Journal of Applied Toxicology

Cover image for Vol. 35 Issue 2

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 - 74
  1. Research Articles

    1. Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits

      Chao Fang, Bo Ning, Ahmed Bilal Waqar, Manabu Niimi, Shen Li, Kaneo Satoh, Masashi Shiomi, Ting Ye, Sijun Dong and Jianglin Fan

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3103

      Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were used to investigate the detrimental effects of bisphenol A (BPA), which has much more common features with humans than mouse and rat especially in the metabolism and cardiovascular system. BPA exposure resulted in insulin resistance, prominent adipose accumulation, hepatic steatosis and myocardial injury. Moreover, BPA exposure also accelerated the development of atherosclerosis in the aortic arch. BPA may exert its toxic effects through eliciting endoplasmic reticulum (ER) stress and an inflammatory reaction.

    2. Effects of homocysteine on mesenchymal cell proliferation and differentiation during chondrogenesis on limb development

      Gilian Fernando Bourckhardt, Manuela Sozo Cecchini, Dib Ammar, Karoline Kobus-Bianchini, Yara Maria Rauh Müller and Evelise Maria Nazari

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3111

      We investigated whether homocysteine (Hcy) can affect cell cycle proteins and mesenchymal differentiation during limb development. An increase of p53, which can be activated by DNA damage and a decrease of PCNA and p21 in Hcy-treated embryos were observed. Additionally, Hcy induced an increase of Pax9 and Sox9 proteins. We have described impairments induced by Hcy, which does not change the morphology of the cartilage mold. These findings provide new insights to understand the cellular basis of Hcy toxicity.

    3. Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X-ray fluorescence microscopy after intratracheal administration with a microsprayer in rats

      Guihua Zhang, Naohide Shinohara, Hirokazu Kano, Hideki Senoh, Masaaki Suzuki, Takeshi Sasaki, Shoji Fukushima and Masashi Gamo

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3109

      The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose-response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration-response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO2 NP microdistribution in rats using X-ray fluorescence microscopy.

    4. Endocrine-disrupting potentials of equine estrogens equilin, equilenin, and their metabolites, in the medaka Oryzias latipes: in silico and DNA microarray studies

      Masaya Uchida, Hiroshi Ishibashi, Ryoko Yamamoto, Akiko Koyanagi, Teruhiko Kusano, Nobuaki Tominaga, Yasuhiro Ishibashi and Koji Arizono

      Article first published online: 22 JAN 2015 | DOI: 10.1002/jat.3098

      Although several previous studies have demonstrated the presence of equine estrogens in the aquatic environment, limited data are currently available on the endocrine-disrupting potentials in fish and the risks they pose to aquatic organisms. To investigate the interactions of major equine estrogens equilin (Eq) and equilenin (Eqn), as well as their metabolites 17α-dihydroequilin, 17β-dihydroequilin, 17α-dihydroequilenin and 17β-dihydroequilenin, with the estrogen receptor α (ERα) of medaka (Oryzias latipes), a three-dimensional model of the ligand-binding domain (LBD) of ERα was built in silico, and docking simulations were performed.

    5. Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans

      Ayako Inokuchi, Ryoko Yamamoto, Fumiyo Morita, Shota Takumi, Hiromi Matsusaki, Hiroshi Ishibashi, Nobuaki Tominaga and Koji Arizono

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3058

      This study was conducted to clarify the biological effects of lithium compounds on Caenorhabditis elegans. Our findings suggest that LiCl and Li2CO3 potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as cytochrome P450, ABC transporter, glutathione S-transferase, and lipid metabolism genes. The results also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans.

    6. Cytotoxicity of luteolin in primary rat hepatocytes: the role of CYP3A-mediated ortho-benzoquinone metabolite formation and glutathione depletion

      Fuguo Shi, Peng Zhao, Xiaobing Li, Hong Pan, Shiping Ma and Li Ding

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3106

      Luteolin, a well-known flavonoid, is widely distributed in the plant kingdom and present in many plant families. It can be found in diets, supplements and herbal medicines. The cytotoxicity of luteolin in hepatocytes was evaluated in this study. An electrophilic ortho-benzoquinone metabolite was identified by liquid chromatography coupled with tandem mass spectrometry in rat liver microsomes and primary rat hepatocytes. The CYP3A-mediated reactive metabolite formation was responsible for the cytotoxicity. Intracellular glutathione depletion by the ortho-benzoquinone metabolite was an initiating event in the cytotoxicity occurrence.

    7. Genomic and gene expression responses to genotoxic stress in PAC2 zebrafish embryonic cell line

      Maja Šrut, Jean-Paul Bourdineaud, Anamaria Štambuk and Göran I. V. Klobučar

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3113

      In this study, we assessed PAC2 cell line responses toward different forms of genotoxic stress by using the battery of tests: the Comet assay, quantitative random-amplified polymorphic DNA, amplified fragment length polymorphism and expression of several DNA repair, oxidative stress response and xenobiotic metabolism genes. PAC2 cell line exhibited genotoxic responses in all used test methods upon direct, and to a lower extent upon indirect acting genotoxicant.

    8. Toxicity of cobalt–chromium nanoparticles released from a resurfacing hip implant and cobalt ions on primary human lymphocytes in vitro

      Olga M. Posada, R. J. Tate and M. H. Grant

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3100

      In implant-related adverse reactions T-lymphocytes play a prominent role in sustaining the chronic inflammatory response. Primary human lymphocytes were isolated and treated with cobalt–chromium (CoCr) wear debris and Co ions, individually, and in combination, for 24, 48 and 120 h. Prolonged exposure to metal debris induced lymphocyte proliferation, suggesting that activation of resting lymphocytes may have occurred. Furthermore, cobalt toxicity may modulate interleukin-2 (IL-2) secretion, which may contribute to the impairment of immune regulation in vivo in patients with metal-to-metal (MoM) implants.

  2. Obituaries

    1. Memorial address to Dr Tohru Inoue

      Yoko Hirabayashi

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3101

  3. Research Articles

    1. Cobalt oxide nanoparticles induced oxidative stress linked to activation of TNF-α/caspase-8/p38-MAPK signaling in human leukemia cells

      Sourav Chattopadhyay, Sandeep Kumar Dash, Satyajit Tripathy, Balaram Das, Santanu Kar Mahapatra, Panchanan Pramanik and Somenath Roy

      Article first published online: 11 JAN 2015 | DOI: 10.1002/jat.3080

      The purpose of this study was to determine the intracellular signaling transduction pathways involved in oxidative stress induced by nanoparticles in cancer cells. Activation of reactive oxygen species (ROS) has some therapeutic benefits in arresting the growth of cancer cells. Cobalt oxide nanoparticles (CoO NPs) are an interesting compound for oxidative cancer therapy. Our results showed that CoO NPs elicited a significant (P <0.05) amount of ROS in cancer cells

    2. Quantitative toxicoproteomic analysis of zebrafish embryos exposed to a retinoid X receptor antagonist UVI3003

      Liang Zheng, Jianlan Yu, Huahong Shi, Liang Xia, Qi Xin, Qiang Zhang, Heng Zhao, Ji Luo, Wenhai Jin, Daoji Li and Junliang Zhou

      Article first published online: 11 JAN 2015 | DOI: 10.1002/jat.3099

      Retinoid X receptor (RXR) antagonists, including some environmental endocrine disruptors, have a teratogenic effect on vertebrate embryos. To investigate the toxicological mechanism on the protein expression level, a quantitative proteomic study was conducted to analyze the proteome alterations of zebrafish (Danio rerio) embryos exposed to gradient concentrations of a representative RXR antagonist UVI3003. Using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling coupled nano high-performance liquid chromatography-tandem mass spectrometry (nano HPLC-MS/MS), in total 6592 proteins were identified, among which 195 proteins were found to be differentially expressed by more than a two-fold change in exposed groups compared with the control.

    3. The toxicity and distribution of iron oxide–zinc oxide core-shell nanoparticles in C57BL/6 mice after repeated subcutaneous administration

      Jun-Won Yun, Jung-Hee Yoon, Byeong-Cheol Kang, Nam-Hyuk Cho, Seung Hyeok Seok, Seung-Kee Min, Ji Hyun Min, Jeong-Hwan Che and Young Keun Kim

      Article first published online: 8 JAN 2015 | DOI: 10.1002/jat.3102

      Therapeutic cancer vaccines promote immune responses by delivering tumour-specific antigens. Recently, we developed iron oxide (Fe3O4)–zinc oxide (ZnO) core-shell nanoparticles (CSNPs) as carriers for antigen delivery into dendritic cells (DCs), and the CSNPs were injected subcutaneously into C57BL/6 mice to examine the systemic toxicity, tissue distribution and excretion of the CSNPs. The doses injected were 0, 4, 20 and 200 mg kg–1 weekly for 4 weeks. No significant changes were observed after the CSNPs administration with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry,and organ weights.

    4. Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents

      Barbara Wiśniowska, Aleksander Mendyk, Jakub Szlęk, Michał Kołaczkowski and Sebastian Polak

      Article first published online: 5 JAN 2015 | DOI: 10.1002/jat.3095

      The changing cardiac safety testing paradigm suggests a shift towards in silico models of cellular electrophysiology and assessment of concomitant block of multiple ion channels. In this study a set of four enhanced 2D-QSAR models, predicting ion currents (IKr, IKs, Ina and ICaL) changes were developed. The models combine in vitro study parameters and physico-chemical descriptors. Proposed models provide information which can guide decisions regarding the risk, and thus avoidance of exclusion of potentially safe and effective drugs.

    5. Tl(I) and Tl(III) alter the expression of EGF-dependent signals and cyclins required for pheochromocytoma (PC12) cell-cycle resumption and progression

      María T. L. Pino and Sandra V. Verstraeten

      Article first published online: 22 DEC 2014 | DOI: 10.1002/jat.3096

      The effects of thallium [Tl(I) and Tl(III)] (5–100 μM) on the PC12 cell cycle were evaluated without (EGF) or with (EGF+) media supplementation with epidermal growth factor (EGF). These cations did not activate EGF receptor (EGFR) in EGF cells, but induced ERK1/2 and Akt phosphorylation. Tl(I) promoted both EGF and EGF+ cell proliferation. In contrast, Tl(III) promoted EGF cell proliferation but delayed EGF+ cell-cycle resumption, which may be related to the toxic effects of this cation in PC12 cells.

    6. All-cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non-polluted areas

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

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

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

    7. Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C δ in human neuroblastoma dopaminergic SH-SY5Y cell lines

      Yunsung Nam, Myung Bok Wie, Eun-Joo Shin, Thuy-Ty Lan Nguyen, Seung-Yeol Nah, Sung Kwon Ko, Ji Hoon Jeong, Choon-Gon Jang and Hyoung-Chun Kim

      Article first published online: 18 DEC 2014 | DOI: 10.1002/jat.3093

      We examined the effects of dopaminergic protectant ginsenoside Re against methamphetamine toxicity using SH-SY5Y neuroblastoma cells. Re treatment exhibited significant protections against mitochondrial oxidative burdens, mitochondrial dysfunctions, mitochondrial translocation of PKCδ and apoptotic events induced by methamphetamine. These protective effects of Re were comparable to those of PKCδ antisense oligonucleotide. Re did not significantly provide additional effects on the protection mediated by PKCδ inhibition. The results suggest that PKCδ is a specific target for Re-mediated protective activity against methamphetamine toxicity.

    8. Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats

      Tanja M. Wildemann, Lynn P. Weber and Steven D. Siciliano

      Article first published online: 18 DEC 2014 | DOI: 10.1002/jat.3092

      The cardiovascular effects of lead and mercury species and their mixtures were investigated in male rats. Exposure occurred for 28 days through the drinking water. A single exposure to methylmercury [MeHg(I)] increased blood pressure and decreased cardiac output, whereas mixtures reversed the effect (antagonism). A single exposure to lead [Pb(II)], mercury [Hg(II)] and MeHg(I) did not affect cardiac electrical activity, whereas co-exposure aggravated it (synergism). Single metal exposures cannot predict the adverse cardiovascular effects of Pb and Hg mixtures.

    9. HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening

      Zenan Wang, Xiaobei Luo, Chukwuemeka Anene-Nzelu, Yu Yu, Xin Hong, Nisha Hari Singh, Lei Xia, Side Liu and Hanry Yu

      Article first published online: 15 DEC 2014 | DOI: 10.1002/jat.3090

      We described the evaluation of HepaRG-tethered spheroids as an in vitro three-dimensional culture system for drug safety testing. The liver specific gene expression level and drug metabolizing enzyme activities in HepaRG tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of seven days. The inducibility of three major cytochrome P450 enzymes was improved in tethered spheroids. Its potential for high throughput drug safety screening could be in favor of by the pharmaceutical industry.

    10. Maternal exposure to 3,3’-iminodipropionitrile targets late-stage differentiation of hippocampal granule cell lineages to affect brain-derived neurotrophic factor signaling and interneuron subpopulations in rat offspring

      Megu Itahashi, Hajime Abe, Takeshi Tanaka, Sayaka Mizukami, Yoh Kikuchihara, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 25 NOV 2014 | DOI: 10.1002/jat.3086

      This study investigated the maternal 3,3’-iminodipropionitrile (IDPN) exposure effect on hippocampal neurogenesis in rat offspring. Pregnant rats were supplemented with IDPN in drinking water during gestation and lactation. Female offspring subjected to analysis had decreased parvalbumin+, reelin+ and phospho-TrkB+ interneurons in the dentate hilus at 200 ppm and increased Arc+ and c-Fos+ granule cells at ≥ 67 ppm. The results suggest that IDPN targets neuronal plasticity of granule cell lineages to cause BDNF downregulation resulting in reduction in GABAergic interneurons.

    11. Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro

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

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

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

    12. Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells

      Yoko Hirabayashi, Isao Tsuboi, Kei Nakachi, Yoichiro Kusunoki and Tohru Inoue

      Article first published online: 21 NOV 2014 | DOI: 10.1002/jat.3088

      The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell compartment, their numerical recovery was significantly delayed. In the case of 21-month-old mice with radiation exposure, Ccnd1, PiK3r1, and Fyn were overexpressed solely in the undifferentiated hematopoietic stem/progenitor cell compartment. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by single-dose radiation, the prolonged effects of radiation seem to modify the xenobiotic processes during aging.

    13. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

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

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

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

    14. Tributyltin alters secretion of interleukin 1 beta from human immune cells

      Shyretha Brown and Margaret Whalen

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3087

      Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint and antifungal agents. Owing to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin-1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors.

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

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

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

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

    16. Acute toxicity of 50 metals to Daphnia magna

      Akira Okamoto, Masumi Yamamuro and Norihisa Tatarazako

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

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

    17. RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights

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

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

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

    18. Impact of di-ethylhexylphthalate exposure on metabolic programming in P19 ECC-derived cardiomyocytes

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

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

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

  4. Review Articles

    1. Impacts of the feed contaminant deoxynivalenol on the intestine of monogastric animals: poultry and swine

      Khaled Ghareeb, Wageha A. Awad, Josef Böhm and Qendrim Zebeli

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3083

      Deoxynivalenol is cereal contaminant, targets the intestinal epithelium with major public health concerns. Emerging evidences suggest that DON produces its toxicity primarily via activation of the mitogen-activated protein kinases (MAPKs) signalling and alteration in the expression of genes of physiological and immunological functions. Furthermore, DON down-regulates the expression of multiple transporters in the enterocytes and modulates mucosal immune responses. This review highlights DON impacts on the intestine and identifies gaps of knowledge that need to be addressed by future research.

  5. Research Articles

    1. Cellular uptake and toxicity effects of silver nanoparticles in mammalian kidney cells

      Mirta Milić, Gerd Leitinger, Ivan Pavičić, Maja Zebić Avdičević, Slaven Dobrović, Walter Goessler and Ivana Vinković Vrček

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3081

      The rapid progress and early commercial acceptance of silver-based nanomaterials is owed to their biocidal activity. Besides embracing the antimicrobial potential of silver nanoparticles (AgNPs), it is imperative to give special attention to the potential adverse health effects of nanoparticles owing to prolonged exposure. Here, we report a detailed study on the in vitro interactions of citrate-coated AgNPs with porcine kidney (Pk15) cells. As uncertainty remains whether biological/cellular responses to AgNPs are solely as a result of the release of silver ions or whether the AgNPs themselves have toxic effects, we investigated the effects of Ag+ on Pk15 cells for comparison.

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

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

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

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

    3. Organ-specific distribution of gold nanoparticles by their surface functionalization

      Jong Kwon Lee, Tae Sung Kim, Ji Young Bae, A. Young Jung, Sang Min Lee, Ji Hyun Seok, Hang Sik Roh, Chi Won Song, Mi Jin Choi, Jinyoung Jeong, Bong Hyun Chung, Yun-Geon Lee, Jayoung Jeong and Wan-Seob Cho

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3075

      To evaluate the role of surface charge on distribution of NPs, 15 nm-sized gold nanoparticles (AuNPs) having 3 different charges (AuNPPEG, AuNPCOOH, or AuNPNH2) were injected intravenously into mice and organ distribution were measured. The organ distribution showed the higher deposition rate depending on their functional groups: AuNPPEG for mesenteric lymph node, kidney, brain, and testis; AuNPCOOH for liver; AuNPNH2 for spleen, lung, and heart. This information is important for directing NPs or improving the kinetic properties of NPs.

    4. Assessment of temperature-induced hERG channel blockade variation by drugs

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

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

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

    5. d-α-tocopheryl polyethylene glycol 1000 succinate-containing vehicles provide no detectable chemoprotection from oxidative damage

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

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

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

    6. Comparison of the kinetics of various biomarkers of benzo[a]pyrene exposure following different routes of entry in rats

      Marjory Moreau and Michèle Bouchard

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

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

    7. Tween-80 and impurity induce anaphylactoid reaction in zebrafish

      Rui Yang, Qiao-Cong Lao, Hang-Ping Yu, Yong Zhang, Hong-Cui Liu, Lin Luan, Hui-Min Sun and Chun-Qi Li

      Article first published online: 27 OCT 2014 | DOI: 10.1002/jat.3069

      This study developed a microplate-based quantitative in vivo zebrafish assay for assessing anaphylactoid reaction. We assessed 10 batches of Tween-80 and 3 Tween-80 impurities (ethylene glycol, 2-chloroethanol and hydrogen peroxide) in this model and found that 3 batches of Tween-80 and one Tween-80 impurity hydrogen peroxide (H2O2) induced anaphylactoid reaction in zebrafish. H2O2 residue in combination with oxidized fatty acid residues in Tween-80 samples, but not Tween-80 itself, may induce anaphylactoid reaction.

    8. 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.

    9. 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.

    10. 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

    11. 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.

    12. 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.

    13. 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.

    14. 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.

    15. 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.

    16. 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.

    17. 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.

    18. 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.

    19. 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).

    20. 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.

    21. 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

    22. 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.

    23. 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.

    24. 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.

    25. 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.

    26. 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.

    27. 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).

    28. 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.

    29. 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.

    30. 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.

    31. 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.

    32. 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.

    33. 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.

    34. 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.

    35. 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.

    36. 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.

    37. 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.

    38. 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.

    39. 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.

    40. 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.

    41. 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.

    42. 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.

    43. 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.

    44. 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.


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