppm MnCl2 · 4H2O, probably involving the disruption of neurogenesis after 800 ppm exposure.

    9. Cylindrospermopsin induces oxidative stress and genotoxic effects in the fish CLC cell line

      Anna Sieroslawska and Anna Rymuszka

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3040

      The aim of the study was to elucidate the prooxidative and genotoxic impact of cylindrospermopsin (CYN) on a common carp (Cyprinus carpio L.) leucocyte cell line (CLC). CYN decreased the reduced to oxidized glutathione ratio, increased the reactive oxygen species (ROS) production and changed superoxide dismutase activity. Genotoxic activity of CYN, manifested as oxidative DNA damage and elevated number of micronuclei, was also detected. The results indicate that CYN is able to exert a wide range of adverse effects in fish leucocytes.

    10. Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2: Evaluation of in vitro topical decontamination efficacy using undamaged skin

      Christopher H. Dalton, Charlotte A. Hall, Helen L. Lydon, J. K. Chipman, John S. Graham, John Jenner and Robert P. Chilcott

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3060

      There is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents from within wounds. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. Two products were shown to be effective and will be subject to further assessment using damaged skin.

    11. Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice

      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.

    12. Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug-induced liver injury in rats

      Yutaka Tonomura, Yuki Kato, Hiroyuki Hanafusa, Yuji Morikawa, Keigo Matsuyama, Takeki Uehara, Motonobu Ueno and Mikinori Torii

      Article first published online: 4 SEP 2014 | DOI: 10.1002/jat.3053

      Traditional biomarkers for liver injury have been used in drug development, whereas the standardized thresholds and performance have not been established in preclinical toxicity study. Therefore, we determined the thresholds using large-scale rat database, and validated the availability of the thresholds in different facility using in-house dataset. However, all biomarkers analyzed showed insufficient predictability for future onset of hepatic lesion. Collectively, the standardized thresholds enable consistent evaluation of the biomarkers among different facilities, whereas a more useful biomarker is required.

    13. Perturbation of cytosolic calcium by 2-aminoethoxydiphenyl borate and caffeine affects zebrafish myofibril alignment

      Hsin-Ju Wu, Tsorng-Harn Fong, Shen-Liang Chen, Jen-Cheng Wei, I-Jong Wang, Chi-Chung Wen, Chao-Yuan Chang, Xing-Guang Chen, Wei-Yu Chen, Hui-Min Chen, Juin-Lin Horng, Yun-Hsin Wang and Yau-Hung Chen

      Article first published online: 4 SEP 2014 | DOI: 10.1002/jat.3057

      The objective of the current study was to investigate the correlation of cytosolic calcium levels and myofibril alignments during zebrafish embryogenesis. We exposed 2-aminoethoxydiphenyl borate and caffeine to zebrafish embryos to disturb the cytosolic calcium levels. Our data show that (1) both enhanced and reduced of cytosolic calcium led to mis-alignment of myofibrils; (2) reduction of cytosolic calcium increases myod expression; and (3) electron density is affected by intracellular calcium reduction. In conclusion, we proposed that cytosolic calcium is important for myofibrils alignment.

    14. Skin absorption of six performance amines used in metalworking fluids

      Lauriane N. Roux, James D. Brooks, James L. Yeatts and Ronald E. Baynes

      Article first published online: 4 SEP 2014 | DOI: 10.1002/jat.3056

      Every year, 10 million workers are exposed to metalworking fluids (MWFs) that may be toxic. There are four types of MWFs: neat oils and three water-based MWFs (soluble oil, semisynthetic and synthetic), which are diluted with water and whose composition varies according to the mineral oils ratio. MWFs also contain various additives. To determine the absorption of six amines used as corrosion inhibitors and biocides in MWFs, porcine skin flow-through diffusion cell experiments were conducted with hydrophilic ethanolamines (mono-, di- and triethanolamine, MEA, DEA and TEA respectively) and a mixture of lipophilic amines (dibutylethanolamine, dicyclohexylamine and diphenylamine).

    15. A representative retinoid X receptor antagonist UVI3003 induced teratogenesis in zebrafish embryos

      Liang Zheng, Ting Xu, Daoji Li and Junliang Zhou

      Article first published online: 3 SEP 2014 | DOI: 10.1002/jat.3051

      Retinoid X receptor (RXR) interfering activity has been detected in different water resources. To study RXR disruptor-induced toxicological effects on vertebrates, embryos of zebrafish (Danio rerio) were exposed to a representative RXR antagonist UVI3003. Results showed that the teratogenic index (LC50/EC50) of UVI3003 was as high as 5.4. UVI3003 induced multiple malformations of embryos, including deformed fins, reduced brains, small jaws, bent tails and edema in hearts, the degree of which became more severe with increasing exposure concentration.

    16. Immunophenotyping does not improve predictivity of the local lymph node assay in mice

      Volker Strauss, Susanne N. Kolle, Naveed Honarvar, Martina Dammann, Sibylle Groeters, Frank Faulhammer, Robert Landsiedel and Bennard van Ravenzwaay

      Article first published online: 3 SEP 2014 | DOI: 10.1002/jat.3042

    17. Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl

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

      Article first published online: 3 SEP 2014 | DOI: 10.1002/jat.3052

      Searching for a broad-range pre-treatment compound for organophosphate intoxication, the mortality-reducing efficacy of five reversible cholinesterase-inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and experimental oxime K-27) was assessed, when injected before exposure to the organophosphate cholinesterase-inhibitor azinphos-methyl. Best in vivo protection from azinphos-methyl-induced mortality was achieved by K-27 and physostigmine, reducing the relative risk (RR) of death to about 1/5. Prophylactic administration of an oxime, such as K-27, before exposure to organophosphorus compounds may be a promising option.

    18. Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells

      Qilong Gao, Huaimin Liu, Yamin Yao, Liang Geng, Xinfeng Zhang, Lifeng Jiang, Bian Shi and Feng Yang

      Article first published online: 1 SEP 2014 | DOI: 10.1002/jat.3049

      The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression.

    19. Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5-dimethylaminophenol in AA8 cells

      Ming-Wei Chao, P��nar Erkekoglu, Chia-Yi Tseng, Wenjie Ye, Laura J. Trudel, Paul L. Skipper, Steven R. Tannenbaum and Gerald N. Wogan

      Article first published online: 1 SEP 2014 | DOI: 10.1002/jat.3046

      Exposure to monocyclic aromatic alkylanilines and their metabolites were significantly and independently associated with ROS generation and bladder cancer incidence. Apropos to this knowledge and information, this study was designed to investigate the protective effects of Ascorbic acid on cytotoxicity, oxidant/antioxidant parameters, cell cyle arrest, Aprt mutation frequency, and epigenetic changes caused by 3,5-Dimethylaminophenol in Chinese Hamster Ovary (CHO) AA8 cells.

    20. In utero and early childhood exposure to arsenic decreases lung function in children

      Rogelio Recio-Vega, Tania Gonzalez-Cortes, Edgar Olivas-Calderon, R. Clark Lantz, A. Jay Gandolfi and Cesar Gonzalez-De Alba

      Article first published online: 15 AUG 2014 | DOI: 10.1002/jat.3023

      The lung is a target organ for adverse health outcomes following exposure to arsenic. The objective of the study was to evaluate the association between urinary levels of arsenic and its metabolites with lung function in children exposed in utero and in early childhood to high arsenic levels through drinking water. Exposure to arsenic through drinking water during in utero and early life was associated with a decrease in FVC and with a restrictive spirometric pattern in the children evaluated.

    21. Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 1: Evaluation of in vitro clotting efficacy in the presence of certain contaminants

      Charlotte A. Hall, Helen L. Lydon, Christopher H. Dalton, J. K. Chipman, John S. Graham and Robert P. Chilcott

      Article first published online: 15 AUG 2014 | DOI: 10.1002/jat.3019

      The treatment of battlefield injuries may be complicated by contamination with toxic chemicals. The aim of this study was to investigate the ex vivo haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). A number of commercial products which may have potential as haemostatic decontaminants were identified which warrant further investigation to establish their decontaminant efficacy.

    22. Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells

      Margarida Gonçalo, João Martins, Ana Silva, Bruno Neves, Américo Figueiredo, Teresa Cruz and Celeste Lopes

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3033

      Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen-presenting capacity. Drugs that cause T-cell mediated cutaneous adverse drug reactions (CARD) showed similar effects on THP-1 cells: allopurinol, which causes severe CADR, and oxypurinol, induced p38 MAPkinase phosphorylation and upregulated genes for HMOX1 and IL8, the latter with an intensity similar to the strong sensitizer, DNFB. Betalactams and carbamazepine had a more irregular effect on signalling pathways (p38 MAPK) and genes studied (IL8, IL12B, CXCL10, CD40 and CD83).

    23. Analysis of drugs of abuse in human plasma by dispersive liquid–liquid microextraction and high-performance liquid chromatography

      P. Fernández, M. Regenjo, A. M. Bermejo, A. M. Fernández, R. A. Lorenzo and A. M. Carro

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3035

      A method consisting of dispersive liquid–liquid microextraction and high-performance liquid chromatography with photodiode array detection (DLLME/HPLC-PDA) was used to determine morphine, 6-acetylmorphine, cocaine, benzoylecgonine and methadone in human plasma. An experimental design based on a Uniform Network Doehlert allowed the optimization of the extraction conditions. The chromatographic method was validated assessing linearity, limits of detection and quantitation, selectivity, precision and accuracy. Finally, the proposed method was successfully applied to 22 plasma samples from drug users.

    24. The relationship between chemical-induced kidney weight increases and kidney histopathology in rats

      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.

    25. Protective role of L-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in Zebrafish

      Chia-Yen Wu, Han-Jung Lee, Chi-Fang Liu, Mallikarjuna Korivi, Hwei-Hsien Chen and Ming-Huan Chan

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3043

      Hair cells are sensitive to the therapeutic drugs, like aminoglycosides which cause hearing loss. Co-administration with L-ascorbic acid, NAC, and apocynin protected neomycin-induced hair cell loss within the neuromasts in zebrafish. These compounds reduced ROS production in neuromasts exposed to neomycin, but did not influence the uptake of neomycin into hair cells. Data implies that prevention of hair cell damage against neomycin by L-ascorbic acid, NAC, and apocynin might be associated with inhibition of ROS production, but not neomycin uptake.

    26. Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats

      Yoko Nishimura, Chiaki Kondo, Yuji Morikawa, Yutaka Tonomura, Mikinori Torii, Jyoji Yamate and Takeki Uehara

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3044

      The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. We selected candidate miRNAs by the analysis of the miRNA microarray dataset derived from comprehensive organs/tissues in normal rats, and confirmed their usefulness in drug-induced rat cardiotoxicity. From the analysis, plasma miR-208 showed the most sensitive and sustainable increase and it appears to be a promising biomarker for drug-induced cardiotoxicity in rats.

    27. In vitro evaluation of the effects of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) on IL-2 production in human T-cells

      Kristin Midgett, Margie M. Peden-Adams, Gary S. Gilkeson and Diane L. Kamen

      Article first published online: 23 JUL 2014 | DOI: 10.1002/jat.3037

      Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)-2 production in the human Jurkat T-cell line and PFOS in healthy human primary T cells. These data demonstrated that PFOA did not impact IL-2 production, but PFOS significantly suppressed IL-2 production in both cell types at dose levels within the high end of the human exposure range.

    28. Characterization of Oryzias latipes glucocorticoid receptors and their unique response to progestins

      Shinichi Miyagawa, Anke Lange, Saki Tohyama, Yukiko Ogino, Takeshi Mizutani, Tohru Kobayashi, Norihisa Tatarazako, Charles R. Tyler and Taisen Iguchi

      Article first published online: 23 JUL 2014 | DOI: 10.1002/jat.3020

      We here report the molecular characterization of medaka (Oryzias latipes) corticosteroid receptors (GRs), and show that GR2 is most likely the subtype mediating glucocorticoid signaling in the medaka. We also found that progestins could activate or inactivate GR2-mediated transcription, depending on the presence or absence of cortisol. These findings advance understanding of the basic mechanisms of GR-mediated transcription in medaka.

    29. 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.

    30. 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.

    31. 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.

    32. 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.

    33. 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.

    34. 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.

    35. 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.

    36. 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.

    37. 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.

    38. 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.

    39. 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.

    40. 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.

    41. 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.

    42. 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.

    43. 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.

    44. 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.

    45. 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.

    46. 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.

    47. 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.

    48. 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.

    49. 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.

    50. 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.

    51. 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.

    52. 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.

    53. 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.

    54. 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 %.

    55. 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.

    56. 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.

    57. 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.

    58. 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.


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